CN114828961B - Compositions and methods for enhancing opioid receptor binding via opioid hexadienoate and optionally substituted hexadienoate - Google Patents
Compositions and methods for enhancing opioid receptor binding via opioid hexadienoate and optionally substituted hexadienoate Download PDFInfo
- Publication number
- CN114828961B CN114828961B CN202080071185.9A CN202080071185A CN114828961B CN 114828961 B CN114828961 B CN 114828961B CN 202080071185 A CN202080071185 A CN 202080071185A CN 114828961 B CN114828961 B CN 114828961B
- Authority
- CN
- China
- Prior art keywords
- opioid
- nalbuphine
- hexadienoate
- naloxone
- composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 102000003840 Opioid Receptors Human genes 0.000 title claims abstract description 41
- 108090000137 Opioid Receptors Proteins 0.000 title claims abstract description 41
- 239000000203 mixture Substances 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 title description 15
- WSWCOQWTEOXDQX-UHFFFAOYSA-N 2,4-Hexadienoic acid Chemical compound CC=CC=CC(O)=O WSWCOQWTEOXDQX-UHFFFAOYSA-N 0.000 title description 13
- 230000002708 enhancing effect Effects 0.000 title description 3
- 208000002193 Pain Diseases 0.000 claims abstract description 13
- 230000036407 pain Effects 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 57
- 239000003814 drug Substances 0.000 claims description 19
- 208000016285 Movement disease Diseases 0.000 claims description 12
- 206010012335 Dependence Diseases 0.000 claims description 9
- 206010002091 Anaesthesia Diseases 0.000 claims description 7
- 230000037005 anaesthesia Effects 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- 208000023105 Huntington disease Diseases 0.000 claims description 6
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 claims description 6
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims description 6
- 206010043118 Tardive Dyskinesia Diseases 0.000 claims description 6
- 208000000323 Tourette Syndrome Diseases 0.000 claims description 6
- 208000016620 Tourette disease Diseases 0.000 claims description 6
- 230000015556 catabolic process Effects 0.000 claims description 6
- 229960004502 levodopa Drugs 0.000 claims description 6
- 230000002980 postoperative effect Effects 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 208000035475 disorder Diseases 0.000 claims description 5
- 238000002638 palliative care Methods 0.000 claims description 5
- 208000012488 Opiate Overdose Diseases 0.000 claims description 4
- 208000018737 Parkinson disease Diseases 0.000 claims description 4
- 230000001965 increasing effect Effects 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims 4
- 229960000805 nalbuphine Drugs 0.000 abstract description 79
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 abstract description 65
- 229960004127 naloxone Drugs 0.000 abstract description 64
- 230000004048 modification Effects 0.000 abstract description 17
- 238000012986 modification Methods 0.000 abstract description 17
- 239000005557 antagonist Substances 0.000 abstract description 7
- 229940124636 opioid drug Drugs 0.000 abstract description 6
- 238000001990 intravenous administration Methods 0.000 abstract description 5
- 230000001225 therapeutic effect Effects 0.000 abstract description 5
- 206010062519 Poor quality sleep Diseases 0.000 abstract description 4
- 238000007918 intramuscular administration Methods 0.000 abstract description 4
- 238000007920 subcutaneous administration Methods 0.000 abstract description 3
- 230000000699 topical effect Effects 0.000 abstract description 3
- 239000003401 opiate antagonist Substances 0.000 abstract description 2
- 230000005764 inhibitory process Effects 0.000 abstract 1
- 239000003607 modifier Substances 0.000 abstract 1
- NETZHAKZCGBWSS-CEDHKZHLSA-N nalbuphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]1(O)CC[C@@H]3O)CN2CC1CCC1 NETZHAKZCGBWSS-CEDHKZHLSA-N 0.000 abstract 1
- YZLZPSJXMWGIFH-BCXQGASESA-N nalbuphine hydrochloride Chemical compound [H+].[Cl-].C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]1(O)CC[C@@H]3O)CN2CC1CCC1 YZLZPSJXMWGIFH-BCXQGASESA-N 0.000 description 81
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 26
- 229940002612 prodrug Drugs 0.000 description 23
- 239000000651 prodrug Substances 0.000 description 23
- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 13
- 229940079593 drug Drugs 0.000 description 13
- 238000001704 evaporation Methods 0.000 description 13
- 230000008020 evaporation Effects 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- 230000000202 analgesic effect Effects 0.000 description 12
- 230000009878 intermolecular interaction Effects 0.000 description 12
- 238000007726 management method Methods 0.000 description 12
- 241000282414 Homo sapiens Species 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 229960002428 fentanyl Drugs 0.000 description 10
- -1 nalbuphine ester Chemical class 0.000 description 10
- 235000011803 sesame oil Nutrition 0.000 description 10
- 239000008159 sesame oil Substances 0.000 description 10
- 229940005483 opioid analgesics Drugs 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 238000001228 spectrum Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- PQKHESYTSKMWFP-WZJCLRDWSA-N beta-Funaltrexamine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]1(O)CC[C@H]3NC(=O)/C=C/C(=O)OC)CN2CC1CC1 PQKHESYTSKMWFP-WZJCLRDWSA-N 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 8
- FRPZMMHWLSIFAZ-UHFFFAOYSA-N 10-undecenoic acid Chemical compound OC(=O)CCCCCCCCC=C FRPZMMHWLSIFAZ-UHFFFAOYSA-N 0.000 description 7
- WSWCOQWTEOXDQX-MQQKCMAXSA-N E-Sorbic acid Chemical compound C\C=C\C=C\C(O)=O WSWCOQWTEOXDQX-MQQKCMAXSA-N 0.000 description 7
- 241000700159 Rattus Species 0.000 description 7
- KHAVLLBUVKBTBG-UHFFFAOYSA-N caproleic acid Natural products OC(=O)CCCCCCCC=C KHAVLLBUVKBTBG-UHFFFAOYSA-N 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 239000013058 crude material Substances 0.000 description 7
- 230000003993 interaction Effects 0.000 description 7
- 229960002703 undecylenic acid Drugs 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- 239000003887 narcotic antagonist Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 6
- 230000036592 analgesia Effects 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 230000002209 hydrophobic effect Effects 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 208000003251 Pruritus Diseases 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000013270 controlled release Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 230000005496 eutectics Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 238000003032 molecular docking Methods 0.000 description 4
- 229960005181 morphine Drugs 0.000 description 4
- 230000004478 pupil constriction Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 229940075554 sorbate Drugs 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229940116224 behenate Drugs 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 description 3
- 229960001736 buprenorphine Drugs 0.000 description 3
- IFKLAQQSCNILHL-QHAWAJNXSA-N butorphanol Chemical compound N1([C@@H]2CC3=CC=C(C=C3[C@@]3([C@]2(CCCC3)O)CC1)O)CC1CCC1 IFKLAQQSCNILHL-QHAWAJNXSA-N 0.000 description 3
- 229960001113 butorphanol Drugs 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 3
- 230000002045 lasting effect Effects 0.000 description 3
- 229960001513 nalbuphine hydrochloride Drugs 0.000 description 3
- 238000006386 neutralization reaction Methods 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 3
- 230000003285 pharmacodynamic effect Effects 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 208000017520 skin disease Diseases 0.000 description 3
- 238000012453 sprague-dawley rat model Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000037317 transdermal delivery Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- JSCUZAYKVZXKQE-JXMROGBWSA-N (2e)-1-bromo-3,7-dimethylocta-2,6-diene Chemical compound CC(C)=CCC\C(C)=C\CBr JSCUZAYKVZXKQE-JXMROGBWSA-N 0.000 description 2
- IJVCSMSMFSCRME-UHFFFAOYSA-N 3-methyl-2,4,4a,5,6,7,7a,13-octahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diol Chemical compound C12CCC(O)C3OC4=C5C32CCN(C)C1CC5=CC=C4O IJVCSMSMFSCRME-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 208000000094 Chronic Pain Diseases 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- 239000012981 Hank's balanced salt solution Substances 0.000 description 2
- GVGLGOZIDCSQPN-PVHGPHFFSA-N Heroin Chemical compound O([C@H]1[C@H](C=C[C@H]23)OC(C)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4OC(C)=O GVGLGOZIDCSQPN-PVHGPHFFSA-N 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 229940127450 Opioid Agonists Drugs 0.000 description 2
- 229940123257 Opioid receptor antagonist Drugs 0.000 description 2
- UQCNKQCJZOAFTQ-ISWURRPUSA-N Oxymorphone Chemical compound O([C@H]1C(CC[C@]23O)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O UQCNKQCJZOAFTQ-ISWURRPUSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 208000000114 Pain Threshold Diseases 0.000 description 2
- 102000057297 Pepsin A Human genes 0.000 description 2
- 108090000284 Pepsin A Proteins 0.000 description 2
- 230000003502 anti-nociceptive effect Effects 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000004621 biodegradable polymer Substances 0.000 description 2
- 229920002988 biodegradable polymer Polymers 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229940114081 cinnamate Drugs 0.000 description 2
