JP7535569B2 - Compositions and methods for improving opioid receptor binding with opioid hexadienoates and optionally substituted hexadienoates - Google Patents

Description

This application is a PCT application of U.S. regular patent application No. 16/540,058, filed August 14, 2019, which claims priority under U.S.C. §119 to U.S. provisional patent application No. 62/885,311, filed August 11, 2019, entitled "Compositions and Methods for Improving Opioid Receptor Binding with Opioid Hexadienoates and Selectively Substituted Hexadienoates."

The present invention relates to opiate-derived compositions for use in therapeutic areas related to opioid receptor modulation.

Nalbuphine (Nubain) was launched in 1979 as an analgesic for moderate to severe pain and has been used effectively in the clinic since then. It is primarily used in combination with anesthetics for pre- and post-operative analgesia and during labor and delivery for acute and chronic pain management. Recently, its uses have expanded to the treatment of movement disorders, skin disorders such as pruritus, and addiction management.

Nalbuphine has also recently been shown to 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, a safe indication of usefulness. Nalbuphine has low oral bioavailability.

Nalbuphine prodrugs designed to improve its pharmacokinetic and pharmacodynamic properties are known. Merriam-Webster defines a prodrug as a pharmacologically inactive substance that is a modified form of a pharmacologically active drug that is converted (by enzymatic action) in the body. Thus, Franklin (WO 2010-GB52211) teaches that nalbuphine can be modified with a phenolic hydroxyl residue.

Additionally, nalbuphine can be conjugated to an amino acid or a short peptide (WO 2011007247, A1). Additionally, nalbuphine can be modified with amino acids and peptides linked to a dicarboxylic acid (WO 2010112942, A1). Additionally, nalbuphine can be modified with amino acids and peptides linked to a carbomate moiety (WO 2009092071, A2). Additionally, Jenkins (WO 2007022535, A2) teaches that nalbuphine can be further modified with a phenol moiety or a nitrogen moiety.

Wang teaches that nalbuphine can be converted to an ester prodrug (Journal of Controlled Release, Volume: 115, Issue: 2, Pages: 140-149, Journal, 2006). Flu (January 11, 2005, TW 226239, B) teaches a delivery system and a nalbuphine prodrug that enhances its bioavailability. More specifically, a formulation for enhancing the bioavailability of nalbuphine includes a vegetable oil, a co-solvent, and an effective amount of a nalbuphine ester prodrug or a pharma- ceutically acceptable salt thereof. One purpose of the prodrug is to enhance the oral bioavailability of nalbuphine and increase the retention time of nalbuphine in the body, thereby prolonging the duration of analgesia and reducing analgesic costs.

Hilfinger (US 20050137141, A1) teaches nalbuphine containing a pharmaceutical species and an amino acid covalently bonded to the pharmaceutical species. Huang (International Journal of Pharmaceutics, Volume: 297, Issue: 1-2, Pages: 162-171, Journal, 2005) teaches the effect of iontophoresis and electroporation on the transdermal delivery of nalbuphine (NA) and its two novel prodrugs, nalbuphine benzoate (NAB) and sebacoyl dinalbuphine ester (SDN), from solutions and hydrogels.

Crooks (WO 2005009377, A2) teaches that forming a duplex prodrug with nalbuphine can significantly increase the transdermal flux of the drug into human skin. Uhrichi (WO 2002009768, A2) teaches therapeutic polyesters and polyamides of nalbuphine. Flu (EP 1149836, A1) teaches the preparation of polynalbuphine derivatives. Pao (Journal of Chromatography, B: Biomedical Sciences and Applications, Volume: 746, Issue: 2, Pages: 241-247, Journal, 2000) teaches the bioavailability of sebacoyl dinalbuphine esters.

Han (International Journal of Pharmaceutics, Volume: 177, Issue: 2, Pages: 201-209, Journal, 1999) teaches novel mucoadhesive buccal disks for controlled delivery of nalbuphine prodrugs: effect of formulation variables on drug release and mucoadhesive performance. Sung (International Journal of Pharmaceutics, Volume: 172, Issue: 1-2, Pages: 17-25, Journal, 1998) teaches controlled release of nalbuphine prodrugs from biodegradable polymer matrices: effect of prodrug hydrophilicity and polymer composition. Yoa-Pu (US 5750534, A) teaches nalbuphine esters that have long-acting analgesic properties.

Shami (EP 85108258.6) teaches that nalbuphine can be further modified to 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.

The pharmacokinetic and pharmacodynamic properties of nalbuphine, its pharmaceutically acceptable salts or esters, or its prodrugs can be further tuned by various delivery systems. Thus, Liu (International Journal of Pharmaceutics, Volume: 257, Issue: 1-2, Pages: 23-31, Journal, 2003) teaches biodegradable polymeric microspheres for controlled delivery of nalbuphine prodrugs. Sung (European Journal of Pharmaceutical Sciences, Volume: 18, Issue: 1, Pages: 63-70, Journal, 2003) teaches transdermal delivery of nalbuphine and its prodrugs by electroporation. Fang (Arzneimittel-Forschung, Volume: 51, Issue: 5, Pages: 408-413, Journal, 2001) teaches transdermal delivery of nalbuphine and nalbuphine pivalate from hydrogels by passive diffusion and iontophoresis.

A distinction must be made between improved oral bioavailability and increased opioid receptor binding for these opioid derivatives. For example, esterification of the phenoxy moiety of nalbuphine (e.g., the 3-docosanoate derivative of nalbuphine) (NB-39) has previously been claimed to improve oral bioavailability. However, when administered orally, the cumulative analgesic effect produced by NB-39 was inferior to equivalent doses of nalbuphine in rats and humans. Furthermore, NB-39 has no significant effect on pupil dilation (miosis) in humans after oral administration, indicating inferior opioid receptor binding.

Naloxone, sold under the brand name Narcan (and others), is a drug used to block the effects of opioids, especially in overdose situations. Additionally, naloxone can be combined with opioids (same pill or compound) to reduce the risk of opioid misuse. For example, it can be added to the coating of a sustained release opiate compound to prevent crushing of the sustained release compound, which can lead to an overdose.

