COMPOSITIONS AND METHODS OF USE FOR OPIOID HEXADIENOATES AND OPTIONALLY SUBSTITUTED HEXADIENOATES

Abstract

The present invention relates to opiate derived compositions and their antagonists useful in therapeutic areas associated with opioid receptor modulation. A 3-hexadienoate modification of the opioids is formulated to improve opiates' engagement of the opioid receptors when given orally. 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. A 3-hexadienoate modification of the opioids antagonists is formulated to improve inhibition of the opioid receptors when given orally. A 3-hexadienoate modification of naloxone or a pharmaceutically acceptable salt of thereof to improve quality of Sobering when given intravenously, intranasally, transdermally, sublingually, rectally, topically, intramuscularly, subcutaneously or via inhalation.

Claims

1. A method for treating a disease or condition, comprising administering an effective amount of a composition to a patient in need of such treatment, wherein said composition comprises an opioid modified with a lipophilic moiety with at least two conjugated double bonds, and wherein said disease or condition is a skin disorder, an addiction, pain or a locomotive disorder.

2. The method of claim 1, wherein said modified opioid is an opioid conjugated with hexadienoate.

3. The method of claim 2, wherein said opioid is selected from the opioids consisting of nalbuphine and naloxone.

4. The method of claim 2, wherein said modified opioid is compound of general formula I ##STR00050## or pharmaceutically acceptable salt of thereof, wherein Y is an opioid selected from the opioids consisting of nalbuphine and naloxone.

5. The method of claim 2, wherein said modified opioid is 3-allyl-4a-hydroxy-7-oxo-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.

6. The method of claim 2, wherein said modified opioid is 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.

7. The method of claim 1, wherein said skin disorder is pruritis.

8. The method of claim 1, wherein said locomotive disorder is a dyskinesia selected from the group consisting of a levodopa-induced dyskinesia, a dyskinesia associated with Tourette's syndrome, a tardive dyskinesia or a dyskinesia associated with Huntington's disease.

9. A method for treating or preventing opioid overdose, comprising administering an effective amount of a composition to a patient who has taken an opioid, wherein said composition comprises an opioid modified with a lipophilic moiety with at least two conjugated double bonds.

10. The method of claim 9, wherein said modified opioid is an opioid conjugated with hexadienoate.

11. The method of claim 10, wherein said opioid is selected from the opioids consisting of nalbuphine and naloxone.

12. The method of claim 10, wherein said modified opioid is compound of general formula I ##STR00051## or pharmaceutically acceptable salt of thereof, wherein Y is an opioid selected from the opioids consisting of nalbuphine and naloxone.

13. The method of claim 10, wherein said modified opioid is 3-allyl-4a-hydroxy-7-oxo-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.

14. The method of claim 10 wherein said modified opioid is 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.

15. A method for pain management or analgesia, comprising administering an effective amount of a composition to a patient who is in need of such treatment, wherein said composition comprises an opioid modified with a lipophilic moiety with at least two conjugated double bonds.

16. The method of claim 15, wherein said modified opioid is an opioid conjugated with hexadienoate.

17. The method of claim 16, wherein said opioid is selected from the opioids consisting of nalbuphine and naloxone.

18. The method of claim 16, wherein said modified opioid is compound of general formula I ##STR00052## or pharmaceutically acceptable salt of thereof, wherein Y is an opioid selected from the opioids consisting of nalbuphine and naloxone.

19. The method of claim 16, wherein said modified opioid is 3-allyl-4a-hydroxy-7-oxo-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.

20. The method of claim 16 wherein said modified opioid is 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.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0045] 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.

[0046] FIG. 1 illustrates NMR 1H spectrum of NB-20 compound, formulated in accordance with at least one embodiment of the present invention.

[0047] FIG. 2 illustrates NMR 1H spectrum of NB-33 compound, formulated in accordance with at least one embodiment of the present invention.

[0048] FIG. 3 illustrates NMR 1H spectrum of NB-39 compound, formulated in accordance with at least one embodiment of the present invention.

[0049] FIG. 4 illustrates NMR 1H spectrum of NB-51 compound, formulated in accordance with at least one embodiment of the present invention.

[0050] FIG. 5 illustrates NMR 1H spectrum of NB-52 compound, formulated in accordance with at least one embodiment of the present invention.

[0051] FIG. 6 illustrates NMR 1H spectrum of NB-56 compound, formulated in accordance with at least one embodiment of the present invention.

[0052] FIG. 7 illustrates NMR 1H spectrum of NB-58 compound, formulated in accordance with at least one embodiment of the present invention.

[0053] FIG. 8 illustrates NMR 1H spectrum of NB-78 compound, formulated in accordance with at least one embodiment of the present invention.

[0054] FIG. 9A illustrates the binding mode and molecular interactions of the most energetically favored conformer of nalbuphine superposed with co-crystallized ligand β-FNA.

[0055] FIG. 9B illustrates the binding mode and molecular interactions of the most energetically favored conformer of naloxone superposed with co-crystallized ligand β-FNA.

[0056] FIG. 10A illustrates the binding mode and molecular interactions of the most energetically favored conformer of NX-90 in the binding site of 4DKL.

