WO2023160004A1 - Composé à cycle fusionné ayant une activité analgésique, son procédé de préparation et son utilisation - Google Patents
Composé à cycle fusionné ayant une activité analgésique, son procédé de préparation et son utilisation Download PDFInfo
- Publication number
- WO2023160004A1 WO2023160004A1 PCT/CN2022/129152 CN2022129152W WO2023160004A1 WO 2023160004 A1 WO2023160004 A1 WO 2023160004A1 CN 2022129152 W CN2022129152 W CN 2022129152W WO 2023160004 A1 WO2023160004 A1 WO 2023160004A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkoxy
- alkyl
- alkylamino
- hydrogen
- aryl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 124
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 230000000202 analgesic effect Effects 0.000 title abstract description 12
- 208000002193 Pain Diseases 0.000 claims abstract description 22
- 201000010099 disease Diseases 0.000 claims abstract description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 14
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 5
- -1 mercapto, mercaptomethyl Chemical group 0.000 claims description 94
- 125000000217 alkyl group Chemical group 0.000 claims description 64
- 125000003545 alkoxy group Chemical group 0.000 claims description 58
- 229910052739 hydrogen Inorganic materials 0.000 claims description 56
- 239000001257 hydrogen Substances 0.000 claims description 56
- 125000003118 aryl group Chemical group 0.000 claims description 50
- 125000003282 alkyl amino group Chemical group 0.000 claims description 47
- 125000000623 heterocyclic group Chemical group 0.000 claims description 47
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 45
- 125000003342 alkenyl group Chemical group 0.000 claims description 25
- 125000000304 alkynyl group Chemical group 0.000 claims description 25
- 125000006654 (C3-C12) heteroaryl group Chemical group 0.000 claims description 24
- 125000001072 heteroaryl group Chemical group 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 20
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 19
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 17
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 13
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 125000004076 pyridyl group Chemical group 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 6
- 208000004296 neuralgia Diseases 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 6
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 239000008187 granular material Substances 0.000 claims description 5
- 208000021722 neuropathic pain Diseases 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000000843 powder Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 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 claims description 4
- 206010016059 Facial pain Diseases 0.000 claims description 4
- 206010019233 Headaches Diseases 0.000 claims description 4
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 230000037396 body weight Effects 0.000 claims description 4
- 231100000869 headache Toxicity 0.000 claims description 4
- 206010022437 insomnia Diseases 0.000 claims description 4
- 208000011580 syndromic disease Diseases 0.000 claims description 4
- 210000001835 viscera Anatomy 0.000 claims description 4
- 206010031009 Oral pain Diseases 0.000 claims description 3
- 230000036528 appetite Effects 0.000 claims description 3
- 235000019789 appetite Nutrition 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 230000006999 cognitive decline Effects 0.000 claims description 3
- 208000010877 cognitive disease Diseases 0.000 claims description 3
- 230000004970 emotional disturbance Effects 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000006071 cream Substances 0.000 claims description 2
- 239000000499 gel Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 239000007937 lozenge Substances 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 239000007921 spray Substances 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 210000000214 mouth Anatomy 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 13
- 208000024891 symptom Diseases 0.000 abstract description 7
- 239000002552 dosage form Substances 0.000 abstract description 2
- 150000002431 hydrogen Chemical class 0.000 description 40
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 22
- 239000000243 solution Substances 0.000 description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 241000700159 Rattus Species 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 239000012141 concentrate Substances 0.000 description 13
- 235000008504 concentrate Nutrition 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- 230000002829 reductive effect Effects 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 7
- 239000007791 liquid phase Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical group O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 230000005856 abnormality Effects 0.000 description 6
- 229940035676 analgesics Drugs 0.000 description 6
- 239000000730 antalgic agent Substances 0.000 description 6
- 210000005013 brain tissue Anatomy 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 125000003367 polycyclic group Chemical group 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000000018 receptor agonist Substances 0.000 description 5
- 229940044601 receptor agonist Drugs 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 4
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 230000008499 blood brain barrier function Effects 0.000 description 4
- 210000001218 blood-brain barrier Anatomy 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 150000003904 phospholipids Chemical class 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 239000012085 test solution Substances 0.000 description 4
- 108090000137 Opioid Receptors Proteins 0.000 description 3
- 102000003840 Opioid Receptors Human genes 0.000 description 3
- 230000032683 aging Effects 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 239000000823 artificial membrane Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 210000001320 hippocampus Anatomy 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- 241000272517 Anseriformes Species 0.000 description 2
- 208000006820 Arthralgia Diseases 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 208000000094 Chronic Pain Diseases 0.000 description 2
- 206010012335 Dependence Diseases 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- 102000048266 Nociceptin Human genes 0.000 description 2
- 108090000622 Nociceptin Proteins 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 208000005298 acute pain Diseases 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 230000006933 amyloid-beta aggregation Effects 0.000 description 2
- 230000001754 anti-pyretic effect Effects 0.000 description 2
- 239000002221 antipyretic Substances 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 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 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 2
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 2
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 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 2
- 102000051367 mu Opioid Receptors Human genes 0.000 description 2
- PULGYDLMFSFVBL-SMFNREODSA-N nociceptin Chemical compound C([C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)[C@@H](C)O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 PULGYDLMFSFVBL-SMFNREODSA-N 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 229940005483 opioid analgesics Drugs 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 2
- 238000005191 phase separation Methods 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000008399 tap water Substances 0.000 description 2
- 235000020679 tap water Nutrition 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 230000000451 tissue damage Effects 0.000 description 2
- 231100000827 tissue damage Toxicity 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 108020001612 μ-opioid receptors Proteins 0.000 description 2
- GLNOAERYNWZGJY-ZETCQYMHSA-N (2s)-2-methylpiperidin-1-ium-2-carboxylate Chemical compound [O-]C(=O)[C@]1(C)CCCC[NH2+]1 GLNOAERYNWZGJY-ZETCQYMHSA-N 0.000 description 1