When administered intravenously, naloxone usually acts within 2 minutes, and when injected intramuscularly, within 5 minutes. It is also available as a nasal spray. The effects of naloxone usually last for about 30 minutes to an hour. Thus, the duration of action of most opioids is longer than that of naloxone, and multiple doses and administrations of naloxone may be required.

Administration of naloxone to an opioid-dependent person can cause opioid withdrawal symptoms, such as restlessness, agitation, nausea, vomiting, increased heart rate and sweating. To prevent this, small doses of naloxone can be administered every few minutes until the desired effect is achieved.

Additional cardiac problems have been reported in individuals with a history of heart disease or who are taking medications that have adverse cardiac effects. Naloxone has been administered and tested in a limited number of subjects and appears to be safe during pregnancy.

Naloxone is a nonselective, competitive opioid receptor antagonist. It works by reversing the central nervous system and respiratory system depression caused by opioids. Naloxone was originally patented in 1961 and approved in the United States in 1971 for the treatment of opioid overdose.

Naloxone, also known as N-allyloxymorphone or 17-allyl-4,5a-epoxy-3,14-dihydroxymorphinan-6-one, is a synthetic morphinan derivative derived from oxymorphone (14-hydroxydihydromorphinone), an opioid analgesic derived from morphine, an opioid analgesic and natural component of the opium poppy.

Naloxone is a racemic mixture of two enantiomers, (-)-naloxone (levonaloxone) and (+)-naloxone (dextronaloxone), of which only the former is active at opioid receptors. The drug is highly lipophilic and can rapidly penetrate the brain, achieving a much higher brain-to-serum ratio than morphine. Opioid antagonists related to naloxone include cyprodime, nalmefene, nalodain, naloxol, and naltrexone.

The chemical half-life of naloxone is such that injectable and nasal forms are commercially available with expiration dates of 24 and 18 months, respectively. A 2018 study showed that the nasal and injectable forms are chemically stable for up to 36 and 28 months, respectively, which prompted the initiation of a still incomplete five-year stability study. This suggests that stockpiles of expired material in community and health care settings may be substantially effective beyond their labeled expiration dates.

Specific articles on opioid antagonists highlight the shortcomings and problems of currently known formulations and the need for improved, more stable compounds that can be used safely in patients suffering from opioid dependence.

The article by Adam Bisaga entitled "As Fentanyl Replaces Heroin, What Should Clinicians Do?" (published in Addiction, Vol. 114, pp. 781-86, https://onlinelibrary.wiley.eom/doi/epdf/10.111/add.14522) notes that high affinity antagonists may not be sufficient to block the effects of fentanyl, so higher doses may be required that border on systemic safety concerns. Furthermore, overdose prevention with fentanyl requires higher doses of naloxone and repeated administrations, which is hampered by a much shorter overdose prevention period for fentanyl than for heroin.

In an article titled "Management of Suspected Opioid Overdoses with Naloxone by Emergency Medical Services Personnel" (published in Comparative Effectiveness Review No. 193 at https://effectivehealthcare.ahrq.qov/sites/default/files/pdf/cer-193-naloxone-final_1.pdf), Roger Chou et al. note that existing dosing guidelines for naloxone may not be sufficient to prevent overdoses of fentanyl and fentanyl analogues.

Rachel Rzasa Lynn et al., in their article titled "Nalacone Dose for Opioid Reversal: Current Evidence and Clinical Implications" (Therapeutic Advances in Drug Society Review, Vol. 9(1), pp. 63-88, published in 2018 at https://www.ncbe.nlm.nih.gOv/pmc/articles/PMC5753997/pdf/10.1177_2042098617744161.pdf), note that a double dose of naloxone administered to patients anesthetized with fentanyl did not result in improved oxygen intake, but a four-fold dose of naloxone did result in significant improvement. He further teaches that the interaction between opioid agonists and the mu opioid receptor may be the greatest determinant of the rate of recovery from the respiratory effects of many opioids, which does not accelerate significantly as the dose of naloxone increases, but rather responds to the minimum effective dose, although in the case of compounds such as buprenorphine, higher doses of naloxone may lose effect. And he cites numerous reports describing fentanyl overdoses that are initially unresponsive to IN naloxone, are only temporarily reversed with IV naloxone, and require further IV doses or continuous infusion to prevent recurrence of toxicity and respiratory depression.

IA Elkiweri et al., in their article entitled "Competitive Substrates for P-Glycoprotein and Organic Anion Protein Transporters Differentially Reduce Blood-Organ Transport of Fentanyl and Loferamide: Pharmacokinetics and Pharmacodynamics in Sprague-Dawley Rats" (published online in 2009 at https://www.ncbinlm.nih.gov/pubmed/19095843), state that naloxone and fentanyl share a transporter for cellular entry that is saturated by high plasma concentrations of fentanyl, preventing rapid entry of naloxone across the BBB regardless of dose.

In an article titled "Pharmacokinetics of Concentrated Naloxone Nasal Spray for Reversal of Opioid Overdose: A Phase I Healthy Volunteer Study" (published in Addiction, 113, pp. 484-93), Rebecca McDonald et al. state that a high-concentration 2 mg naloxone intranasal (i.n) spray has an initial absorption rate comparable to an intramuscular (i.m) 0.4 mg injection and can be used as a take-home antidote. He suggests that high doses of i.n. naloxone can be administered without the risk of "over-antagonism."

Jiten Ranchhodbhai Patel et al. disclose a carbamate of naloxone containing a novel hydrazide group (Publication No. WO 2013093931 - Application No. PCT/IN2012/00590, filed September 6, 2012).

Baohua Huang et al., in their article entitled "Human Plasma-Mediated Hypoxic Activation of Indolequinone Naloxone Prodrugs" (Bioorganic & Medicinal Chemistry Letters in 2009, 19(17), 5016-5020), describe that indolequinone naloxone prodrugs can reverse opiate-induced hypoxia.

