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WO2021029914A1 - Compositions et procédés pour améliorer la mobilisation de récepteur opioïde par des héxadiénoates d'opioïdes et des héxadiénoates éventuellement substitués - Google Patents

Compositions et procédés pour améliorer la mobilisation de récepteur opioïde par des héxadiénoates d'opioïdes et des héxadiénoates éventuellement substitués Download PDF

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WO2021029914A1
WO2021029914A1 PCT/US2020/021599 US2020021599W WO2021029914A1 WO 2021029914 A1 WO2021029914 A1 WO 2021029914A1 US 2020021599 W US2020021599 W US 2020021599W WO 2021029914 A1 WO2021029914 A1 WO 2021029914A1
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compound
opioid
hexadienoate
naloxone
nalbuphine
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Georgiy Nikonov
Levon Isakulyan
Michael V. Voronkov
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Kappa Pharma LLC
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Kappa Pharma LLC
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Priority claimed from US16/540,058 external-priority patent/US11186585B2/en
Application filed by Kappa Pharma LLC filed Critical Kappa Pharma LLC
Priority to EP20852037.9A priority Critical patent/EP4010078A4/fr
Priority to JP2022509137A priority patent/JP7535569B2/ja
Priority to CA3149152A priority patent/CA3149152A1/fr
Priority to MX2022001520A priority patent/MX2022001520A/es
Priority to CN202080071185.9A priority patent/CN114828961B/zh
Publication of WO2021029914A1 publication Critical patent/WO2021029914A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/20—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C219/22—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22—Bridged ring systems
    • C07D221/26—Benzomorphans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22—Bridged ring systems
    • C07D221/28—Morphinans
    • 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

Definitions

  • the present invention relates to opiate derived compositions, used in therapeutic areas associated with opioid receptor modulation.
  • Nalbuphine Nalbuphine was launched in 1979 as an analgesic for moderate to severe pain and has effectively been used in the clinic since. It is primarily used in conjunction with anesthetics for pre- and post-operative analgesia and in labor and delivery for acute and chronic pain management. Recently its uses have been expanded to the treatment of locomotive disorders, dermatological conditions such as pruritus and addiction management.
  • Nalbuphine could prevent opiate tolerance and dependence in chronic pain management. It is the only narcotic analgesic of its type that is not subject to the Controlled Substances Act, an indication of its safe utility. Nalbuphine has a low oral bioavailability.
  • Nalbuphine prodrugs designed to improve its pharmacokinetic and pharmacodynamic properties.
  • Merriam-Webster defines a prodrug as a pharmacologically inactive substance that is the modified form of a pharmacologically active drug to which it is converted (as by enzymatic action) in the body.
  • Franklin WO 2010-GB52211 teaches that Nalbuphine could be modified at phenolic hydroxyl residue.
  • Nalbuphine could be coupled to an amino acid or short peptide (WO 2011007247, A1). Also, Nalbuphine could be modified with dicarboxylic acid linked amino acid and peptide (WO 2010112942, A1). Further yet, Nalbuphine could be modified with carbomate moiety linked amino acid and peptide (WO 2009092071, A2). Moreover, Jenkins (WO 2007022535, A2) teaches that Nalbuphine could be further modified on its phenolic or nitrogen moiety.
  • Hilfinger US 20050137141, A1 teaches of Nalbuphine including a pharmaceutical species and an amino acid having a covalent bond to the pharmaceutical species.
  • Huang International Journal of Pharmaceutics, Volume: 297, Issue: 1-2, Pages: 162-171, Journal, 2005) teaches of the effects of iontophoresis and electroporation on transdermal delivery of Nalbuphine (NA) and its two novel prodrugs: Nalbuphine benzoate (NAB) and sebacoyl dinalbuphine ester (SDN) from solutions as well as from hydrogels.
  • NAB Nalbuphine benzoate
  • SDN sebacoyl dinalbuphine ester
  • Crooks (WO 2005009377, A2) teaches that forming duplex prodrugs including Nalbuphine can provide significant increase in the transdermal flux of drugs across human skin.