- KNCMKWVOMRUHKZ-AATRIKPKSA-N (e)-2,5-dimethylhex-3-ene Chemical compound CC(C)\C=C\C(C)C KNCMKWVOMRUHKZ-AATRIKPKSA-N 0.000 description 1
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 1
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000006071 3,3-dimethyl-1-butenyl group Chemical group 0.000 description 1
- DAGAQTLMZAEUKX-UHFFFAOYSA-N 3-bromo-1h-pyrrolo[2,3-c]pyridine Chemical compound N1=CC=C2C(Br)=CNC2=C1 DAGAQTLMZAEUKX-UHFFFAOYSA-N 0.000 description 1
- USSIQXCVUWKGNF-UHFFFAOYSA-N 6-(dimethylamino)-4,4-diphenylheptan-3-one Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 USSIQXCVUWKGNF-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 description 1
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 206010008479 Chest Pain Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000005171 Dysmenorrhea Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical class NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- 208000036626 Mental retardation Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 208000006550 Mydriasis Diseases 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 208000001294 Nociceptive Pain Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 101100244562 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) oprD gene Proteins 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- ZTVQQQVZCWLTDF-UHFFFAOYSA-N Remifentanil Chemical compound C1CN(CCC(=O)OC)CCC1(C(=O)OC)N(C(=O)CC)C1=CC=CC=C1 ZTVQQQVZCWLTDF-UHFFFAOYSA-N 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 206010038678 Respiratory depression Diseases 0.000 description 1
- WINXNKPZLFISPD-UHFFFAOYSA-M Saccharin sodium Chemical compound [Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 WINXNKPZLFISPD-UHFFFAOYSA-M 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical group [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 206010045171 Tumour pain Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 125000005055 alkyl alkoxy group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001483 arginine derivatives Chemical class 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 230000003592 biomimetic effect Effects 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 description 1
- ILUWVORABZTBIU-UHFFFAOYSA-N chloromethyl 2-methylpropanoate Chemical compound CC(C)C(=O)OCCl ILUWVORABZTBIU-UHFFFAOYSA-N 0.000 description 1
- MFSHZGFPADYOTO-UHFFFAOYSA-N chloromethyl methyl carbonate Chemical compound COC(=O)OCCl MFSHZGFPADYOTO-UHFFFAOYSA-N 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- USVZFSNDGFNNJT-UHFFFAOYSA-N cyclopenta-1,4-dien-1-yl(diphenyl)phosphane (2,3-dichlorocyclopenta-1,4-dien-1-yl)-diphenylphosphane iron(2+) Chemical compound [Fe++].c1cc[c-](c1)P(c1ccccc1)c1ccccc1.Clc1c(cc[c-]1Cl)P(c1ccccc1)c1ccccc1 USVZFSNDGFNNJT-UHFFFAOYSA-N 0.000 description 1
- VTTDFSNKIMAQTB-UHFFFAOYSA-N cyclopentylboronic acid Chemical compound OB(O)C1CCCC1 VTTDFSNKIMAQTB-UHFFFAOYSA-N 0.000 description 1
- MAWOHFOSAIXURX-UHFFFAOYSA-N cyclopentylcyclopentane Chemical group C1CCCC1C1CCCC1 MAWOHFOSAIXURX-UHFFFAOYSA-N 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004855 decalinyl group Chemical group C1(CCCC2CCCCC12)* 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 108700023159 delta Opioid Receptors Proteins 0.000 description 1
- 102000048124 delta Opioid Receptors Human genes 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- KPHWPUGNDIVLNH-UHFFFAOYSA-M diclofenac sodium Chemical compound [Na+].[O-]C(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl KPHWPUGNDIVLNH-UHFFFAOYSA-M 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 150000005332 diethylamines Chemical class 0.000 description 1
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229960002428 fentanyl Drugs 0.000 description 1
- 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 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- XUCNUKMRBVNAPB-UHFFFAOYSA-N fluoroethene Chemical compound FC=C XUCNUKMRBVNAPB-UHFFFAOYSA-N 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000487 histidyl group Chemical class [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000036046 immunoreaction Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000006984 memory degeneration Effects 0.000 description 1
- 208000023060 memory loss Diseases 0.000 description 1
- 230000006996 mental state Effects 0.000 description 1
- 229960001797 methadone Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- MUTCAPXLKRYEPR-ITWZMISCSA-N methyl (e,3r,5s)-7-[4-bromo-2,3-bis(4-fluorophenyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyhept-6-enoate Chemical compound COC(=O)C[C@H](O)C[C@H](O)\C=C\N1C(C(C)C)=C(Br)C(C=2C=CC(F)=CC=2)=C1C1=CC=C(F)C=C1 MUTCAPXLKRYEPR-ITWZMISCSA-N 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 229960002085 oxycodone Drugs 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 238000013148 permeation assay Methods 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- QDQVXVRZVCTVHE-YFKPBYRVSA-N propan-2-yl (2s)-2-aminopropanoate Chemical compound CC(C)OC(=O)[C@H](C)N QDQVXVRZVCTVHE-YFKPBYRVSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229960003394 remifentanil Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- GGCSSNBKKAUURC-UHFFFAOYSA-N sufentanil Chemical compound C1CN(CCC=2SC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 GGCSSNBKKAUURC-UHFFFAOYSA-N 0.000 description 1
- 229960004739 sufentanil Drugs 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-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
- 230000008733 trauma Effects 0.000 description 1
- 206010044652 trigeminal neuralgia Diseases 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229940063674 voltaren Drugs 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4192—1,2,3-Triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- 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
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P25/06—Antimigraine agents
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having three nitrogen atoms as the only ring hetero atoms
- C07F9/6518—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/6574—Esters of oxyacids of phosphorus
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
- C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present application relates to the technical field of medicines, in particular to a class of condensed ring compounds and their compositions as active ingredients, and the use of such compounds and their compositions for preparing analgesic drugs.
- Pain is a self-protective reaction caused by tissue damage or potential tissue damage, accompanied by physiological conditions such as emotional anxiety and tension, and is a common symptom or accompanying symptom of many clinical diseases. Pain is divided into acute pain and chronic pain. Acute pain is mainly caused by surgery, severe physical trauma, etc. Chronic pain is usually caused by nociceptive pain, inflammation, neuropathic pain, migraine, etc.
- Analgesics are a class of drugs that act on the central nervous system and can effectively relieve or eliminate pain without affecting other sensations. They are of great significance in first aid.
- opioid alkaloids Opioids
- NSAIDs nonsteroidal anti-inflammatory drugs
- Opioid receptors include the classical mu, delta, kappa and nonclassical nociceptin (NOP) receptors.
- ⁇ receptor agonists have the strongest analgesic effect, but usually increase addiction and even cause respiratory depression; ⁇ receptor agonists are less addictive, but the analgesic effect is far less than ⁇ receptor agonists; The analgesic effect of receptor agonists is between the two, but it is easy to cause side effects such as hallucinations, mydriasis, and irritability.
- the current mainstream opioid receptor agonists mainly include morphine, oxycodone, fentanyl, sufentanil, remifentanil, and methadone. Worryingly, the current abuse of opioids has also led researchers to expand into new research directions, but most of them are in the early clinical stage.