I. Ukrainets et al., Chemistry of Heterocyclic Compounds (2009), 45(4), pp. 405-416, disclose a study of 3-O-acyl derivatives of naloxone as potential prodrugs.

Xuemiei Peng et al., in their article "Pharmacological Properties of Butorphans Containing Divalent Ligands Linked to μ, δ, and κ Opioid Receptors with Nalbuphine and Nalacone" (published in Journal of Medicinal Chemistry (May 2007), 50(9), 2254-2258), disclose butorphans containing a divalent ligand linked to naloxone.

I. Romanov et al., in Russian Patent Publication (RU 2221566 - published January 20, 2004), describe that esters of N-substituted 14-hydroxymorphinan can be used as highly effective, low-toxicity antirelapse agents with sustained anti-protective effects after a single subcutaneous or intramuscular injection.

I. Romanov et al., in Russian Patent Publication (RU 2215741 - published Nov. 10, 2003), describe a method for preparing N-substituted 14-hydroxymorphinan esters.

Euro-Celtique, S. a., Chevchuk et al., in Patent Publication No. WO 2003070191 (PCT/US/2003/004999 - published Aug. 28, 2003), describe a method for preventing pain using a tamper-resistant transdermal device containing a 3-acyl substituted antagonist.

Lu Zhengtang discloses the preparation of naloxone esters in Chinese Patent No. CN1204649 (published Jan. 13, 1999).

S. Lazar et al., in an article entitled "Synthesis and Biological Activity of Phosphate and Sulfate Esters of Naloxone and Naltrexone" (European Journal of Medicinal Chemistry (1994), Vol. 29(1), pp. 45-53), describe the synthesis and biological activity of phosphate and sulfate esters of naloxone.

Hussein et al., Pharmaceutical Research (1988), vol. 5(9), pp. 615-18, report that various prodrugs of naloxone in which the 3-phenoxy group is esterified are free of bitterness and have better oral bioavailability in dogs.

Elie Gabriel Shami describes benzoate prodrug derivatives of 3-hydroxymorphinan in European Patent Publication No. EP 170090. The above publication is incorporated herein by reference.

None of these cited publications describe the combination of naloxone with hexadienoate contained in the molecule or show that such a molecule results in a substantially more effective and long-lasting neutralizing/sedative effect when administered to humans.

The present invention includes novel modifications of opioids and their antagonists that result in higher opioid receptor binding when administered orally. More specifically, the present invention includes modifications of opiate receptor modulators (e.g., nalbuphine, buprenorphine, hydromorphine, morphine, pentazocine, butorphanol, naloxone, etc.) or related compounds suitable for improving opiate binding to opioid receptors when administered orally.

The present invention further includes, but is not limited to, methods for reducing the poor oral bioavailability of opiates when used for the following conditions: pain management, palliative care, anesthesia (e.g., post-operative), skin conditions (e.g., pruritus), addiction (detoxification or management), and certain movement disorders (e.g., levodopa-induced dyskinesia (LID) in Parkinson's disease, dyskinesia associated with Tourette's syndrome, tardive dyskinesia, Huntington's disease, etc.).

The present invention involves a novel modification of an opioid agent (e.g., nalbuphine) that, when administered orally, has the unexpected result of increasing opioid receptor binding. This novel modification therefore provides superior quality of care and allows for a broader range of therapeutic indications, including chronic diseases requiring oral administration of opioids.

The present invention involves novel modifications of opioid antagonists, such as the combination of naloxone with hexadienoate contained in the molecule, which provides a substantially more effective and long-lasting neutralizing/sedative effect when administered to a human or patient.

The novel features of the present invention will be further explained with reference to the following drawings.
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

1 shows an NMR 1H spectrum of the NB-20 compound prepared in accordance with at least one embodiment of the present invention. 1 shows an NMR 1H spectrum of an NB-33 compound prepared in accordance with at least one embodiment of the present invention. 1 shows an NMR 1H spectrum of an NB-39 compound prepared in accordance with at least one embodiment of the present invention. 1 shows an NMR 1H spectrum of an NB-51 compound prepared in accordance with at least one embodiment of the present invention. 1 shows an NMR 1H spectrum of the NB-52 compound prepared in accordance with at least one embodiment of the present invention. 1 shows an NMR 1H spectrum of an NB-56 compound prepared in accordance with at least one embodiment of the present invention. 1 shows an NMR 1H spectrum of an NB-58 compound prepared in accordance with at least one embodiment of the present invention. 1 shows an NMR 1H spectrum of an NB-78 compound prepared in accordance with at least one embodiment of the present invention. The binding mode and molecular interactions of the most energetically favorable conformer of nalbuphine superimposed with the co-crystallized ligand β-FNA are shown. The binding mode and molecular interactions of the most energetically favorable conformer of naloxone superimposed with the co-crystallized ligand β-FNA are shown. 4 shows the binding mode and molecular interactions of the most energetically favorable conformer of NX-90 in the binding site of DKL. 1 shows the binding mode and molecular interactions of the most energetically favorable conformer of NB-33 in the binding site of 4DKL. 1 shows the molecular interactions with Met 151 exhibited by conformers of NB-33 with binding modes similar to the most energetically favorable conformer. 1 shows the binding mode and molecular interactions of the most energetically favorable conformer of NB-39 in the binding site of 4DKL. Shown are the most energetically favorable conformers of nalbuphine (yellow), naloxone (pink), and co-crystallized β-FNA (white) superimposed onto the opioid binding site of 4DKL. The most energetically favorable conformers of NX-90 (blue), NB-33 (red), NB-39 (cyan) and co-crystallized β-FNA (white) are shown superimposed onto the opioid binding site of 4DKL. 1 shows hydrophobic (red) and hydrophilic (yellow) contact preference regions on the molecular surface of the binding site of 4DKL with docked conformers of NX-90, NB-33, and NB-39, respectively, in accordance with at least one embodiment. 1 shows hydrophobic (red) and hydrophilic (yellow) contact preference regions on the molecular surface of the binding site of 4DKL with docked conformers of NX-90, NB-33, and NB-39, respectively, in accordance with at least one embodiment. 1 shows hydrophobic (red) and hydrophilic (yellow) contact preference regions on the molecular surface of the binding site of 4DKL with docked conformers of NX-90, NB-33, and NB-39, respectively, in accordance with at least one embodiment. Graph 1 shows the superior analgesic properties of NB-33 according to at least one embodiment compared to an equimolar dose of the parent opioid NB.