  • Uhrich (WO 2002009768, A2) teaches of therapeutic polyesters and polyamides of Nalbuphine.
  • Flu (EP 1149836, A1) teaches of preparation of polynalbuphine derivatives.
  • Pao Journal of Chromatography, B: Biomedical Sciences and Applications, Volume: 746, Issue: 2, Pages: 241-247, Journal, 2000) teaches of bioavailability of sebacoyl dinalbuphine ester.
  • Shami (EP 85108258.6) teaches that Nalbuphine can be further modified into 3- acetylsalicylate. Additional Nalbuphine prodrugs are disclosed in US 6569449, B1; CN 1107333, A; EP 615756, A1; and International Journal of Pharmaceutics, Volume: 38, Issue: 1-3, Pages: 199-209, Journal, 1987.
  • Naloxone sold under the brandname Narcan (and others), is a medication used to block the effects of opioids, especially in overdose situations. Naloxone may also be combined with an opioid (in the same pill or compound), to decrease the risk of opioid misuse. For instance, it could be added to the coating for a sustained release opiate compound, to prevent crushing of the sustained release compound, which could lead to an overdose.
  • Naloxone When given intravenously, Naloxone typically works within two minutes, and when injected into a muscle, it works within five minutes. It may also be used as a nasal spray. The effects of Naloxone typically last for about half an hour to an hour. Thus, multiple doses and administration of Naloxone may be required, as the duration of action of most opioids is greater than that of Naloxone.
  • Naloxone is a non-selective and competitive opioid receptor antagonist. It works by reversing the depression of the central nervous system and respiratory system caused by opioids. Naloxone was originally patented in 1961 and approved for opioid overdose treatment in the United States in 1971.
  • Naloxone also known as N-allylnoroxymorphone or as 17-allyl-4,5a-epoxy-3,14- dihydroxymorphinan-6-one, is a synthetic morphinan derivative and was derived from oxymorphone (14- hydroxydihydromorphinone), an opioid analgesic Oxymorphone, in turn, was derived from morphine, an opioid analgesic and naturally occurring constituent of the opium poppy.
  • Naloxone is a racemic mixture of two enantiomers, (-)-naloxone (levonaloxone) and (+)-naloxone (dextronaloxone), only the former of which is active at opioid receptors.
  • the drug is a highly lipophilic, allowing it to rapidly penetrate the brain and to achieve a far greater brain to serum ratio than that of morphine.
  • Opioid antagonists related to Naloxone include cyprodime, nalmefene, nalodeine, naloxol, and naltrexone.
  • Rachael Rzasa Lynn et al. describes in the article entitled “Nalaxone Dosage for Opioid Reversal: Current Evidence and Clinical Implications” (published in Therapeutic Advances in Drug Society Review, Vol. 9(1), pp. 63-88, 2018 at https://www.ncbi.nlm.nih.gOv/pmc/articles/PMC5753997/pdf/10.1177 2042098617744161.pdf) that double dose of naloxone administered to patient anesthetized with fentanyl produced no improvement in oxygen intake, while quadruple dose of naloxone produced significant improvements.
  • the interactions between the opioid agonist and the mu-opioid receptor may be the greatest determinant of the speed of recovery from the respiratory effects of many opioids, which may not markedly accelerate with increasing doses of naloxone, but rather respond to a minimum effective dose, while for compounds like buprenorphine, higher doses of naloxone may even lose efficacy.
  • esters of N-substituted 14-hydroxymorphinans could be used as highly effective low toxic an antirelapse agent with prolonged opioprotective effect being after a single s.c. or i.m. injection.
  • Lu Zhengtang discloses in the Chinese Patent No. CN 1204649 (published 01-13- 1999) preparation of naloxone esters.
  • Elie Gabriel Shami describes in European Patent Publication No. EP 170090 that benzoate ester prodrug derivatives of 3-hydroxymorphinans.
  • the aforementioned publications are incorporated herein, as part of the specification.