[0057] FIG. 10B illustrates the binding mode and molecular interactions of the most energetically favored conformer of NB-33 in the binding site of 4DKL.

[0058] FIG. 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.

[0059] FIG. 10D illustrates the binding mode and molecular interactions of the most energetically favored conformer of NB-39 in the binding site of 4DKL.

[0060] FIG. 11A illustrates the most energetically favored conformer of nalbuphine (yellow), naloxone (pink) and co-crystalized β-FNA (white) superposed in the opioid binding site of 4DKL.

[0061] FIG. 11B illustrates the most energetically favored conformers of NX-90 (blue), NB-33 (red), NB-39 (cyan) and co-crystalized β-FNA (white) superposed in the opioid binding site of 4DK.

[0062] 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.

DETAILED DESCRIPTION

[0063] 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.

[0064] The various aspects and features of the present invention and the composition is described with reference to TABLE 1, which illustrates the 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, NB-78.

[0065] Examples of NMR 1H 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.

[0066] Surprisingly, 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. Thus, for example, 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. Furthermore, a significant effect of NB-33 on pupil dilation (miosis) was observed in humans, which indicated superior receptor engagement.

[0067] Unexpectedly, when examining the effects of at least one embodiment of the present invention, was found that the position and the number of unsaturated sites of the ester of the phenoxy moiety is unique for hexadienic backbone and required for a superior engagement of opioid receptors. Thus, 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.

[0068] Moreover, evaluating at least one embodiment of the present invention, it was found that Nalbuphine 3-hexadienoate has a unique and distinct opiate receptor signature of its own with human recombinant opiate receptors expressed in cells.

[0069] In accordance with at least one embodiment, the compounds of present invention comprise a general formula I or pharmaceutically acceptable salt of thereof

##STR00001##

wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 or R.sub.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.

[0070] In at least one embodiment, 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.

[0071] In at least one embodiment, 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.

[0072] In another embodiment, 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.

[0073] In at least one further embodiment, 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.

[0074] In at least one embodiment, 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.

[0075] In yet another embodiment, 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.

[0076] In a further one or more embodiments, 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.

[0077] The following are further examples of compounds prepared in accordance with at least one embodiment of the present invention. The chemical name, composition and coding name for each of the compounds in Examples 1 is shown in TABLE 1 below.

EXAMPLE 1

[0078] (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, Nalbuphino-Geranyl, (NB-20). Potassium bicarbonate (280 mg, 2.0 mmol) was added to 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 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 .sup.1H.

[0079] 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, nalbuphinofarnesyl, (NB-28). This compound was prepared according to the procedure of NB-20, by substituting geranyl bromide for farnesyl bromide. The crude material was purified by column chromatography (silicagel, EtOAc/Heptanes, 1:1). The colorless oil was obtained after evaporation of selected fractions, yield 53%, purity 93% by HPLC. The structure was confirmed by NMR

[0080] 3 -(cyclobutylmethyl)-4a,7-dihydroxy-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl undec-10-enoate, nalbuphino-undecelenoate, (NB-31). EDCI (1.04 g, 5.4 mmol) was added to undecylenic acid (1.0 g, 5.4 mmol) in THF (30 mL) at 0° C. with stirring. 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. 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, EtOAc/Heptanes, 1:1). The white solid was formed after evaporation of selected fractions, yield 2.2 g (78%), purity 95% by HPLC. The structure was confirmed by NMR .sup.1H.

[0081] 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, Nalbuphino-geranoate, (NB-32). This compound was prepared according to the procedure of NB-31, by substituting undecylenic acid for geranyc acid. 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 .sup.1H.

[0082] 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, Nalbuphino-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) at 0° C. with stirring. 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. 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, EtOAc/Heptanes, 1:1). The white crystals were formed after evaporation of selected fractions, yield 2.05 g (75%), purity 98% by HPLC. The structure was confirmed by NMR .sup.1H.

[0083] 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, Nalbuphino-sorbate, hydrochloride, (NB-56). HC1 (gas) was bubbled into the solution of nalbuphino-sorbate (NB-33) (0.4 g, 0.89 mmol) in MTBE (15 mL) at 0° C. The white precipitate was formed immediately. The reaction mixture was stirred for 1 h and the solid was filtered, washed with MTBE and dried in vacuum. The yield 0.35 g (81%), purity 98% by HPLC. The structure was confirmed by NMR .sup.1H.

[0084] 3-(cyclobutylmethyl)-4a,7-dihydroxy-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl docosanoate, Nalbuphino-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) at 0° C. with stirring. 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. 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, EtOAc/Heptanes, 1:2). The white solid was formed after evaporation of selected fractions, yield 1.45 g (73%), purity 97% by HPLC. The structure was confirmed by NMR .sup.1H. Synthesis and properties of NB-39 was also described in U.S. Pat. No. 5,750,534.

[0085] 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, Nalbuphino-isobutyrate, NB-isovaleroate, (NB-46). This compound was prepared according to the procedure of NB-31, by substituting undecylenic acid for isovaleric acid. The crude material was purified by column chromatography (silicagel, EtOAc/Heptanes, 1:1). The white crystals were formed after evaporation of selected fractions, yield 54%, and purity 95% by HPLC. The structure was confirmed by NMR .sup.1H.

