TWI342210B - 2-aminobenzoyl derivatives - Google Patents
2-aminobenzoyl derivatives Download PDFInfo
- Publication number
- TWI342210B TWI342210B TW093118235A TW93118235A TWI342210B TW I342210 B TWI342210 B TW I342210B TW 093118235 A TW093118235 A TW 093118235A TW 93118235 A TW93118235 A TW 93118235A TW I342210 B TWI342210 B TW I342210B
- Authority
- TW
- Taiwan
- Prior art keywords
- group
- hydrogen
- compound
- pharmaceutically acceptable
- decyl
- Prior art date
Links
- -1 2-aminobenzoyl Chemical class 0.000 title claims description 19
- 150000001875 compounds Chemical class 0.000 claims description 31
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 20
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 9
- 238000009472 formulation Methods 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 150000002431 hydrogen Chemical group 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- 208000018737 Parkinson disease Diseases 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- SFDJOSRHYKHMOK-UHFFFAOYSA-N nitramide Chemical compound N[N+]([O-])=O SFDJOSRHYKHMOK-UHFFFAOYSA-N 0.000 claims description 4
- 239000003755 preservative agent Substances 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 125000005015 aryl alkynyl group Chemical group 0.000 claims description 3
- 125000006612 decyloxy group Chemical group 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000003995 emulsifying agent Substances 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- MHZGKXUYDGKKIU-UHFFFAOYSA-N Decylamine Chemical compound CCCCCCCCCCN MHZGKXUYDGKKIU-UHFFFAOYSA-N 0.000 claims description 2
- 229940035676 analgesics Drugs 0.000 claims description 2
- 239000000730 antalgic agent Substances 0.000 claims description 2
- 125000005018 aryl alkenyl group Chemical group 0.000 claims description 2
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- 238000013270 controlled release Methods 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 claims description 2
- 229940125723 sedative agent Drugs 0.000 claims description 2
- 239000000932 sedative agent Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000003381 stabilizer Substances 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims 1
- 238000005235 decoking Methods 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 230000000069 prophylactic effect Effects 0.000 claims 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 17
- 230000000694 effects Effects 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- HCZHHEIFKROPDY-UHFFFAOYSA-N kynurenic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC(=O)C2=C1 HCZHHEIFKROPDY-UHFFFAOYSA-N 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- YGPSJZOEDVAXAB-UHFFFAOYSA-N kynurenine Chemical compound OC(=O)C(N)CC(=O)C1=CC=CC=C1N YGPSJZOEDVAXAB-UHFFFAOYSA-N 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 10
- 208000035475 disorder Diseases 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 239000003981 vehicle Substances 0.000 description 8
- PLRACCBDVIHHLZ-UHFFFAOYSA-N 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Chemical compound C1N(C)CCC(C=2C=CC=CC=2)=C1 PLRACCBDVIHHLZ-UHFFFAOYSA-N 0.000 description 7
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 7
- 101001135571 Mus musculus Tyrosine-protein phosphatase non-receptor type 2 Proteins 0.000 description 7
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 7
- VCKPUUFAIGNJHC-UHFFFAOYSA-N 3-hydroxykynurenine Chemical compound OC(=O)C(N)CC(=O)C1=CC=CC(O)=C1N VCKPUUFAIGNJHC-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 6
- 206010036790 Productive cough Diseases 0.000 description 6
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229910052707 ruthenium Inorganic materials 0.000 description 6
- 208000024794 sputum Diseases 0.000 description 6
- 210000003802 sputum Anatomy 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000033001 locomotion Effects 0.000 description 5
- 210000003141 lower extremity Anatomy 0.000 description 5
- 208000015122 neurodegenerative disease Diseases 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 4
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 4
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 4
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 208000006011 Stroke Diseases 0.000 description 4
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 4
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 230000003492 excitotoxic effect Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000004770 neurodegeneration Effects 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- 229940116269 uric acid Drugs 0.000 description 4
- 208000024827 Alzheimer disease Diseases 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- 241000282414 Homo sapiens Species 0.000 description 3