- Antipyretic and analgesic drugs are a class of drugs that can relieve fever and relieve local pain. They exert antipyretic and analgesic effects by inhibiting the synthesis and release of prostaglandins (PGs) in the hypothalamus, and usually have anti-inflammatory effects. These drugs are better for local pain, neuralgia, joint pain, menstrual pain and other dull pain, but less effective for other kinds of pain. At present, the commonly used ones are: aspirin, ibuprofen, voltaren, and chinoli, etc., but the use of such drugs needs to be considered in different situations.
- PGs prostaglandins
- Analgesics currently have relatively large side effects. Therefore, the development of high-quality analgesics is still imminent.
- the invention provides a novel condensed ring compound and its composition.
- the compound has strong stability and significant analgesic activity, and is suitable for being developed into various dosage forms.
- the compound provided by the present invention can overcome the deficiencies of the prior art, has high efficacy in vivo, has long-lasting analgesic effect, and has no obvious side effects.
- the present invention provides a compound of formula I:
- Y is selected from CH, or N;
- R 1 , R 2 , and R 3 are each independently selected from hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, Carboxyl, acetyl, formaldehyde, methylsulfonyl, ethylsulfonyl, benzyl, picolyl, C 1 - 8 alkyl, C 1 - 8 alkoxy, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6-18 aryl, C 3-12 heteroaryl; the above-mentioned alkyl , alkoxy, carbocyclyl, heterocyclyl, aryl, heteroaryl can be further optionally replaced by the following One or more groups A are substituted;
- R4 is selected from
- T is selected from O, or S;
- n is selected from 1, 2, or 3;
- R 5 and R 6 are each independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylamino, or R 5 and R 6 are connected to form a ring ;
- R 7 is selected from C 1 - 8 alkyl, C 1 - 8 alkoxy, C 1 - 8 alkylamino, C 2 - 8 alkenyl, C 2 - 8 alkynyl, C 3 - 8 carbocyclyl, C 2-8 heterocyclyl, C 6-18 aryl, C 3-12 heteroaryl; the above - mentioned alkyl , alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl
- the group and the heteroaryl group can be further optionally substituted by one or more of the following groups A;
- R 8 and R 9 are each independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylamino, or R 8 and R 9 are connected to form a ring ;
- R a and R b are each independently selected from hydrogen, C 1-8 alkyl , C 1-8 alkoxy, C 1-8 alkylamino, or R a and R b are connected to form a ring;
- R c and R d are each independently selected from hydrogen, C 1-8 alkyl , C 1-8 alkoxy, C 1-8 alkylamino, or R c and R d are connected to form a ring;
- X1 is selected from O, or N;
- R 10 is selected from C 1 - 8 alkyl, C 1 - 8 alkoxy, C 1 - 8 alkylamino, C 2 - 8 alkenyl, C 2 - 8 alkynyl, C 3 - 8 carbocyclyl, C 2-8 heterocyclyl, C 6-18 aryl, C 3-12 heteroaryl; the above - mentioned alkyl , alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl
- the group and the heteroaryl group can be further optionally substituted by one or more of the following groups A;
- R 11 is selected from hydrogen, C 1 - 8 alkyl, C 1 - 8 alkoxy, C 1 - 8 alkylamino, C 2 - 8 alkenyl, C 2 - 8 alkynyl, C 3 - 8 carbocyclyl , C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl; the above-mentioned alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl , aryl, heteroaryl can be further optionally substituted by one or more of the following groups A;
- X 2 and X 3 are each independently selected from O, NH, or S;
- R 12 and R 13 are each independently selected from hydrogen, Na, K, C 1-8 alkyl , C 1-8 alkoxy, C 1-8 alkylamino, C 2-8 alkenyl, C 2-8 Alkynyl, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl, or R 12 , R 13 are connected to form a ring; the above-mentioned alkyl, alkane Oxygen, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl can be further optionally replaced by one or more of the following hydrogen, halogen, hydroxy, hydroxymethyl, hydroxy Ethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, methoxy, ethoxy, carboxyl, acetyl, formalde
- R 14 is selected from hydrogen, C 1-8 alkyl , C 1-8 alkoxy, C 1-8 alkylamino ;
- R 15 selected from
- Z is selected from CH, or N;
- R 16 is selected from hydrogen, C 1-8 alkyl , C 1-8 alkoxy , C 1-8 alkylamino,
- R is selected from hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, cyano, trifluoromethyl, methoxy, ethoxy, isopropoxy, methyl Thio, acetyl, methylsulfonyl, ethylsulfonyl;
- R 18 is selected from C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl; the above carbocyclyl, heterocyclyl, aryl, heteroaryl
- the group can be further optionally substituted by one or more of the following groups A;
- Group A is: hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, carboxyl, acetyl, formaldehyde, Methanesulfonyl, ethylsulfonyl, phenyl, benzyl, pyridyl, picolyl, C1-8 alkyl, C1-8 alkoxy, C1-8 alkylamino.
- the compound provided by the present invention has the following structure of formula II:
- the compound provided by the present invention has the following structure of formula III:
- the compound provided by the present invention has the structure of the following formula IV:
- the compound provided by the present invention has the following structure of formula V:
- Y is selected from CH, or N;
- R is selected from hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, Cyano, trifluoromethyl, carboxyl, acetyl, formaldehyde, methylsulfonyl, ethylsulfonyl, benzyl, picolyl, C 1 - 8 alkyl, C 1 - 8 alkoxy, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl; wherein, the above-mentioned alkyl, alkoxy, carbocyclyl, heterocyclyl, aryl, Heteroaryl can be further optionally substituted by one or more of the following groups A;
- R 1 is selected from hydrogen, halogen, hydroxyl, hydroxymethyl, cyano, trifluoromethyl , C 1-8 alkyl, C 1-8 alkoxy; more preferably, R 1 is hydrogen .
- R is selected from hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, Cyano, trifluoromethyl, carboxyl, acetyl, formaldehyde, methylsulfonyl, ethylsulfonyl, benzyl, picolyl, C 1 - 8 alkyl, C 1 - 8 alkoxy, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl; wherein, the above-mentioned alkyl, alkoxy, carbocyclyl, heterocyclyl, aryl, Heteroaryl can be further optionally substituted by one or more of the following groups A;
- R is selected from hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, carboxyl, acetyl, formaldehyde Base, methylsulfonyl, ethylsulfonyl, benzyl, picolyl, C 1 - 8 alkyl, C 1 - 8 alkoxy, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl;
- R2 is selected from F, Cl, hydroxyl, hydroxyethyl, methoxy, cyano, trifluoromethyl, methylsulfonyl.