[0086] 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, Nalbuphino-3,3-dimethylacrylate, (NB-51). This compound was prepared according to the procedure of NB-31, by substituting undecylenic acid for 3,3-dimethyl acrylic acid. The crude material was purified by column chromatography (silicagel, EtOAc/Heptanes, 1:1). The white crystals were formed after evaporation of selected fractions, yield 77%, purity 95% by HPLC. The structure was confirmed by NMR .sup.1H.

[0087] 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, Nalbuphino-2,3-dimethylacrylate, (52). This compound was prepared according to the procedure of NB-31, by substituting undecylenic acid for 2,3-dimethyl acrylic acid. The crude material was purified by column chromatography (silicagel, EtOAc/Heptanes, 1:1). The white crystals were formed after evaporation of selected fractions, yield 75%, purity 96% by HPLC. The structure was confirmed by NMR .sup.1H.

[0088] 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, Nalbuphino-2-methoxycrotonate, (NB-58). 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 .sup.1H.

[0089] 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, Nalbuphino-hexadienoate-acetate (NB-76). NB-33 (0.5 g, 1.1 mmol) was stirred in acetic anhydride (7.0 mL) at 40-50° C. overnight. EtOH (20 mL) was added and the reaction mixture was evaporated. The residue was twice purified by column chromatography (silicagel, EtOAc/Heptanes, 1:2). The white crystals were formed after evaporation of selected fractions, yield 1.45 g (50%), purity 97% by HPLC. The structure was confirmed by NMR .sup.1H.

[0090] 3-(cyclobutylmethyl)-4a,7-dihydroxy-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl cinnamate, Nalbuphino-cynnamate, (NB-78). This compound was prepared according to the procedure of NB-31, by substituting undecylenic acid for 2-trans-cynnamic acid. The crude material was purified by column chromatography (silicagel, EtOAc/Heptanes, 1:1). The white crystals were formed after evaporation of selected fractions, yield 67%, purity 94% by HPLC. The structure was confirmed by NMR .sup.1H.

TABLE-US-00001 TABLE 1 Stable Stable in Analgesia N Name, Structure Code in sGIF plasma (rat) 1 [00002] NB n/a n/a moderate 3-(cyclobutylmethyl)-1,2,3,4,5,6,7,7a-octahydro- 4aH-4,12-methanobenzofuro[3,2-e]isoquinoline- 4a,7,9-triol Chemical Formula: C21H27NO4 Molecular Weight: 357.45 2 [00003] NB- 20 No No No (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 Chemical Formula: C31H43NO4 Molecular Weight: 493.69 3 [00004] NB- 28 No No No 3-(cyclobutylmethyl)-9-(((2E,6E)-3,7,11- trimethyldodeca-2,6,10-trien-l-yl)oxy)- 1,2,3,4,5,6,7,7a-octahydro-4aH-4,12- methanobenzofuro[3,2-e]isoquinoline-4a,7-diol Chemical Formula: C36H51NO4 Molecular Weight: 561.81 4 [00005] NB- 31 Yes No Inactive 3-(cyclobutylmethyl)-4a,7-dihydroxy- 2,3,4,4a,5,6,7,7a- octahydro-1H-4,12-methanobenzofuro[3,2- e]isoquinolin-9-y1 undec-10-enoate Chemical Formula: C32H45NO5 Molecular Weight: 523.71 5 [00006] NB- 33 Yes No Excellent 3-(cyclobutylmethyl)-4a,7-dihydroxy- 2,3,4,4a,5,6,7,7a-octahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-9-y1 (2E,4E)- hexa-2,4-dienoate Chemical Formula: C27H33NO5 Molecular Weight: 451.56 6 [00007] NB- 56 Yes No No 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 Chemical Formula: C27H34ClNO5 Molecular Weight: 488.02 7 [00008] NB- 32 Yes No Inactive 3-(cyclobutylmethyl)-4a,7-dihydroxy- 2,3,4,4a,5,6,7,7a-octahydro-1H-4,12- (E)-3,7- methanobenzofuro[3,2-e]isoquinolin-9-y1 dimethylocta-2,6-dienoate Chemical Formula: C31H41NO5 Molecular Weight: 507.67 8 [00009] NB- 39 Yes No Inactive 3-(cyclobutylmethyl)-4a,7-dihydroxy- 2,3,4,4a,5,6,7,7a-octahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-9-y1 docosanoate Chemical Formula: C43H69NO5 Molecular Weight: 680.03 9 [00010] NB- 51 Yes No Inactive 3-(cyclobutylmethyl)-4a,7-dihydroxy- 2,3,4,4a,5,6,7,7a-octahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-9-y1 3- methylbut-2-enoate Chemical Formula: C26H33NO5 Molecular Weight: 439.55 10 [00011] NB- 58 No No No 3-(cyclobutylmethyl)-4a,7-dihydroxy- 2,3,4,4a,5,6,7,7a-octahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-9-y1 2- methoxybut-2-enoate Chemical Formula: C26H33NO6 Molecular Weight: 455.55 11 [00012] NB- 46 Yes Yes No 3-(cyclobutylmethyl)-4a,7-dihydroxy- 2,3,4,4a,5,6,7,7a-octahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-9-y1 isobutyrate Chemical Formula: C25H33NO5 Molecular Weight: 427.54 12 [00013] NB- 52 Yes No Inactive 3-(cyclobutylmethyl)-4a,7-dihydroxy- 2,3,4,4a,5,6,7,7a-octahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-9-y1 (E)-2- methylbut-2-enoate Chemical Formula: C26H33NO5 Molecular Weight: 439.55 13 [00014] NB- 76 Yes No moderate 7-acetoxy-3-(cyclobutylmethyl)-4a-hydroxy- 2,3,4,4a,5,6,7,7a-octahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-9-y1 (2E,4E)- hexa-2,4-dienoate Chemical Formula: C29H35NO6 Molecular Weight: 493.60 14 [00015] NB- 78 Yes No Inactive 3-(cyclobutylmethyl)-4a,7-dihydroxy- 2,3,4,4a,5,6,7,7a-octahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-9-y1 cinnamate Chemical Formula: C30H33NO5 Molecular Weight: 487.60