- 108010068073 Kynurenine-oxoglutarate transaminase Proteins 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 239000001110 calcium chloride Substances 0.000 description 3
- 229910001628 calcium chloride Inorganic materials 0.000 description 3
- 235000011148 calcium chloride Nutrition 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 208000015114 central nervous system disease Diseases 0.000 description 3
- QWJNFFYFEKXZBF-UHFFFAOYSA-N cyanocyanamide Chemical compound N#CNC#N QWJNFFYFEKXZBF-UHFFFAOYSA-N 0.000 description 3
- 206010015037 epilepsy Diseases 0.000 description 3
- 231100000063 excitotoxicity Toxicity 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 210000001320 hippocampus Anatomy 0.000 description 3
- 201000001881 impotence Diseases 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 208000020016 psychiatric disease Diseases 0.000 description 3
- 208000019116 sleep disease Diseases 0.000 description 3
- 239000002689 soil Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 230000002485 urinary effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- WJXSWCUQABXPFS-UHFFFAOYSA-N 3-hydroxyanthranilic acid Chemical compound NC1=C(O)C=CC=C1C(O)=O WJXSWCUQABXPFS-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- 241000282465 Canis Species 0.000 description 2
- 201000010374 Down Syndrome Diseases 0.000 description 2
- 206010056438 Growth hormone deficiency Diseases 0.000 description 2
- 208000023105 Huntington disease Diseases 0.000 description 2
- 208000013016 Hypoglycemia Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- YGPSJZOEDVAXAB-QMMMGPOBSA-N L-kynurenine Chemical compound OC(=O)[C@@H](N)CC(=O)C1=CC=CC=C1N YGPSJZOEDVAXAB-QMMMGPOBSA-N 0.000 description 2
- 102000016267 Leptin Human genes 0.000 description 2
- 108010092277 Leptin Proteins 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 208000019695 Migraine disease Diseases 0.000 description 2
- 208000005314 Multi-Infarct Dementia Diseases 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- 208000028017 Psychotic disease Diseases 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 206010044688 Trisomy 21 Diseases 0.000 description 2
- 201000004810 Vascular dementia Diseases 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 229960005261 aspartic acid Drugs 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 230000019771 cognition Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000002124 endocrine Effects 0.000 description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 2
- 230000035558 fertility Effects 0.000 description 2
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 208000031424 hyperprolactinemia Diseases 0.000 description 2
- 230000002218 hypoglycaemic effect Effects 0.000 description 2
- 208000026278 immune system disease Diseases 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 2
- 229940039781 leptin Drugs 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 206010027599 migraine Diseases 0.000 description 2
- 230000001613 neoplastic effect Effects 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 230000000384 rearing effect Effects 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 230000008733 trauma Effects 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- VIYKYVYAKVNDPS-HKGPVOKGSA-N (2s)-2-azanyl-3-[3,4-bis(oxidanyl)phenyl]propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1.OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 VIYKYVYAKVNDPS-HKGPVOKGSA-N 0.000 description 1
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical group NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 description 1
- PFYJDRSQYMPDDE-UHFFFAOYSA-N 1-azidooxydecane Chemical compound N(=[N+]=[N-])OCCCCCCCCCC PFYJDRSQYMPDDE-UHFFFAOYSA-N 0.000 description 1
- LOTKRQAVGJMPNV-UHFFFAOYSA-N 1-fluoro-2,4-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C([N+]([O-])=O)=C1 LOTKRQAVGJMPNV-UHFFFAOYSA-N 0.000 description 1
- IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 description 1
- ZHWBVLQKHJDBLI-UHFFFAOYSA-N 2,4-dinitro-9h-fluorene Chemical compound C1C2=CC=CC=C2C2=C1C=C([N+](=O)[O-])C=C2[N+]([O-])=O ZHWBVLQKHJDBLI-UHFFFAOYSA-N 0.000 description 1
- KVGYXTGNRLNIPY-UHFFFAOYSA-N 2-amino-1,7-dihydropurin-6-one 7,9-dihydro-3H-purine-2,6,8-trione Chemical compound N1C(=O)NC=2NC(=O)NC2C1=O.N1C(N)=NC=2N=CNC2C1=O KVGYXTGNRLNIPY-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical group NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 description 1
- 206010002027 Amyotrophy Diseases 0.000 description 1
- 241000272525 Anas platyrhynchos Species 0.000 description 1
- 240000006439 Aspergillus oryzae Species 0.000 description 1
- 235000002247 Aspergillus oryzae Nutrition 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- 206010063094 Cerebral malaria Diseases 0.000 description 1
- 208000019888 Circadian rhythm sleep disease Diseases 0.000 description 1