The present invention involves the formation of opiate-derived compositions containing hexadienoate and opioid residues in a single molecule for use in therapeutic areas related to the modulation of opioid receptors.

Various aspects and features of the invention and compositions are described with reference to Table 1, which shows selected properties of compounds NB, NB-20, NB-28, NB-31, NB-32, NB-33, NB-39, NB-46, NB-51, NB-52, NB-56, NB-58, NB-76, and NB-78.

Examples of NMR 1H spectra of selected compounds (examples include NB-20, NB-33, NB-39, NB-51, NB-52, NB-56, NB-58, and NB-78) prepared according to at least one embodiment of the present invention are shown in Figures 1-8, respectively.

Surprisingly, the 3-hexadienoate derivatives of opioids produced according to at least one embodiment of the present invention produced higher opioid receptor binding than the parent opioid compounds. Thus, for example, nalbuphine 3-hexadienoate (NB-33) produced superior analgesic effects in rats and humans when administered orally than equivalent doses of both nalbuphine 3-docosanoate (NB-39) and nalbuphine (NB). Furthermore, a significant effect of NB-33 on pupil dilation (miosis) was observed in humans, indicating superior receptor binding.

Unexpectedly, when examining the efficacy of at least one embodiment of the present invention, it was discovered that the location and number of ester unsaturation sites of the phenoxy moiety are inherent to the hexadiene backbone and are necessary for superior binding to opioid receptors. Thus, nurbuphine 3-alkenoates (e.g., NB-33) produced superior analgesic effects in rats to the parent opioid, whereas other unsaturated acid derivatives of nalbuphine (e.g., NB-31, NB-32, NB-52, or NB-78) did not produce analgesic effects.

Further, while evaluating at least one embodiment of the present invention, it was found that nalbuphine 3-hexadienoate has its own unique and distinct opiate receptor signature with human recombinant opiate receptors expressed in cells.

According to at least one embodiment, the compound of the present invention comprises Formula I or a pharma- ceutically acceptable salt thereof.

式Ｉ

Formula I

wherein R ₁ , R ₂ , R ₃ , R ₄ or R ₅ is selected from the group consisting of H, optionally substituted C1-3 and OAlk, the double bond has an E or Z geometry, and Y is an opioid residue.

In at least one embodiment, the present invention further relates to a method for reducing the poor oral bioavailability of opiates when used in the following disorders, including, but not limited to, pain management, palliative care, anesthesia (e.g., post-operative), skin disorders (e.g., pruritus), addiction (detoxification or management), and certain movement disorders (e.g., levodopa-induced dyskinesia (LID) in Parkinson's disease, and dyskinesia associated with Tourette's syndrome, tardive dyskinesia, and Huntington's disease).

In at least one embodiment, the present invention is an optionally substituted hexadienoate that is a phenoxy moiety modification of a suitable opiate receptor modulator or related compound to improve binding of the opiate to the opioid receptor when administered orally.

In another embodiment, the present invention is an optionally substituted hexadienoate that is a 3-phenoxy moiety modification of a suitable opiate receptor modulator, including but not limited to hydromorphine, morphine, nalbuphine, pentazocine, butorphanol, buprenorphine, naloxone or related compounds, formulated to improve binding of the opiate to the opioid receptor when administered orally.

In at least one further embodiment, the present invention is a 3-hexadienoate modification of a suitable opiate receptor modulator or related compound prepared to improve binding of the opiate to the opioid receptor when administered orally.

In at least one embodiment, the present invention is a 3-hexadienoate modification of nalbuphine or a pharma- ceutically acceptable salt thereof to improve opioid receptor binding when administered orally.

In yet another embodiment, the present invention is a 3-hexadienoate modification of nalbuphine or a pharma- ceutically acceptable salt thereof for improving the quality of pain control when administered orally.

In one or more further embodiments, the present invention is a 3-hexadienoate modification of nalbuphine or a pharma- ceutically acceptable salt thereof for improving the quality of pain control when administered intravenously, intranasally, transdermally, sublingually, rectally, topically, intramuscularly, subcutaneously, or via inhalation.

The following are further examples of compounds prepared in accordance with at least one embodiment of the present invention. The chemical name, composition and code name of each compound in Example 1 are shown in Table 1 below.

Example 1
(E)-3-(cyclobutylmethyl)-9-((3,7-dimethylocta-2,6-dien-1-yl)oxy)-1,2,3,4,5,6,7,7a-octahydro-4aH-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diol, nalbufino-geranyl, (NB-20). Potassium bicarbonate (280 mg, 2.0 mmol) was added to a suspension of nalbuphine hydrochloride (400 mg, 1.0 mmol) in acetone (20 mL) and toluene (20 mL) at room temperature. Geranyl bromide (320 mg, 1.5 mmol) was added. The reaction mixture was stirred under reflux for 4 h and at room temperature overnight. The reaction mixture was evaporated and the residue was purified by column chromatography (silica gel, EtOAc/heptane/MeOH, 1:1:0.10). A colourless oil was formed after evaporation of selected fractions in 45% yield and 91% purity by HPLC. The structure was confirmed by NMR ¹ H.

3-(Cyclobutylmethyl)-9-(((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)oxy)-1,2,3,4,5,6,7,7a-octahydro-4aH-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diol, nalbufino-farnesyl, (NB-28). This compound was prepared according to the procedure of NB-20, substituting farnesyl bromide for geranyl bromide. The crude material was purified by column chromatography (silica gel, EtOAc/heptane, 1:1). A colorless oil was obtained after evaporation of selected fractions in 53% yield and 93% purity by HPLC. The structure was confirmed by ^1H NMR.