EXAMPLE 2

Stability in the Simulated Gastro-Intestinal Fluid (sGIF).

[0091] Stability of NB-33 in the simulated gastro-intestinal fluid (sGIF) was evaluated as below and individual compound data was summarized in Table 1.

[0092] sGIF is 0.5% solution of pepsine (Alfa Aesar, Pepsin, porcine stomach) in 0.1N aqueous HCl. Each derivative (50 mg) was mixed with sGIF (50 mL) and incubated at 37° C. on a shaker. The hydrolysis and release of Nalbuphine was monitored by HPLC at T=0 hr,

[0093] 0.5 hr, 1 hr, 2 hr, and 4 hr. The acceptance criteria was defined as NLT 80% of the derivative still intact after 4 hrs.

EXAMPLE 3

Stability in Human Plasma

[0094] Stability of NB-56 in human plasma was evaluated as below and the individual compound data was summarized in Table 1.

[0095] NB-56 (1.0 mg) was dissolved in 10 mL of plasma (Plasma Pooled Normal Human Plasma, Na-citrate, Innovative Research) with stirring for 10 min at 20 0 C. The solution was incubated at 37 0 C. 1 mL of solution was taken for each test sample. MeCN (0.05 mL) was added to sample solution. Shaking for 1 min followed by centrifugation (15 min, 14.000r/m). Supernatant was filtered off and extracted with EtOAc (2×20 mL). The combined extract was dried over MgSO4 and concentrated in vacuum. The residue was dissolved in MeOH (20 μL). The solution was used for HPLC injection.

[0096] The hydrolysis and release of Nalbuphine was monitored by HPLC at T=0 hr, 0.5 hr, 1 hr, 2 hr, and 4 hr. The acceptance criteria was defined as NLT than 20% of hydrolysis after 4 hrs.

EXAMPLE 4

[0097]

TABLE-US-00002 TABLE 2 Human recombinant opiate receptor data for NB-33 NB-33 Assay <1 uM >1 uM mu (MOR) (h) (agonist effect) mu (MOR) (h) (antagonist effect) X X kappa (KOR) (h) (agonist effect) X kappa (KOR) (h) (antagonist effect) delta (DOR) (h) (agonist effect) X delta (DOR) (h) (antagonist effect)

[0098] Human recombinant opiate receptor (mu, kappa or delta) expressed in CHO-K1 cells were used. Test compound (NB-33)/or vehicle was incubated with the cells (4×10E5/mL) in modified HBSS pH 7.4 buffer at 370 C for 30 min. The reaction was evaluated for cAMP levels by TR-FRET. Compounds were screened at 0.3, 1 and 3 uM. by Eurofins Pharma Discovery Services.

[0099] Data for compound NB-33 is summarized in Table 2.

EXAMPLE 5

[0100] 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.

[0101] Thirty Sprague-Dawley rats (12 week old; male) were randomly assigned to 10 groups and each group was gavaged with one of the following treatments: 1. Sesame oil; 2. Nalbuphine (in sesame oil; 60 uM/kg), 3. NB-31 (in sesame oil; 60 uM/kg), 4. NB-32 (in sesame oil; 60 uM/kg), 5. NB-33 (in sesame oil; 60 uM/kg), 6. NB-39 (in sesame oil; 60 uM/kg), 7. NB-51 (in sesame oil; 60 uM/kg), 8. NB-52 (in sesame oil; 60 uM/kg), 9. NB-76 (in sesame oil; 60 uM/kg), 10. NB-78 (in sesame oil; 60 uM/kg). Each rat received only one oral dose.

[0102] The antinociceptive activity was assessed as in Anesth Analg 2003; 97; 806-9 using the cold ethanol tail-flick test. The testing temperature was set at −20° C. and the cutoff time was 40 seconds. All rats were tested at T=0 immediately before medication. Measurements of the antinociceptive thresholds of saline, nalbuphine and nulbuphine derivatives were done at T=0 hr, 0.25 hr, 0.5 hr, 1 hr, 1.5 hr, 2 hr, 3 hr and 5 hr followed oral administration.