- 208000006561 Cluster Headache Diseases 0.000 description 1
- 244000241257 Cucumis melo Species 0.000 description 1
- 235000015510 Cucumis melo subsp melo Nutrition 0.000 description 1
- 206010048843 Cytomegalovirus chorioretinitis Diseases 0.000 description 1
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 1
- 208000027534 Emotional disease Diseases 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 208000014770 Foot disease Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 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
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010020850 Hyperthyroidism Diseases 0.000 description 1
- 206010021639 Incontinence Diseases 0.000 description 1
- 206010062717 Increased upper airway secretion Diseases 0.000 description 1
- 102000006541 Ionotropic Glutamate Receptors Human genes 0.000 description 1
- 108010008812 Ionotropic Glutamate Receptors Proteins 0.000 description 1
- 208000001456 Jet Lag Syndrome Diseases 0.000 description 1
- RNXYXIKLWRRZNU-UHFFFAOYSA-N Kynuramine Natural products NCCCC(=O)C1=CC=CC=N1 RNXYXIKLWRRZNU-UHFFFAOYSA-N 0.000 description 1
- 108010031676 Kynureninase Proteins 0.000 description 1
- 102100037652 Kynurenine 3-monooxygenase Human genes 0.000 description 1
- 108010033242 Kynurenine 3-monooxygenase Proteins 0.000 description 1
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 1
- 229920004011 Macrolon® Polymers 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N N-acetyl-para-amino-phenol Natural products CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- BYHJHXPTQMMKCA-QMMMGPOBSA-N N-formyl-L-kynurenine Chemical compound [O-]C(=O)[C@@H]([NH3+])CC(=O)C1=CC=CC=C1NC=O BYHJHXPTQMMKCA-QMMMGPOBSA-N 0.000 description 1
- 208000037212 Neonatal hypoxic and ischemic brain injury Diseases 0.000 description 1
- 208000036110 Neuroinflammatory disease Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- 235000005764 Theobroma cacao ssp. cacao Nutrition 0.000 description 1
- 235000005767 Theobroma cacao ssp. sphaerocarpum Nutrition 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- 238000010162 Tukey test Methods 0.000 description 1
- 206010046543 Urinary incontinence Diseases 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
- 230000000648 anti-parkinson Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 229940125688 antiparkinson agent Drugs 0.000 description 1
- 239000000939 antiparkinson agent Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 125000001204 arachidyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000036983 biotransformation Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 235000001046 cacaotero Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000004706 cardiovascular dysfunction Effects 0.000 description 1
- 230000001925 catabolic effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 208000018912 cluster headache syndrome Diseases 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 208000001763 cytomegalovirus retinitis Diseases 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 210000001787 dendrite Anatomy 0.000 description 1
- 208000002925 dental caries Diseases 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000002461 excitatory amino acid Effects 0.000 description 1
- 239000003257 excitatory amino acid Substances 0.000 description 1
- 231100000318 excitotoxic Toxicity 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002518 glial effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000004295 hippocampal neuron Anatomy 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N hydroxylamine group Chemical group NO AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 208000033915 jet lag type circadian rhythm sleep disease Diseases 0.000 description 1
- 230000009191 jumping Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- QLPVTIQQFGWSQQ-UHFFFAOYSA-N kynuramine Chemical compound NCCC(=O)C1=CC=CC=C1N QLPVTIQQFGWSQQ-UHFFFAOYSA-N 0.000 description 1
- 102000005447 kynureninase Human genes 0.000 description 1
- 230000006742 locomotor activity Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000002175 menstrual effect Effects 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 210000000933 neural crest Anatomy 0.000 description 1
- 230000003959 neuroinflammation Effects 0.000 description 1
- 230000003961 neuronal insult Effects 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- JOUIQRNQJGXQDC-ZYUZMQFOSA-L nicotinate D-ribonucleotide(2-) Chemical compound O1[C@H](COP([O-])([O-])=O)[C@@H](O)[C@@H](O)[C@@H]1[N+]1=CC=CC(C([O-])=O)=C1 JOUIQRNQJGXQDC-ZYUZMQFOSA-L 0.000 description 1