- 229960002069 diamorphine Drugs 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- UKMSUNONTOPOIO-UHFFFAOYSA-N docosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCC(O)=O UKMSUNONTOPOIO-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000004520 electroporation Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- ZHYZQXUYZJNEHD-VQHVLOKHSA-N geranic acid Chemical compound CC(C)=CCC\C(C)=C\C(O)=O ZHYZQXUYZJNEHD-VQHVLOKHSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000007954 hypoxia Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 102000051367 mu Opioid Receptors Human genes 0.000 description 2
- 230000003232 mucoadhesive effect Effects 0.000 description 2
- 239000000014 opioid analgesic Substances 0.000 description 2
- 229960005118 oxymorphone Drugs 0.000 description 2
- 230000037040 pain threshold Effects 0.000 description 2
- VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 description 2
- 229960005301 pentazocine Drugs 0.000 description 2
- 229940111202 pepsin Drugs 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 230000010344 pupil dilation Effects 0.000 description 2
- 229940075993 receptor modulator Drugs 0.000 description 2
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 2
- 108020001612 μ-opioid receptors Proteins 0.000 description 2
- FOFMBFMTJFSEEY-YFVJMOTDSA-N (2e,6e)-1-bromo-3,7,11-trimethyldodeca-2,6,10-triene Chemical group CC(C)=CCC\C(C)=C\CC\C(C)=C\CBr FOFMBFMTJFSEEY-YFVJMOTDSA-N 0.000 description 1
- XAOWELGMJQTJQR-WYIOCLOVSA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-prop-2-enyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol Chemical compound C([C@H]1[C@H](N(CC[C@@]112)CC=C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC XAOWELGMJQTJQR-WYIOCLOVSA-N 0.000 description 1
- UZHSEJADLWPNLE-PIKADFDJSA-N (4s,4ar,7as,12br)-4a,9-dihydroxy-3-prop-2-enyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one Chemical compound O=C([C@H]1O2)CC[C@]3(O)[C@@H]4CC5=CC=C(O)C2=C5[C@]13CCN4CC=C UZHSEJADLWPNLE-PIKADFDJSA-N 0.000 description 1
- UIERETOOQGIECD-ONEGZZNKSA-M (e)-2-methylbut-2-enoate Chemical compound C\C=C(/C)C([O-])=O UIERETOOQGIECD-ONEGZZNKSA-M 0.000 description 1
- NVPNCVRJVRLJMU-ARJAWSKDSA-N (z)-2-methoxybut-2-enoic acid Chemical group CO\C(=C/C)C(O)=O NVPNCVRJVRLJMU-ARJAWSKDSA-N 0.000 description 1
- FRPZMMHWLSIFAZ-UHFFFAOYSA-M 10-undecenoate Chemical compound [O-]C(=O)CCCCCCCCC=C FRPZMMHWLSIFAZ-UHFFFAOYSA-M 0.000 description 1
- TVYRJQXMQNZLNO-UHFFFAOYSA-N 3-acetyl-2-hydroxybenzoic acid Chemical compound CC(=O)C1=CC=CC(C(O)=O)=C1O TVYRJQXMQNZLNO-UHFFFAOYSA-N 0.000 description 1
- IYNWSQDZXMGGGI-NUEKZKHPSA-N 3-hydroxymorphinan Chemical class C1CCC[C@H]2[C@H]3CC4=CC=C(O)C=C4[C@]21CCN3 IYNWSQDZXMGGGI-NUEKZKHPSA-N 0.000 description 1
- YYPNJNDODFVZLE-UHFFFAOYSA-M 3-methylbut-2-enoate Chemical compound CC(C)=CC([O-])=O YYPNJNDODFVZLE-UHFFFAOYSA-M 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 102100033350 ATP-dependent translocase ABCB1 Human genes 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 206010001497 Agitation Diseases 0.000 description 1
- 235000021357 Behenic acid Nutrition 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 206010013654 Drug abuse Diseases 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- 206010013954 Dysphoria Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 108010047230 Member 1 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 1
- WJBLNOPPDWQMCH-MBPVOVBZSA-N Nalmefene Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=C)O)CC1)O)CC1CC1 WJBLNOPPDWQMCH-MBPVOVBZSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 208000026251 Opioid-Related disease Diseases 0.000 description 1
- 108010089503 Organic Anion Transporters Proteins 0.000 description 1
- 102000007990 Organic Anion Transporters Human genes 0.000 description 1
- 240000001090 Papaver somniferum Species 0.000 description 1
- 235000008753 Papaver somniferum Nutrition 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 206010038678 Respiratory depression Diseases 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- BVCZEBOGSOYJJT-UHFFFAOYSA-N ammonium carbamate Chemical group [NH4+].NC([O-])=O BVCZEBOGSOYJJT-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000000729 antidote Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- UKMSUNONTOPOIO-UHFFFAOYSA-M behenate Chemical compound CCCCCCCCCCCCCCCCCCCCCC([O-])=O UKMSUNONTOPOIO-UHFFFAOYSA-M 0.000 description 1
- 229940116226 behenic acid Drugs 0.000 description 1
- 125000003910 behenoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 230000003185 calcium uptake Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 230000002517 constrictor effect Effects 0.000 description 1
- 239000000599 controlled substance Substances 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- DUSHUSLJJMDGTE-ZJPMUUANSA-N cyproterone Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 DUSHUSLJJMDGTE-ZJPMUUANSA-N 0.000 description 1
- 229960003843 cyproterone Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 229930008392 geranic acid Natural products 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- AHAREKHAZNPPMI-UHFFFAOYSA-N hexadiene group Chemical group C=CC=CCC AHAREKHAZNPPMI-UHFFFAOYSA-N 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 230000005661 hydrophobic surface Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010832 independent-sample T-test Methods 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- RDOIQAHITMMDAJ-UHFFFAOYSA-N loperamide Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)N(C)C)CCN(CC1)CCC1(O)C1=CC=C(Cl)C=C1 RDOIQAHITMMDAJ-UHFFFAOYSA-N 0.000 description 1
- 229960001571 loperamide Drugs 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- INAXVFBXDYWQFN-XHSDSOJGSA-N morphinan Chemical class C1C2=CC=CC=C2[C@]23CCCC[C@H]3[C@@H]1NCC2 INAXVFBXDYWQFN-XHSDSOJGSA-N 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229960005297 nalmefene Drugs 0.000 description 1
- RGPDIGOSVORSAK-STHHAXOLSA-N naloxone hydrochloride Chemical compound Cl.O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C RGPDIGOSVORSAK-STHHAXOLSA-N 0.000 description 1
- 229960005250 naloxone hydrochloride Drugs 0.000 description 1
- 229940053685 naloxone nasal spray Drugs 0.000 description 1
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 1
- 229960003086 naltrexone Drugs 0.000 description 1
- 229940065778 narcan Drugs 0.000 description 1
- 239000004081 narcotic agent Substances 0.000 description 1
- 239000004084 narcotic analgesic agent Substances 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 230000003040 nociceptive effect Effects 0.000 description 1
- 201000000988 opioid abuse Diseases 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-M pivalate Chemical compound CC(C)(C)C([O-])=O IUGYQRQAERSCNH-UHFFFAOYSA-M 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000417 polynaphthalene Polymers 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000001179 pupillary effect Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000035900 sweating Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- UIERETOOQGIECD-ONEGZZNKSA-N tiglic acid Chemical compound C\C=C(/C)C(O)=O UIERETOOQGIECD-ONEGZZNKSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- CRDAMVZIKSXKFV-UHFFFAOYSA-N trans-Farnesol Natural products CC(C)=CCCC(C)=CCCC(C)=CCO CRDAMVZIKSXKFV-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- ZHYZQXUYZJNEHD-UHFFFAOYSA-N trans-geranic acid Natural products CC(C)=CCCC(C)=CC(O)=O ZHYZQXUYZJNEHD-UHFFFAOYSA-N 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C219/20—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C219/22—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
- C07D221/26—Benzomorphans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
- C07D221/28—Morphinans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
- C07D489/08—Oxygen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Addiction (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Psychiatry (AREA)
- Psychology (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to opioid-derived compositions and antagonists thereof useful in the therapeutic arts related to the modulation of opioid receptors. The invention prepares a 3-hexadienoate modifier of opioid drugs, which is used for improving the combination of opioid drugs and opioid receptors during oral administration. A3-hexadienoate modification of nalbuphine or a pharmaceutically acceptable salt thereof is formulated for improving the quality of pain management upon intravenous, intranasal, transdermal, sublingual, rectal, topical, intramuscular, subcutaneous or inhalation administration. A3-hexadienoate modification of an opioid antagonist is formulated for improving the inhibition of opioid receptors upon oral administration. A3-hexadienoate modification of naloxone or a pharmaceutically acceptable salt thereof is also formulated for improving the wakefulness upon intravenous, intranasal, transdermal, sublingual, rectal, topical, intramuscular, subcutaneous or inhalation administration.
Description
The present application is PCT application No. 16/540,058, a non-provisional U.S. patent application filed on day 8, 14, 2019, and claims priority of "U.S. patent law" No. 119 of the previous U.S. provisional patent entitled "compositions and methods for enhancing opioid receptor binding by opioid hexadienoate and optionally substituted hexadienoate" filed on day 8, 11, 2019.
Technical Field
The present invention relates to opioid-derived compositions for use in the therapeutic field associated with opioid receptor modulation.
Background
Nalbuphine (Nubain) was proposed in 1979 as a moderately to severely painful analgesic, and has been used clinically as yet. It is used primarily in combination with narcotics for pre-and post-operative analgesia and for acute and chronic pain management at delivery. Recently, its use has expanded to the treatment of dyskinesias, dermatological disorders (itching) and addiction management.
