SK75999A3 - 3-pyridyl enantiomers and their use as analgesics - Google Patents

Info

Publication number

SK75999A3

SK75999A3 SK759-99A SK75999A SK75999A3 SK 75999 A3 SK75999 A3 SK 75999A3 SK 75999 A SK75999 A SK 75999A SK 75999 A3 SK75999 A3 SK 75999A3

Authority

SK

Slovakia

Prior art keywords

compound

group

ethenyl

azetidine

mmol

Prior art date

1996-12-10

Links

• Espacenet
• Global Dossier
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• 239000000730 antalgic agent Substances 0.000 title abstract description 17
• 229940035676 analgesics Drugs 0.000 title abstract description 11
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 396
• 238000000034 method Methods 0.000 claims abstract description 128
• 208000002193 Pain Diseases 0.000 claims abstract description 64
• 230000036407 pain Effects 0.000 claims abstract description 59
• 238000011282 treatment Methods 0.000 claims abstract description 52
• 150000003839 salts Chemical class 0.000 claims abstract description 41
• 241000124008 Mammalia Species 0.000 claims abstract description 9
• 230000016273 neuron death Effects 0.000 claims abstract description 4
• 229910052739 hydrogen Inorganic materials 0.000 claims description 297
• 239000000203 mixture Substances 0.000 claims description 135
• 229910052799 carbon Inorganic materials 0.000 claims description 131
• 229910052757 nitrogen Inorganic materials 0.000 claims description 131
• -1 azetidinylmethoxy Chemical group 0.000 claims description 92
• JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 80
• 229910052801 chlorine Inorganic materials 0.000 claims description 76
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 68
• 239000002243 precursor Substances 0.000 claims description 57
• 229910052731 fluorine Inorganic materials 0.000 claims description 53
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 50
• 229910052794 bromium Inorganic materials 0.000 claims description 49
• 230000000694 effects Effects 0.000 claims description 46
• 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 claims description 40
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 39
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 20
• 229960005181 morphine Drugs 0.000 claims description 20
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 19
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 16
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 15
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 13
• 238000002360 preparation method Methods 0.000 claims description 13
• HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 12
• 230000008569 process Effects 0.000 claims description 12
• 239000002253 acid Substances 0.000 claims description 11
• 239000003795 chemical substances by application Substances 0.000 claims description 10
• CKLJMWTZIZZHCS-UWTATZPHSA-N D-aspartic acid Chemical compound OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 claims description 9
• 239000002585 base Substances 0.000 claims description 9
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 9
• 206010061218 Inflammation Diseases 0.000 claims description 8
• VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 8
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
• 230000004054 inflammatory process Effects 0.000 claims description 8
• 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 8
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
• UOWHCAKKYIRMSX-UHFFFAOYSA-N [N].C1CNC1 Chemical compound [N].C1CNC1 UOWHCAKKYIRMSX-UHFFFAOYSA-N 0.000 claims description 7
• 239000003638 chemical reducing agent Substances 0.000 claims description 7
• IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 7
• 150000002148 esters Chemical class 0.000 claims description 7
• 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims description 7
• 230000002829 reductive effect Effects 0.000 claims description 7
• 229910052727 yttrium Inorganic materials 0.000 claims description 7
• 239000008194 pharmaceutical composition Substances 0.000 claims description 6
• 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 5
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 5
• AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 claims description 5
• 150000001408 amides Chemical class 0.000 claims description 5
• SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 5
• 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 5
• 239000012442 inert solvent Substances 0.000 claims description 5
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
• 125000001424 substituent group Chemical group 0.000 claims description 5
• 125000006678 phenoxycarbonyl group Chemical group 0.000 claims description 4
• 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
• CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 claims description 3
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
• 125000000129 anionic group Chemical group 0.000 claims description 3
• 229960005261 aspartic acid Drugs 0.000 claims description 3
• AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 claims description 3
• 238000003776 cleavage reaction Methods 0.000 claims description 3
• 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
• 150000004678 hydrides Chemical class 0.000 claims description 3
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
• 239000012038 nucleophile Substances 0.000 claims description 3
• 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 3
• 230000007017 scission Effects 0.000 claims description 3
• KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
• VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
• PSZYNBSKGUBXEH-UHFFFAOYSA-M naphthalene-1-sulfonate Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-M 0.000 claims description 2
• MKTAGSRKQIGEBH-SSDOTTSWSA-N tebanicline Chemical compound C1=NC(Cl)=CC=C1OC[C@@H]1NCC1 MKTAGSRKQIGEBH-SSDOTTSWSA-N 0.000 claims description 2
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
• 125000005490 tosylate group Chemical group 0.000 claims description 2
• VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
• 150000003512 tertiary amines Chemical class 0.000 claims 6
• WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 claims 4
• 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims 4
• 229910010082 LiAlH Inorganic materials 0.000 claims 3
• SPRIOUNJHPCKPV-UHFFFAOYSA-N hydridoaluminium Chemical compound [AlH] SPRIOUNJHPCKPV-UHFFFAOYSA-N 0.000 claims 3
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims 2
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims 2
• 150000001539 azetidines Chemical class 0.000 claims 2
• 239000004202 carbamide Substances 0.000 claims 2
• 150000002081 enamines Chemical class 0.000 claims 2
• 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 2
• 150000003571 thiolactams Chemical class 0.000 claims 2
• 238000006477 desulfuration reaction Methods 0.000 claims 1
• 230000002401 inhibitory effect Effects 0.000 claims 1
• 238000005978 reductive desulfurization reaction Methods 0.000 claims 1
• 230000003110 anti-inflammatory effect Effects 0.000 abstract description 6
• 239000002260 anti-inflammatory agent Substances 0.000 abstract description 3
• 229940121363 anti-inflammatory agent Drugs 0.000 abstract description 3
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 371