3-(Cyclobutylmethyl)-4a,7-dihydroxy-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-ylundec-10-enoate, nalbuphine-undecylenoate, (NB-31). EDCI (1.04 g, 5.4 mmol) was added to undecylenic acid (1.0 g, 5.4 mmol) in THF (30 mL) with stirring at 0° C. The 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-dimethylaminopyridine (0.22 g, 1.8 mmol) were added at 0° C. Stirring was continued for 1 h at 0° C. and overnight at room temperature. The reaction mixture was filtered, the filtrate was evaporated, and the residue was purified by column chromatography (silica gel, EtOAc/heptane, 1:1). After evaporation of selected fractions, a white solid was formed with a yield of 2.2 g (78%) and a purity of 95% by HPLC. The structure was confirmed by NMR ^1H .

3-(Cyclobutylmethyl)-4a,7-dihydroxy-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl (E)-3,7-dimethylocta-2,6-dienoate, nalbufino-geranoate, (NB-32). This compound was prepared according to the procedure of NB-31, substituting geranic acid for undecylenic acid. The crude material was purified by column chromatography (silica gel, EtOAc/heptane, 1:1). After evaporation of selected fractions, a white solid was formed in 67% yield and 96% purity by HPLC. The structure was confirmed by ^1H NMR.

3-(Cyclobutylmethyl)-4a,7-dihydroxy-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl (2E,4E)-hexa-2,4-dienoate, nalbuphine-sorbate, (NB-33). EDCI (1.16 g, 6.1 mmol) was added to hexadienoic acid (0.68 g, 6.1 mmol) in THF (30 mL) with stirring at 0° C. The reaction mixture was stirred for 10 min and nalbuphine hydrochloride (2.39 g, 6.1 mmol), trimethylamine (1.2 g, 12 mmol) and 4-dimethylaminopyridine (0.25 g, 2 mmol) were added at 0° C. Stirring was continued for 1 h at 0° C. and overnight at room temperature. The reaction mixture was filtered, the filtrate was evaporated, and the residue was purified by column chromatography (silica gel, EtOAc/heptane, 1:1). White crystals were formed after evaporation of selected fractions, the yield was 2.05 g (75%), and the purity was 98% by HPLC. The structure was confirmed by NMR ^1H .

3-(Cyclobutylmethyl)-9-(((2E,4E)-hexa-2,4-dienoyl)oxy)-4a,7-dihydroxy-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-3-ium chloride, nalbufino-sorbate, hydrochloride, (NB-56). HCl (g) was bubbled into a solution of nalbufino-sorbate (NB-33) (0.4 g, 0.89 mmol) in MTBE (15 mL) at 0° C. A white precipitate formed immediately. The reaction mixture was stirred for 1 h and the solid was filtered, washed with MTBE and dried under vacuum. Yield 0.35 g (81%), purity 98% by HPLC. Structure confirmed by ¹ H NMR.

3-(Cyclobutylmethyl)-4a,7-dihydroxy-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-9-yl docosanoate, nalbufino-docosanoate, (NB-39). EDCI (0.56 g, 2.9 mmol) was added to behenic acid (1.0 g, 2.9 mmol) in THF (50 mL) with stirring at 0° C. The reaction mixture was stirred for 30 min and nalbuphine hydrochloride (1.16 g, 2.9 mmol), trimethylamine (0.29 g, 2.9 mmol) and 4-dimethylaminopyridine (0.12 g, 1.0 mmol) were added at 0° C. Stirring was continued for 1 h at 0° C. and overnight at room temperature. The reaction mixture was filtered, the filtrate was evaporated, and the residue was purified by column chromatography (silica gel, EtOAc/heptane, 1:2). After evaporation of selected fractions, a white solid was formed with a yield of 1.45 g (73%) and a purity of 97% by HPLC. The structure was confirmed by NMR ^1H . Further synthesis and properties of NB-39 are described in US Patent 5,750,534.

3-(Cyclobutylmethyl)-4a,7-dihydroxy-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl isobutyrate, nalbufino-isobutyrate, NB-isovaleroate, (NB-46). This compound was prepared according to the procedure of NB-31, substituting isovaleric acid for undecylenic acid. The crude material was purified by column chromatography (silica gel, EtOAc/heptane, 1:1). White crystals were formed after evaporation of selected fractions in 54% yield and 95% purity by HPLC. The structure was confirmed by ^1H NMR.

3-(Cyclobutylmethyl)-4a,7-dihydroxy-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl 3-methylbut-2-enoate, nalbupino-3,3-dimethylacrylate, (NB-51). This compound was prepared according to the procedure of NB-31, substituting 3,3-dimethylacrylic acid for undecylenic acid. The crude material was purified by column chromatography (silica gel, EtOAc/heptane, 1:1). White crystals were formed after evaporation of selected fractions in 77% yield and 95% purity by HPLC. The structure was confirmed by ^1H NMR.

3-(Cyclobutylmethyl)-4a,7-dihydroxy-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl (E)-2-methylbut-2-enoate, nalbupino-2,3-dimethylacrylate, (NB-52). This compound was prepared according to the procedure of NB-31, substituting 2,3-dimethylacrylic acid for undecylenic acid. The crude material was purified by column chromatography (silica gel, EtOAc/heptane, 1:1). White crystals were formed after evaporation of selected fractions in 75% yield and 96% purity by HPLC. The structure was confirmed by ^1H NMR.

3-(Cyclobutylmethyl)-4a,7-dihydroxy-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl 2-methoxybut-2-enoate, nalbufino-2-methoxycrotonate, (NB-58). This compound was prepared according to the procedure of NB-31, substituting 2-methoxy-crotonic acid for undecylenic acid. The crude material was purified twice by column chromatography (silica gel, EtOAc/heptane, 1:1). A white oil was formed after evaporation of selected fractions in 27% yield and 94% purity by HPLC. The structure was confirmed by NMR ^1H .