- 108090000277 nicotinate-nucleotide diphosphorylase (carboxylating) Proteins 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940127240 opiate Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- PXBFMLJZNCDSMP-UHFFFAOYSA-N ortho-aminobenzoylamine Natural products NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 238000012402 patch clamp technique Methods 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 208000033300 perinatal asphyxia Diseases 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 208000026435 phlegm Diseases 0.000 description 1
- 208000006155 precocious puberty Diseases 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- FGVVTMRZYROCTH-UHFFFAOYSA-N pyridine-2-thiol N-oxide Chemical group [O-][N+]1=CC=CC=C1S FGVVTMRZYROCTH-UHFFFAOYSA-N 0.000 description 1
- GJAWHXHKYYXBSV-UHFFFAOYSA-N quinolinic acid Chemical compound OC(=O)C1=CC=CN=C1C(O)=O GJAWHXHKYYXBSV-UHFFFAOYSA-N 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000001932 seasonal effect Effects 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000016978 synaptic transmission, cholinergic Effects 0.000 description 1
- 230000024587 synaptic transmission, glutamatergic Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001519 thymoleptic effect Effects 0.000 description 1
- 238000010415 tidying Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- 230000008736 traumatic injury Effects 0.000 description 1
- KCOSVQHBILQVFB-UHFFFAOYSA-N trimethyl-[[3-[3-[(trimethylammonio)methyl]phenyl]azophenyl]methyl]ammonium Chemical compound C[N+](C)(C)CC1=CC=CC(N=NC=2C=C(C[N+](C)(C)C)C=CC=2)=C1 KCOSVQHBILQVFB-UHFFFAOYSA-N 0.000 description 1
- 125000000430 tryptophan group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- FBZONXHGGPHHIY-UHFFFAOYSA-N xanthurenic acid Chemical compound C1=CC=C(O)C2=NC(C(=O)O)=CC(O)=C21 FBZONXHGGPHHIY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
-
- 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
- A61K31/13—Amines
- A61K31/132—Amines having two or more amino groups, e.g. spermidine, putrescine
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/18—Feminine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/22—Anxiolytics
-
- 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
- A61P25/26—Psychostimulants, e.g. nicotine, ***e
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- 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]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
- C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
- C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Pain & Pain Management (AREA)
- Hematology (AREA)
- Heart & Thoracic Surgery (AREA)
- Psychiatry (AREA)
- Gynecology & Obstetrics (AREA)
- Urology & Nephrology (AREA)
- Cardiology (AREA)
- Ophthalmology & Optometry (AREA)
- Epidemiology (AREA)
- Obesity (AREA)
- Addiction (AREA)
- Anesthesiology (AREA)
- Rheumatology (AREA)
- Child & Adolescent Psychology (AREA)
- Immunology (AREA)
- Emergency Medicine (AREA)
- Pregnancy & Childbirth (AREA)
- Dermatology (AREA)
- Vascular Medicine (AREA)
Description
1342210 六、發明說明： 【發明所屬之技術領域】 本發明係有關新賴2-胺基笨甲酿基衍生物，含有彼等 的藥學調配物，與該等化合物在治療或預防多種疾病所用 醫藥品的製造中之用途。 【先前技術】 本發明係概括地有關新穎化合物，彼等在治療中的用 途，及含有彼等的藥學調配物。 胺基酸色胺酸會在生物體内透過”犬尿胺酸途徑 (kynurenine pathway)，，生物地轉化(Beadle, G. W.，Mitchell，H. K.，and Nyc，J. F.，Proc. Nat，Acad. SC” 33, 155 (1948);參閱
Charles Heidelberger, Mary E. Gullberg, Agnes Fay Morgan, and Samuel Lepkovsky TRYPTOPHAN METABOLISM. I. CONCERNING THE MECHANISM OF THE MAMMALIAN CONVERSION OF TRYPTOPHAN INTO KYNURENINE, KYNURENIC ACID, AND NICOTINIC ACID. J. Biol. Chem. (1949) 179:143-150)。所有食物色胺酸 中超過95%會代謝成為犬尿胺酸（w〇lf, Η. - Studies on tryptophan metabolism in man. Scand J Clin Lab Invest 136(suppL): 1-186, 1974)。於周圍組織，特別是肝内，色胺 酸的，咕環會被色胺酸二加氧酶（tryptophan dioxgenase)或 σ引0朵胺 2,3-二加氧酶（indoleamine 2,3-dioxgenase)任一者所 改質，導致甲醯基犬尿胺酸的形成。之後，犬尿胺酸甲醯 基轉移酶(kynurenine formylase)迅速將甲醯基犬尿胺酸轉化 4 成L-犬尿胺酸，其為犬尿胺酸途徑的關鍵化合物（w, Eugene Knox and Alan H. Mehler THE CONVERSION OF TRYPTOPHAN TO KYNURENINE IN LIVER. I. THE COUPLED TRYPTOPHAN PEROXIDASE-OXIDASE SYSTEM FORMING FORMYL KYNURENINE J. Biol. Chem. (1950) 187:419-430)。L-犬尿胺酸係以低濃度存在於 血液、腦和周圍器官之中且其可以透過大型中性胺基酸載 體容易地穿過血-腦障壁(the blood-brain 犬尿胺酸 於哺乳動物組織内係由三種不同的酵素予以新陳代謝：犬 尿胺酸3-經化酶(kynurenine 3-hydroxylase)，其形成3-經基 犬尿胺酸（3-hydroxy-kynurenine) (3-HK);犬尿胺酸酶 (kynureninase)，其形成鄰胺基笨曱酸(anthranilicacid);與犬 尿胺酸胺基轉移酶（kynurenine aminotransferase) (KAT)，其 促成犬尿喹琳酸(kynurenic acid)之形成。3-HK會由相同的 KAT代謝而產生黃尿酸(xanthurenic acid)，為該途徑中一種 在新陳代謝上惰性之副產物；或由犬尿胺酸酶代謝而得3-經基鄰胺基苯曱酸(3-hydroxyanthranilic acid)，其於最終會 轉化成為°比°定-2,3-二缓酸(quinolinic acid)。最後，D比咬-2,3-二竣酸為°比咬-2,3-二竣S交鱗S曼核糖基轉移酶(quinolinic acid phosphoribosyltransferase)所代謝而產生於驗酸單核苷酸 (nicotinic acid mononucleotide)，及隨後的降解產物包括終端 產物NAD+ 〇 犬尿胺酸、3-羥基犬尿胺酸和吡咬-2,3-二羧酸都是 此分解代謝級聯(catabolic cascade)的神經活性中間產物。3- 1342210
羥基犬尿胺酸為一種自由基產生劑，其業經證明會引起細 胞洞亡(apoptosis)的誘導、興奮性毒性(excit〇t〇xicity)的增 強、白内障形成、神經變性疾病、中風、創傷性受傷、神 經病毒性疾病和神經發炎。吡啶_2,3·二羧酸為一種N-甲基 天冬胺酸(N-methyl-D-aspartate) (NMDA)受體激動劑和 自由基產生劑，且因此其可能引起興奮性毒性、神經變性 疾病、中風、創傷性腦受傷、癲癇、腦型瘧、周產期低氧 血症(perinatalhypoxia)、神經病毒性疾病和神經發炎。内源 性吡咬-2,3-二羧酸可能導致nmda受體活化而促進興奮性 毒性和神經毒性而導致由NMDA受體所媒介的生理學和病 理學程序。於三種神經活性犬尿胺酸中，犬尿喹啉酸(KYNa) 已經在最近受到最大的注意。二十年前首先被述及為神經 抑制性化合物’ KYNA ’於非生理的高濃度之下，為一種· 離子移變性榖胺酸受體(ionotropic glutamate receptors)的廣