  • the present invention involves a novel modification of opioids and their antagonists that leads to higher opioid receptor engagement when given orally. More specifically, the present invention involves modification of the appropriate opiate receptor modulators (e.g. Nalbuphine, Buprenorphine, Hydromorphine, Morphine, Pentazocine, Butorphanole, Naloxone, etc.) or related compounds to improve opiates’ engagement of the opioid receptors when given orally.
  • opiate receptor modulators e.g. Nalbuphine, Buprenorphine, Hydromorphine, Morphine, Pentazocine, Butorphanole, Naloxone, etc.
  • the present invention further involves methods of mitigating opiate low oral bioavailability when opiates are used, without limitation, for the following conditions: pain management, palliative care, anesthesiology (e.g. postoperatively), skin disorders (e.g. pruritus), addictions (detox or management), certain locomotive disorders (e.g. levodopa-induced dyskinesias (LID) in Parkinson’s disease, the dyskinesias associated with Tourette’s syndrome, tardive dyskinesia, Huntington’s disease, etc.
  • pain management e.g. postoperatively
  • skin disorders e.g. pruritus
  • addictions detox or management
  • certain locomotive disorders e.g. levodopa-induced dyskinesias (LID) in Parkinson’s disease, the dyskinesias associated with Tourette’s syndrome, tardive dyskinesia, Huntington’s disease, etc.
  • the present invention involves a novel modification of the opioid agent (e.g. Nalbuphine) that provides unexpected results of increasing the engagement of opioid receptors when given orally.
  • the opioid agent e.g. Nalbuphine
  • this novel modification provides superior quality of care and allows for a wider range of therapeutic indications, including chronic conditions that require oral administration of the opioid.
  • the present invention involves a novel modification of the opioid antagonist, such as Naloxone combination with a hexadienoate included in the molecule, which provides substantially more effective and long-lasting neutralizing/sobering effect when administered to a person or patient.
  • opioid antagonist such as Naloxone combination with a hexadienoate included in the molecule
  • FIGURE 1 illustrates NMR 1 H spectrum of NB-20 compound, formulated in accordance with at least one embodiment of the present invention.
  • FIGURE 2 illustrates NMR 1 H spectrum of NB-33 compound, formulated in accordance with at least one embodiment of the present invention.
  • FIGURE 3 illustrates NMR 1 H spectrum of NB-39 compound, formulated in accordance with at least one embodiment of the present invention.
  • FIGURE 4 illustrates NMR 1 FI spectrum of NB-51 compound, formulated in accordance with at least one embodiment of the present invention.
  • FIGURE 5 illustrates NMR 1 FI spectrum of NB-52 compound, formulated in accordance with at least one embodiment of the present invention.
  • FIGURE 6 illustrates NMR 1 FI spectrum of NB-56 compound, formulated in accordance with at least one embodiment of the present invention.
  • FIGURE 7 illustrates NMR 1 FI spectrum of NB-58 compound, formulated in accordance with at least one embodiment of the present invention.
  • FIGURE 8 illustrates NMR 1 FI spectrum of NB-78 compound, formulated in accordance with at least one embodiment of the present invention.
  • FIGURE 9A illustrates the binding mode and molecular interactions of the most energetically favored conformer of nalbuphine superposed with co-crystallized ligand b-FNA.
  • FIGURE 9B illustrates the binding mode and molecular interactions of the most energetically favored conformer of naloxone superposed with co-crystallized ligand b-FNA.
  • FIGURE 10A illustrates the binding mode and molecular interactions of the most energetically favored conformer of NX-90 in the binding site of 4DKL.
  • FIGURE 10B illustrates the binding mode and molecular interactions of the most energetically favored conformer of NB-33 in the binding site of 4DKL.
  • FIGURE 10C illustrates molecular interaction with Met 151 shown by the conformer of NB-33 with the binding mode similar to the most energetically favored conformer.
  • FIGURE 10D illustrates the binding mode and molecular interactions of the most energetically favored conformer of NB-39 in the binding site of 4DKL.
  • FIGURE 11 A illustrates the most energetically favored conformer of nalbuphine (yellow), naloxone (pink) and co-crystalized b-FNA (white) superposed in the opioid binding site of 4DKL.