It has also recently been shown that nalbuphine can prevent opioid tolerance and dependency in chronic pain management. Nalbuphine is the only narcotic analgesic not constrained by the "law of controlled substances", which proves its safety in use. The oral bioavailability of nalbuphine is low.
Known prodrugs of nalbuphine aim to improve their pharmacokinetic and pharmacodynamic properties. The Welch dictionary defines a prodrug as a pharmacologically inactive substance, i.e., a modified form of a pharmacologically active drug that is converted in vivo (by enzymatic action). Thus Franklin (WO 2010-GB 52211) indicates that nalbuphine can be modified at phenolic hydroxyl residues.
Furthermore, nalbuphine can be coupled to amino acids or short peptides (WO 2011007247, A1). Nalbuphine can also be modified using dicarboxylic acid linked amino acids and peptides (WO 2010112942, A1). In addition, modification of nalbuphine can also be performed using amino acid and peptide linkages with ammonium carbamate groups (WO 2009092071, A2). Furthermore, jenkins (WO 2007022535, A2) indicates that nalbuphine can be further modified in its phenolic or nitrogen groups.
Wang states that nalbuphine can be converted to an ester prodrug (journal of controlled release, volume number: 115, period number: 2, page numbers: 140-149, journal, 2006). Flu (month 11 2005, TW 226239, b) indicates that delivery systems and nalbuphine prodrugs can increase their bioavailability. More specifically, formulations that enhance the bioavailability of nalbuphine include a vegetable oil, a co-solvent, and an effective amount of a nalbuphine ester prodrug or a pharmaceutically acceptable salt thereof. One purpose of the prodrugs is to increase the oral bioavailability of nalbuphine and extend the retention time of nalbuphine in the body, thus maintaining a longer analgesic period and reducing the analgesic costs.
Hilfinger (US 20050137141, A1) refers to nalbuphine comprising a drug and an amino acid comprising a covalent bond to the drug. Huang (International journal of pharmacy, volume No. 297, period No. 1-2, pages No. 162-171, journal 2005) states iontophoresis and electroporation for transdermal delivery of Nalbuphine (NA) and two novel prodrugs: nalbuphine benzoate (NAB) and sebacoyl bisbutamol ester (SDN) (from solutions as well as hydrogels).
The formation of dual prodrugs comprising nalbuphine is pointed out by the blood-pressure sensor (WO 2005009377, A2) to significantly increase the transdermal flux of drugs from human skin. Uhrich (WO 2002009768, A2) indicates therapeutic polyesters and polyamides of nalbuphine. Flu (EP 1149836, A1) indicates the preparation of a derivative of the polynaphthalene. Pao (journal of chromatography B, journal of biomedical science and applications, volume No. 746, journal No. 2, pages No. 241-247, journal, 2000) indicates the bioavailability of sebacoyl bisbutaline ester.
Han (J.International pharmaceutical Co., ltd., volume No. 177, period No. 2, pages No. 201-209, J1999) states that novel mucoadhesive buccal tablets for controlled release of nalbuphine prodrugs: effects of formulation variables on drug release and mucoadhesive properties. Sung (J.International pharmaceutical Co., ltd., volume No. 172, period No. 1-2, page No. 17-25, J.1998) indicates the controlled release of nalbuphine prodrugs in biodegradable polymer matrices: the effect of prodrug hydrophilicity and polymer composition. Yoa-Pu (US 5750434, A) indicates that nalbuphine has a long-acting analgesic effect.
Sham (EP 85108258.6) indicates that nalbuphine can be further modified to 3-acetylsalicylic acid. The following references disclose other nalbuphine prodrugs: US 6569449, B1; CN 1107333, a; EP 615756, A1; international journal of pharmacy, volume No.: 38, futures number: 1-3, page number: 199-209, journal, 1987.
The pharmacokinetic and pharmacodynamic properties of nalbuphine, a pharmaceutically acceptable salt, ester or prodrug thereof may be modulated by a variety of delivery systems. The biodegradable polymer microspheres for the controlled release of nalbuphine prodrugs are indicated by the Thus Liu (International journal of pharmacy, volume number 257, period number 1-2, pages number 23-31, journal, 2003). Sung (journal of European pharmaceutical science, volume number: 18, period number: 1, pages number: 63-70, journal, 2003) indicates transdermal delivery of nalbuphine and its prodrugs by electroporation. Fang (study of medicine, volume number: 51, period number: 5, page number: 408-413, journal, 2001) indicates transdermal delivery of nalbuphine and nalbuphine trimethylacetate by passive diffusion and iontophoresis.
It is necessary to distinguish between two cases that increase oral bioavailability and increase opioid receptor binding of these opioid derivatives. For example, esterification of nalbuphine phenoxy groups (e.g., 3-behenate derivatives of nalbuphine) (NB-39) has previously been reported to improve oral availability. However, when orally administered, NB-39 produced less cumulative analgesia in rats and humans than an equivalent dose of nalbuphine. Furthermore, NB-39 did not significantly affect pupil dilation (constriction) in humans after oral administration, indicating poor opioid receptor binding.
Naloxone brand name "Narcan" (and other brand names) is a drug used to block opioid effects, especially in excess. Naloxone may also be administered in combination with an opioid (in the same tablet or compound) in order to reduce the risk of opioid abuse. For example, naloxone may be added to a coating of a sustained release opioid to prevent the sustained release compound from breaking, resulting in an overdose.
Naloxone is generally effective within two minutes when administered intravenously and within five minutes when injected into the muscle. It can also be used as nasal spray. The action of naloxone is generally continued for about half an hour to one hour. Thus, multiple administrations of naloxone may be required, as most opioids act for a duration of time greater than Yu Naluo ketone.
Administration of naloxone to opioid-dependent individuals may cause withdrawal symptoms of the opioid, such as dysphoria, agitation, nausea, vomiting, increased heart rate, and sweating. To prevent this, a small dose of naloxone is administered every few minutes until the desired effect is achieved.
Further heart problems have arisen in individuals with a past history of heart disease or individuals taking medications that have a negative impact on the heart. Naloxone has been administered to a limited number of subjects and tested, and the results indicate that naloxone appears to be safe during gestation.
Naloxone is a non-selective, competitive opioid receptor antagonist. It acts by reversing the inhibitory effects of opioids on the central nervous system and respiratory system. Naloxone was originally patented in 1961 and approved in 1971 for opioid overdose treatment in the united states.
Naloxone, also known as N-allylnoroxymorphone or 17-allyl-4, 5 a-epoxy-3, 14-dihydroxymorphinan-6-one, is a synthetic morphinan derivative derived from oxymorphone (14-hydroxydihydromorphone), an opioid analgesic oxymorphone, which in turn is derived from morphine (an opioid analgesic, the natural component of poppy).
Naloxone is a racemic mixture of two enantiomers (-) -naloxone (levo-naloxone) and (+) -naloxone (dextro-naloxone), only the former being active at opioid receptors. The drug is highly lipophilic and thus can penetrate the brain rapidly, and the brain-to-serum ratio achieved is much greater than morphine. Opioid antagonists associated with naloxone include cyproterone, nalmefene, nalodeine, naloxol and naltrexone.
The chemical half-life of naloxone is as follows: the shelf lives of commercially available injectable and nasal dosage forms were 24 months and 18 months, respectively. One 2018 study noted that the chemical stabilization period for nasal and injectable dosage forms was 36 months and 28 months, respectively, which prompted the initiation of an incomplete five-year stability study. This suggests that expired materials stored in communities and healthcare environments may still be effective far beyond the expiration date on their labels.
Some papers on opioid antagonists emphasize the shortcomings and problems of the presently known formulations and the need for more stable modified compounds that are safe for opioid addicted patients.
One name of Adam Bisaga is "what should the clinician do when fentanyl replaces heroin? "articles (published in addiction, volume 114, pages 781-86, https://onlinelibrary.wiley.eom/doi/epdf/ 10.1111/add.14522) It is described that high affinity antagonists may not be sufficient to block the effect of fentanyl and that higher doses may be required, but this presents systemic safety issues. Furthermore, fentanyl overdose prevention requires higher doses of naloxone and repeated dosing, whereas the window of fentanyl overdose prevention is much shorter than that of heroin.
Roger Chou et al, entitled "emergency medical service personnel use naloxone to manage suspected opioid overdose" (published in the relative effectiveness review at 193,https://effectivehealthcare.ahrq.gov/ sites/default/files/pdf/cer-193-naloxone-final_1.pdf) The existing guidelines for naloxone administration may be insufficient to prevent excessive use of fentanyl and fentanyl analogs.
Rachael Rzasa Lynn et al, entitled "naloxone dose to achieve opioid reversal: existing evidence and clinical significance "(published in society of pharmaceutical treatment progress, volume 9 (1), pages 63-88, 2018,https:// www.ncbi.nlm.nih.gOv/pmc/articles/PMC5753997/pdf/10.1177_2042098617744161.pdf) The article (a) describes that there is no improvement in oxygen uptake when double doses of naloxone are administered to patients with fentanyl anesthesia, but a significant improvement when quadruple doses of naloxone are administered. Furthermore, he also notes that the interaction between opioid agonists and mu opioid receptors may be the greatest determinant of recovery rate from the respiratory effects of many opioids, may not accelerate significantly with increasing naloxone doses, but rather react to the least effective dose, whereas even higher doses of naloxone may fail for compounds such as buprenorphine. He then cited a number of reports describing the initial intranasal administration of naloxone to a fentanyl excess No response, intravenous naloxone (if any) only achieves a transient reversal, requiring additional intravenous or continuous infusion to prevent toxicity and respiratory depression recurrence.