效性枯抗劑。问>辰度的KYNA為抗痛擎劑η可提供對(¾卷 性毒性傷害的優良保護作用。於遠較為低的濃度之下， KYNA可作為NMDA受體的甘胺酸共激動性部位之競爭性 阻斷劑且可作為私驗酸乙醯膽驗受體的非競爭性抑制 劑。從ΚΥΝΑ對此兩種Ca2+-可穿透性受體的親和度係在人 類腦内的KYNA含量範圍内且相當地接近嚅齒動物腦的 (較低)KYNA含量之事實可推測出在榖胺酸能性 (glutamatergic)和膽鹼能性(cholinergic)神經傳遞中的生理功 能。對於此種作用的直接支持也已經有提供者，例如，經 由在大鼠紋狀體(striatum)内的活體内(in vivo)研究所提出 6 者，其中KYNA含量的減低會增進對興奮性毒性傷害的易 傷性且，相反地，將ΚΥΝΑ輕微增多會抑制榖胺酸的釋放 (Schwarcz R, Pellicciari R. Manipulation of brain kynurenines· glial targets, neuronal effects, and clinical opportunities. J Pharmacol Exp Ther. 2002 : 303:1-10) 〇 由於犬尿胺酸業經推測不僅會參與神經變性失調 症和發作性失調症，而且也在大多數於病因學上各異的 CNS疾病中扮有其角色，因此調制财的形&具有其重要 性。我們提出本文所說明的2-胺基苯甲醯基衍生物(似·犬尿 胺酸化合物）’其可以用於此種治療性介入之中。所推出的 作用機制可為，但是不限於，抑制犬尿胺酸途徑中的酵素， 及/或抑制中間化合物’及/或抑制自由基形成。 【發明内容】 本發明係有關具有式(I)的化合物：
A為伸烷暮; 及其立體韻物㈣學上可接受的鹽，其中： A為伸炊某；R，R々R2獨立地為氫、齒 ，其中：
基、芳基稀基、芳基块基、經基燒基、 句乳、囹暴、齒燒 希基、炔基、芳基烷 確基、胺基、氰基、
IlSic基、脈基、脉基、酿胺基、經基、硫醇基、酿氧基、 資氣基、烧氧基、叛基、獄基酿胺基、S-烧基或燒硫醇基； X為〉^^伸烧基、>c=〇或>〇=8或單一鍵；且γ為氫、鹵 基、鹵烷基、芳基、雜環基、雜芳基、烷基、烯基、快基、 芳基烷基、芳基烯基、芳基炔基、羥基烷基、硝基、胺基、 氰基、氰胺基、胍基、脉基、醯胺基、經基、硫醇基、醯 氧基、疊氮基、烷氧基、羧基、羰基醯胺基、s_烷基或院硫 醇基、笨乙烯基、該苯乙烯基可在環上含有多達4個獨立 地選自下列之中的取代基··鹵基、!|烷基、芳基、雜環基、 雜芳基、烧基、烯基、炔基、芳基烧基、芳基烯基、芳基 炔基、羥基烷基、硝基、胺基、氰基、氰胺基、胍基、脒 基、醯胺基、羥基、硫醇基、醯氧基、疊氮基、烷氧基、 S-烷基、烧硫醇基或-COQ，此處Q為羥基、&烷氧基、 胺基、一-Cm烷基胺基、二-Q·6烷基胺基、羥基胺基、 烧氧胺基或芳基-CM-烷氧基胺基，不過要排除⑻其中同時 地X為>00、Y為甲基、A為CH2CH2、R為μ氧基、 Ri為Η或甲醯基且艮為Η之化合物，與(b)其中部份體 _a(r2)-nh-x-Y 為 _CH2CH(C0q>NH2 或 _CH(鹵炫 基)-CH(COQ)-NH2的化合物。 於對本發明化合物的一般性無影響之下，一亞組 的本發明較佳化合物(式II)係由下述事實所界定：R為氫、 甲基或f氧基、R,為氫或帽基、心為氫或絲、且R3 為氫、錄、鹵絲、絲、雜縣、雜芳基、燒基、稀 基、块基、芳躲基、絲烯基、芳絲基、縣烧基、 硝基、胺基、氰基、氰胺基、胍基、脒基、醯胺基、羥基、 硫醇基、醯氧基、疊氮基、烷氧基、羧基、羰基醯胺基、 S-烧基或烧硫醇基；及其立體異構物和藥學上可接受之隨。
R
(II) 另一亞組本發明化合物係由下述事實所定義：於式(1)中，x 為呋喃基、2-二氫呋喃基、2-四氫呋喃基、或(2_R\c〇〇、) 笨基、其中任何一者可含有1-2個選自下列之中的取代基： CM炫基、CM烧氧基、〇H、項基且γ為氫或苯乙稀基， 該笨乙烯基的環上含有多達兩個獨立地選自下列之中的取 代基：鹵素、CM烷基、CM烷氧基、〇H、硝基、芳基、芳 基-CM烧基、絲基_CM烧氧基；及其立體異構物和藥學 上可接受之鹽。 本發明在其範圍内也包括藥學調配物，其含有作為活 性物質的-治療有效量之式(1)化合物或其藥學上可接受的 鹽以及式_涵蓋_何可麟異構&，或異構物的混合 物’組合著-或多種藥學上可接受的稀釋劑、防腐劑、增 冷劑、乳化劑、佐劑、卿辦3細，制是在藥學或獸 醫學调配射_者。本發鴨學調崎可賴適以供給 人類及/或動物投服所用。 式(I)化合物可用來治療及/或預防，及/或減低與中 風、絕血、CNS創傷、低糖血症和手術相關聯的神經元損 害；CNS失調症’包括神經變性疾病例如阿茲海默爾氏症 (Alzheimer's disease)、肌萎縮性側索硬化(amyotrophie iatei>al sclerosis)、亨丁頓氏病(Huntington's disease)、帕金森氏症 (Parkinson’s disease)、和唐氏徵候群(Down's syndrome);以 及治療或預防興奮性胺基酸過度刺激的不良後果；精神失 調症’例如睡眠失調症、癲癇和其他痙攣失調症；焦慮； 精神性疾病；精神病；老年癡呆症；多梗塞性癡呆症；長 年疼痛(痛覺缺失(analgesia));青光眼；CMV視網膜炎；尿 失禁；與誘導性麻醉；以及增強認識力，與防止鴉片耐受 性和脫瘾徵狀(withdrawal symptom^) 〇 作為可以經由投服本發明化合物獲得治療的目前 所涵盍的狀況之進一步詳細說明解釋，此等狀況包括陽萎 陽萎’心A管失調症包括高血壓，預防血液凝結、抗炎、 神經病、生物壽命相關的失調症例如時差，二十四小時週 期睡眠失調症例如延緩睡眠徵候群，轉換工作問題，和季 節相關性失調症，例如季節性情感性失調症(SAD);内分泌 ’支狀例如避孕和不育症、早熟症⑽s ，經 則徵候君夢’高泌乳素血症(hyperprolactinemia)，與生長激素 缺乏症，贅生性疾病(neoplasticdisease)，包括癌症和其他增 生性疾病（良性與腫瘤前態生長）；免疫系統失調症包括 AIDS ’與老邁相關的狀況；眼科學疾病；叢集性頭痛(cluster headache)，偏頭痛；皮膚保護，糖尿病穩定化與體重增加 失調症(瘦素(leptin) ’肥胖症）；以及作為動物養育的助劑， 例如生育，發育期，毛皮顏色的調節。 【發明之詳細說明】 於對本發明化合物的一般性無影響之下，除了上 面已經提及的諸亞組之外，另一亞組的本發明較佳化合物 係由下述事實所界^ :於_巾，χ為2,4二视苯基，A 為(¾¾或CHfHCOOH且R2和Y各為氫。 另一亞組的本發明較佳化合物係由下述事實所界 定：於式(I)中，&為氫且有至少一種下列諸條件，亦即：R 為5-甲氧基；及/或A為CH2CH2或CH2CHC〇〇H，且於此 兩亞組之中，Ri較佳者也為氫。於本發明化合物中X和γ 的範例組合’特別是r1=H的情況中者，為下面所述者： X為-C0-且Y為2-呋喃基；或 X為-C0-且Y為2-四氫呋喃基；或 X為-CHr且Y為2-四氫呋喃基；或 X為且γ為2-乙醯氡基笨基；或 X為-C0-且Y為3,4-二羥基苯乙烯基或3,4_二羥基 肉桂醯氧基。 本發明也在其範圍之内包括藥學調配物，其含有 作為活性物質的一治療有效量之式①化合物或其藥學上可 接受的鹽以及式(I)所涵蓋的任何可能的異構物，或異構物 的说合物，伴隨著-或多種藥學上可接受的稀釋劑、防腐 丄342210 :、增溶劑、乳化劑、佐劑、賦形劑和載劑，特別是在藥 予或獸醫學調配物中制者。本發日學調配物可經調適 以供給人類及/或動物投服所用。 根據本發明的藥學調配物較佳者具有至少一種下 列特性之特徵： (0其可經調適以健口、經直腸、非經腸、透頻、 肺内(例如經由吸入)或透皮投服所用； 馨 （π)其係呈單位劑型，每一單位劑量包括在 0·0025-1〇〇〇毫克範圍内的該至少一種成員之量； (iii)其為一種控制釋放型調配物，其中該至少一種 成員係以一種預定的控制速率釋放出。 用於經口投服之時，該藥學調配物可以採用例如 鍵劑、膠囊、乳液、溶液、糖漿或懸浮液之形式。用於非 經腸投服之時’該調配物可以採用例如針藥劑’或者在水 性或油性媒劑内的懸浮液、溶液或乳液之形式。對於懸浮 • 劑 '安定劑及/或分散劑之需求當然係考慮到活性化合物所 具在特別具體實例中所使用的媒劑内之溶解度或其他點之 事實。邊调配物可以加添地含有例如生理相容性防腐劑和 抗氧化劑。於局部應用所用的調配物，例如軟膏、洗液或 糊劑之中，可以將活性成分與習用的油質性或乳化性賦形 劑混合。 該藥學調配物也可以用含有習用的栓藥基質例如 可可豆脂或其他甘油脂肪酸酯的栓藥形式使用。或者，可 以將調配物製成貯積形式(depot form)來使用，其可在一段 12 預先選定的時間内於體内將活性調配物慢慢地釋放出來， 再者’本發明化合物可以經由使用透頰、肺内或透皮輸送 糸統來投服。 此外，式I化合物及彼等的鹽與其他活性成分，尤 其疋其他的神經安定劑，胸腺安定劑(thymoleptics)、解焦劑 (anxiohtics)、鎮靜劑、止痛劑、抗帕金森氏症劑(多巴胺能 和非多巴胺能藥物)或類似者，也落於本發明範圍之内。 本發明式化合物可用來治療及/或預防，及/或減低 與中風、絕血、CNS創傷、低糖血症和手術相關聯的神經 疋才貝害’ CNS失調症’包括神經變性疾病例如阿茲海默爾 氏症、肌萎縮性側索硬化、亨丁頓氏病、帕金森氏症、和 唐氏徵信群，治療或預防興奮性胺基酸過度刺激的不良後 果’精神失5周症，例如睡眠失調症、癲癇和其他痙擎失調 症；焦慮；精神性疾病；精神病；老年癡呆症；多梗塞性 癡呆症；齡疼礙錢缺失）；f光眼；CMy視網臈炎； 尿失禁；與_性麻醉；以及增強認識力，與防止鴆片耐 文性和脫癮徵狀。 作為可以經由概本發瓶合物獲得治療的目前 ^蓋的狀況之進一步詳細朗解釋，此等狀況包括陽萎 心血管失雛包減域，爾錢凝結、抗炎、 -十四小時週 例如延_徵候群，轉歡作問題，和季 :目祖失_，例如恤情感性失調症; 例如避孕和打症、早_〇3_“ 子、、足病、生物哥命相關的失調症例如時差 内分泌 puberty) 1342210 前徵候群，高泌乳素血症(hyperprolactinemia)，與生長激素 缺乏症；贅生性疾病(neoplastic disease)，包括癌症和其他增 生性疾病（良性與腫瘤前態生長）；免疫系統失調症包括 AIDS ;與老邁相關的狀況；眼科學疾病；叢集性頭痛(duster headache)，偏頭痛；皮膚保護，糖尿病穩定化與體重增加 失調症(瘦素(leptin)，肥胖症）；以及作為動物養育的助劑， 例如生育，發育期，毛皮顏色的調節。 本發明要用下面的實施例於以闡明。要了解者， 下面諸實施例僅為示範說明用且無意於任何方面限制本發 明的範圍。 【實施方式】 堂轰H : 2·(2-胺基笨曱醯基)-N-(2,4-二硝基苯基)乙 胺.