[0103] The data, as illustrated in the last column of Table 1 indicates excellent and superior results for NB-33.

EXAMPLE 6

[0104] Double-blind, NB hydrochloride and NB-39 controlled, trial of the antinociceptive effect of oral NB-33 in healthy volunteers. Each of the three healthy volunteers was assigned a set of 6 non-transparent gelatin capsules as follows: 2×NB hydrochloride (MW=393.4; 39 mg), 2×NB-33 (MW=451.6; 45 mg) and 2×NB-39 (MW=680.0; 68 mg). Each week a healthy volunteer would receive a pill from the assigned set in a random fashion and take it orally. At T=0 hr, 0.25 hr, 0.5 hr, 1 hr, 1.5 hr, 2 hr, 3 hr and 5 hr followed oral administration a heat pain threshold was measured (hot water at 50° C.) as well as miosis.

[0105] Following one week of a wash out period, each volunteer repeated the protocol until all pills from the assigned set were administered. The individual data for heat pain threshold as % MPE=[(test latency−baseline latency)/(baseline latency)]×100 and for miosis as % MPE=[(test diameter−baseline diameter)/(baseline diameter)]×100 are shown in Table 2 and Table 3 respectively.

[0106] 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.

TABLE-US-00003 TABLE 3 % MPE (analgesia) 0 hr 0.25 hr 0.5 hr 1 hr 1.5 hr 2 hr 2.5 hr 3 hr 5 hr 33 (45 mg) 0.0 0.0 24.0 80.0 140.0 124.0 96.0 60.0 24.0 33 (45 mg) 0.0 8.3 66.7 183.3 87.5 191.7 112.5 45.8 20.8 33 (45 mg) 0.0 3.7 48.1 59.3 114.8 185.2 133.3 118.5 44.4 33 (45 mg) 0.0 31.3 37.5 50.0 68.8 81.3 31.3 25.0 18.8 33 (45 mg) 0.0 30.0 37.5 67.5 97.5 157.5 112.5 27.5 22.5 33 (45 mg) 0.0 0.0 19.2 100.0 115.4 111.5 119.2 157.7 115.4 NB (35 mg) 0.0 0.0 5.6 50.0 100.0 94.4 66.7 22.2 −5.6 NB (35 mg) 0.0 29.5 39.3 34.4 54.1 54.1 82.0 32.8 27.9 NB (35 mg) 0.0 5.3 10.5 42.1 68.4 94.7 57.9 68.4 5.3 NB (35 mg) 0.0 56.3 50.0 87.5 112.5 162.5 106.3 37.5 26.7 NB (35 mg) 0.0 5.3 21.1 47.4 73.7 57.9 36.8 57.9 5.3 NB (35 mg) 0.0 21.4 35.7 57.1 78.6 50.0 35.7 0.0 0.0 39 (68 mg) 0.0 0.0 10.0 10.0 15.0 10.0 5.0 10.0 0.0 39 (68 mg) 0.0 17.6 11.8 5.9 11.8 23.5 0.0 11.8 0.0 39 (68 mg) 0.0 13.3 40.0 73.3 93.3 93.3 46.7 40.0 6.7 39 (68 mg) 0.0 6.2 6.2 10.8 −7.7 33.8 −6.2 9.2 −9.2 39 (68 mg) 0.0 8.3 55.6 11.1 19.4 0.0 16.7 0.0 −2.8 39 (68 mg) 0.0 0.0 15.0 5.0 5.0 0.0 5.0 0.0 5.0

TABLE-US-00004 TABLE 4 % MPE (miosis) 0 hr 0.25 hr 0.5 hr 1 hr 1.5 hr 2 hr 2.5 hr 3 hr 5 hr 33 (45 mg) 0.0 −8.8 3.4 24.0 20.6 37.8 46.4 3.4 3.4 33 (45 mg) 0.0 0.3 26.7 40.4 36.5 46.2 63.7 36.5 36.5 33 (45 mg) 0.0 20.0 33.3 42.2 42.2 42.2 29.5 15.6 9.3 33 (45 mg) 0.0 0.0 −6.3 33.9 33.9 42.9 33.9 25.0 17.2 33 (45 mg) 0.0 −5.0 26.7 26.7 36.5 46.2 46.2 36.5 33.7 33 (45 mg) 0.0 26.7 26.7 40.4 46.2 55.9 65.7 29.0 32.1 NB (35 mg) 0.0 3.1 9.4 21.9 17.2 18.8 18.8 6.2 6.2 NB (35 mg) 0.0 9.4 37.5 46.9 65.6 31.3 3.1 6.2 3.1 NB (35 mg) 0.0 6.7 0.0 6.7 25.0 55.6 50.0 33.3 22.2 NB (35 mg) 0.0 0.0 9.4 21.9 17.2 31.3 25.0 21.9 6.2 NB (35 mg) 0.0 3.2 9.7 45.2 45.2 58.1 25.8 16.1 9.7 NB (35 mg) 0.0 2.9 8.8 −2.9 29.4 11.8 26.5 20.6 7.8 39 (68 mg) 0.0 10.3 14.9 37.9 37.9 14.9 14.9 24.1 3.4 39 (68 mg) 0.0 0.0 0.0 6.7 6.7 0.0 6.7 0.0 0.0 39 (68 mg) 0.0 25.0 16.7 22.2 33.3 25.0 11.1 11.1 11.1 39 (68 mg) 0.0 12.5 9.4 18.8 21.9 17.2 6.2 0.0 0.0 39 (68 mg) 0.0 20.0 26.7 36.7 23.3 16.7 13.3 3.3 13.3 39 (68 mg) 0.0 3.1 9.4 21.9 25.0 6.2 9.4 0.0 3.1