- R is selected from hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, Cyano, trifluoromethyl, carboxyl, acetyl, formaldehyde, methylsulfonyl, ethylsulfonyl, benzyl, picolyl, C 1 - 8 alkyl, C 1 - 8 alkoxy, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl; wherein, the above-mentioned alkyl, alkoxy, carbocyclyl, heterocyclyl, aryl, Heteroaryl can be further optionally substituted by one or more of the following groups A;
- R is selected from hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, carboxyl, acetyl, formaldehyde Base, methylsulfonyl, ethylsulfonyl, benzyl, picolyl, C 1 - 8 alkyl, C 1 - 8 alkoxy, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl;
- R3 is selected from hydrogen, or methyl.
- L is in
- R 5 and R 6 are each independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylamino, or R 5 and R 6 are connected to form a ring;
- R 5 and R 6 are each independently selected from hydrogen, or C 1-8 alkyl ;
- R and R are both hydrogen
- R 7 is selected from C 1 - 8 alkyl, C 1 - 8 alkoxy, C 1 - 8 alkylamino, C 2 - 8 alkenyl, C 2 - 8 alkynyl, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl; the above-mentioned alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, Aryl and heteroaryl can be further optionally substituted by one or more of the following groups A;
- R 7 is C 1 - 8 alkyl
- R 7 is selected from isopropyl or tert-butyl
- L is in
- R 8 and R 9 are each independently selected from hydrogen, C 1-8 alkyl , C 1-8 alkoxy, C 1-8 alkylamino, or R 8 and R 9 are connected to form a ring;
- R 8 and R 9 are each independently selected from hydrogen, or C 1-8 alkyl ;
- R and R are both hydrogen
- X 1 is selected from O, or N;
- X 1 is O, at this time R 11 does not exist;
- R 10 is selected from C 1 - 8 alkyl, C 1 - 8 alkoxy, C 1 - 8 alkylamino, C 2 - 8 alkenyl, C 2 - 8 alkynyl, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl; the above-mentioned alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, Aryl and heteroaryl can be further optionally substituted by one or more of the following groups A;
- R 10 is selected from C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylamino , C 2-8 alkenyl , C 2-8 alkynyl, C 3-8 carbocycle Base, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl;
- R 10 is selected from methyl, or isopropyl
- R 11 is selected from C 1 - 8 alkyl, C 1 - 8 alkoxy, C 1 - 8 alkylamino, C 2 - 8 alkenyl, C 2 - 8 alkynyl, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl; the above-mentioned alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, Aryl and heteroaryl can be further optionally substituted by one or more of the following groups A; in particular, X is N at this time;
- L is in
- R a and R b are each independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylamino, or R a and R b are connected to form a ring ;
- R a and R b are each independently selected from hydrogen, or C 1-8 alkyl ;
- R a and R b are both hydrogen;
- R c and R d are each independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylamino, or R a and R b are connected to form a ring ;
- R c and R d are each independently selected from hydrogen, or C 1-8 alkyl ;
- both R a and R b are hydrogen, or one of R a and R b is hydrogen, and the other is methyl;
- L is in
- X 2 and X 3 are each independently selected from O, NH, or S;
- X 2 and X 3 are each independently selected from O, or NH;
- R 12 and R 13 are each independently selected from hydrogen, Na, K, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylamino , C 2-8 alkenyl , C 2 - 8 alkynyl, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl, or R 12 and R 13 are connected to form a ring; wherein, the above-mentioned alkyl Alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl can be further optionally replaced by one or more of the following hydrogen, halogen, hydroxyl, methylol hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, methoxy, ethoxy, carboxyl, acetyl
- R 12 and R 13 are each independently selected from hydrogen, Na, C 1-8 alkyl, C 6-18 aryl, or R 12 and R 13 are connected to form a 5-6 membered ring;
- R 16 is selected from hydrogen, C 1-8 alkyl , C 1-8 alkoxy, C 1-8 alkylamino, or
- R 4 is in
- T is selected from O, or S;
- m is selected from 1, 2, or 3;
- m is selected from 1, or 2;
- R 14 is selected from hydrogen, C 1-8 alkyl , C 1-8 alkoxy, C 1-8 alkylamino;
- R 14 is selected from hydrogen, or C 1-8 alkyl ;
- R 14 is selected from hydrogen, methyl, or ethyl
- the above Z is selected from CH, or N;
- R is selected from hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, cyano, trifluoromethyl, methoxy, ethoxy, isopropoxy, Methylthio, acetyl, methylsulfonyl, ethylsulfonyl;
- R 17 is selected from hydroxyl, methylthio, isopropoxy, acetyl;
- R 18 is selected from C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl; the above carbocyclyl, heterocyclyl, aryl, hetero
- the aryl group can be further optionally substituted by one or more of the following groups A;
- R 18 is selected from C 5 - 6 carbocyclyl, or C 2 - 5 heterocyclyl; wherein, the above-mentioned carbocyclyl and heterocyclyl can be further optionally replaced by one or more of the following groups A replace;
- Group A is: hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, carboxyl, acetyl, formaldehyde, Methanesulfonyl, ethylsulfonyl, phenyl, benzyl, pyridyl, picolyl, C1-8 alkyl, C1-8 alkoxy, C1-8 alkylamino.
- the compound provided by the invention has the following structure:
- the present invention provides compounds comprising the above compounds, or solvates, pharmaceutically acceptable salts, enantiomers, diastereoisomers, racemic mixtures (as active compounds) Component) and the pharmaceutical composition of inert carrier.
- composition the applicable composition form comprises: injection, powder, spray, inhalant, tablet, pill, capsule, lozenge, jelly, powder, granule, gel, cream, Ointments, patches, suppositories, suspensions, syrups.
- composition wherein the active ingredient occupies a unit dose of 0.01 mg-1.0 g of the body weight of the individual in need of treatment.
- the present invention provides the use of the above-mentioned pharmaceutical composition in the preparation of medicines for treating and/or preventing related diseases or conditions.
- the related diseases or conditions include neuropathic pain, oral pain, facial pain, internal organ pain, headache, insomnia, cognitive decline, appetite disturbance, emotional disturbance, sunset syndrome, Alzheimer's disease.
- a method of treating a disease or condition comprises administering to a subject in need thereof a therapeutically effective amount of said compound or said composition.