Elkiweri et al reduce the blood organ transport of fentanyl and loperamide to varying degrees on competing substrates named "p-glycoprotein and organic anion transporter: pharmacokinetics and pharmacodynamics in Sprague-Dawley rats (published online in 2009)https://www.ncbi.nlm.nih.gov/pubmed/19095843) Naloxone and fentanyl share a single cellular influx transporter that is saturated due to the high concentration of fentanyl in the plasma, and therefore naloxone cannot flow rapidly across the BBB regardless of dose.
The pharmacokinetics of Rebecca McDonald et al in terms of opioid overdose reversal is known as "concentrated naloxone nasal spray: phase I healthy volunteer studies "(published in addiction, volume 113, pages 484-93) describe that the early absorption of a high concentration 2mg of naloxone intranasal (i.n.) spray, similar to an intramuscular (i.m.) 0.4mg injection, can be used as a household antidote. He indicated that high doses of naloxone could be administered intranasally without the risk of excessive antagonism.
Jiten Ranchhodbhai Patel et al disclose (published WO 2013093931-application PCT/IN20 12/00590, filed on 9/6 2012) a novel hydrazide group comprising naloxone carbamates.
Baohua Huang et al describe in the paper entitled "human plasma mediated hypoxia activation of indoloquinone based naloxone prodrugs" (published in bioorganic chemistry and medicinal chemistry communication, 19 (17), 5016-5020) in 2009 that indoloquinone based naloxone prodrugs can reverse opioid-induced hypoxia.
Ukrainets et al disclose the study of naloxone 3-O-acyl derivatives as potential prodrugs thereof in publications heterocyclic chemistry (2009, 45 (4), pages 405-416).
Xuemei Peng et al disclose bivalent ligands comprising nalbuphine linked to nalbuphine in articles entitled "pharmacological properties of bivalent ligands comprising butorphanol linked to nalbuphine and naloxone at mu, delta and K opioid receptors" (published in journal of pharmaceutical chemistry (5 months of 2007), 50 (9), 2254-2258).
Romanov et al, in russian patent publication (RU 2221566-published 1/20 2004), describe the use of N-substituted 14-hydroxy morphinan esters as highly potent low-toxicity anti-restoratives, which can produce long-term opioid protection following a single subcutaneous or intramuscular injection.
The preparation of N-substituted 14-hydroxymorphinan esters is described in Russian patent publication (RU 2215741-11/10/2003).
Euro-Celtique, S.a., chevchuk et al, WO 2003070191 (PCT/US/2003/004999-published 8.28. 2003) describes methods for preventing pain using an anti-destructive skin device incorporating a 3-acyl-substituted antagonist.
Lu zhengtan discloses a process for the preparation of naloxone esters in Chinese patent No. CN 1204649 (published 1/13 1999).
S. Lazar et al describe the synthesis and bioactivity of phosphate and sulfate esters of naloxone in articles entitled "synthesis and bioactivity of phosphate and sulfate esters of naloxone" (published in J.European pharmaceutical chemistry (1994), vol.29 (1), pp.45-53).
Hussein et al (drug Industry (1988), vol.5 (9), pp.615-18), describe that various naloxone prodrugs (3-phenoxy esterified) have no bitter taste and have higher buccal bioavailability in dogs.
Elie Gabriel Shami benzoate prodrug derivatives of 3-hydroxy morphinans are described in European patent publication No. EP 170090. The above publications are incorporated by reference into this specification and form a part of this specification.
None of the cited publications describe the use of naloxone in combination with an hexadienoate contained within the molecule, nor does it suggest that such a molecule would result in and provide a substantially more effective, longer lasting neutralization/wakefulness upon administration to an individual.
Disclosure of Invention
The present invention relates to a novel modification of opioid and antagonists thereof that increases opioid receptor binding upon oral administration. More particularly, the present invention relates to suitable opioid receptor modulators (e.g., nalbuphine, buprenorphine, hydromorphine, morphine, pentazocine, butorphanol, naloxone, etc.) or modifications of related compounds that improve opioid binding to opioid receptors upon oral administration.
The present invention further relates to methods of alleviating the problem of low oral bioavailability of opioids when used in, but not limited to, the following conditions: pain management, palliative care, anesthesia (e.g., post-operative), skin disorders (e.g., pruritus), addiction (withdrawal or management), certain movement disorders (e.g., parkinson's disease levodopa induced catabolism (LID), movement disorders associated with tourette's syndrome, tardive dyskinesia, and huntington's disease), and the like.
The present invention relates to a novel modification of opioid drugs (e.g., nalbuphine) that can provide unexpected results, namely, increased opioid receptor binding upon oral administration. Thus, the novel modifications provide superior care and are suitable for a variety of therapeutic indications, including chronic conditions where oral opioid administration is required.
The present invention relates to novel modifications of opioid antagonists, such as naloxone in combination with an hexadienoate contained within the molecule, which will provide a substantially more effective, longer lasting neutralization/wakefulness when administered to an individual or patient.
The novel features of the invention will be further described with reference to the following drawings.
Drawings
The patent or application file contains at least one drawing executed in color. Upon request, the patent office will provide copies of this patent or patent application publication (containing a color drawing) after a necessary fee has been paid.
FIG. 1 shows NMR1H spectra of NB-20 compounds formulated in accordance with at least one embodiment of the present invention.
FIG. 2 shows NMR1H spectra of NB-33 compounds formulated in accordance with at least one embodiment of the present invention.
FIG. 3 shows NMR1H spectra of NB-39 compounds formulated in accordance with at least one embodiment of the present invention.
FIG. 4 shows NMR1H spectra of NB-51 compounds formulated in accordance with at least one embodiment of the present invention.
FIG. 5 shows NMR1H spectra of NB-52 compounds formulated in accordance with at least one embodiment of the present invention.
FIG. 6 shows NMR1H spectra of NB-56 compounds formulated in accordance with at least one embodiment of the present invention.
FIG. 7 shows NMR1H spectra of NB-58 compounds formulated in accordance with at least one embodiment of the present invention.
FIG. 8 shows an NMR1H spectrum of NB-78 compounds formulated in accordance with at least one embodiment of the present invention.
Figure 9A shows the binding pattern and intermolecular interactions of the most favored conformational isomer of nalbuphine (superimposed with the co-crystallizing ligand β -FNA).
Fig. 9B shows the binding pattern and intermolecular interactions of the most favored conformational isomer of naloxone (superimposed with the co-crystallizing ligand β -FNA).
Figure 10A shows the binding pattern and intermolecular interactions of the most favored NX-90 conformational isomer in the 4DKL binding site.
Fig. 10B shows the binding pattern and intermolecular interactions of the most favored NB-33 conformational isomer in the 4DKL binding site.
FIG. 10C shows intermolecular interactions with Met 151 (as shown by the NB-33 conformational isomer), with binding patterns similar to the most favored conformational isomer.
Fig. 10D shows the binding pattern and intermolecular interactions of the most favored NB-39 conformational isomer in the 4DKL binding site.
Figure 11A shows the most popular nalbuphine (yellow), naloxone (pink) conformational isomers and the addition of eutectic β -FNA (white) in the 4DKL opioid binding site.
Fig. 11B shows the most favored NX-90 (blue), NB-33 (red), NB-39 (cyan) conformational isomers and the addition of eutectic β -FNA (white) in the 4DKL opioid binding site.
Figures 12A-12C show hydrophobic (red) and hydrophilic (yellow) contact preference zones on the surface of a 4DKL binding site molecule in contact with, respectively, the n x-90, NB-33 and NB-39 docking conformational isomers in at least one example.
Fig. 13 includes chart 1, which shows that NB-33 in at least one embodiment has superior analgesic properties compared to an equimolar dose of the parent opioid NB.
Detailed Description
The present invention includes forming opioid-derived compositions comprising hexadienoate and opioid residues in a single molecule for use in the therapeutic arts related to opioid receptor modulation.
Various aspects and features of the present invention and compositions are described with reference to Table 1, table 1 shows selected characteristics 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.
Examples of NMR 1H spectra 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.
Surprisingly, 3-hexadienoate derivatives of opioids prepared according to at least one embodiment of the present invention may increase opioid receptor binding compared to the parent opioid compounds. Thus, when orally administered, nalbuphine 3-hexadienoate (NB-33) produced analgesia in rats and humans superior to equivalent doses of nalbuphine 3-behenate (NB-39) and Nalbuphine (NB). Furthermore, NB-33 was observed to have a significant effect on pupil dilation (constriction) in humans, indicating excellent opioid receptor binding.
Unexpectedly, when studying the effect of at least one embodiment of the present invention, it was found that the position and number of sites of unsaturation of the oxy group ester is unique to the hexadiene backbone, a condition required for optimal binding to the opioid receptor. Thus, nalbuphine 3-alkanoate (e.g., NB-33) has better analgesic effects than the parent opioid, whereas other unsaturated acid derivatives of nalbuphine (e.g., NB-31, NB-32, NB-52 or NB-78) do not produce analgesic effects in rats.