[0107] Independent samples t-test was used to compare the means of % MPE analgesia and miosis in the two pairs of samples: NB-33 and NB and NB-33 and NB-39. All analyses were made using SPSS (v.25).

[0108] * Bold indicates statistical significance at α=0.05

[0109] Tables 5A-D illustrate comparison of analgesia and miosis between NB-33 and NB, NB-39.

TABLE-US-00005 TABLE 5A Analgesia, NB-33 vs. NB hrs T p-value 0.25 −.705 .497 0.5 1.182 .264 1 1.730 .114 1.5 1.699 .120 2 2.258 .048 2.5 1.982 .076 3 1.486 .168 5 1.895 .087

TABLE-US-00006 TABLE 5B Analgesia, NB-33 vs. NB-39 hrs t p-value 0.25  .700 .506 0.5 1.467 .173 1 3.110 .011 1.5 4.558 .001 2 5.027 .001 2.5 5.380 .000 3 2.656 .039 5 2.642 .025

TABLE-US-00007 TABLE 5C Miosis, NB-33 vs. NB hrs t p-value 0.25 .217 .836 0.5 .716 .491 1 1.295 .224 1.5 .318 .757 2 1.328 .232 2.5 2.624 .025 3 1.022 .331 5 2.018 .071

TABLE-US-00008 TABLE 5D Miosis, NB-33 vs. NB-39 hrs t p-value 0.25 −.893 .393 0.5 .751 .470 1 1.843 .095 1.5 1.985 .075 2 7.253 .000 2.5 5.982 .001 3 2.713 .022 5 2.732 .031

[0110] Table 6A and Graph 1 in Table 6B 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.

[0111] Table 6A and Graph 1 in Table 6B 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-US-00009 TABLE 6A WO#10656913 AB137003 Species/Strain/Sex: Rate Randall-Selitto (g) Pre- Post-dose Treatment Route Dose No. treatment 0.5 hr 1 hr 2 hr 4 hr 6 hr Vehicle SC 5 1 92 73 98 92 65 75 (0.9% NaCl) mL/kg 2 97 68 88 72 69 62 3 86 68 76 92 97 97 4 91 86 82 77 83 53 5 83 91 57 69 64 61 Mean 89.8 77.2 80.2 80.4 75.6 69.6 SEM 2.4 4.8 6.8 4.9 6.3 7.7 PT#1225608 SC 3 1 89 78 63 58 64 50 AFC-2 mg/kg 2 92 89 62 71 66 71 NB.HCl 3 100 93 92 103 93 82 4 80 107 90 69 93 69 5 91 134 96 93 61 85 Mean 90.4 100.2 80.6 78.8 75.4 71.4 SEM 3.2 9.6 7.5 8.3 7.2 6.2 PT#1225607 SC 3.9 1 93 121 98 99 83 79 AFC-1 mg/kg 2 82 120 103 94 71 64 NB-33.HCl 3 98 207 199 214 136 101 4 80 161 73 102 63 65 5 96 96 86 85 97 85 Mean 89.8 141.0* 111.8 118.8 90.0 78.8 SEM 3.7 19.5 22.4 24.0 12.9 6.9

[0112]

[0113] The data on the Graph 1 shows that NB-33 has superior analgesic properties to the equimolar dose of the parent opioid NB.

EXAMPLE 7

[0114] This invention is exemplified by but not limited to the following compounds, illustrated below. The following compounds, shown in TABLE 7 below, provide non-limiting examples of various opioids, modified by hexadienoate in accordance with at least one embodiment.

TABLE-US-00010 TABLE 7 [00016] Nalbuphino-3-hexadienoate [00017] Naloxone-3-hexadienoate [00018] Naltrexone-3-hexadienoate [00019] Butorphanolo-3-hexadienoate [00020] Metopon hexadienoate [00021] Hydromorphone hexadienoate [00022] Levorphanol hexadienoate [00023] Morphino-3-hexadienoate [00024] Nalorphino-3-hexadienoate [00025] Cyclazocine hexadienoate [00026] Ketocyclazocine hexadienoate [00027] Diprenorphine hexadienoate [00028] Etorphine hexadienoate [00029] Levorphanol hexadienoate [00030] Oxymorphone hexadienoate [00031] Tapentadol hexadienoate [00032] Nalbuphino-3-(5-methyl)hexadienoate [00033] Naloxone-3-(5-methyl)hexadienoate [00034] Naltrexone-3-(5-methyl)hexadienoate [00035] Butorphanolo-3-(5-methyl)hexadienoate [00036] Metopon 5-methylhexadienoate [00037] Hydromorphone 5-methylhexadienoate [00038] Levorphanol 5-methylhexadienoate [00039] Morphino-3-(5-methyl)hexadienoate [00040] Nalorphino-3-(5-methyl)hexadienoate [00041] Cyclazocine 5-methylhexadienoate [00042] Ketocyclazocine 5-methylhexadienoate [00043] Diprenorphine 5-methylhexadienoate [00044] Etorphine 5-methylhexadienoate [00045] Levorphanol 5-methylhexadienoate [00046] Oxymorphone 5-methylhexadienoate [00047] Tapentadol 5-methylhexadienoate

EXAMPLE 8

Molecular Docking of Nalbuphine/Naloxone Opioid Antagonists Into μ-Opioid Receptor

[0115] The human μ-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 dissociation constants (Ki) were calculated from the equation ΔG=RT1n(K.sub.i), where ΔG represents binding free energy which is equivalent to GBVI/WSA dG scoring function, R is the gas constant and T the temperature. The Ki was computed starting from the binding free energy values at a fixed temperature (300 K).

[0116] Both antagonists 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. Differently from nalbuphine, the hydroxyl group of naloxone attached to the tertiary carbon atom (14-position) participates in additional hydrogen bonding to Asp 147.

[0117] FIG. 9A illustrates the binding mode and molecular interactions of the most energetically favored conformer of nalbuphine superposed with co-crystallized ligand β-FNA. FIG. 9B illustrates the binding mode and molecular interactions of the most energetically favored conformer of naloxone superposed with co-crystallized ligand β-FNA.

[0118] 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. Differently from nalbuphine, the hydroxyl group of naloxone attached to the tertiary carbon atom (14-position) participates in additional hydrogen bonding to Asp 147.

[0119] FIG. 10A illustrates the binding mode and molecular interactions of the most energetically favored conformer of NX-90 in the binding site of 4DKL.

[0120] FIG. 10B illustrates the binding mode and molecular interactions of the most energetically favored conformer of NB-33 in the binding site of 4DKL.

[0121] FIG. 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.

[0122] FIG. 10D illustrates the binding mode and molecular interactions of the most energetically favored conformer of NB-39 in the binding site of 4DKL.

[0123] FIG. 11A illustrates the most energetically favored conformer of nalbuphine (yellow), naloxone (pink) and co-crystalized β-FNA (white) superposed in the opioid binding site of 4DKL. FIG. 11B illustrates the most energetically favored conformers of NX-90 (blue), NB-33 (red), NB-39 (cyan) and co-crystalized β-FNA (white) superposed in the opioid binding site of 4DK.

[0124] Computed dissociation constants (Ki) of NX-90, NB-33, NB-39 established the higher affinity to the μ-receptor (NB-33, NB-39) or a little lower affinity (NX-90) in comparison to the affinities of nalbuphine and naloxone. Analogously to the most energetically favored conformers of naloxone and nalbuphine, NX-90, NB-33 and NB-39 retain the crucial hydrogen bonding to the residue of Asp147. In this docking mode the “message” attached to the nitrogen atom is delivered to the correct “address” sited on the exact area of the binding pocket of the μ-receptor. However, unlike the binding mode of known μ-antagonists (e.g. nalbuphine and naloxone; FIG. 11A) the rigid frames of NX-90, NB-33 and NB-39 are rotated by 180° in the binding site (FIG. 11B). Conversely, the binding mode that describes binding of nalbuphine and naloxone is not possible for all computed conformers of NB-33, NB-39 and NX-90.

[0125] Furthermore, 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. Simultaneously, the residues Cys217, Thr218, Asn127, Gln124, Trp133, Leu219 build the extra complementary hydrophobic molecular surface surrounding this hexadienyl “tail” inside the binding pocket (FIGS. 12A and 12B), whereas no discernible hydrophobic surface exists in the areas of binding site surrounding the highly flexible and lacking conjugation docosanoyl “tail” (FIG. 12C).

[0126] 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.

[0127] These examples, particularly in FIGS. 9-12 confirm at least one feature of the present invention, i.e., that modifying an opioid with a lipophilic moiety with at least two conjugated double bonds improves interactions with the opioid receptor.

[0128] These examples also confirm another feature of the present invention, i.e., that modifying an opioid with a lipophilic moiety with at least two conjugated double bonds improves interactions with the opioid receptor by rotating the opioid in the active site by 180° C. and creating additional modes of interactions with the receptor including a unique hydrophobic pocket.

[0129] These examples further confirm another feature of the present invention, i.e., that modifying an opioid with a lipophilic moiety with at least two conjugated double bonds changes properties of the opioid at least in some embodiments of the present invention.

[0130] These examples confirm yet another feature of the present invention, i.e., that modifying an opioid with a lipophilic moiety with at least two conjugated double bonds improves antagonistic properties of the opioid at least in some embodiments of the present invention.

Improved Performance of Opioid Receptor Antagonists

[0131] As described above, in addition to the improved performance and analgesic qualities of opiates, the present invention also includes at least one embodiment where hexadienoate improves performance of opioid receptor antagonists, such as, for example, Naloxone.