將犬尿胺· 2HBr (Kynuramine· 2HBr) (125毫克)溶解於 裝在50立方厘米(cc)燒瓶中的5立方厘米絕對酒精之中。 然後加入71毫克2,4-二硝基氟苯在5立方厘米Et〇H中的 洛液(形成一透明黃色溶液）。於5分鐘之後，將2立方厘米 10% NaHC〇3溶液逐滴導到燒瓶内。將反應物置於室溫下 整個晚上。於次日早上’將所形成的淡黃色沉澱物過渡， 用水和乙醇洗祿且在超高真空(UHV)下乾燥而得8〇毫克的 14 產物(約63%產率）。 3必胺基苯曱醒基)-2-(2,4·二確基笨胺基)丙 酸
將L-犬尿胺酸（125毫克)溶解於裝在5〇立方厘米燒瓶 中的5立方厘米絕對酒精之中。然後加入71毫克2,4-二硝 基氟笨在5立方縣EtOH巾的溶液(形成—透明黃色溶 液）。於5分鐘之後，將2立方厘求i〇%NaHc〇3溶液逐滴 導到燒瓶内。將反應物置於室溫下整個晚上。於次日早上， 將所形成的淡黃色沉澱物過濾，用水和乙醇洗滌且在超高 真空(UHV)下乾燥而得8〇毫克的產物(約71%產率）。 本發明也包括式(I)化合物的藥學上可接受之鹽 類，以及式(I)所涵蓋的可能異構物，包括分開地與摻合物 t者。 【本發明化合物的生物學檢驗】 實驗1 : 使用MPTP-處理過的小鼠於有/無亞底限劑量 (subthreshold dosage)的L-多巴(L-Dopa)之下進行抗_帕金森 氏症活性之評定 C57 BL/6 小鼠。於送到實驗室之後，使, 與固定照糸左Μ主，ίο I 貫驗至之後’使小鼠在—有控制溫度(2出。C)
且”有在照光時間内⑽愚聽時)才試驗。所有試驗都是 在，常照光房間内實施。每一試驗小室(亦即活性試驗籠子) 都疋放置在有12鮮厚度的魅和前板且具有減弱照光之 動物：使用六個月大，體重22_25克的雄 隔音木質箱内。 行為測量與裝置：使用一種自動化裝置來測量 MPTP和對照組小鼠的自然及域藥物誘導運動活性，該裝 置包括Macrolon製的嚅齒動物試驗籠子(4〇 χ 25 χ 15厘 米），每一個都放置在兩系列的紅外光束之内(不同的高度， 系列為低者，另一系列為高者，比丨厘米深度的鋸屑表 面刀別向出2厘米和8厘米）。測量下列參數： LOCOMOTION(移動），使用低格紅外光束測量。只有在小 鼠於水平面上，繞著試驗籠子行走時才記錄下計數。後腿 直立(REARING)係於整段時間内，在至少有一高位光束被 中斷時登記，亦即，所登記的計數次數係正比於後腿直立 所花的時間之量。總活動(TOTAL ACTIVITY)係用一與試驗 籠子固定地接觸之感測器（類似於安裝在有一平衡錘 (counterweight)的桿子上的留聲機針頭(gramophone needle) 之唱頭(pick-up))測量的。該感測器可記錄從試驗籠子接收 到的所有類型之振動例如經由移動和後腿直立兩者以及搖 動、顫動、搔彳爪和整理所產生的振動。 行為測量(移動、後腿直立與總活動）：在MPTP注 射(2 X 40毫克/仟克，皮下注射(s.c.)，24小時間隔)12天之 後，用2-(2-胺基苯甲醯基>Ν·(2,4·二硝基苯基)乙胺（〇 3小 3、〇毫克/仟克）或媒劑(1〇%DMSO，1%CMC)經腹膜内(ip) / 主射小鼠且於其後立即放置於活動試驗小室之内並且監測 比等的運動行為60分鐘。於60分鐘之後，用5毫克/仟克 L-多巴(Dopa)皮下注射(s.c)小鼠且接著將小鼠重放於試驗 小室之内且再維持活動測量240分鐘。每一劑分隔兩天， 從最低劑量起始。 表1呈現出有用亞底限劑量的L-多巴投服過且用 2-(2-胺基笨甲醯基)-N-(2,4-二硝基笨基)乙胺或媒劑投服過 的MPTP-處理小鼠與對照小鼠所得平均(±標準偏差)移動、 後腿直立和總活動之計數。星號(*)表出1%的有效水平 (Tukey 試驗）。 處理 触粒 xmi 媒劑 1000±145 920土181 10937±2812 MPTP+媒劑 200±90 225±72 4530±937 娜丁?+0.3窆克/汗兖2-(2-臟苯甲租基)-汴 (2,4-二硝基苯基)乙胺 273±64 290±73 5160土1093 MPTP+1 S 克/什克 2-(2-臟苯甲粗基)-Ν·(2,4-二硝基苯基)乙胺 473±108* 582±145* 6250±625* ΜΡΤΡ+3耷克奸克2-(2-KS苯甲酸基)-Ν-(2,4· 二硝基苯基)乙胺 510*107* 731土110* 6563±781* ΜΡΤΡ+10毫克肝克2-(2-鰱苯甲酸基)-Ν-(2,4-二硝基苯截乙胺 470±110* 619±1〇2+ 6250±625* 相對於MPTP-處理媒劑小鼠，在L-多巴之前的頭6〇 分鐘’任何劑量的2-(2-胺基苯曱醯基)_N-(2,4-二硝基笨基) 乙胺都沒有效應。不過，在與亞底限劑量的L_多巴一起犄 服之時，2-(2-胺基苯曱醯基)_Ν·(2,4-二硝基苯基)乙胺明^ 地改善所有三種參數。相對於ΜΡΤΡ-處理媒劑小鼠，2_(2_ 胺基苯甲醯基)-Ν-(2,4-二硝基笨基）乙胺（1、3或1〇毫克/ 仟克）都可明顯地改善ΜΡΤΡ-處理小鼠的移動、後腿直立和 總活動。 給媒劑對照動物投服2-(2-胺基笨曱醯基)#(2 4_ 二硝基笨基)乙胺對於任何變數都沒有影響。 實驗2 : 在新鮮離析出的大鼠海馬區神經元内的NMDA-活化電流之電生理學鑑定。 海馬區神經元之離析：將Wistar大鼠(12-14天大 者)於沒有麻醉之下斷頭並取出海馬區。將其用人工切成片 (0.2-0.4毫米）’置於含有下列的溶液内(mM) : 15〇NaQ ; $ KC1; 1.25 NaH2P04; 2 CaCl2; 2 MgCl2; 26 NaHC03; 20 葡 萄糖。將該等切片置於此溶液内在室溫下預溫浸30分鐘。 在各有〇.4亳克/毫升得自米麴菌(Aspergillus oryzae)的蛋白 酶’具有較低0八2+漢度(〇.5 mM)的相同溶液内進行酵素處魯 理。在酵素溶液内的該溫浸係在32。(：下10分鐘内進行。 隨後將該等切片保持於含有正常CA2+濃度的無酵素溶液内 且於6-8小時之内用來取得神經元。於整個程序中，都使用 95% 〇2和5% c〇2氣體混合物將溶液連續地飽和以維持在 pH7.4。要將細胞解離時，係將切片轉移到含有下列的細胞 外溶液之内(mM): l50Naa ; 5 κα ; 2 CaCl2; 1〇N_2 經基 乙基六氫吡井-N'-2-乙你黃酸（Hepes) ; pH係使用NaOH調 · 整到7.4。以振動解離法(vibrocjissociati〇n met_)從海馬區 切片的CA區和CA3區離析出單細胞。彼等具有1〇_丨5微 米之直瓜且保有一小部份的樹突(dencjrjt丨c tree)。於離析之 後’彼等通常適合於用來記錄1_2小時。 食鹽水和化學品：細胞外溶液的含量為如下所列 者(單位 mM) : 130 NaQ、5 KC卜 2 CaCl2、2〇 N-2-經基乙 基六氫0比井-Ν’-2·乙燒石黃酸(Hepes) ; 〇 1 TTX、10 μΜ 甘胺酸、300mlVn-天冬胺酸；pH係使用NaOH調整到7.4。 19 1342210 細胞内溶液的含量為如下所列者(單位囊⑽ CSF、20 Tris-HCl (pH = 7.2)。L·天冬胺酸和甘胺酸溶液係 在實驗當天製備的。 試驗用物質2-(2-胺基苯甲酿基沖似-二肖基苯 基)乙胺係經溶解在DMSO之中。 電流記錄與數據分析：使用，，跳動桌(jumping table)’’ 設備（Pharma Robot，Kiev)以快速”濃度夾”法 ("concentration damp” method)施加含有藥物的溶液。電流 係經於整個細胞組態中使用膜片箝制技術⑦站冰ciamp technique)記錄的。電流的記錄係使用EPC-7L/M膜片籍制 放大器(patch-clamp amplifier)實施的。 NMDA-活化電流：電流係在3kHz過濾(三極有源 Bessel濾波器)對NMDA活化電流以60〇〇μ5每點的速率數 位地採樣。NMDA-誘發的透膜電流係在對照溶液和試驗溶 液中含有ΙΟμΜ甘胺酸和300μΜ L-天冬胺酸的存在中測 量的。電流係在將電位保持於-70mV之下記錄的。 計算：於不同物質濃度下的電流之抑制係對至少4 個電池予以平均。物質的影響係測量成平均比例1/1〇，此處 I為在物質的作用下之電流且1〇為對照條件下的電流。S D 表標準偏差。 10认Μ 2(2-胺基笨曱醯基)-N-2,4-二硝基笨基乙胺 對於NMDA-活化電流的作用： 20 個別爾池：ΙΑ) 2-(2-胺基苯甲醒基)-N-(2,4-二硝基苯基)乙胺 ΙΟμΜ 1 2 3 平均値 +SD 92,77 77,15 80,17 83,36 8,28 1342210 * 此實驗揭露出2-(2-胺基笨曱醯基)-N-(2,4-二硝基苯基) 乙胺對於NMDA受體具有阻斷活性。 【圖式簡單說明】 無圖式 【主要元件符號說明】 無
21
Claims (1)
1342210 Wi. E 七、申請專利範圍： 1. 一種具有式(II)的化合物