Furthermore, as a result of evaluating at least one embodiment of the present invention, it was found that nalbuphine 3-hexadienoate has unique and vivid opioid receptor characteristics, and expresses human recombinant opioid receptors in cells.
According to at least one embodiment, the compounds of the present invention comprise formula I or a pharmaceutically acceptable salt thereof
Wherein R is 1 、R 2 、R 3 、R 4 Or R is 5 Selected from H, optionally substituted C1-3 and OAlk, the double bond having E or Z geometry and Y being an opioid residue.
In at least one embodiment, the present invention further relates to a method of alleviating the problem of low oral bioavailability of opioids when the opioid is used in (but not limited to) the following conditions: pain management, palliative care, anesthesia (e.g., post-operative), skin disorders (e.g., pruritus), addiction (withdrawal or management), certain movement disorders (e.g., parkinson's disease levodopa induced catabolism (LID), movement disorders associated with tourette's syndrome, tardive dyskinesia, and huntington's disease), and the like.
In at least one embodiment, the present invention relates to an optionally substituted hexadienoate ester of a suitable opioid receptor modulator or phenoxy group modification of a related compound for improving opioid binding to opioid receptors upon oral administration.
In another embodiment, the invention relates to a suitable opioid receptor modulator (including but not limited to hydromorphine, morphine, nalbuphine, pentazocine, butorphanol, buprenorphine, naloxone) or an optionally substituted hexadienoate of a related compound 3-phenoxy group modification for improved opioid binding to opioid receptors upon oral administration.
In at least another embodiment, the present invention relates to a 3-hexadienoate modification of suitable opioid receptor modulators or related compounds for improving opioid binding to opioid receptors upon oral administration.
In at least one embodiment, the present invention relates to a 3-hexadienoate modification of nalbuphine or a pharmaceutically acceptable salt thereof for use in improving opioid receptor binding upon oral administration.
In another embodiment, the invention relates to a 3-hexadienoate modification of nalbuphine or a pharmaceutically acceptable salt thereof for improving the quality of pain management upon oral administration.
In another or more embodiments, the present invention relates to a 3-hexadienoate modification of nalbuphine or a pharmaceutically acceptable salt thereof for improving the quality of pain management upon intravenous, intranasal, transdermal, sublingual, rectal, topical, intramuscular, subcutaneous or inhalation administration.
Further examples of compounds prepared according to at least one embodiment of the present invention are provided below. The chemical name, composition and code of each compound in example 1 are shown in table 1 below.
Example 1
(E) -3- (cyclobutanemethyl) -9- ((3, 7-dimethyloct-2, 6-diethylenetriamine-1-yl) oxy) -1,2,3,4,5,6,7 a-octahydro-4 aH-4, 12-methanobenzofuro [3,2-e]Isoquinoline-4 a, 7-diol, nalbuphine-geranyl, (NB-20). To a suspension of nalbuphine hydrochloride (400 mg,1.0 mmol) in acetone (20 mL) and toluene (20 mL) was added potassium bicarbonate (280 mg,2.0 mmol) at room temperature. Geranyl bromide (320 mg,1.5 mmol) was added. The reaction mixture was stirred under reflux for 4 hours and at room temperature overnight. The reaction mixture was evaporated and the residue purified by column chromatography (silica gel, etOAc/heptane/methanol, 1:1:0.10). After evaporation of the selected fractions, a colourless oil was formed, with a yield of 45% and a purity of 91% as determined by HPLC. By NMR 1 H confirms the structure.
3- (Cyclobutanemethyl) -9- (((2E, 6E) -3,7, 11-trimethyldodecyl-2, 6, 10-triethylenetetramine-1-yl) oxy) -1,2,3,4,56,7 a-octahydro-4 aH-4, 12-methanobenzofuro [3,2-e ]]Isoquinoline-4 a, 7-diol, nalbuphine-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). After evaporation of the selected fractions, a colourless oil was obtained, determined by HPLC, in a yield of 53% and a purity of 93%. By NMR 1 H confirms the structure.
3- (Cyclobutanemethyl) -4a, 7-dihydroxy-2, 3, 4a,5,6,7 a-octahydro-1H-4, 12-methanobenzofuro [3,2-e ]]Isoquinolin-9-yl undec-10-enoate, nalbuphine-undecenoate, (NB-31). EDCI (1.04 g,5.4 mmol) was added to a solution of undecylenic acid (1.0 g,5.4 mmol) in THF (30 mL) at 0deg.C with constant stirring. The reaction mixture was stirred for 10 minutes, 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 0deg.C. Stirring was continued for 1 hour at 0 ℃ and at room temperature overnight. The reaction mixture was filtered, the filtrate evaporated and the residue purified by column chromatography (silica gel, etOAc/heptane, 1:1). After evaporation of the selected fractions, a white solid formed, with a yield of 78% (2.2 g) and a purity of 95% as determined by HPLC. By NMR 1 H confirms the structure.
3- (Cyclobutanemethyl) -4a, 7-dihydroxy-2, 3, 4a,5,6,7 a-octahydro-1H-4, 12-methanobenzofuro [3,2-e ]]Isoquinolin-9-yl (E) -3, 7-dimethyloct-2, 6-dienoate, nalbuphine-savolate, (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 the selected fractions, a white solid formed, 67% yield and 96% purity as determined by HPLC. By NMR 1 H confirms the structure.
3- (Cyclobutanemethyl) -4a, 7-dihydroxy-2, 3, 4a,5,6,7 a-octahydro-1H-4, 12-methanobenzofuro [3,2-e ]]Isoquinolin-9-yl (2E, 4E) -2, 4-hexadienoate, nalbuphine-sorbate, (NB-33). EDCI (1.16 g,6.1 mmol) was added to a solution of hexadienoic acid (0.68 g,6.1 mmol) in THF (30 mL) at 0deg.C with constant stirring. The reaction mixture was stirredNalbuphine hydrochloride (2.39 g,6.1 mmol), trimethylamine (1.2 g,12 mmol) and 4-dimethylaminopyridine (0.25 g,2 mmol) were added at 0deg.C for 10 min. Stirring was continued for 1 hour at 0 ℃ and at room temperature overnight. The reaction mixture was filtered, the filtrate evaporated and the residue purified by column chromatography (silica gel, etOAc/heptane, 1:1). After evaporation of the selected fractions, white crystals were formed, with a yield of 75% (2.05 g) and a purity of 98% as determined by HPLC. By NMR 1 H confirms the structure.
3- (Cyclobutanomethyl) -9- (((2E, 4E) -hex-2, 4-dienoyl) oxy) -4a, 7-dihydroxy-2, 3, 4a,5,6,7 a-octahydro-1H-4, 12-methanobenzofuro [3,2-e ]]Isoquinoline-3-onium chloride, nalbuphine-sorbate, hydrochloric acid, (NB-56). HCl (gas) was blown into a solution of nalbuphine-sorbate (NB-33) (0.4 g,0.89 mmol) in MTBE (15 mL) at 0deg.C. The reaction mixture was stirred for 1 hour, the solid was filtered, washed with MTBE, and dried in vacuo. The yield was 81% (0.35 g) and the purity was 98% as determined by HPLC. By NMR 1 H confirms the structure.
3- (Cyclobutanemethyl) -4a, 7-dihydroxy-2, 3, 4a,5,6,7 a-octahydro-1H-4, 12-methanobenzofuro [3,2-e ]]Isoquinolin-9-yl behenate, nalbuphine-behenate, (NB-39). EDCI (0.56 g,2.9 mmol) was added to a solution of behenic acid (1.0 g,2.9 mmol) in THF (50 mL) at 0deg.C with constant stirring. The reaction mixture was stirred for 30 minutes, 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 0deg.C. Stirring was continued for 1 hour at 0 ℃ and at room temperature overnight. The reaction mixture was filtered, the filtrate evaporated and the residue purified by column chromatography (silica gel, etOAc/heptane, 1:2). After evaporation of the selected fractions, a white solid formed, with a yield of 73% (1.45 g) and a purity of 97% as determined by HPLC. By NMR 1 H confirms the structure. U.S. patent 5750534 also describes the synthesis and properties of NB-39.
3- (Cyclobutanemethyl) -4a, 7-dihydroxy-2, 3, 4a,5,6,7 a-octahydro-1H-4, 12-methanobenzofuro [3,2-e ]]Isoquinolin-9-yl isobutyrate, nalbuphine-isobutyrate, (NB-46)). This compound was prepared according to the procedure of NB-31, substituting isobutyric acid for undecylenic acid. The crude material was purified by column chromatography (silica gel, etOAc/heptane, 1:1). After evaporation of the selected fractions, white crystals were formed, 54% yield and 95% purity as determined by HPLC. By NMR 1 H confirms the structure.
3- (Cyclobutanemethyl) -4a, 7-dihydroxy-2, 3, 4a,5,6,7 a-octahydro-1H-4, 12-methanobenzofuro [3,2-e ]]Isoquinolin-9-yl 3-methylbut-2-enoate, nalbuphine-3, 3-dimethacrylate, (NB-51). This compound was prepared according to the procedure of NB-31, substituting 3, 3-dimethacrylate for undecylenic acid. The crude material was purified by column chromatography (silica gel, etOAc/heptane, 1:1). After evaporation of the selected fractions, white crystals were formed, 77% yield and 95% purity as determined by HPLC. By NMR 1 H confirms the structure.