  • FIGURE 11 B illustrates the most energetically favored conformers of NX-90 (blue), NB-33 (red), NB-39 (cyan) and co-crystalized b-FNA (white) superposed in the opioid binding site of 4DK.
  • FIGS. 12A-C show Hydrophobic (red) and hydrophilic (yellow) contact preference areas on the molecular surface of the binding site of 4DKL with the docked conformer of NX-90, NB-33 and NB-39, respectively, in accordance with at least one embodiment.
  • FIG. 13 shows Graph 1 , illustrating superior analgesic properties of the NB-33, according to at least one embodiment, in comparison to the equimolar dose of the parent opioid NB.
  • the present invention includes formation of an opiate derived compositions including hexadienoate and opioid residue in a single molecule, which is used in therapeutic areas associated with opioid receptor modulation.
  • FIGS 1-8 Examples of NMR 1 H spectrums of selected compounds (examples including NB-20, NB-33, NB-39, NB-51, NB-52, NB-56, NB-58, NB-78), formulated in accordance with at least one embodiment of the present invention are shown in FIGS 1-8, respectively.
  • 3-hexadienoate derivative of an opioid created in accordance with at least one embodiment of the present invention, produced higher opioid receptor engagement than the parent opioid compound.
  • Nalbuphine 3-hexadienoate (NB-33) produced superior to the equivalent dose of both Nalbuphine 3-docosanoate (NB-39) and Nalbuphine (NB) analgesia in rats and humans, when given orally.
  • NB-33 a significant effect of NB-33 on pupil dilation (miosis) was observed in humans, which indicated superior receptor engagement.
  • Nulbuphine 3-alkenoate (e.g. NB-33) produced better analgesia than the parent opioid, while other unsaturated acid derivatives of Nalbuphine (e.g. NB-31, NB-32, NB-52, or NB-78) produced no analgesia in rats.
  • Nalbuphine 3-hexadienoate has a unique and distinct opiate receptor signature of its own with human recombinant opiate receptors expressed in cells.
  • the compounds of present invention comprise a general formula I or pharmaceutically acceptable salt of thereof
  • R 1 , R 2 , R3, R 4 or R 5 are selected from a group comprising H, optionally substituted C1-3 and OAlk), double bonds have E or Z geometry, and Y is an opioid residue.
  • the present invention further relates to methods of mitigating opiate low oral bioavailability when opiates are used in the following, but not limited to, conditions: pain management, palliative care, anesthesiology (e.g. postoperatively), skin disorders (e.g. pruritus), addictions (detox or management), certain locomotive disorders (e.g. levodopa-induced dyskinesias (LID) in Parkinson’s disease, and the dyskinesias associated with Tourette’s syndrome, tardive dyskinesia and Huntington’s disease), etc.
  • anesthesiology e.g. postoperatively
  • skin disorders e.g. pruritus
  • addictions detox or management
  • certain locomotive disorders e.g. levodopa-induced dyskinesias (LID) in Parkinson’s disease, and the dyskinesias associated with Tourette’s syndrome, tardive dyskinesia and Huntington’s disease
  • the present invention is an optionally substituted hexadienoate of a phenoxy moiety modification of the appropriate opiate receptor modulators or related compounds to improve opiates’ engagement of the opioid receptors when given orally.
  • the present invention is a is an optionally substituted hexadienoate of a 3-phenoxy moiety modification of the appropriate opiate receptor modulators, including, but not limited to, Hydromorphine, Morphine, Nalbuphine, Pentazocine, Butorphanol, Buprenorphine, Naloxone or related compounds, formulated to improve opiates’ engagement of the opioid receptors when given orally.
  • appropriate opiate receptor modulators including, but not limited to, Hydromorphine, Morphine, Nalbuphine, Pentazocine, Butorphanol, Buprenorphine, Naloxone or related compounds, formulated to improve opiates’ engagement of the opioid receptors when given orally.
  • the present invention is a 3-hexadienoate modification of the appropriate opiate receptor modulators or related compounds, formulated to improve opiates’ engagement of the opioid receptors when given orally.