其中R為氫、甲基或甲氧基，R!為氫或甲醯基，R2為氫 或叛基，且％為氫、鹵基、齒院基、芳基、雜環基、雜 芳基、烷基、烯基、炔基、芳基烷基、芳基烯基、芳基 炔基、羥基烷基、硝基、胺基、氱基、氰胺基、胍基、脒 基、醯胺基、羥基、硫醇基、醯氧基、疊氮基、烷氧基、 綾基、知基醯胺基、S-烧基或烷硫醇基；及其立體異構 物和藥學上可接受之鹽。 ’根據申睛專利範圍第1項所述化合物，其為3-(2-胺基苯 _"基）2-(2,4_二硝笨胺基)丙酸，及其立體異構物和藥 予上可接雙之鹽。 .根據申請專利範圍第1項所述化合物，其為2-(2-胺基笨 基）N-(2,4-二硝基笨基)乙胺，及其立體異構物和藥 予上可接受之鹽。 4二種藥學調配物，其含有—治療有效量之 申，範圍第丨項至第—員所述化合物種= ”構物和藥學上可接受之鹽組合著至少—種選自下 22 1342210. ·. 100年丨月21曰修正替換頁 列之中的藥學上可接受的成分：稀釋劑、防腐劑、增溶 劑、乳化劑、佐劑、賦形劑和載劑。 5.根據申請專利範圍第4項之藥學調配物，其具有至少一 種下列特性之特徵： (0其可經調適以供經口、經直腸、非經腸、透頰内、 肺内或透皮投服所用； (11)其係呈單位劑型，每一單位劑量包括在〇 〇〇25· I 〇〇〇 毫克範圍内的該至少一種成員之量； (iii) 其為一種控制釋放型調配物，其中該至少一種化 · 合物係以一種預定的控制速率釋放出； (iv) 其加添地包括至少一種選自下列之中的已知治療 活性成分：神經安定劑，胸腺安定劑(thym〇leptks)、解 焦劑(amciolitics)、鎮靜劑、止痛劑、抗帕金森氏症劑。 6. -種根據申請專利範圍第i項至第3項任一項所述化合 物，及其立體異構物和藥學上可接受之鹽，作為製造用 於治療或預防帕金森氏症的藥學調配物之用途。 鲁 7. -種根據申請專利範圍第4項或第5項所述藥學調配物 作為製造麟治療或預防帕金森氏症的醫藥品之用途。 23
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IL15666903A IL156669A0 (en) | 2003-06-26 | 2003-06-26 | 2-aminobenzoyl derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW200503672A TW200503672A (en) | 2005-02-01 |
| TWI342210B true TWI342210B (en) | 2011-05-21 |
Family
ID=32587677
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW093118235A TWI342210B (en) | 2003-06-26 | 2004-06-24 | 2-aminobenzoyl derivatives |
Country Status (32)
| Country | Link |
|---|---|
| US (1) | US8309767B2 (zh) |
| EP (1) | EP1644316B1 (zh) |
| JP (1) | JP4646907B2 (zh) |
| KR (1) | KR101115196B1 (zh) |
| CN (1) | CN1835910B (zh) |
| AR (1) | AR044786A1 (zh) |
| AT (1) | ATE460391T1 (zh) |
| AU (1) | AU2004249012B2 (zh) |
| BR (1) | BRPI0411382A (zh) |
| CA (1) | CA2527112C (zh) |
| CY (1) | CY1110043T1 (zh) |
| DE (1) | DE602004025937D1 (zh) |
| DK (1) | DK1644316T3 (zh) |
| EA (1) | EA011255B1 (zh) |
| ES (1) | ES2341958T3 (zh) |
| HK (1) | HK1094795A1 (zh) |
| HN (1) | HN2004000224A (zh) |
| IL (1) | IL156669A0 (zh) |
| IS (1) | IS8235A (zh) |
| MX (1) | MXPA06000022A (zh) |
| NO (1) | NO20060420L (zh) |
| NZ (1) | NZ544908A (zh) |
| PA (1) | PA8605401A1 (zh) |
| PE (1) | PE20050230A1 (zh) |
| PL (1) | PL1644316T3 (zh) |
| PT (1) | PT1644316E (zh) |
| SI (1) | SI1644316T1 (zh) |
| TW (1) | TWI342210B (zh) |
| UA (1) | UA85187C2 (zh) |
| UY (1) | UY28382A1 (zh) |
| WO (1) | WO2004112690A2 (zh) |
| ZA (1) | ZA200600640B (zh) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1869002A (zh) | 2005-05-27 | 2006-11-29 | 中国科学院上海药物研究所 | 一类非甾体雄激素受体调节剂、其制备方法和用途 |
| US7622495B2 (en) | 2006-10-03 | 2009-11-24 | Neurim Pharmaceuticals (1991) Ltd. | Substituted aryl-indole compounds and their kynurenine/kynuramine-like metabolites as therapeutic agents |
| CN104884452A (zh) | 2012-11-20 | 2015-09-02 | 沃泰克斯药物股份有限公司 | 用作吲哚胺2,3-二氧化酶的抑制剂的化合物 |
| JP6664814B2 (ja) * | 2014-08-18 | 2020-03-13 | 国立大学法人大阪大学 | 新規２−アミノベンゾイル誘導体 |
| WO2019178013A1 (en) * | 2018-03-14 | 2019-09-19 | Albert Einstein College Of Medicine | Immunoregulatory role of 3-oh-kynurenamine and uses thereof |
| US11911376B2 (en) | 2020-03-30 | 2024-02-27 | The Regents Of The University Of Colorado | Methods for preventing and treating retinal damage |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT305987B (de) | 1969-12-18 | 1973-03-26 | Degussa | Verfahren zur Herstellung von neuen Aminoketonen |
| GB1334884A (en) * | 1970-12-18 | 1973-10-24 | Sumitomo Chemical Co | Aminoalcohols and their conversion to aminoketones |
| JPS5336455B2 (zh) | 1973-02-03 | 1978-10-03 | ||
| US4018823A (en) * | 1976-04-20 | 1977-04-19 | Morton-Norwich Products, Inc. | 4',5'-Dimethoxy-2',3-diaminopropiophenone dihydrochloride |
| FR2569185B1 (fr) | 1984-08-20 | 1986-09-05 | Lafon Labor | Derives de 1-(aminophenyl)-2-amino-ethanone, procede de preparation et utilisation en therapeutique |
-
2003
- 2003-06-26 IL IL15666903A patent/IL156669A0/xx not_active IP Right Cessation
-
2004
- 2004-06-16 AR ARP040102095A patent/AR044786A1/es not_active Application Discontinuation