3- (Cyclobutanemethyl) -4a, 7-dihydroxy-2, 3, 4a,5,6,7 a-octahydro-1H-4, 12-methanobenzofuro [3,2-e ]]Isoquinolin-9-yl (E) -2-methylbut-2-enoate, nalbuphine-2, 3-dimethacrylate, (52). This compound was prepared according to the procedure of NB-31, substituting 2.3-dimethacrylate for undecylenic acid. The crude material was purified by column chromatography (silica gel, etOAc/heptane, 1:1). After evaporation of the selected fractions, white crystals were formed, 75% yield and 96% purity as determined by HPLC. By NMR 1 H confirms the structure.
3- (Cyclobutanemethyl) -4a, 7-dihydroxy-2, 3, 4a,5,6,7 a-octahydro-1H-4, 12-methanobenzofuro [3,2-e ] ]Isoquinolin-9-yl 2-methylbut-2-enoate, nalbuphine-2-methoxy crotonate, (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). After evaporation of the selected fractions, a white oil was formed, with a yield of 27% and a purity of 94% as determined by HPLC. By NMR 1 H confirms the structure.
7-acetoxy-3- (cyclobutanemethyl) -4 a-hydroxy-2, 3, 4a,5,6,7 a-octahydro-1H-4, 12-methanobenzofuro [3,2-e ]]Isoquinolin-9-yl (2E, 4E) -2, 4-hexadienoate, nalbuphine-hexadienoate-acetate, (NB-76). At 40-NB-33 (0.5 g,1.1 mmol) was stirred overnight in acetic anhydride (7.0 mL) at 50deg.C. EtOH (20 mL) was added and the reaction mixture evaporated. The residue was purified twice by column chromatography (silica gel, etOAc/heptane, 1:2). After evaporation of the selected fractions, white crystals were formed, with a yield of 50% (1.45 g) and a purity of 97% as determined by HPLC. By NMR 1 H confirms the structure.
3- (Cyclobutanemethyl) -4a, 7-dihydroxy-2, 3, 4a,5,6,7 a-octahydro-1H-4, 12-methanobenzofuro [3,2-e ]]Isoquinolin-9-yl cinnamate, nalbuphine-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). After evaporation of the selected fractions, white crystals were formed, 67% yield and 94% purity as determined by HPLC. By NMR 1 H confirms the structure.
TABLE 1
Example 2Stability in simulated gastrointestinal fluids (sGIF).
Stability evaluation of NB-33 in simulated gastrointestinal fluids (sGIF) is as follows, and Table 1 summarizes the compound data.
sGIF is a 0.5% aqueous solution of pepsin (Alfa Angstrom, pepsin, pig stomach) in 0.1N HCl. Each derivative (50 mg) was mixed with sGIF (50 mL) and cultured on a shaker at 37 ℃. Hydrolysis and release of nalbuphine was monitored by HPLC at t=0 hours, 0.5 hours, 1 hour, 2 hours and 4 hours. An acceptable criterion is that not less than 80% of the derivative remains intact after 4 hours.
Example 3-Stability in human plasma.
Stability of NB-56 in human plasma was evaluated as follows and Table 1 summarizes the compound data.
NB-56 (1.0 mg) was dissolved in 10mL of plasma (pooled normal human plasma, sodium citrate, innovative Ind.) while stirring at 20℃for 10 min. The solution was incubated at 37 ℃. 1mL of the solution was taken for each sample. To the sample solution was added MeCN (0.05 mL). Shaking for 1 minute, followed by centrifugation (15 minutes, 14.000 r/m). The supernatant was filtered off and extracted with EtOAc (2X 20 mL). Using MgSO 4 The mixed extract was dried and concentrated in vacuo. The residue was dissolved in methanol (20. Mu.l). The solution was used for HPLC injection.
Hydrolysis and release of nalbuphine was monitored by HPLC at t=0 hours, 0.5 hours, 1 hour, 2 hours and 4 hours. An acceptable criterion is that no less than 20% of the derivative is hydrolysed after 4 hours.
Example 4
TABLE 2Human recombinant opioid receptor data for NB-33
Human recombinant opioid receptors (μ, κ, or δ) expressed in CHO-K1 cells were used. The test compound (NB-33)/or carrier was incubated with cells (4X 10E 5/mL) in modified HBSS pH 7.4 buffer for 30 minutes at 37 ℃. The cAMP levels of the reaction are assessed by TR-FRET. Compounds of 0.3uM, 1uM and 3uM were screened by the euler drug discovery service company.
Table 2 summarizes the data for compound NB-33.
Example 5
Sprague-Dawley rats were tested 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; males) were randomly assigned to 10 groups, each group being treated by gavage with one of the following treatments: 1. sesame oil; 2. nalbuphine (in sesame oil; 60 uM/kg); NB-31 (in sesame oil; 60 uM/kg); NB-32 (in sesame oil; 60 uM/kg); NB-33 (in sesame oil; 60 uM/kg); NB-39 (in sesame oil; 60 uM/kg); NB-51 (in sesame oil; 60 uM/kg); NB-52 (in sesame oil; 60 uM/kg); NB-76 (in sesame oil; 60 uM/kg); NB-78 (in sesame oil; 60 uM/kg). Each rat took the drug only once.
Antinociceptive activity was assessed by cold ethanol tail flick test (as described in anesthesia and analgesia; 2003; 97; 806-9). The test temperature was set at-20℃and the off-time was 40 seconds. All rats were tested immediately prior to dosing at t=0. The antinociceptive thresholds of saline, nalbuphine and nalbuphine derivatives were measured at t=0 hours, 0.25 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 3 hours and 5 hours after oral administration.
The data shown in the last column of Table 1 shows that NB-33 results are good.
Example 6
Double blind NB hydrochloric acid and NB-39 control experiments with healthy volunteers orally administered NB-33 against nociceptive effects. Three healthy volunteers were each dispensed with a group of drugs comprising the following 6 opaque gelatin capsules: 2 XNB hydrochloric acid (MW=393.4; 39 mg), 2 XNB-33 (MW=451.6; 45 mg) and 2 XNB-39 (MW=680.0; 68 mg). Each healthy volunteer was randomized to obtain one dose from the dispensing group weekly and orally. Thermal pain threshold (50 ℃ hot water) and pupil constriction were measured at t=0 hours, 0.25 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 3 hours and 5 hours after oral administration.
After a one week elution period, each volunteer repeatedly performed the regimen until all of the drug in the dispensing group was orally administered. Tables 2 and 3 show the data of thermal pain threshold% MPE = [ (test latency-baseline latency/(baseline latency) ]x100 and pupil constriction% MPE = [ (test diameter) -baseline diameter/(baseline diameter) ]x100, respectively.
Tables 3, 4 and 5A-D show that the analgesic and pupil-narrowing effects of NB-33 are superior to those of the parent opioid NB and the parent opioid prodrug NB-39 when taken orally. As shown in tables 5A-D, differences in analgesic and pupillary constriction effects are statistically significant.
TABLE 3 Table 3
TABLE 4 Table 4
The% MPE analgesia and pupil constriction averages of two pairs of samples were compared by independent sample t-test:
NB-33 and NB, and NB-33 and NB-39. All analyses were performed using SPSS (v.25).
* Bold indicates that there is a statistical significance at a=0.05.
Tables 5A-D show comparisons of analgesic and pupil constriction between NB-33 and NB-39.
Table 6A below and table 1 in fig. 13 show the results of other experiments of NB-33 on Randall-Selitto rats, demonstrating their efficacy and benefits (including higher stability) relative to the base compound.
Table 6A below and table 1 in fig. 13 show the results of other experiments of NB-33 on Randall-Selitto rats, demonstrating their efficacy and benefits (including higher stability) relative to the base compound.
TABLE 6A
WO #10656913 AB137003 species/line/sex: ratio of
The data on graph 1 in fig. 13 shows that the analgesic properties of NB-33 are superior to those of the parent opioid NB at equimolar doses. FIG. 13 graphically illustrates the results of 1310NB-33 (labeled 1310 in FIG. 13) relative to base NB compound NB (labeled 1320).
Example 7
The present invention is exemplified by, but not limited to, the following compounds (shown below). The following compounds (as shown in table 7 below) provide non-limiting examples of various opioids modified with hexadienoic acid esters as described in at least one example.
TABLE 7
Example 8Molecular docking of nalbuphine/naloxone opioid antagonists to the mu opioid receptors.
The human m opioid receptor crystal structure was downloaded from the RCSB protein database (PDB entry: 4DKL, https:// www.rcsb.org/structure/4 DKL). Silicon chip screening was performed using the MOE docking program (part of the MOE simulation module 2014.0901). According to the equation Δg=rtin (K i ) Calculate dissociation constant (Ki)Wherein 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 starting from the binding free energy at the fixed temperature (300K).
The antagonists nalbuphine and naloxone show a key interaction between Asp 147 and its ammonium groups. It is well known that this binding to Asp 147 is typical for most known opioid agonists/antagonists. Other repeated interactions of nalbuphine and naloxone are the binding of the hydroxyl group attached to the aryl ring (3-position) with water molecules, helping to stabilize the inactive state of the opioid receptor. Unlike nalbuphine, the naloxone hydroxyl group attached to the tertiary carbon atom (position 14) is involved in other Asp 147 hydrogen bonding activities.