- the compound disclosed in the invention has the function of inhibiting the deposition of ⁇ -amyloid protein.
- the compound disclosed in the present invention has more significant analgesic effect.
- the compounds disclosed in the present invention have stronger blood-brain barrier penetration and greater in vivo exposure, especially compound RE-33, which is the most excellent in the above aspects.
- amino group herein refers to a functional group having 1 nitrogen atom and 0, 1, or 2 hydrogen atoms.
- the halogen herein refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
- C1-8 alkyl refers to a straight chain, side chain or cyclic hydrocarbon group having 1 to 8 carbon atoms.
- C1-8 alkoxy refers to a straight-chain, side-chain or cyclic hydrocarbon group having 1 to 8 carbon atoms inserted into an -OH or -O- group at any reasonable position.
- C1-8 alkylamino refers to a group in which -N-, -NH-, -NH2 atomic groups are inserted at any reasonable position of "C1-8 alkyl". For example, methylamino, ethylamino, diisopropylamino, N-methyl-n-propylamino, di-n-propylamino, N-ethylisopropylamino, 2-(isopropylamino)ethyl and the like.
- C2-8 alkenyl refers to a straight chain, branched chain or cyclic hydrocarbon group containing at least one carbon-carbon double bond in a molecule having 2 to 8 carbon atoms.
- C2-8 alkynyl refers to a straight-chain, branched-chain or cyclic hydrocarbon group containing at least one carbon-carbon triple bond in a molecule having 2 to 8 carbon atoms.
- C3-8 carbocyclyl refers to a saturated or unsaturated alicyclic hydrocarbon group having 3 to 8 carbon atoms.
- the cyclic hydrocarbon group can be selected from one ring, or polycyclic fused, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopentyl, dicyclopentyl, methylcyclohexyl, ethyl Cyclohexyl, decalinyl, 3-cyclopentyl-1-propyl, 1,3-cyclohexadienyl, 1-methyl-1-cyclohexenyl, etc.
- C2-8 heterocyclic group refers to a saturated or unsaturated monocyclic or polycyclic group with at least one ring containing heteroatoms with 2 to 8 carbon atoms.
- Each ring of this type of polycyclic heterocycloalkyl group may have Different connection methods, such as fusion, bridging, spiro, etc.
- pyrrolidinyl piperidinyl, morpholinyl, homopiperazinyl, 4-pyrrolidin-1-yl-piperidinyl, 3-methylpiperidinyl, N-methylpiperidinyl, N-ethyl Piperidinyl, furyl, thienyl, pyrazolyl, oxazolyl, tetrahydro-3-thiol, 4-methyl-1-piperazineethyl, etc.
- C6-18 aryl refers to a group containing at least one aromatic ring with 6 to 18 carbon atoms.
- each ring of the polycyclic aryl group can have different connection methods, such as fused , bridging, etc., and the fused rings may be saturated or unsaturated.
- fused e.g., fused , bridging, etc.
- the fused rings may be saturated or unsaturated.
- C3-12 heteroaryl refers to a monocyclic or polycyclic aromatic heterocyclic group with 3 to 12 carbon atoms and containing at least one heteroatom, and each ring of the polycyclic heteroaryl group can have different connections , such as fused, bridged, etc., such as furyl, thienyl, imidazolyl, oxazolyl, pyridyl, pyrimidinyl, indolyl, pyrazinyl, quinolinyl, pyridazinyl, indenyl, indanyl base, benzofuryl, etc.
- the double bond-containing compounds of the present invention include all configurational isomers (such as cis and trans isomers).
- hetero atom in the present invention includes nitrogen atom, oxygen atom, phosphorus atom, boron atom, sulfur atom, selenium atom and the like.
- the compounds of the present invention possess one or more asymmetric centers and the present invention therefore relates to the use of all optical isomers and stereoisomers of these compounds and mixtures thereof. It also includes the use of compounds with tautomers and their mixtures.
- the compounds of the present invention contain basic nitrogen atoms (heterocyclic or aliphatic amino groups, etc.), and are easily oxidized by oxidants such as oxygen in the air and hydrogen peroxide to be selected from N-oxides to generate other compounds of the present invention.
- the converted N-oxide derivatives are therefore part of the group selected from the compounds of the present invention.
- each instance of a substituent is selected from the available variable definitions independently of other selections to define the variable. Accordingly, each substituent may be the same as or different from the other substituents.
- Treatment refers to the effect of significantly reversing, alleviating the symptoms of the individual's disease, or causing the reversal of the progress of the disease by administering a drug or a pharmaceutical composition to the individual.
- “Individuals in need of treatment” in the present invention refer to warm-blooded animals or cold-blooded animals, such as humans, rats, mice, rabbits, dogs, pigs, sheep, chickens, ducks, geese, cats, cows, horses, etc.
- the “compounds and their salts” mentioned in the present invention refer to the complexes formed by the combination of the compound and the corresponding acid. This property depends on the characteristics of the compound.
- the addition salt of the compound and the acid for example, an inorganic acid salt such as Hydrochloride, sulfate, hydrobromide, etc.
- Organic acid salts such as maleate, fumarate, acetate, propionate, malate, tartrate, malonate, succinate, citrate, cinnamate, mandelate , Methanesulfonate, p-toluenesulfonate, salicylate, etc.
- the “compounds and their salts” mentioned in the present invention also refer to the addition salts of the compounds and bases, salts of inorganic bases such as sodium salts, potassium salts, ammonium salts, calcium salts, magnesium salts and the like.
- Salts of organic amines such as diethylamine salts, ethylenediamine salts, meglumine salts, tromethamine salts, arginine salts, lysine salts, histidine salts, piperidine salts, etc.
- in the present invention refers to substances that help individuals to take or absorb the active substances in the pharmaceutical composition, and will not cause obvious adverse effects on patients or individuals, including glucose, disintegrants, fillers, Flavoring agent, lubricant, fatty acid ester, hydroxymethyl cellulose, stabilizer, emulsifier, colorant, starch, sodium saccharin, cellulose, etc.
- the "disease or disease” in the present invention refers to neuropathic pain, joint pain, postoperative pain, obstetrical pain, herpes zoster pain, gout, joint degeneration pain, discogenic pain, trigeminal neuralgia, intractable headache , tumor pain, angina pectoris, idiopathic chest and abdominal pain, oral pain, facial pain, internal organ pain, etc.
- the “disease or disease” mentioned in the present invention also includes insomnia, Alzheimer's disease, sunset syndrome, Parkinson's disease, memory loss, inattention, mental retardation, addiction and the like.