- 2004-06-18 PE PE2004000604A patent/PE20050230A1/es not_active Application Discontinuation
- 2004-06-22 PA PA20048605401A patent/PA8605401A1/es unknown
- 2004-06-23 UY UY28382A patent/UY28382A1/es not_active Application Discontinuation
- 2004-06-24 CN CN200480017943XA patent/CN1835910B/zh not_active Expired - Fee Related
- 2004-06-24 HN HN2004000224A patent/HN2004000224A/es unknown
- 2004-06-24 BR BRPI0411382-9A patent/BRPI0411382A/pt not_active IP Right Cessation
- 2004-06-24 DK DK04744907.9T patent/DK1644316T3/da active
- 2004-06-24 WO PCT/IL2004/000567 patent/WO2004112690A2/en active Search and Examination
- 2004-06-24 CA CA2527112A patent/CA2527112C/en not_active Expired - Fee Related
- 2004-06-24 US US10/562,197 patent/US8309767B2/en not_active Expired - Fee Related
- 2004-06-24 MX MXPA06000022A patent/MXPA06000022A/es active IP Right Grant
- 2004-06-24 PT PT04744907T patent/PT1644316E/pt unknown
- 2004-06-24 AU AU2004249012A patent/AU2004249012B2/en not_active Ceased
- 2004-06-24 DE DE602004025937T patent/DE602004025937D1/de not_active Expired - Lifetime
- 2004-06-24 EA EA200600115A patent/EA011255B1/ru not_active IP Right Cessation
- 2004-06-24 UA UAA200600303A patent/UA85187C2/ru unknown
- 2004-06-24 JP JP2006516814A patent/JP4646907B2/ja not_active Expired - Fee Related
- 2004-06-24 ES ES04744907T patent/ES2341958T3/es not_active Expired - Lifetime
- 2004-06-24 EP EP04744907A patent/EP1644316B1/en not_active Expired - Lifetime
- 2004-06-24 TW TW093118235A patent/TWI342210B/zh not_active IP Right Cessation
- 2004-06-24 PL PL04744907T patent/PL1644316T3/pl unknown
- 2004-06-24 SI SI200431416T patent/SI1644316T1/sl unknown
- 2004-06-24 ZA ZA200600640A patent/ZA200600640B/en unknown
- 2004-06-24 AT AT04744907T patent/ATE460391T1/de not_active IP Right Cessation
- 2004-06-24 NZ NZ544908A patent/NZ544908A/en unknown
- 2004-06-24 KR KR1020057025006A patent/KR101115196B1/ko not_active IP Right Cessation
-
2006
- 2006-01-16 IS IS8235A patent/IS8235A/is unknown
- 2006-01-25 NO NO20060420A patent/NO20060420L/no not_active Application Discontinuation
-
2007
- 2007-02-27 HK HK07102168.5A patent/HK1094795A1/xx not_active IP Right Cessation
-
2010
- 2010-05-25 CY CY20101100463T patent/CY1110043T1/el unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2049482B1 (en) | Positively charged water-soluble prodrugs of aryl- and heteroarylacetic acids with very fast skin penetration rate | |
| IL271443B2 (en) | Preparations and methods for regulating hair growth | |
| JPH08510479A (ja) | 眼の炎症障害を処置するための３‐ベンゾイルフェニル酢酸誘導体を含む局所的に投与可能な組成物 | |
| EA027976B1 (ru) | Анестезирующие соединения и способы их применения | |
| EP3906240A1 (en) | Compositions and methods for modulating hair growth | |
| JP2002526408A5 (zh) | ||
| PL154186B1 (en) | Method for manufacturing arylic derivatives of the hydroxamic acid | |
| JP2012131829A (ja) | そう痒状態の処置のためのｍｇｌｕｒ５アンタゴニストの使用 | |
| EP1263425B1 (en) | Use of comt inhibitors as analgesics | |
| TWI342210B (en) | 2-aminobenzoyl derivatives | |
| AU2007204757B2 (en) | Lanthionine-related compounds for the treatment of inflammatory diseases | |
| JP2014514259A (ja) | 疼痛および他の障害の処置のための化合物および方法 | |
| JP2007506435A (ja) | 神経ペプチドｆｆ受容体２アゴニストによる神経因性疼痛の処置 | |
| FR2791891A1 (fr) | Utilisation de la tianeptine pour l'obtention de medicaments destines au traitement des pathologies de la neurodegenerescence | |
| JP2007518673A5 (zh) | ||
| JP3513876B2 (ja) | メラトニン作用性類似物としてのインドール誘導体 | |
| JPH03209355A (ja) | アリールアルキルアミド含有の神経変性疾患治療剤 | |
| CA2453445C (fr) | Derives de pyridin-2-yl-methylamine pour le traitement de la dependance aux opioides | |
| NZ759233B2 (en) | Compositions and methods for modulating hair growth | |
| JP2009161481A (ja) | ヘビ毒筋壊死因子阻害剤 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Annulment or lapse of patent due to non-payment of fees |