7-Acetoxy-3-(cyclobutylmethyl)-4a-hydroxy-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl-(2E,4E)-hexa-2,4-dienoate, nalbufino-hexadienoate-acetate (NB-76). NB-33 (0.5 g, 1.1 mmol) was stirred overnight in acetic anhydride (7.0 mL) at 40-50 °C. EtOH (20 mL) was added and the reaction mixture was evaporated. The residue was purified twice by column chromatography (silica gel, EtOAc/heptane, 1:2). White crystals were formed after evaporation of selected fractions in a yield of 1.45 g (50%) with a purity of 97% by HPLC. The structure was confirmed by ^1H NMR.

3-(Cyclobutylmethyl)-4a,7-dihydroxy-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-ylcinnamate, nalbufino-cinnamate, (NB-78). This compound was prepared according to the procedure of NB-31, substituting 2-trans-cinnamic acid for undecylenic acid. The crude material was purified by column chromatography (silica gel, EtOAc/heptane, 1:1). White crystals were formed after evaporation of selected fractions in 67% yield and 94% purity by HPLC. The structure was confirmed by ^1H NMR.

Example 2: Stability in simulated gastrointestinal fluid (sGIF).
The stability of NB-33 in simulated gastrointestinal fluid (sGIF) was evaluated as follows and individual compound data are summarized in Table 1.

sGIF is a 0.5% solution of pepsin (Alfa Aesar, Pepsin, Pig stomach) in 0.1 N aqueous HCl. Each derivative (50 mg) was mixed with sGIF (50 mL) and incubated on a shaker at 37° C. The hydrolysis and release of nalbuphine was monitored by HPLC at T=0, 0.5, 1, 2 and 4 hours.
The acceptance criterion was defined as an NLT where 80% of the derivative remained intact after 4 hours.

Example 3: Stability in human plasma.
The stability of NB-56 in human plasma was evaluated as follows and the individual compound data are summarized in Table 1.

NB-56 (1.0 mg) was dissolved in 10 mL of plasma (pooled normal human plasma, sodium citrate, Innovative Research) with stirring for 10 min at 20°C. The solution was incubated at 37°C. 1 mL of solution was taken for each test sample. MeCN (0.05 mL) was added to the sample solution. After shaking for 1 min, it was centrifuged (15 min, 14.000 r/m). The supernatant was filtered off and extracted with EtOAc (2 x 20 mL). The combined extracts were dried over _MgSO4 and concentrated under vacuum. The residue was dissolved in MeOH (20 μl). This solution was used for HPLC injection.

Nalbuphine hydrolysis and release were monitored by HPLC at T = 0, 0.5, 1, 2 and 4 hours. Acceptance criteria was defined as NLT > 20% hydrolysis after 4 hours.

(Example 4)

Human recombinant opiate receptors (μ, κ or δ) expressed in CHO-K1 cells were used. Test compound (NB-33)/or vehicle was incubated with cells (4×10E5/mL) in modified HBSS pH 7.4 buffer at 370° C. for 30 min. Reactions were assessed for cAMP levels by TR-FRET. Compounds were screened at 0.3, 1 and 3 uM using Eurfins Pharma Discovery Services.

Data for compound NB-33 are summarized in Table 2.
Example 5
Studies on Sprague-Dawley rats were performed using nalbuphine, NB-31, NB-32, NB-33 , NB39, NB-51, NB-52, NB-76 and NB-78.

Thirty Sprague-Dawley rats (12 weeks old; male) were randomly assigned to 10 groups and each group was gavaged with one of the following treatments: 1. sesame oil, 2. nalbuphine (60 uM/kg in sesame oil), 3. NB-31 (60 uM/kg in sesame oil), 4. NB-32 (60 uM/kg in sesame oil), 5. NB-33 (60 uM/kg in sesame oil), 6. NB-39 (60 uM/kg in sesame oil), 7. NB-51 (60 uM/kg in sesame oil), 8. NB-52 (60 uM/kg in sesame oil), 9. NB-76 (60 uM/kg in sesame oil), 10. NB-78 (60 uM/kg in sesame oil). Each rat was orally dosed only once.

Antinociceptive activity was assessed using the cold ethanol tail-flick test as in Anesth Analg 2003;97;806-9. The test temperature was set at -20°C and the cut-off time was 40 seconds. All rats were tested at T=0 immediately before dosing. Measurements of antinociceptive thresholds for saline, nalbuphine and nurbufin derivatives were performed at T=0, 0.25, 0.5, 1, 1.5, 2, 3 and 5 hours after oral administration.

The data show excellent results for NB-33, as shown in the last column of Table 1.

(Example 6)
A double-blind, NB hydrochloride and NB-39 controlled study of the antinociceptive effects of oral NB-33 in healthy volunteers. Three healthy volunteers were each assigned a set of six opaque gelatin capsules as follows: 2x NB hydrochloride (MW=393.4; 39 mg), 2x NB-33 (MW=451.6; 45 mg) and 2x NB-39 (MW=680.0; 68 mg). Every week, healthy volunteers randomly received a tablet from their assigned set to take orally. Heat pain threshold (50°C hot water) and miosis were measured at T=0, 0.25, 0.5, 1, 1.5, 2, 3 and 5 hours after oral dosing.

After a one-week washout period, each volunteer repeated the protocol until all tablets of their assigned set had been administered. Individual data for heat pain threshold as %MPE=[(test latency-baseline latency)/(baseline latency)]×100 and miosis as %MPE=[(test diameter-baseline diameter)/(baseline diameter)]×100 are shown in Tables 2 and 3, respectively.

Tables 3, 4, and 5A-D show that NB-33, when administered orally, provided superior analgesia and miosis to both the parent opioid NB and the parent opioid prodrug NB-39. As shown in Tables 5A-D, the differences in analgesia and miosis were statistically significant.

Independent samples t-tests were used to compare the means of %MPE analgesia and miosis in two paired samples: NB-33 vs. NB, and NB-33 vs. NB-39. All analyses were performed using SPSS (v.25).

*Bold indicates statistical significance at α=0.05.
Tables 5A-D show a comparison of analgesia and miosis between NB-33 and NB, and between NB-33 and NB-39.

Table 6A and Graph 1 of Figure 13 show further testing results of NB-33 in Randall-Serit rats, demonstrating its efficacy and advantages (including improved stability) compared to the base compound.