- composition refers to a specific amount of the compound provided by the present invention, or any product obtained directly or indirectly from the specific amount of the compound provided by the present invention.
- the compounds of the present invention can be used alone or in combination with one or more other drugs for the treatment and prevention of diseases or symptoms described by the compounds of the present invention. Combined use can have more significant curative effect.
- the compound of the present invention occupies a unit dose of 0.01 mg to 1.0 g, more preferably 0.1 mg to 0.5 g, of the body weight of an individual in need of treatment.
- Figure 1 shows the results of the analgesic test of the compounds of the present invention and TM.
- Fig. 2 shows the ⁇ -amyloid deposition inhibitory activity of the compounds of the present invention.
- Embodiment one the preparation of intermediate E
- Embodiment two the preparation of compound RE-01
- intermediate H 2.5g, 0.01mol, 1.0eq
- dichloromethane 100mL
- HOBt 1.g, 0.01mol, 1.0eq
- EDCI 1.9g , 0.01mol, 1.0eq
- intermediate E stirred at room temperature for 6 hours
- concentrated under reduced pressure washed with water (2*50mL)
- Embodiment three the preparation of compound RE-22 and compound RE-23
- Embodiment four the preparation of compound RE-24
- Embodiment five the preparation of compound RE-25
- Embodiment six the preparation of compound RE-28
- Embodiment seven the synthesis of compound TM
- Dissolve SM01 (7.5g, 45.28mmol) in a mixed solvent of acetonitrile (45mL) and water (75mL), add triethylamine (13.75g, 135.85mmol), the system exotherms, cool the reaction system to 10°C, add Boc Acetonitrile solution (15 mL) of acid anhydride (14.83 g, 67.93 mmol) was added dropwise, stirred at room temperature for 70 h, and the reaction was detected by TLC.
- Dissolve IM01 (8.88g, 38.73mmol) in dichloromethane (60mL), add benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU, 14.69g, 38.73mmol) and N,N-diisopropylethylamine (DIPEA, 13.02g, 100.7mmol), stirred for 0.5h, then added DCM solution (40mL) dissolved in SM02 (10.00g, 63.85mmol), and reacted overnight at room temperature , TLC detected that the reaction was complete.
- HBTU benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate
- DIPEA N,N-diisopropylethylamine
- IM03 (6.0 g, 17.16 mmol) was dissolved in dioxane (50 mL), and trifluoroacetic acid (TFA, 9.78 g, 85.82 mmol) was added under ice cooling, stirred overnight, and the reaction was detected by TLC.
- TFA trifluoroacetic acid
- reaction solution was concentrated to dryness to obtain a brown oil, namely the crude compound IM04 (6.5 g), which was fed to the next step according to 100% without further treatment.
- SM03 (8.08g, 29.06mmol) was dissolved in N,N-dimethylformamide (DMF, 70mL), the solution was khaki, and 1H-1,2,3-triazole (4.01g, 58.12mmol ) and cesium carbonate (18.94g, 58.12mmol), the temperature was raised to 40°C, a small amount of gas was released, and cuprous iodide (0.277g, 1.45mmol) was added, the solution gradually turned green, and the temperature rise was not obvious, and the temperature was raised to 70°C, and stirred After 1 h, TLC detected that the reaction was complete.
- DMF N,N-dimethylformamide
- IM04 (3.0g, 10.48mmol) was dissolved in dichloromethane (30mL), and IM05 (2.30g, 10.48mmol), DIPEA (6.77g, 52.40mmol), HBTU (3.98g, 10.48mmol) were added successively in an ice bath , start the reaction (as the reaction proceeds, the solution color gradually turns brownish red), the reaction is stirred overnight, and TLC detects that the reaction is complete.
- Embodiment 8 Preparation of compound RE-31
- Embodiment 9 Preparation of compound RE-32
- Embodiment 10 Preparation of compound RE-33
- Embodiment 11 Preparation of compound RE-37
- Embodiment 12 Preparation of compound RE-38
- Embodiment 14 The influence of acetic acid writhing method to measure the pain of mice
- the concentrations of the above compounds were 0.26mg/mL, 0.33mg/mL, 0.33mg/mL, 0.32mg/mL, 0.33mg/mL, 0.35mg/mL, 0.44mg/mL, 0.46mg/mL, 0.35mg/mL, 0.32mg/mL, 0.33mg/mL, 0.31mg/mL, 0.33mg/mL, 0.32mg/mL, 0.34mg/mL, 0.43mg/mL, 0.46mg/mL, 0.32mg/mL and 0.36mg/mL ( The molar concentration of each compound is the same).
- mice Sixty 18-22g female KM mice were divided into 20 groups with 3 mice in each group.
- the administration group and the TM control group were injected intraperitoneally with 0.4 mL of the newly prepared compound solution, and the model group was injected with the same volume of water for injection intraperitoneally.
- each mouse was intraperitoneally injected with 0.2 mL of 0.6% glacial acetic acid solution, and at the same time recorded the times of writhing in each mouse within 20 minutes, and calculated the average value. The result is shown in Figure 1.
- Example 15 ⁇ -amyloid deposition inhibitory activity
- Accelerated aging mice (SAMP8), 63 males (8 months old at the start of the study), were divided into 9 groups with 7 mice in each group.
- the non-intervention group drank tap water normally; experimental group 1-experimental group 8 respectively drank tap water containing compounds (RE-01, RE-23, RE-31, RE-32, RE-33, RE-37, RE-45 , RE-47) solution, the dosage is 0.1mg/kg/day.
- Sections were immunostained with streptavidin-biotin using the VECTASTATIN ABC kit. After incubation in 10% normal goat serum for one hour, the anti- ⁇ -amyloid (A ⁇ ) antibody was diluted 10-fold with PBS and incubated overnight at 4°C. The next day, wash with PBS, incubate with biotinylated anti-rabbit secondary antibody for 1.5 hours, wash with PBS, and incubate with peroxidase-labeled streptavidin for 1.5 hours. Immunoreactions were visualized and samples prepared with DAB.
- Immunoreactive A ⁇ -like granules in the hippocampus were counted under a microscope. A ⁇ -like immunoreactive granules were observed as brown deposits in the hippocampus. Each individual was counted using one slice.
- ⁇ -amyloid-like immunoreactivity in the hippocampus was observed in the untreated group of accelerated aging mice (SAMP8).
- SAMP8 accelerated aging mice
- SAM8 experimental groups 1 to 8 of accelerated aging mice
- Embodiment 16 Compound Parallel Artificial Membrane Permeation Model (PAMPA) test disclosed by the present invention
- the compound was diluted into a 25 ⁇ g/mL solution with a buffer solution with a pH of 7.4; the pig brain lipid extract (PBL) was dissolved in dodecane to form a 20 mg/mL solution as a phospholipid film; Add 4 ⁇ L of PBL solution dropwise on the vinyl fluoride membrane to form a phospholipid membrane simulating the environment in the brain; add 300 ⁇ L/well buffer solution above the phospholipid membrane as an acceptor tube, and add 150 ⁇ L/well of 25 ⁇ g/mL compound to another 96-well plate
- the solution is used as a donor tube, and each drug has three parallel holes; the two plates are stacked so that the phospholipid membrane can contact the donor solution to form a sandwich structure, and placed in a constant temperature environment at 37°C for 18 hours; the 96-hole filter plate
- the medium solution was taken out and transferred to a blank 96-well plate, and the OD value was measured at 340 nm.
- the data show that the compounds disclosed in the present invention have stronger ability to penetrate the blood-brain barrier than the reference compound TM, wherein compounds RE-31, RE-32, RE-33, RE-35, RE-38 and RE-45 pass through the blood-brain barrier
- the ability is 11 to 16 times that of TM. It shows that the compounds disclosed in the present invention can more advantageously pass through the blood-brain barrier and reach the brain, so as to more effectively play the role of treating brain diseases.
- mice 12 male SD rats, 180g-220g, were fed adaptively for 3 days before the experiment.
- Preparation of the test product Weigh the appropriate amount of the test product TM, RE-33, RE-37 and RE-38 respectively, place them in reagent bottles, add an appropriate amount of 0.5% carboxymethyl cellulose solution, and prepare TM, RE-33 , RE-37 and RE-38 concentrations are respectively 2.0mg/mL, 2.4mg/mL, 2.5mg/mL and 2.6mg/mL (molar concentration of each compound is the same) of the test solution.
- Test method Rats were randomly divided into 4 groups, including TM group, RE-33 group, RE-37 group and RE-38 group, with 3 rats in each group. Each animal was given the newly prepared corresponding test solution by gavage respectively. The dosage was 4 mg/kg in TM group, 4.8 mg/kg in RE-33 group, 5.0 mg/kg in RE-37 group and 5.2 mg/kg in RE-38 group. Fast for 16-17 hours before administration, and 4 hours after administration, and water is not allowed during the whole process.
- Observation of general clinical symptoms During the whole process of the experiment, observe the general state of the experimental animals. The observation contents include: changes in food intake and water intake of rats, changes in body weight, abnormality in coat color, abnormality in behavior and mental state, eye, Whether there are abnormal secretions in the ears, mouth and nose, and whether there is any abnormality in urine and stool. If there is an abnormality, it will be recorded immediately and the cause of the abnormality will be analyzed.
- the maximum blood drug concentration of the compounds disclosed in the present invention is more than 120%, and the exposure is more than 130% of it, especially RE-33, which is the best in terms of maximum blood drug concentration and in vivo exposure prominent, and there is no abnormality in the observation of general clinical symptoms, indicating that the compounds disclosed in the present invention have higher bioavailability.
- Embodiment 18 Rat brain tissue distribution experiment
- mice 12 male SD rats, 180g-220g, were fed adaptively for 3 days before the experiment.
- Preparation of the test product Weigh the appropriate amount of the test product TM, RE-33, RE-37 and RE-38 respectively, place them in reagent bottles, add an appropriate amount of 0.5% carboxymethyl cellulose solution, and prepare TM, RE-33 , RE-37 and RE-38 concentrations are respectively 2.0mg/mL, 2.4mg/mL, 2.5mg/mL and 2.6mg/mL (molar concentration of each compound is the same) of the test solution.
- Test method Rats were randomly divided into 4 groups, including TM group, RE-33 group, RE-37 group and RE-38 group, with 3 rats in each group. Each animal was given the newly prepared corresponding test solution by gavage respectively. The dosage is 4 mg/kg in TM group, 4.8 mg/kg in RE-33 group, 5.0 mg/kg in RE-37 group and 5.2 mg/kg in RE-38 group; Eat for 4 hours, the whole process can not help water.
- Sampling and detection Animals in each group were sacrificed 3.0 hours after intragastric administration, the brain tissue was separated, homogenized, and analyzed by LC-MS/MS to detect TM. The results are shown in the table below. The results are shown in Table 3.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Rheumatology (AREA)
- Hospice & Palliative Care (AREA)
- Anesthesiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
L'invention concerne un composé à cycle fusionné ayant une activité analgésique telle que représentée dans la formule I, ainsi que son procédé de préparation et son utilisation. Le composé a une activité analgésique remarquable, peut être développé en médicaments pour le traitement de diverses maladies telles que les symptômes de douleur et la maladie d'Alzheimer, et est également approprié pour être développé sous diverses formes posologiques.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210176037.4 | 2022-02-25 | ||
CN202210176037 | 2022-02-25 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2023160004A1 true WO2023160004A1 (fr) | 2023-08-31 |
Family
ID=86647946
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2022/129152 WO2023160004A1 (fr) | 2022-02-25 | 2022-11-02 | Composé à cycle fusionné ayant une activité analgésique, son procédé de préparation et son utilisation |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN115925699B (fr) |
WO (1) | WO2023160004A1 (fr) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN117736193A (zh) * | 2023-12-19 | 2024-03-22 | 南京知和医药科技有限公司 | 一种氘代稠环化合物及其制备方法与用途 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002028839A1 (fr) * | 2000-10-06 | 2002-04-11 | Neurogen Corporation | Derives de benzimidazole et d'indole en tant que modulateurs des recepteurs de la corticoliberine |
CN104334544A (zh) * | 2012-06-04 | 2015-02-04 | 埃科特莱茵药品有限公司 | 苯并咪唑脯氨酸衍生物 |
CN105793258A (zh) * | 2013-12-03 | 2016-07-20 | 埃科特莱茵药品有限公司 | (S)-(2-(6-氯-7-甲基-1H-苯并[d]咪唑-2-基)-2-甲基吡咯烷-1-基)(5-甲氧基-2-(2H-1,2,3-三唑-2-基)苯基)甲酮作为食欲素受体拮抗剂的结晶盐形式 |
CN105793257A (zh) * | 2013-12-03 | 2016-07-20 | 埃科特莱茵药品有限公司 | (S)-(2-(6-氯-7-甲基-1H-苯并[d]咪唑-2-基)-2-甲基吡咯啶-1-基)(5-甲氧基-2-(2H-1,2,3-三唑-2-基)苯基)甲酮的晶形及其作为食欲素受体拮抗剂的用途 |
CN105873921A (zh) * | 2013-12-04 | 2016-08-17 | 埃科特莱茵药品有限公司 | 苯并咪唑-脯氨酸衍生物的用途 |
WO2021213923A1 (fr) * | 2020-04-19 | 2021-10-28 | Idorsia Pharmaceuticals Ltd | Utilisation médicale de daridorexant |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100173941A1 (en) * | 2006-06-09 | 2010-07-08 | Astrazeneca Ab | Muscarinic Receptor Agonists that are Effective in the Treatment of Pain, Alzheimer's Disease and Schizophrenia |
CN106478502B (zh) * | 2015-08-29 | 2021-04-27 | 上海翰森生物医药科技有限公司 | 1,2,3,4-四氢异喹啉衍生物、其制备方法和应用 |
JP6768674B2 (ja) * | 2015-09-11 | 2020-10-14 | 大日本住友製薬株式会社 | 新規ベンズイミダゾール化合物およびその医薬用途 |
TWI738753B (zh) * | 2016-03-31 | 2021-09-11 | 日商武田藥品工業股份有限公司 | 雜環化合物 |
MX2018015082A (es) * | 2016-06-07 | 2019-04-22 | Jiangsu Hengrui Medicine Co | Derivado de fenilpropanamida y metodo de fabricacion y su aplicacion farmaceutica. |
US10316038B2 (en) * | 2017-01-25 | 2019-06-11 | Aclaris Therapeutics, Inc. | Pyrrolopyrimidine ITK inhibitors for treating inflammation and cancer |
-
2022
- 2022-11-02 CN CN202211366859.5A patent/CN115925699B/zh active Active
- 2022-11-02 WO PCT/CN2022/129152 patent/WO2023160004A1/fr unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002028839A1 (fr) * | 2000-10-06 | 2002-04-11 | Neurogen Corporation | Derives de benzimidazole et d'indole en tant que modulateurs des recepteurs de la corticoliberine |
CN104334544A (zh) * | 2012-06-04 | 2015-02-04 | 埃科特莱茵药品有限公司 | 苯并咪唑脯氨酸衍生物 |
CN105793258A (zh) * | 2013-12-03 | 2016-07-20 | 埃科特莱茵药品有限公司 | (S)-(2-(6-氯-7-甲基-1H-苯并[d]咪唑-2-基)-2-甲基吡咯烷-1-基)(5-甲氧基-2-(2H-1,2,3-三唑-2-基)苯基)甲酮作为食欲素受体拮抗剂的结晶盐形式 |
CN105793257A (zh) * | 2013-12-03 | 2016-07-20 | 埃科特莱茵药品有限公司 | (S)-(2-(6-氯-7-甲基-1H-苯并[d]咪唑-2-基)-2-甲基吡咯啶-1-基)(5-甲氧基-2-(2H-1,2,3-三唑-2-基)苯基)甲酮的晶形及其作为食欲素受体拮抗剂的用途 |
CN105873921A (zh) * | 2013-12-04 | 2016-08-17 | 埃科特莱茵药品有限公司 | 苯并咪唑-脯氨酸衍生物的用途 |
WO2021213923A1 (fr) * | 2020-04-19 | 2021-10-28 | Idorsia Pharmaceuticals Ltd | Utilisation médicale de daridorexant |
Also Published As
Publication number | Publication date |
---|---|
CN115925699A (zh) | 2023-04-07 |
CN115925699B (zh) | 2023-10-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9861627B2 (en) | 4-(8-methoxy-1-((1-methoxypropan-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-1 H-imidazo[4,5-C]quinolin-7-yl)-3,5-dimethylisoxazole and its use as bromodomain inhibitor | |
BRPI0805826B1 (pt) | compostos espiro-substituídos, composição farmacêutica e uso | |
WO2014183520A1 (fr) | Dérivé de miazines de tiophène, son procédé de préparation et ses applications médicales | |
US11453642B2 (en) | Oxygenated amino- or ammonium-containing sulfonic acid, phosphonic acid and carboxylic acid derivatives and their medical use | |
JP2021527112A (ja) | ニューロキニン−1受容体アンタゴニストとしての化合物およびその使用 | |
JP6107650B2 (ja) | テトラヒドロカルボリン誘導体 | |
JP2020506878A (ja) | Trek(twik関連kチャネル)チャネルのアクチベータ | |
TW201625620A (zh) | 作為蛋白去乙醯酶抑制劑及雙蛋白去乙醯酶蛋白激酶抑制劑之雜環氧肟酸及其使用方法 | |
WO2018103626A1 (fr) | Dérivé d'alloprégnénolone soluble dans l'eau et son utilisation | |
WO2023160004A1 (fr) | Composé à cycle fusionné ayant une activité analgésique, son procédé de préparation et son utilisation | |
JP2004501136A (ja) | Nmda受容体の選択的拮抗薬としてのアミジン誘導体 | |
WO2021078227A1 (fr) | Dérivé d'hétéroaryle fusionné, son procédé de préparation et son utilisation en médecine | |
CN110256408B (zh) | 一种二芳基吡唑化合物及包含该化合物的组合物及其用途 | |
JP2023535692A (ja) | 腸内分解性共薬、その調製及び使用 | |
WO2020191283A1 (fr) | Formes cristallines et amorphes de la n-(5-((4-éthylpipérazine-1-yl)méthyl)pyridine-2-yl)-5-fluoro-4-(3-isopropyl-2-méthyl-2h-indazol-5-yl)pyrimidine-2-amine et ses sels, ainsi que ses procédés de préparation et ses méthodes d'utilisations thérapeutiques | |
JP2022517396A (ja) | Egfr阻害剤の塩、結晶形及びその製造方法 | |
US20170007610A1 (en) | Novel heterobicyclic compounds as kappa opioid agonists | |
JPH08504441A (ja) | アザノルアダマンタン | |
WO2019134510A1 (fr) | Composé de sel d'ammonium quaternaire de peptide court et son utilisation | |
ES2672326T3 (es) | Analogos de tiazolidinona deuterados como agonistas para el receptor de la hormona folículo estimulante | |
TW202328073A (zh) | Ep4拮抗劑化合物及其鹽、多晶型及其製備方法和用途 | |
JP2002155080A (ja) | ヒドラジド誘導体を有効成分とする医薬 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22928266 Country of ref document: EP Kind code of ref document: A1 |