  • the present invention is a 3-hexadienoate modification of Nalbuphine or a pharmaceutically acceptable salt of thereof to improve engagement of the opioid receptors when given orally.
  • the present invention is a 3-hexadienoate modification of Nalbuphine or a pharmaceutically acceptable salt of thereof to improve quality of pain management when given orally.
  • the present invention is a 3-hexadienoate modification of Nalbuphine or a pharmaceutically acceptable salt of thereof to improve quality of pain management when given intravenously, intranasally, transdermally, sublingually, rectally, topically, intramuscularly, subcutaneously or via inhalation.
  • Geranyl bromide (320 mg, 1.5 mmol) was added. The reaction mixture was stirred under reflux for 4 h and overnight at room temperature. The reaction mixture was evaporated and the residue was purified by column chromatography (silicagel, EtOAc/Heptanes/MeOH, 1 :1 :0.10). The colorless oil was formed after evaporation of selected fractions, yield 45%, purity 91% by HPLC. The structure was confirmed by NMR 1 H.
  • reaction mixture was stirred for 10 min and Nalbuphine hydrochloride (2.13 g, 5.4 mmol), trimethylamine (1.1 g, 10.9 mmol) and 4-dimethylaminopyidine (0.22 g, 1.8 mmol) were added at O °C. The stirring was continued for 1 h at 0 °C and at room temperature overnight. The reaction mixture was filtered, filtrate was evaporated, and the residue was purified by column chromatography (silicagel,
  • the crude material was purified by column chromatography (silicagel, EtOAc/Heptanes, 1 :1). The white solid was formed after evaporation of selected fractions, yield 67%, and purity 96% by HPLC. The structure was confirmed by NMR 1 H.
  • This compound was prepared according to the procedure of NB-31, by substituting undecylenic acid for 2-methoxy-crotonyc acid.
  • the crude material was twice purified by column chromatography (silicagel, EtOAc/Heptanes, 1 :1).
  • the white oils were formed after evaporation of selected fractions, yield 27%, purity 94% by HPLC.
  • the structure was confirmed by NMR 1 H.
  • EXAMPLE 2 Stability in the simulated gastro-intestinal fluid (sGIF).
  • NB-56 (1.0 mg) was dissolved in 10 mL of plasma (Plasma Pooled Normal Human
  • Tests on Sprague-Dawley rats were conducted using Nalbuphine, NB-31, NB-32, NB-33, NB-33, NB39, NB-51, NB-52, NB-76 and NB-78.
  • the antinociceptive activity was assessed as in Anesth Analg 2003; 97; 806-9 using the cold ethanol tail-flick test.
  • Tables 3, 4, and 5A-D illustrate that NB-33 resulted in analgesia and miosis superior to both the parent opioid NB and the parent opioid prodrug NB-39 when given orally. The differences in analgesia and miosis were statistically significant as indicated in Table 5A-D.
  • %MPE analgesia
  • Tables 5A-D illustrate comparison of analgesia and miosis between NB-33 and
  • Table 6A and Graph 1 in FIG. 13 below illustrate additional testing results for the NB-33 on Randall-Selitto rats, demonstrating its efficacy and benefits (including greater stability) in comparison to base compound.
  • Table 6A and Graph 1 in FIG. 13 below illustrate additional testing results for the NB-33 on Randall-Selitto rats, demonstrating its efficacy and benefits (including greater stability) in comparison to base compound.
  • FIG. 13 illustrate in the graphical form the results for 1310 NB-33, marked 1310, in comparison to the base NB compound NB, marked 1320 in FIG. 13.
  • EXAMPLE 8 Molecular docking of nalbuphine/naloxone opioid antagonists into m-opioid receptor.
  • the human m-opioid receptor crystal structures were downloaded from the RCSB Protein Data Bank [PDB entry: 4DKL, https://www.rcsb.org/structure/4DKL).
  • the in silico screening was carried out with the MOE Dock program, part of the MOE Simulation module 2014.0901.
  • the Ki was computed starting from the binding free energy values at a fixed temperature (300 K).
  • nalbuphine and naloxone demonstrate the key interaction of Asp 147 with their ammonium group. It is known that this bonding to Asp 147 is typical for the most known opioid agonists/antagonists.
  • the other duplicate interaction of nalbuphine and naloxone is bonding of the hydroxyl group attached to the aryl ring (3-position) to the water molecule, which contributes in stabilizing the inactive state of opioid receptors.
  • the hydroxyl group of naloxone attached to the tertiary carbon atom (14-position) participates in additional hydrogen bonding to Asp 147.
  • FIGURE 9A illustrates the binding mode and molecular interactions of the most energetically favored conformer of nalbuphine superposed with co-crystallized ligand b-FNA.
  • FIGURE 9B illustrates the binding mode and molecular interactions of the most energetically favored conformer of naloxone superposed with co-crystallized ligand b-FNA.
  • Nalbuphine and naloxone is bonding of the hydroxyl group attached to the aryl ring (3-position) to the water molecule, which contributes in stabilizing the inactive state of opioid receptors.
  • the hydroxyl group of naloxone attached to the tertiary carbon atom (14- position) participates in additional hydrogen bonding to Asp 147.
  • FIGURE 10A illustrates the binding mode and molecular interactions of the most energetically favored conformer of NX-90 in the binding site of 4DKL.
  • FIGURE 10B illustrates the binding mode and molecular interactions of the most energetically favored conformer of NB-33 in the binding site of 4DKL.
  • FIGURE 10C illustrates molecular interaction with Met 151 shown by the conformer of NB-33 with the binding mode similar to the most energetically favored conformer.
  • FIGURE 10D illustrates the binding mode and molecular interactions of the most energetically favored conformer of NB-39 in the binding site of 4DKL.
  • FIGURE 11 A illustrates the most energetically favored conformer of nalbuphine (yellow), naloxone (pink) and co-crystalized b-FNA (white) superposed in the opioid binding site of 4DKL.
  • FIGURE 11 B illustrates the most energetically favored conformers of NX-90 (blue), NB-33 (red), NB-39 (cyan) and co-crystalized b- FNA (white) superposed in the opioid binding site of 4DK.
  • both NX-90 and NB-33 have the unique hydrogen bonding to Met 151 through the hydroxyl group attached to the tertiary carbon atom (14-position). This interaction makes both NX-90 and NB-33 different from NB-39 which hydroxyl group at cyclohexane fragment (6-position) forms the hydrogen bond with Lys A233 instead.
  • the second differentiating factor for both NX-90 and NB- 33 is that the rigid conjugated system of the residue of hexadienoic acid has the extraordinary hydrophobic cylindrical molecular surface.
  • FIGS. 12A-C show Hydrophobic (red) and hydrophilic (yellow) contact preference areas on the molecular surface of the binding site of 4DKL with the docked conformer of NX-90, shown in FIG. 12A; NB-33, shown in FIG. 12B and NB-39, shown in FIG. 12C.
  • the present invention also includes at least one embodiment where hexadienoate improves performance of opioid receptor antagonists, such as, for example, Naloxone.
  • the present invention and particularly the hexadienoate has been combined and tested with at least one specie (or multiple species) from the Naloxone group or compound.
  • the Naloxone having hexadienoate, is included in the molecule, and provides substantially more effective and long-lasting neutralizing/soberingeffect when administered to a subject.
  • EDCI.HCI (1.36 g, 7.12 mmol) was added to hexadienoic acid (0.74 g, 6.61 mmol) in THF (50 mL) at 0 °C with stirring. Triethylamine (1.39 g, 13.8 mmol) was added. Stirring for 2 h at 0 °C. Naloxone hydrochloride (2.00 g, 5.5 mmol and 4-dimethylaminopyidine (0.10 g, 0.82 mmol) were added at 0 °C. The stirring was continued for 1 h at 0 °C and at room temperature overnight.
  • opioids can be used for the treatment of the following medical conditions: pain management, a palliative care, a postoperative anesthesiology, a skin disorder, an addiction, a locomotive disorder, a ievodopa-induced dyskinesias (LID) in Parkinson’s disease, a dyskinesias associated with Tourette’s syndrome, a tardive dyskinesia and a Huntington’s disease and others.
  • LID ievodopa-induced dyskinesias
  • the potency and effectiveness of the opioids used for the treatment of these medical conditions affects how successful the treatment is.
  • opioids modified with Hexadienoates will be more effective in treating the aforementioned conditions, because they have higher engagement of opioid receptors.
  • one of the composition compounds that is formulated based on the present invention may be utilized for treatment of one of the medical conditions such as a pain management, a palliative care, a postoperative anesthesiology, a skin disorder (e.g. pruritus), an addiction (detox or management), and/or a locomotive disorder (e.g. levodopa-induced dyskinesias (LID) in Parkinson’s disease, and the dyskinesias associated with Tourette’s syndrome, tardive dyskinesia and Huntington’s disease).
  • a pain management e.g. a palliative care
  • a postoperative anesthesiology e.g. pruritus
  • an addiction detox or management
  • a locomotive disorder e.g. levodopa-induced dyskinesias (LID) in Parkinson’s disease, and the dyskinesias associated with Tourette’s syndrome, tardive dyskinesia and Huntington’s disease
  • NX-90 Data for compound NX-90 is summarized in Table 10. It shows that NX-90 is not a pharmacologically inert compound and has a distinct opioid signature of its own, similar to the pharmacological profile of naloxone. Separately, it shown that NB-33 is not a pharmacologically inert compound and has a distinct opioid signature of its own, similar to the pharmacological profile of NB.

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Abstract

La présente invention concerne des compositions dérivées d'opiacés et leurs antagonistes utiles dans des domaines thérapeutiques associées à la modulation des récepteurs opioïdes. Une modification de 3-hexanediénoate des opioïdes est formulée pour améliorer la mobilisation d'opiacés des récepteurs opioïdes lorsqu'ils sont administrés par voie orale. L'invention concerne une modification de 3-hexanediénoate de Nalbuphine ou d'un sel pharmaceutiquement acceptable de celle-ci pour améliorer la qualité de la gestion de la douleur lorsqu'elle est administrée par voie intraveineuse, intranasale, transdermique, sublinguale, rectale, topique, intramusculaire, sous-cutanée ou par inhalation. Une modification de 3-hexanediénoate des antagonistes d'opioïdes est formulée pour améliorer l'inhibition des récepteurs opioïdes lorsqu'ils sont administrés par voie orale. L'invention concerne une modification de 3-hexanediénoate de Naloxone ou d'un sel pharmaceutiquement acceptable de celle-ci pour améliorer la qualité du sevrage lorsqu'elle est administrée par voie intraveineuse, intranasale, transdermique, sublinguale, rectale, topique, intramusculaire, sous-cutanée ou par inhalation.
PCT/US2020/021599 2019-08-11 2020-03-07 Compositions et procédés pour améliorer la mobilisation de récepteur opioïde par des héxadiénoates d'opioïdes et des héxadiénoates éventuellement substitués Ceased WO2021029914A1 (fr)

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EP20852037.9A EP4010078A4 (fr) 2019-08-11 2020-03-07 Compositions et procédés pour améliorer la mobilisation de récepteur opioïde par des héxadiénoates d'opioïdes et des héxadiénoates éventuellement substitués
JP2022509137A JP7535569B2 (ja) 2019-08-11 2020-03-07 オピオイドヘキサジエノエート及び選択的に置換されたヘキサジエノエートによってオピオイド受容体の結合を改善する組成物並びに方法
CA3149152A CA3149152A1 (fr) 2019-08-11 2020-03-07 Compositions et procedes pour ameliorer la mobilisation de recepteur opioide par des hexadienoates d'opioides et des hexadienoates eventuellement substitues
MX2022001520A MX2022001520A (es) 2019-08-11 2020-03-07 Composiciones y metodos para mejorar activacion de receptor de opioide por hexadienoatos opioides y hexadienoatos opcionalmente sustituidos.
CN202080071185.9A CN114828961B (zh) 2019-08-11 2020-03-07 通过阿片类己二烯酸酯和任选取代的己二烯酸酯增强阿片受体结合的组合物及方法

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