• 238000005481 NMR spectroscopy Methods 0.000 description 202
• 239000000460 chlorine Substances 0.000 description 197
• 239000000243 solution Substances 0.000 description 186
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 181
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 169
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 152
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 103
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 102
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 101
• 238000004458 analytical method Methods 0.000 description 94
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 85
• 239000007787 solid Substances 0.000 description 84
• 239000000741 silica gel Substances 0.000 description 83
• 229910002027 silica gel Inorganic materials 0.000 description 83
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 78
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 76
• 239000000047 product Substances 0.000 description 75
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 73
• 239000002904 solvent Substances 0.000 description 71
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 67
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 67
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 56
• 239000003921 oil Substances 0.000 description 55
• 235000019198 oils Nutrition 0.000 description 55
• 238000006243 chemical reaction Methods 0.000 description 50
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 46
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 42
• 239000011541 reaction mixture Substances 0.000 description 41
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 39
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 38
• 239000000284 extract Substances 0.000 description 37
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 35
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 35
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
• 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 description 30
• 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 description 29
• 235000019441 ethanol Nutrition 0.000 description 28
• 230000004044 response Effects 0.000 description 28
• 229920006395 saturated elastomer Polymers 0.000 description 28
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 28
• 239000012458 free base Substances 0.000 description 27
• 238000012360 testing method Methods 0.000 description 26
• 239000012267 brine Substances 0.000 description 24
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 24
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
• 239000012043 crude product Substances 0.000 description 22
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
• 241001465754 Metazoa Species 0.000 description 21
• QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 20
• 239000012230 colorless oil Substances 0.000 description 20
• 238000003756 stirring Methods 0.000 description 19
• KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 18
• OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 18
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
• 238000004587 chromatography analysis Methods 0.000 description 17
• 239000000543 intermediate Substances 0.000 description 17
• 239000011734 sodium Substances 0.000 description 17
• 229920002554 vinyl polymer Polymers 0.000 description 17
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 16
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
• 230000000875 corresponding effect Effects 0.000 description 16
• NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 16
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
• 239000003446 ligand Substances 0.000 description 15
• ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 15
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 14
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 14
• 239000012298 atmosphere Substances 0.000 description 14
• 210000004027 cell Anatomy 0.000 description 14
• 239000007924 injection Substances 0.000 description 14
• 238000002347 injection Methods 0.000 description 14
• 239000012044 organic layer Substances 0.000 description 14
• QVHJQCGUWFKTSE-YFKPBYRVSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound OC(=O)[C@H](C)NC(=O)OC(C)(C)C QVHJQCGUWFKTSE-YFKPBYRVSA-N 0.000 description 13
• CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 13
• 230000000202 analgesic effect Effects 0.000 description 13
• FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 13
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 13
• 229940002612 prodrug Drugs 0.000 description 13
• 239000000651 prodrug Substances 0.000 description 13
• 238000000746 purification Methods 0.000 description 13
• AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 13
• 239000011780 sodium chloride Substances 0.000 description 13
• 239000000725 suspension Substances 0.000 description 13
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 12
• 229930040373 Paraformaldehyde Natural products 0.000 description 12
• 241000700159 Rattus Species 0.000 description 12
• IADUEWIQBXOCDZ-UHFFFAOYSA-N azetidine-2-carboxylic acid Chemical compound OC(=O)C1CCN1 IADUEWIQBXOCDZ-UHFFFAOYSA-N 0.000 description 12
• 230000027455 binding Effects 0.000 description 12
• 229940079593 drug Drugs 0.000 description 12
• 239000003814 drug Substances 0.000 description 12
• 239000001257 hydrogen Substances 0.000 description 12
• 229910052763 palladium Inorganic materials 0.000 description 12
• 229920002866 paraformaldehyde Polymers 0.000 description 12
• LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 12
• WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 11
• 239000008346 aqueous phase Substances 0.000 description 11
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 11
• 238000001727 in vivo Methods 0.000 description 11
• 208000004296 neuralgia Diseases 0.000 description 11
• 239000007858 starting material Substances 0.000 description 11
• 239000003039 volatile agent Substances 0.000 description 11
• GRFNBEZIAWKNCO-UHFFFAOYSA-N 3-pyridinol Chemical compound OC1=CC=CN=C1 GRFNBEZIAWKNCO-UHFFFAOYSA-N 0.000 description 10
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 10
• RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 10
• 239000000706 filtrate Substances 0.000 description 10
• 238000010438 heat treatment Methods 0.000 description 10
• 239000000463 material Substances 0.000 description 10
• 239000002609 medium Substances 0.000 description 10
• 208000021722 neuropathic pain Diseases 0.000 description 10
• 239000000843 powder Substances 0.000 description 10
• 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 10
• DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
• 230000015572 biosynthetic process Effects 0.000 description 9
• 239000003054 catalyst Substances 0.000 description 9
• 238000001914 filtration Methods 0.000 description 9
• 210000002683 foot Anatomy 0.000 description 9
• UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 9
• 230000009467 reduction Effects 0.000 description 9
• 238000006722 reduction reaction Methods 0.000 description 9
• IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 9
• 239000012414 tert-butyl nitrite Substances 0.000 description 9
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