Table 6A and Graph 1 of Figure 13 show further testing results of NB-33 in Randall-Serit rats, demonstrating its efficacy and advantages (including improved stability) compared to the base compound.

The data in graph 1 in Figure 13 show that NB-33 has superior analgesic properties to the parent opioid NB at equimolar doses. Figure 13 shows in graphical form the results for 1310NB-33, labeled 1310, compared to the base NB compound NB, labeled 1320 in Figure 13.

(Example 7)
The present invention is exemplified, but not limited, by the following compounds shown below: The following compounds shown in Table 7 below provide non-limiting examples of various opioids modified with hexadienoate in accordance with at least one embodiment.

(Example 8) Molecular docking of nalbuphine/naloxone opioid antagonists to the μ-opioid receptor.

The crystal structure of the human m-opioid receptor was downloaded from the RCSB Protein Data Bank [PDB entry: 4DKL, https://www.rcsb.org/structure/4DKL]. In silico screening was performed using the MOE Dock program, which is part of the MOE simulation module 2014.0901. Dissociation constants ( _Ki ) were calculated from the equation ΔG = RTln( _Ki ), where ΔG represents the binding free energy equal to the GBVI/WSA dG scoring function, R is the gas constant, and T is the temperature. _Ki was calculated from the binding free energy values at a fixed temperature (300 K).

Both antagonists, nalbuphine and naloxone, show a significant interaction of Asp 147 with their ammonium groups. This binding to Asp 147 is known to be typical of most known opioid agonists/antagonists. Another overlapping interaction of nalbuphine and naloxone is the binding of the hydroxyl group attached to the aryl ring (position 3) with a water molecule, which contributes to the stabilization of the inactive state of the opioid receptor. Unlike nalbuphine, the hydroxyl group of naloxone attached to the tertiary carbon atom (position 14) participates in an additional hydrogen bond to Asp 147.

Figure 9A shows the binding mode and molecular interactions of the most energetically favorable conformer of nalbuphine superimposed with the co-crystallized ligand β-FNA. Figure 9B shows the binding mode and molecular interactions of the most energetically favorable conformer of naloxone superimposed with the co-crystallized ligand β-FNA.

In nalbuphine and naloxone, the hydroxyl group attached to the aryl ring (position 3) binds water molecules and contributes to stabilizing the inactive state of the opioid receptor. Unlike nalbuphine, the hydroxyl group of naloxone attached to the tertiary carbon atom (position 14) participates in an additional hydrogen bond to Asp 147.

Figure 10A shows the binding mode and molecular interactions of the most energetically favorable conformer of NX-90 in the binding site of 4DKL.

Figure 10B shows the binding mode and molecular interactions of the most energetically favorable conformer of NB-33 in the binding site of 4DKL.

Figure 10C shows the molecular interactions with Met 151 exhibited by conformers of NB-33 with binding modes similar to the most energetically favorable conformer.

Figure 10D shows the binding mode and molecular interactions of the most energetically favorable conformer of NB-39 in the binding site of 4DKL.

Figure 11A shows the most energetically favorable conformers of nalbuphine (yellow), naloxone (pink), and co-crystallized β-FNA (white) superimposed on the opioid binding site of 4DKL. Figure 11B shows the most energetically favorable conformers of NX-90 (blue), NB-33 (red), NB-39 (cyan), and co-crystallized β-FNA (white) superimposed on the opioid binding site of 4DK.

The calculated dissociation constants (K _i ) of NX-90, NB-33, and NB-39 demonstrated higher (NB-33, NB-39) or slightly lower (NX-90) affinity for the m-receptor compared to that of nalbuphine and naloxone. As well as the most energetically favorable conformers of naloxone and nalbuphine, NX-90, NB-33, and NB-39 retain a critical hydrogen bond to the Asp147 residue. In this docking mode, the "message" attached to the nitrogen atom is transmitted to a precise "address" located in a precise region of the binding pocket of the m-receptor. However, unlike the binding modes of known m-antagonists (e.g., nalbuphine and naloxone; Figure 11A), the conformers of NX-90, NB-33, and NB-39 rotate 180° at the binding site (Figure 11B). Conversely, the binding modes explaining the binding of nalbuphine and naloxone are not possible for all calculated conformers of NB-33, NB-39 and NX-90.

Additionally, both NX-90 and NB-33 have a unique hydrogen bond to Met 151 via a hydroxyl group attached to a tertiary carbon atom (position 14). This interaction makes both NX-90 and NB-33 different from NB-39, where a hydroxyl group on the cyclohexane fragment (position 6) instead forms a hydrogen bond with Lys A233. A second differentiating factor for both NX-90 and NB-33 is that the rigid conjugated system of hexadienoic acid residues has an exceptionally hydrophobic cylindrical molecular surface. Together, residues Cys217, Thr218, Asn127, Gln124, Trp133, and Leu219 build an extra complementary hydrophobic molecular surface surrounding this hexadienyl "tail" within the binding pocket (Figures 12A and 12B), whereas no discernible hydrophobic surface is present in the region of the binding site surrounding the highly flexible, unconjugated docosanoyl "tail" (Figure 12C).

Figures 12A-C show the hydrophobic (red) and hydrophilic (yellow) contact preference regions on the molecular surface of the binding site of 4DKL with the docked conformers of NX-90 (Figure 12A), NB-33 (Figure 12B), and NB-39 (Figure 12C).

In particular, in Figures 9-12, these examples confirm at least one feature of the present invention, namely, that modifying an opioid with a lipophilic moiety having at least two conjugated double bonds improves interaction with the opioid receptor.

These examples confirm another feature of the present invention, namely, that modifying the opioid with a lipophilic moiety having at least two conjugated double bonds improves interaction with the opioid receptor by rotating the opioid 180° at the active site to generate an additional mode of interaction with the receptor that involves a unique hydrophobic pocket.

These examples further confirm another feature of the present invention, namely, that modifying an opioid with a lipophilic moiety having at least two conjugated double bonds alters the properties of the opioid in at least some embodiments of the present invention.