Figure 9A shows the binding pattern and intermolecular interactions of the most favored conformational isomer of nalbuphine (superimposed with the co-crystallizing ligand β -FNA). Fig. 9B shows the binding pattern and intermolecular interactions of the most favored conformational isomer of naloxone (superimposed with the co-crystallizing ligand β -FNA).
In nalbuphine and naloxone, the hydroxyl group attached to the aryl ring (3-position) is bound to a water molecule, helping to stabilize the inactive state of the opioid receptor. Unlike nalbuphine, the naloxone hydroxyl group attached to the tertiary carbon atom (position 14) is involved in other Asp 147 hydrogen bonding activities.
Figure 10A shows the binding pattern and intermolecular interactions of the most favored NX-90 conformational isomer in the 4DKL binding site.
Fig. 10B shows the binding pattern and intermolecular interactions of the most favored NB-33 conformational isomer in the 4DKL binding site.
FIG. 10C shows intermolecular interactions with Met 151 (as shown by the NB-33 conformational isomer), with binding patterns similar to the most favored conformational isomer.
Fig. 10D shows the binding pattern and intermolecular interactions of the most favored NB-39 conformational isomer in the 4DKL binding site.
Figure 11A shows the most popular nalbuphine (yellow), naloxone (pink) conformational isomers and the addition of eutectic β -FNA (white) in the 4DKL opioid binding site. Fig. 11B shows the most favored NX-90 (blue), NB-33 (red), NB-39 (cyan) conformational isomers and the addition of eutectic β -FNA (white) in the 4DKL opioid binding site.
The calculated dissociation constants (Ki) for NX-90, NB-33, NB-39 indicate that the affinity for the m-receptor is higher than (NB-33, NB-39) or lower than (NX-90) for nalbuphine and naloxone. Similar to the most popular conformational isomers of naloxone and nalbuphine, NX-90, NB-33 and NB-39 retain the critical hydrogen bonding to the Asp147 residue. In this docking mode, a "message" attached to the nitrogen atom is delivered to the correct "address" on the precise region of the m-receptor binding pocket. However, unlike the binding patterns of known m antagonists (e.g., nalbuphine and naloxone; FIG. 11A), the rigid framework of NX-90, NB-33 and NB-39 is rotated 180 at the binding site (FIG. 11B). In contrast, the binding patterns describing nalbuphine and naloxone binding are not applicable to all calculated conformational isomers of NB-33, NB-39 and NX-90.
In addition, NX-90 and NB-33 undergo unique hydrogen bonding with Met 151 through a hydroxyl group attached to the tertiary carbon atom (position 14). This interaction causes NX-90 and NB-33 to form hydrogen bonds with Lys A233, unlike NB-39, i.e., the hydroxyl group at the cyclohexane fragment (6-position). The second distinguishing factor of NX-90 and NB-33 is that the rigid coupling system of hexadienoic acid residues has a particularly hydrophobic columnar molecular surface. At the same time, residues Cys217, thr218, asn127, gln124, trp133, leu219 create additional complementary hydrophobic molecular surfaces around the hexadienyl "tail" within the binding pocket (fig. 12A and 12B), whereas there are no discernible hydrophobic surfaces in the binding site region around the highly flexible and poorly coupled docosanoyl "tail" (fig. 12C).
FIGS. 12A-12C show the hydrophobic (red) and hydrophilic (yellow) contact preference zones on the surface of the 4DKL binding site molecule in contact with NX-90 (as shown in FIG. 12A), NB-33 (as shown in FIG. 12B) and NB-39 (as shown in FIG. 12C) docking conformational isomers, respectively.
These examples (particularly the examples in fig. 9-12) demonstrate at least one feature of the present invention, namely that modification of opioid drugs with lipophilic groups comprising at least two conjugated double bonds can improve interactions with opioid receptors.
These examples also demonstrate another feature of the present invention, namely that modifying an opioid with a lipophilic group comprising at least two conjugated double bonds can improve interactions with opioid receptors by rotating the opioid 180 ° at the active site and creating other modes of interaction with the receptor (including unique hydrophobic pockets).
These examples further demonstrate another feature of the present invention that modifying opioid using a lipophilic group comprising at least two conjugated double bonds can at least alter opioid properties in certain embodiments of the present invention.
These examples also demonstrate another feature of the present invention that modifying an opioid with a lipophilic group comprising at least two conjugated double bonds may at least improve the opioid antagonistic properties in certain embodiments of the present invention.
Improved performance of opioid receptor antagonists
As noted above, the present invention includes at least one embodiment in which hexadienoate is shown to improve the performance of opioid antagonists (e.g., naloxone) in addition to the improved performance and analgesic quality of the opioid.
In at least one embodiment, the present invention (particularly hexadienoate) is combined with and tested with at least one (or more) of the naloxone group or compounds.
In at least one embodiment of the invention, naloxone (comprising hexadienoate) is included in the molecule that, when administered to a subject, will provide a substantially more effective, longer lasting neutralization/wakefulness.
In at least one embodiment of the present invention, compounds NX-90 and NX-97 of the following formulas (as shown in Table 8 below) were synthesized and analyzed.
TABLE 8
Upon administration to a subject, a wakeful effect may be noted. Such a compound, known as naloxone-sorbate (NX-90), may be used and synthesized in accordance with at least one embodiment of the present invention. The procedure for preparing the compounds according to at least one embodiment is as follows.
EDCI. HCl (1.36 g,7.12 mmol) was added to a solution of hexadienoic acid (0.74 g,6.61 mmol) in THF (50 mL) at 0deg.C with constant stirring. Triethylamine (1.39 g,13.8 mmol) was added. Stirred at 0℃for 2 hours. Naloxone hydrochloride (2.00 g,5.5 mmol) and 4-dimethylaminopyridine (0.10 g,0.82 mmol) were added at 0deg.C. Stirring was continued for 1 hour at 0 ℃ and at room temperature overnight. The reaction mixture was filtered, the filtrate evaporated and the residue purified twice by column chromatography (silica gel, etOAc/heptane/triethylamine, 2:1:0.5%). After evaporation of the selected fractions, white crystals were formed in a yield of 32% (0.75 g) as determined by HPLC with a purity of 98%. By NMR 1 H confirms the structure.
The following results and specific benefits (including stability data) were obtained and confirmed by studying the properties of the NX-90 compounds.
Table 9-NX-90 (. Alpha. -1-91) stability (GIF) (detected by Alfachem Corp.).
From the results and observations, as shown in table 9, the improvement in NX-90 is evident compared to the well-known drug naloxone.
Table 11 below further shows examples of combinations of NB-33 or similar compounds with different opioid drugs and NX-90 with opioid antagonists described in at least one embodiment of this invention.
It is well documented and well known that opioids can be used to treat the following conditions: pain management, palliative care, postoperative anesthesia, dermatological disorders, addiction, movement disorders, parkinsonian levodopa induced catabolism (LID), movement disorders associated with tourette's syndrome, tardive dyskinesia, huntington's disease, and the like. The efficacy and effectiveness of opioids used to treat these conditions can affect the degree of success of the treatment.
Accordingly, the better the opioid receptor binding, the more effective the outcome of treating the disorder according to at least one embodiment of the invention. For example, opioid drugs modified with hexadienoic acid esters are more effective in treating the above conditions because of their better opioid receptor binding.
Thus, in at least one embodiment of the present invention, a synthetic compound formulated in accordance with the present invention (e.g., NB-33 or NX-90, etc.) may be used to treat one of the following conditions: pain management, palliative care, anesthesia (e.g., post-operative), skin disorders (e.g., pruritus), addiction (withdrawal or management), and/or movement disorders (e.g., parkinson's disease levodopa-induced catabolism (LID), movement disorders associated with tourette's syndrome, tardive dyskinesia, and huntington's disease).
Example 9
Table 10Human recombinant opioid receptor data for NX 90 are shown.
Human recombinant opioid receptors (μ, κ, or δ) expressed in CHO-K1 cells were used. Test compounds ((NX-90)/or carrier and cells (4X 10E 5/mL) were incubated in modified HBSS pH 7.4 buffer for 30 min at 37℃the cAMP levels (cAMP and/or calcium flux) of the reaction were assessed by TR-FRET.
Table 10 summarizes the data for compound NB-90. It is shown in the table that NX-90 is not a pharmacologically inert compound and has its unique opioid characteristics similar to those of naloxone. In addition, it is shown in the table that NB-33 is not a pharmacologically inert compound and has unique opioid characteristics similar to the pharmacological characteristics of NB.
These results are very surprising since such modifications (e.g., NB-39) at the 3-phenoxy position (comprising fatty acids) are considered in the art to be prodrugs and, by definition, pharmacologically inert compounds. According to at least one embodiment of the invention, NX-90 and NB-33 are not pharmacologically inert and do not belong to prodrugs.
In all cases it is understood that the above-described examples and compounds are intended to illustrate the many possible specific embodiments which represent applications of the present invention. Various other arrangements may be readily devised in accordance with the principles of the present invention without departing from the spirit and scope of the invention.
TABLE 11
Claims (8)
1. A compound which is nalbuphine-3-hexadienoate or naloxone-3-hexadienoate, or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein the compound increases opioid binding to opioid receptors when administered orally to a patient.
3. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment of a condition selected from the group consisting of: pain management, palliative care, postoperative anesthesia, dermatological disorders, addiction, movement disorders, parkinsonian levodopa-induced catabolism (LID), movement disorders associated with tourette's syndrome, tardive dyskinesia, and huntington's disease.