[0132] In at least one embodiment, 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.

[0133] In at least one embodiment of the present invention, the Naloxone, having hexadienoate, is included in the molecule, and provides substantially more effective and long-lasting neutralizing/sobering effect when administered to a subject.

[0134] In at least one embodiment of the present invention, a compound NX-90 and NX-97 having the below formula has been synthesized and analyzed, as shown in TABLE 8 below.

TABLE-US-00011 TABLE 8 1 [00048] NX-90 3-allyl-4a-hydroxy-7-oxo-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 Chemical Formula: C.sub.25H.sub.27NO.sub.5 Molecular Weight: 421.49 2 [00049] NX-97 3-allyl-4a-hydroxy-7-oxo-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 hydrochloride Chemical Formula: C.sub.25H.sub.28ClNO.sub.5 Molecular Weight: 457.95

[0135] Sobering effect may be noted when administered to a subject. This compound may be utilized and synthetized in accordance with at least one embodiment of the present invention is referenced and named Naloxone-sorbate, (NX-90). The preparation of the compound based on at least one embodiment may proceed as follows.

[0136] 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. Stirring for 2 h at 0° C. Naloxone hydrochloride (2.00 g, 5.5 mmol and 4-dimethylaminopyridine (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. The reaction mixture was filtered, filtrate was evaporated, and the residue was twice purified by column chromatography (silicagel, EtOAc/Heptanes/Triethylamine, 2:1:0.5%). The white crystals were formed after evaporation of selected fractions, yield 0.75 g (32%), purity 98% by HPLC. The structure was confirmed by NMR .sup.1H.

[0137] The properties of the NX-90 compound have been studied and the following results and specific benefits, including stability data, have been obtained and confirmed.

TABLE-US-00012 TABLE 9 NX-90 Stability (GIF) Batch Number Alpha-1-91 (Tested by Alfacheminvent LLC). PRODUCT NAME: NX-90 BATCH NO.: MFG DATE: SAMPLE SIZE: PACKAGING Alpha-1-91 Mar. 21, 2019 5.0 MG/2.0 ML TYPE: Glass vial (upright) ASSAY STABILITY TESTING STATUS: CONDITIONS: INTERVALS: COMPLETED: GIF, 37° C., INITIAL, Mar. 22, 2019 shaker 1, 2, 4, 8, 24 HRS

TABLE-US-00013 TEST Specifications Initial 1 h 2 h 4 h 8 h 24 h Product Clear solution Conforms Conf. Conf. Conf. Conf. Conf. Appearance HPLC Assay: Report results 99.3 99.2 99.3 98.4 95.1 93.0 (Area %) Single impurity: Report results 0.6 0.7 0.6 0.6 0.7 0.6 RRT = 0.93 (Area %) Single impurity: Report results — — — 0.9 2.3 5.5 RRT = 0.67 (Area %)

[0138] Based on the results and observations, shown in Table 9, the NX-90 has shown significant improvements over the well-known drug Naloxone.

[0139] Examples of the combination of NB-33 or similar compounds with different opiates and NX-90 with opiate antagonists in accordance with at least one embodiment of the present invention is further shown in Appendix A.

[0140] It is well documented and commonly known that 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 levodopa-induced dyskinesias (LID) in Parkinson's disease, a dyskinesias associated with Tourette's syndrome, a tardive dyskinesia and a Huntington's disease and others. The potency and effectiveness of the opioids used for the treatment of these medical conditions affects how successful the treatment is.

[0141] Respectively, the higher engagement of opioid receptors produces more effective results for the treating such conditions in accordance with at least one embodiment of the present invention, For example, opioids modified with hexadienoates will be more effective in treating the aforementioned conditions, because they have higher engagement of opioid receptors.

[0142] Thus, in at least one embodiment of the present invention, one of the composition compounds that is formulated based on the present invention, as for example NB-33 or NX-90 (or others) 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).

EXAMPLE 9

[0143]

TABLE-US-00014 TABLE 10 demonstrates human recombinant opiate receptor data for NX 90. NX-90 Assay <1 uM >1 uM mu (MOR) (h) (agonist effect) mu (MOR) (h) (antagonist effect) X X kappa (KOR) (h) (agonist effect) kappa (KOR) (h) (antagonist effect) X X delta (DOR) (h) (agonist effect) delta (DOR) (h) (antagonist effect) X

[0144] Human recombinant opiate receptor (mu, kappa or delta) expressed in CHO-K1 cells were used. Test compound (NX-90)/or vehicle was incubated with the cells (4×10E5/mL) in modified HBSS pH 7.4 buffer at 370 C for 30 min. The reaction was evaluated 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.

[0145] 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.

[0146] These results are highly surprising as the prior art suggests that such modifications of 3-phenoxy position with fatty acids (e.g. NB-39) are pro-drugs and by definition are pharmacologically inert compounds. In accordance with at least one embodiment of the present invention, the NX-90 and NB-33 are shown not pharmacologically inert and are not pro-drugs.

[0147] In all cases it is 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 arrangements can be readily devised in accordance with the principles of the present invention without departing from the spirit and the scope of the invention.