These examples confirm another feature of the present invention, namely, that modifying an opioid with a lipophilic moiety having at least two conjugated double bonds improves the antagonistic properties of the opioid in at least some embodiments of the present invention.

Improved Efficacy of Opioid Receptor Antagonists In addition to the improved efficacy and analgesic efficacy of opiates as described above, the present invention also includes at least one embodiment in which the hexadienoate improves the efficacy of an opioid receptor antagonist, such as, for example, naloxone.

In one or more embodiments, the present invention, particularly hexadienoate, has been tested in combination with one or more species (or species) from the naloxone group or compound.

In at least one embodiment of the present invention, naloxone with hexadienoate is included in the molecule, providing a substantially more effective and long-lasting neutralizing/sedative effect when administered to a subject.

In at least one embodiment of the present invention, compounds NX-90 and NX-97 were synthesized and analyzed having the following formulae, as shown in Table 8 below:

A sedative effect may be observed when administered to a subject. This compound may be used and synthesized in accordance with at least one embodiment of the present invention and is referred to as naloxone-sorbate (NX-90). The manufacture of the compound in accordance with at least one embodiment may proceed as follows:

EDCI.HCl (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. Stir at 0° C. for 2 h. Naloxone hydrochloride (2.00 g, 5.5 mmol) and 4-dimethylaminopyridine (0.10 g, 0.82 mmol) were added at 0° C. Stirring was continued for 1 h at 0° C. and overnight at room temperature. The reaction mixture was filtered, the filtrate was evaporated and the residue was purified twice by column chromatography (silica gel, EtOAc/heptane/triethylamine, 2:1:0.5%). White crystals formed after evaporation of selected fractions. Yield was 0.75 g (32%) by HPLC, purity was 98%. The structure was confirmed by NMR ¹ H.

The properties of the NX-90 compound have been studied and the following results, including stability data, and specific advantages have been obtained and confirmed:

Based on the results and observations shown in Table 9, NX-90 showed significant improvement over the well-known drug, naloxone.

In accordance with at least one embodiment of the present invention, examples of combinations of NB-33 or similar compounds with different opiates, and combinations of NX-90 with opiate antagonists are further shown in Table 11 below.

It is well documented and commonly known that opioids can be used to treat the following medical conditions: pain management, palliative care, post-operative anesthesia, skin disorders, addiction, movement disorders, levodopa-induced dyskinesia (LID) in Parkinson's disease, and dyskinesias associated with Tourette's syndrome, tardive dyskinesia, and Huntington's disease. The potency and efficacy of opioids used to treat these medical conditions impacts the success of the treatment.

Respectively, higher opioid receptor binding produces more effective results for the treatment of such diseases according to at least one embodiment of the present invention. For example, hexadienoate modified opioids will be more effective in treating the above-mentioned diseases due to their higher opioid receptor binding.

Thus, in at least one embodiment of the present invention, one of the composition compounds prepared according to the present invention, e.g., NB-33 or NX-90 (or others), can be used to treat one of the medical disorders, such as pain management, palliative care, post-operative anesthesia, skin disorders (e.g., pruritus), poisoning (detoxification or management), and/or movement disorders (e.g., levodopa-induced dyskinesia (LID) in Parkinson's disease, Tourette's syndrome, tardive dyskinesia, dyskinesia associated with Huntington's disease, etc.).

(Example 9)

Human recombinant opiate receptors (μ, κ or δ) expressed in CHO-K1 cells were used. Test compound (NX-90)/or vehicle was incubated with cells (4x10E5/mL) in modified HBSS pH 7.4 buffer at 370°C for 30 min. Responses were assessed for cAMP levels (cAMP and/or calcium flux) by TR-FRET. Compounds were screened at 0.1, 0.3, and 1 uM by Eurofins Pharma Discovery Services.

Data for compound NX-90 are summarized in Table 10. NX-90 is a pharmacologically inactive compound and is shown to have inherent opioid properties similar to the pharmacological profile of naloxone. Separately, NB-33 is not a pharmacologically inactive compound and is shown to have inherent opioid properties similar to the pharmacological profile of NB.

These results are quite surprising since the prior art suggests that such modifications at the 3-phenoxy position to fatty acids (e.g., NB-39) are prodrugs and, by definition, pharmacologically inactive compounds. In accordance with at least one embodiment of the present invention, NX-90 and NB-33 have been shown to be neither pharmacologically inactive nor prodrugs.

In all cases, it will be understood that the above-described examples and compounds are merely illustrative of the many possible specific embodiments which represent applications of the present invention. Numerous and varied other configurations can be readily devised in accordance with the principles of the present invention without departing from the spirit and scope of the invention.

Claims (8)

A compound which is nalbufino-3-hexadienoate or naloxone-3-hexadienoate, or a pharma- ceutically acceptable salt thereof. 10. The compound of claim 1, wherein the compound increases opioid receptor binding of an opiate when orally administered to a patient. 2. Use of a compound according to claim 1 in the manufacture of a medicament for treating one of the medical disorders from the group consisting of pain management, palliative care, post-operative anesthesia, skin disorders, poisoning, movement disorders, levodopa-induced dyskinesia (LID) in Parkinson's disease, Tourette's syndrome, tardive dyskinesia and dyskinesia associated with Huntington's disease . A composition comprising the compound of claim 1 . 5. Use of the composition of claim 4 in the manufacture of a medicament for increasing opioid receptor binding, comprising administering to a subject an effective amount of the composition of claim 4 . 10. Use of the composition of claim 4 in the manufacture of a medicament for pain management, comprising administering to a subject an effective amount of the composition of claim 4. Use of the composition of claim 4 in the manufacture of a medicament for treating skin diseases, poisoning, movement disorders, levodopa-induced dyskinesia (LID) in Parkinson's disease, Tourette's syndrome, tardive dyskinesia or dyskinesia associated with Huntington's disease by administering to a patient an effective amount of the composition of claim 4 . 10. Use of the composition of claim 4 in the manufacture of a medicament for the treatment of opioid overdose, comprising administering to a subject an effective amount of the composition of claim 4 .

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