4. 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.
6. 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.
7. Use of a composition according to claim 4 for the preparation of a medicament for the treatment of dermatological disorders, addiction, movement disorders, parkinson's disease, levodopa-induced catabolism (LID), movement disorders associated with tourette's syndrome, tardive dyskinesia or huntington's disease.
8. Use of the composition of claim 4 in the manufacture of a medicament for treating opioid overdose conditions, comprising administering to a subject an effective amount of the composition of claim 4.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201962885311P | 2019-08-11 | 2019-08-11 | |
| US62/885,311 | 2019-08-11 | ||
| US16/540,058 | 2019-08-14 | ||
| US16/540,058 US11186585B2 (en) | 2018-08-17 | 2019-08-14 | Compositions and methods of enhancing opioid receptor engagement by opioid hexadienoates and optionally substituted hexadienoates |
| PCT/US2020/021599 WO2021029914A1 (en) | 2019-08-11 | 2020-03-07 | Compositions and methods of enhancing opioid receptor engagement by opioid hexadienoates and optionally substituted hexadienoates |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114828961A CN114828961A (en) | 2022-07-29 |
| CN114828961B true CN114828961B (en) | 2024-03-29 |
Family
ID=74571142
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202080071185.9A Active CN114828961B (en) | 2019-08-11 | 2020-03-07 | Compositions and methods for enhancing opioid receptor binding via opioid hexadienoate and optionally substituted hexadienoate |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP4010078A4 (en) |
| JP (1) | JP7535569B2 (en) |
| CN (1) | CN114828961B (en) |
| CA (1) | CA3149152A1 (en) |
| MX (1) | MX2022001520A (en) |
| WO (1) | WO2021029914A1 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017091827A1 (en) * | 2015-11-29 | 2017-06-01 | Thottathil John K | Novel alpha-hydroxy carboxylic acid and derivatives and other gras based prodrugs of oxycodone and uses thereof |
Family Cites Families (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4668685A (en) | 1984-07-05 | 1987-05-26 | E.I. Du Pont De Nemours And Company | Substituted benzoate ester prodrug derivatives of 3-hydroxymorphinans, which are analgesics or narcotic antagonists |
| DE69427551T2 (en) * | 1993-03-15 | 2002-05-16 | National Science Council, Taipeh/T'ai-Pei | Nalbuphine esters and medicines containing them with delayed drug delivery |
| CN1050130C (en) | 1997-07-04 | 2000-03-08 | 卢正堂 | Naloxonate and naltrexonate and series product and preparation method |
| DE60001487T2 (en) | 2000-04-27 | 2003-12-24 | Oliver Yoa-Pu Hu | polynalbuphine derivative |
| TWI226239B (en) | 2000-05-15 | 2005-01-11 | You-Pu Hu | Novel oral pharmaceutical composition containing nalbuphine ester prodrug |
| MXPA03000821A (en) | 2000-07-27 | 2004-03-18 | Univ Rutgers | Therapeutic polyesters and polyamides. |
| US20040033253A1 (en) | 2002-02-19 | 2004-02-19 | Ihor Shevchuk | Acyl opioid antagonists |
| WO2005009377A2 (en) | 2003-07-23 | 2005-02-03 | University Of Kentucky Research Foundation | Novel oral bioavailable prodrugs |
| US20050137141A1 (en) | 2003-10-24 | 2005-06-23 | John Hilfinger | Prodrug composition |
| EP1928881A2 (en) | 2005-08-19 | 2008-06-11 | Pharmacofore, Inc. | Prodrugs of active agents |
| WO2011011543A1 (en) | 2009-07-21 | 2011-01-27 | Nektar Therapeutics | Oligomer-opioid agonist conjugates |
| US20090192095A1 (en) | 2008-01-18 | 2009-07-30 | Shire Llc | Amino acid and peptide prodrugs of opioid analgesics with reduced gi side-effects |
| BRPI1015108A2 (en) | 2009-04-02 | 2016-04-26 | Shire Llc | opioid dicarboxylic acid-linked amino acid and peptide prodrugs and their uses |
| AU2010272233A1 (en) | 2009-07-17 | 2012-02-09 | Shire Llc | Novel carbamate amino acid and peptide prodrugs of opioids and uses thereof |
| US20110190267A1 (en) * | 2010-01-05 | 2011-08-04 | Shire Pharmaceuticals, Inc. | Prodrugs of opioids and uses thereof |
| US8461171B2 (en) | 2010-02-09 | 2013-06-11 | QRxPharma Ltd. | Hybrid opioid compounds and compositions |
| ES2555258T3 (en) * | 2010-04-02 | 2015-12-30 | Zynerba Pharmaceuticals, Inc. | Opioid prodrugs administrable transdermally, compositions that do not induce abuse and procedures for the use of opioid prodrugs |
| CA2822528C (en) | 2010-12-28 | 2017-07-18 | Euro-Celtique S.A. | A combination of an opioid agonist and an opioid antagonist in the treatment of parkinson's disease |
| US9987269B2 (en) | 2015-04-27 | 2018-06-05 | 3St Research Llc | Alpha-hydroxy carboxylic acid and derivatives and other GRAS-based prodrugs of oxymorphone and uses thereof |
| US10449190B2 (en) * | 2015-04-27 | 2019-10-22 | John K. Thottathil | Alpha-hydroxy carboxylic acid and derivatives and other GRAS-based prodrugs of opioids and uses thereof |
| US9974858B2 (en) * | 2015-08-29 | 2018-05-22 | Medrx Co., Ltd | Percutaneous absorption composition |
| WO2018191472A1 (en) | 2017-04-14 | 2018-10-18 | Kempharm, Inc. | Levorphanol prodrugs and processes for making and using them |
| US11186585B2 (en) * | 2018-08-17 | 2021-11-30 | Kappa-Pharma LLC | Compositions and methods of enhancing opioid receptor engagement by opioid hexadienoates and optionally substituted hexadienoates |
-
2020
- 2020-03-07 EP EP20852037.9A patent/EP4010078A4/en active Pending
- 2020-03-07 CA CA3149152A patent/CA3149152A1/en active Pending
- 2020-03-07 CN CN202080071185.9A patent/CN114828961B/en active Active
- 2020-03-07 JP JP2022509137A patent/JP7535569B2/en active Active
- 2020-03-07 MX MX2022001520A patent/MX2022001520A/en unknown
- 2020-03-07 WO PCT/US2020/021599 patent/WO2021029914A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017091827A1 (en) * | 2015-11-29 | 2017-06-01 | Thottathil John K | Novel alpha-hydroxy carboxylic acid and derivatives and other gras based prodrugs of oxycodone and uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2022544564A (en) | 2022-10-19 |
| JP7535569B2 (en) | 2024-08-16 |
| CN114828961A (en) | 2022-07-29 |
| MX2022001520A (en) | 2022-07-21 |
| EP4010078A4 (en) | 2023-08-09 |
| WO2021029914A1 (en) | 2021-02-18 |
| CA3149152A1 (en) | 2021-02-18 |
| EP4010078A1 (en) | 2022-06-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101589846B1 (en) | Benzoic acid, benzoic acid derivatives and heteroaryl carboxylic acid conjugates of hydromorphone, prodrugs, methods of making and use thereof | |
| US11851439B2 (en) | Compositions and methods of use for opioid hexadienoates and optionally substituted hexadienoates | |
| CN102480959B (en) | Benzoic acid, benzoic acid derivatives and heteroaryl carboxylic acid conjugates of hydrocodone, prodrugs, methods of making and use thereof | |
| CA2448665C (en) | Sustained-release analgesic compounds | |
| CA2740087C (en) | Gaba conjugates and methods of use thereof | |
| JP2010511717A (en) | Prodrugs and how to create and use them | |
| AU2010266209B2 (en) | Phenylethanoic acid, phenylpropanoic acid and phenylpropenoic acid conjugates and prodrugs of hydrocodone, methods of making and use thereof | |
| MXPA05009757A (en) | Compounds and methods for lowering the abuse potential and extending the duration of action of a drug. | |
| AU2002305816A1 (en) | Sustained-release analgesic compounds | |
| JP2008539253A (en) | TRPV1 agonist compounds and methods for making and using TRPV1 agonist compounds | |
| CA2781436C (en) | Arachidonic acid analogs and methods for analgesic treatment using same | |
| JP6518595B2 (en) | Therapeutic and / or preventive agent for pain comprising 1-indansulfamide derivative | |
| US20190255036A1 (en) | Compound and method for reducing neuropathic pain and depression | |
| HUP0500024A2 (en) | 6-aminomorphinane derivatives, their use and pharmaceutical compositions containing them | |
| JP2002501923A (en) | Therapeutic compounds | |
| WO2007072749A1 (en) | Antitussive agent | |
| CN114828961B (en) | Compositions and methods for enhancing opioid receptor binding via opioid hexadienoate and optionally substituted hexadienoate | |
| KR101285645B1 (en) | Analgesic | |
| Sinatra et al. | Oral and parenteral opioid analgesics for acute pain management | |
| CN101898977A (en) | GABA (Gamma-Aminobutyric Acid) conjugates and using method thereof | |
| Chakraborty | Opioid codrugs for pain management | |
| HK40007565A (en) | Methods for the synthesis of deuterated dextromethorphan |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |