WO2010029995A1 - Agent thérapeutique contre la douleur - Google Patents
Agent thérapeutique contre la douleur Download PDFInfo
- Publication number
- WO2010029995A1 WO2010029995A1 PCT/JP2009/065911 JP2009065911W WO2010029995A1 WO 2010029995 A1 WO2010029995 A1 WO 2010029995A1 JP 2009065911 W JP2009065911 W JP 2009065911W WO 2010029995 A1 WO2010029995 A1 WO 2010029995A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pain
- substituted
- unsubstituted
- therapeutic agent
- preventive
- Prior art date
Links
- 208000002193 Pain Diseases 0.000 title claims abstract description 223
- 230000036407 pain Effects 0.000 title claims abstract description 217
- 239000003814 drug Substances 0.000 title claims abstract description 70
- 229940124597 therapeutic agent Drugs 0.000 title claims abstract description 65
- 150000003839 salts Chemical class 0.000 claims abstract description 46
- 206010058019 Cancer Pain Diseases 0.000 claims abstract description 35
- 125000006848 alicyclic heterocyclic group Chemical group 0.000 claims abstract description 33
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 32
- 208000004550 Postoperative Pain Diseases 0.000 claims abstract description 32
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 32
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims abstract description 31
- 201000011510 cancer Diseases 0.000 claims abstract description 31
- 208000004296 neuralgia Diseases 0.000 claims abstract description 29
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 26
- 125000003118 aryl group Chemical group 0.000 claims abstract description 25
- 238000002512 chemotherapy Methods 0.000 claims abstract description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 14
- 239000004480 active ingredient Substances 0.000 claims abstract description 13
- 230000000069 prophylactic effect Effects 0.000 claims abstract description 9
- -1 tetrahydroisoquinolyl Chemical group 0.000 claims description 61
- 230000003449 preventive effect Effects 0.000 claims description 47
- 206010065390 Inflammatory pain Diseases 0.000 claims description 34
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 33
- 229910052757 nitrogen Inorganic materials 0.000 claims description 30
- 208000021722 neuropathic pain Diseases 0.000 claims description 27
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 7
- 125000005434 dihydrobenzoxazinyl group Chemical group O1N(CCC2=C1C=CC=C2)* 0.000 claims description 4
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 4
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 125000005505 thiomorpholino group Chemical group 0.000 claims description 3
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- FDSSYPNUQHQSIQ-ONEGZZNKSA-N (2e)-penta-2,4-dienamide Chemical class NC(=O)\C=C\C=C FDSSYPNUQHQSIQ-ONEGZZNKSA-N 0.000 abstract description 5
- 206010061218 Inflammation Diseases 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 description 120
- 125000001424 substituent group Chemical group 0.000 description 33
- 238000012360 testing method Methods 0.000 description 31
- 238000011282 treatment Methods 0.000 description 26
- 241000700159 Rattus Species 0.000 description 25
- 239000002904 solvent Substances 0.000 description 25
- 241000725303 Human immunodeficiency virus Species 0.000 description 22
- 230000000694 effects Effects 0.000 description 22
- 238000000034 method Methods 0.000 description 22
- 230000006399 behavior Effects 0.000 description 19
- 230000002265 prevention Effects 0.000 description 18
- 230000006872 improvement Effects 0.000 description 17
- 229910052736 halogen Inorganic materials 0.000 description 16
- 239000000203 mixture Substances 0.000 description 16
- 150000002367 halogens Chemical class 0.000 description 15
- 238000010171 animal model Methods 0.000 description 14
- 239000007864 aqueous solution Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 241001465754 Metazoa Species 0.000 description 12
- 229930012538 Paclitaxel Natural products 0.000 description 12
- 208000000114 Pain Threshold Diseases 0.000 description 12
- 125000001589 carboacyl group Chemical group 0.000 description 12
- 238000002347 injection Methods 0.000 description 12
- 239000007924 injection Substances 0.000 description 12
- 229960001592 paclitaxel Drugs 0.000 description 12
- 230000037040 pain threshold Effects 0.000 description 12
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 12
- 230000000202 analgesic effect Effects 0.000 description 10
- 230000004044 response Effects 0.000 description 10
- 125000004434 sulfur atom Chemical group 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 9
- 208000033808 peripheral neuropathy Diseases 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 238000011161 development Methods 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 7
- 239000000014 opioid analgesic Substances 0.000 description 7
- 229940005483 opioid analgesics Drugs 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 229910052717 sulfur Inorganic materials 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 208000004454 Hyperalgesia Diseases 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 210000003141 lower extremity Anatomy 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 229920000609 methyl cellulose Polymers 0.000 description 6
- 239000001923 methylcellulose Substances 0.000 description 6
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 6
- 208000005877 painful neuropathy Diseases 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 208000035154 Hyperesthesia Diseases 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 108010025083 TRPV1 receptor Proteins 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 125000003282 alkyl amino group Chemical group 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 125000004430 oxygen atom Chemical group O* 0.000 description 5
- 239000002464 receptor antagonist Substances 0.000 description 5
- 229940044551 receptor antagonist Drugs 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 125000003107 substituted aryl group Chemical group 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- 206010027476 Metastases Diseases 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
- 239000001961 anticonvulsive agent Substances 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
- 210000000988 bone and bone Anatomy 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 229940127089 cytotoxic agent Drugs 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 4
- 208000034783 hypoesthesia Diseases 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 230000009401 metastasis Effects 0.000 description 4
- 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 4
- 210000005036 nerve Anatomy 0.000 description 4
- 201000001119 neuropathy Diseases 0.000 description 4
- 230000007823 neuropathy Effects 0.000 description 4
- 231100000862 numbness Toxicity 0.000 description 4
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 230000001953 sensory effect Effects 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 4
- 229960001052 streptozocin Drugs 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000001356 surgical procedure Methods 0.000 description 4
- SJGVXVZUSQLLJB-UHFFFAOYSA-N 1-isoquinolin-5-yl-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC(=O)NC1=CC=CC2=CN=CC=C12 SJGVXVZUSQLLJB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 102000003566 TRPV1 Human genes 0.000 description 3
- 230000005856 abnormality Effects 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 125000005236 alkanoylamino group Chemical group 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 description 3
- 125000005115 alkyl carbamoyl group Chemical group 0.000 description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001647 drug administration Methods 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 201000008482 osteoarthritis Diseases 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229920001592 potato starch Polymers 0.000 description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 229940095064 tartrate Drugs 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- ROGUAPYLUCHQGK-UHFFFAOYSA-N 1-piperazinecarboxamide, 4-(3-chloro-2-pyridinyl)-n-[4-(1,1-dimethylethyl)phenyl]- Chemical compound C1=CC(C(C)(C)C)=CC=C1NC(=O)N1CCN(C=2C(=CC=CN=2)Cl)CC1 ROGUAPYLUCHQGK-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 208000008035 Back Pain Diseases 0.000 description 2
- 206010005949 Bone cancer Diseases 0.000 description 2
- 208000018084 Bone neoplasm Diseases 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 206010010774 Constipation Diseases 0.000 description 2
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 2
- 208000001640 Fibromyalgia Diseases 0.000 description 2
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 2
- 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 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 206010028813 Nausea Diseases 0.000 description 2
- 206010029174 Nerve compression Diseases 0.000 description 2
- 208000001294 Nociceptive Pain Diseases 0.000 description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 101000835619 Rattus norvegicus Tubulin-specific chaperone A Proteins 0.000 description 2
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 2
- 206010038678 Respiratory depression Diseases 0.000 description 2
- 206010041349 Somnolence Diseases 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- 229940123237 Taxane Drugs 0.000 description 2
- 206010062129 Tongue neoplasm Diseases 0.000 description 2
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 description 2
- 229940122803 Vinca alkaloid Drugs 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- 208000005298 acute pain Diseases 0.000 description 2
- 125000002723 alicyclic group Chemical group 0.000 description 2
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000006229 amino acid addition Effects 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 239000003416 antiarrhythmic agent Substances 0.000 description 2
- 229940125681 anticonvulsant agent Drugs 0.000 description 2
- 125000003435 aroyl group Chemical group 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 210000003050 axon Anatomy 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- DRCMAZOSEIMCHM-UHFFFAOYSA-N capsazepine Chemical compound C1C=2C=C(O)C(O)=CC=2CCCN1C(=S)NCCC1=CC=C(Cl)C=C1 DRCMAZOSEIMCHM-UHFFFAOYSA-N 0.000 description 2
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 210000000038 chest Anatomy 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000000000 cycloalkoxy group Chemical group 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
- 230000006378 damage Effects 0.000 description 2
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 201000004101 esophageal cancer Diseases 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 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 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000002350 laparotomy Methods 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229960005181 morphine Drugs 0.000 description 2
- YUTIXVXZQIQWGY-UHFFFAOYSA-N n-[4-[6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl]oxy-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=CC=C2SC(NC(=O)C)=NC2=C1OC(N=CN=1)=CC=1C1=CC=C(C(F)(F)F)C=C1 YUTIXVXZQIQWGY-UHFFFAOYSA-N 0.000 description 2
- 230000008693 nausea Effects 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 230000000399 orthopedic effect Effects 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 229960001412 pentobarbital Drugs 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- RGCLLPNLLBQHPF-HJWRWDBZSA-N phosphamidon Chemical compound CCN(CC)C(=O)C(\Cl)=C(/C)OP(=O)(OC)OC RGCLLPNLLBQHPF-HJWRWDBZSA-N 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 125000004929 pyrrolidonyl group Chemical group N1(C(CCC1)=O)* 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 229940076279 serotonin Drugs 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 2
- 125000005942 tetrahydropyridyl group Chemical group 0.000 description 2
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 2
- 201000006134 tongue cancer Diseases 0.000 description 2
- 231100000027 toxicology 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
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 2
- 206010044652 trigeminal neuralgia Diseases 0.000 description 2
- 206010046766 uterine cancer Diseases 0.000 description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 2
- 229960004528 vincristine Drugs 0.000 description 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 2
- 230000008673 vomiting Effects 0.000 description 2
- DTPWKUZPRRLULE-MRVPVSSYSA-N (3R)-5-amino-3-hydroxy-3,4-dihydro-1H-quinolin-2-one Chemical compound Nc1cccc2NC(=O)[C@H](O)Cc12 DTPWKUZPRRLULE-MRVPVSSYSA-N 0.000 description 1
- ZEUITGRIYCTCEM-KRWDZBQOSA-N (S)-duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 description 1
- YCDWBIUKUBHSKQ-FMIVXFBMSA-N (e)-n-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-3-[2-piperidin-1-yl-6-(trifluoromethyl)pyridin-3-yl]prop-2-enamide Chemical compound C=12CC(O)CCC2=CC=CC=1NC(=O)\C=C\C1=CC=C(C(F)(F)F)N=C1N1CCCCC1 YCDWBIUKUBHSKQ-FMIVXFBMSA-N 0.000 description 1
- 125000005871 1,3-benzodioxolyl group Chemical group 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- ZKAMEFMDQNTDFK-UHFFFAOYSA-N 1h-imidazo[4,5-b]pyrazine Chemical compound C1=CN=C2NC=NC2=N1 ZKAMEFMDQNTDFK-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 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
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- JFRYYGVYCWYIDQ-UHFFFAOYSA-N 4-[3-(trifluoromethyl)pyridin-2-yl]-n-[5-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide Chemical compound N1=CC(C(F)(F)F)=CC=C1NC(=O)N1CCN(C=2C(=CC=CN=2)C(F)(F)F)CC1 JFRYYGVYCWYIDQ-UHFFFAOYSA-N 0.000 description 1
- AZIPPWRWQSPDCA-UHFFFAOYSA-N 4-[3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxylic acid Chemical compound C1CN(C(=O)O)CCN1C1=NC=CC=C1C(F)(F)F AZIPPWRWQSPDCA-UHFFFAOYSA-N 0.000 description 1
- PIGLNTUJPAEVJZ-UHFFFAOYSA-N 5-[4-(trifluoromethyl)phenyl]penta-2,4-dienoic acid Chemical compound OC(=O)C=CC=CC1=CC=C(C(F)(F)F)C=C1 PIGLNTUJPAEVJZ-UHFFFAOYSA-N 0.000 description 1
- 125000006043 5-hexenyl group Chemical group 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 101800004538 Bradykinin Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000000094 Chronic 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
- 229920000742 Cotton Polymers 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 208000016192 Demyelinating disease Diseases 0.000 description 1
- 206010012305 Demyelination Diseases 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- 101710121417 Envelope glycoprotein Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 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
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000004044 Hypesthesia Diseases 0.000 description 1
- 208000004404 Intractable Pain Diseases 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 102100035792 Kininogen-1 Human genes 0.000 description 1
- 239000001358 L(+)-tartaric acid Substances 0.000 description 1
- 235000011002 L(+)-tartaric acid Nutrition 0.000 description 1
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- 208000008930 Low Back Pain Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 239000004727 Noryl Substances 0.000 description 1
- 229920001207 Noryl Polymers 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010065016 Post-traumatic pain Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 208000020764 Sensation disease Diseases 0.000 description 1
- 206010040026 Sensory disturbance Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 208000032140 Sleepiness Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 102100021696 Syncytin-1 Human genes 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 230000003376 axonal effect Effects 0.000 description 1
- 125000003725 azepanyl group Chemical group 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000005452 bending Methods 0.000 description 1
- 125000004601 benzofurazanyl group Chemical group N1=C2C(=NO1)C(=CC=C2)* 0.000 description 1
- 125000004622 benzoxazinyl group Chemical group O1NC(=CC2=C1C=CC=C2)* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 125000002993 cycloalkylene group Chemical group 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000004090 cyclononenyl group Chemical group C1(=CCCCCCCC1)* 0.000 description 1
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 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 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229960002866 duloxetine Drugs 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000003195 fascia Anatomy 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229960002870 gabapentin Drugs 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000026781 habituation Effects 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 125000000268 heptanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
- 229960001340 histamine Drugs 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 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
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000000629 knee joint Anatomy 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 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
- 230000037353 metabolic pathway Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000004126 nerve fiber Anatomy 0.000 description 1
- 230000007383 nerve stimulation Effects 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 210000000929 nociceptor Anatomy 0.000 description 1
- 108091008700 nociceptors Proteins 0.000 description 1
- 125000001400 nonyl 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])[H] 0.000 description 1
- 125000005485 noradamantyl group Chemical group 0.000 description 1
- 239000002767 noradrenalin uptake inhibitor Substances 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 description 1
- 125000002347 octyl 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])[H] 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000000010 osteolytic effect Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000005961 oxazepanyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000011458 pharmacological treatment Methods 0.000 description 1
- 238000001050 pharmacotherapy Methods 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 description 1
- 229960001233 pregabalin Drugs 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000001107 psychogenic effect Effects 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000005494 pyridonyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008085 renal dysfunction Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 1
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000003772 serotonin uptake inhibitor Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 230000037321 sleepiness Effects 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 210000003594 spinal ganglia Anatomy 0.000 description 1
- 210000001032 spinal nerve Anatomy 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000005338 substituted cycloalkoxy group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000004588 thienopyridyl group Chemical group S1C(=CC2=C1C=CC=N2)* 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 150000003751 zinc Chemical class 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
- A61K31/435—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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
-
- 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
- A61K31/02—Halogenated hydrocarbons
- A61K31/025—Halogenated hydrocarbons carbocyclic
- A61K31/03—Halogenated hydrocarbons carbocyclic aromatic
-
- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
-
- 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
- A61K31/075—Ethers or acetals
- A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
-
- 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
- A61K31/11—Aldehydes
-
- 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
- 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
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/4035—Isoindoles, e.g. phthalimide
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- 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
- A61K31/415—1,2-Diazoles
-
- 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
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
-
- 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
- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
-
- 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
- A61K31/41—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
- A61K31/4196—1,2,4-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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
-
- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
-
- 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
- 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
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
Definitions
- the present invention is associated with inflammatory pain, postoperative pain, diabetic neuropathic pain, HIV-related pain, cancer pain, and cancer chemotherapy containing a pentadienamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention relates to a preventive and / or therapeutic agent for pain (pain) selected from pain.
- pain is nociceptive pain caused by persistent stimulation of nociceptors by endogenous pain substances, etc., and neuropathic pain caused by abnormalities in the function of nerve fibers involved in nerve transmission , And psychogenic pain.
- Inflammatory pain included in nociceptive pain is pain associated with inflammation caused by osteoarthritis, rheumatoid arthritis, cancer, surgery, trauma, etc.
- pain-causing substances bradykinin, serotonin in peripheral damaged tissues
- the production of pain-inducing substances prostaglandins, inflammatory cytokines, etc.
- Non-steroidal anti-inflammatory analgesics and opioid analgesics are used to treat inflammatory pain.
- conventional NSAIDs have side effects such as gastrointestinal disorders (digestive ulcers, bleeding), renal dysfunction, and decreased platelet aggregation function, so their use may be limited in pain management of inflammatory pain.
- opioid analgesics have side effects such as constipation, nausea, vomiting, drowsiness, respiratory depression, etc. If the dose is reduced to avoid such risks, the pain may not be relieved appropriately. Therefore, development of a therapeutic agent for inflammatory pain having a strong analgesic action and few side effects is desired.
- TRPV1 Transient Receptor Potential Vanilloid 1 receptor antagonist capsazepine and N- (4-tert-butylphenyl) -4- (3-chloropyridin-2-yl ) Tetrahydropyrazine-1 (2H) -carboxamide (BCTC), 1-isoquinolin-5-yl-3- (4-trifluoromethylbenzyl) urea (A-425619), N- (4- [6- (4- Trifluoromethylphenyl) pyrimidin-4-yloxy] benzothiazol-2-yl) acetamide (AMG517) is known to be effective in animal models of inflammatory pain [The Journal of Pharmacology The Journal of Pharmacologic and Experimental Therapeutics, 2003, 304, p.56; 2003, 306, p.387; 2005, 314 , P. 410; ibid, 2007, 323, p. 128].
- Postoperative pain is one of the biggest acute pains experienced by patients, but recently, postoperative pain is not just a pain that is considered as an acute pain, but also a concept of prolonged postoperative pain As refractory chronic pain, it has been elucidated that it can be a cause of pain afterwards.
- Specific examples of postoperative pain include chest thoracotomy, pain after laparotomy, pain after mastectomy, pain after orthopedic surgery, pain after tooth extraction, and the like.
- local anesthetics using nerve blocks, NSAIDs, opioid analgesics and the like are used for pharmacological treatment of postoperative pain.
- NSAIDs and opioid analgesics are known for the above-mentioned side effects, and due to these side effects, doses cannot be increased, and there are cases where sufficient analgesic effects for treatment cannot be obtained. Therefore, development of a postoperative pain therapeutic agent having a strong analgesic action and few side effects is desired.
- TRPV1 receptor antagonist A-425619 and (E) -N- (7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)- 3- (2- (Piperidin-1-yl) -6- (trifluoromethyl) pyridin-3-yl) acrylamide (AMG0347) is known to be effective in animal models of postoperative pain [The ⁇ The Journal of Pharmacology and Experimental Therapeutics, 2005, Vol.314, p.410; Anesthesiology, 2008, 108 Volume, p.1100].
- Cancer pain is a symptom that appears as cancer progresses, and 30 to 50% of all cancer patients experience 75 to 95% of patients with metastatic or advanced cancer.
- causes of the pain include inflammation around the cancer, nerve compression caused by the cancer, bone metastasis, and the like. Pain causes discomfort and dysfunction and significantly reduces the patient's quality of life (QOL).
- QOL quality of life
- TRPV1 receptor antagonist 4- (3-trifluoromethylpyridin-2-yl) piperazine-1-carboxylic acid (5-trifluoromethylpyridine-2- Il) amide (JNJ-17203212) and capsazepine are known to be effective in animal models of cancer pain [The Journal of Neuroscience, 2005, Volume 25 , P. 3126; Neuroscience Letter, 2006, volume 393, p. 70].
- Neuropathic pain includes post-herpetic neuralgia, diabetic neuropathic pain, HIV-related pain, trigeminal neuralgia, fibromyalgia, etc., as well as pain associated with cancer chemotherapy.
- chemotherapy may be used for the purpose of treating, prolonging life, relieving symptoms, and improving quality of life (QOL).
- Vinca alkaloid preparations such as vincristine used in chemotherapy, taxane preparations such as paclitaxel, platinum complex preparations such as cisplatin, as side effects, damage the axon function of nerve cells, pain and numbness, sensory disturbances, etc. May cause peripheral neuropathy.
- Diabetic neuropathic pain is intractable pain that develops with diabetic neuropathy. Diabetic neuropathy is the most frequently developed peripheral neuropathy and is said to occur in about 30% of diabetic patients [Journal of Neurology, Volume 243. , P.431 (1996)]. The onset mechanism of diabetic neuropathic pain is unclear, but the functional and plasticity of the peripheral and central nervous systems is affected by neuronal axonal atrophy and demyelination, ion channel abnormalities, polyol metabolic pathway abnormalities, etc. It is believed to be caused as a result of changes [Diabetologia, Vol. 43, p.957 (2000); Diabetes Metab. Res. Rev.], Volume 19, p.S9 (2003)].
- Treatment includes gabapentin, pregabalin, duloxetine, capuisaicin ointment, tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin / noradrenaline reuptake inhibitors, antiepileptic drugs, anticonvulsants, antiarrhythmic drugs, etc.
- TRPV1-selective receptor antagonists Although there has been no report on the analgesic action of TRPV1-selective receptor antagonists using diabetic neuropathic pain model animals, it is known that anti-TRPV1 serum is effective in diabetic neuropathic pain model animals [European Journal of Pharmacology, 2001, Vol. 422, p. 83]. In addition, it has been revealed that the function of TRPV1 receptor is enhanced in dorsal root ganglia of diabetic animals, indicating that TRPV1 receptor may be involved in diabetic pain [Journal ⁇ Of Biological Chemistry (Journal of biological chemistry), 2005, Vol.280, p.618].
- HIV-related pain is one of the most frequent symptoms of neuropathy in HIV infection and AIDS and is seen in more than 1/3 of patients with neuropathy [CNS Drugs, 2005 , Volume 19, p.325].
- the mechanism of HIV-related pain is not well understood, but recent research suggests that the action of the envelope glycoprotein gp120 present on the surface of HIV virus on nerves or glial cells is involved in the development of pain.
- TRPV1 receptor antagonist containing a compound used in the present invention as an active ingredient is known (see Patent Document 1).
- the object of the present invention is to provide inflammatory pain, postoperative pain, diabetic neuropathic pain, HIV-related pain, cancer pain, and cancer chemistry containing, for example, a pentadienamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient. It is to provide a preventive and / or therapeutic agent for pain selected from pain associated with therapy.
- the present invention relates to the following (1) to (48).
- R 1 represents a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group
- R 2 represents substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group or substituted or unsubstituted alicyclic heterocyclic group.
- R 3 represents a hydrogen atom, or together with R 4 and an adjacent nitrogen atom, forms a substituted or unsubstituted heterocyclic group
- R 4 represents substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group or substituted or unsubstituted alicyclic heterocyclic group.
- R 5 , R 6 and R 7 are the same or different and each represents a hydrogen atom or methyl), or a pharmaceutically acceptable salt thereof as an active ingredient.
- a prophylactic and / or therapeutic agent for pain selected from diabetic neuropathic pain, HIV-related pain, cancer pain, and pain associated with cancer chemotherapy.
- R 3 and R 4 together with the adjacent nitrogen atom form a substituted or unsubstituted thiomorpholino.
- R 3 and R 4 together with the adjacent nitrogen atom form a substituted or unsubstituted piperidino or substituted or unsubstituted piperazinyl, and / or the prevention of pain according to (1) or (2) Therapeutic agent.
- R 4 is substituted or unsubstituted aryl.
- a method for preventing and / or treating pain selected from HIV-related pain, cancer pain, and pain associated with cancer chemotherapy.
- the method for preventing and / or treating pain according to (28), wherein the pain is postoperative pain.
- the method for preventing and / or treating pain according to (28), wherein the pain is cancer pain.
- the method for preventing and / or treating pain according to (28), wherein the pain is pain associated with cancer chemotherapy.
- the method for preventing and / or treating pain according to (28), wherein the pain is diabetic neuropathic pain.
- the method for preventing and / or treating pain according to (28), wherein the pain is HIV-related pain.
- a prophylactic and / or therapeutic agent for pain selected from inflammatory pain, postoperative pain, diabetic neuropathic pain, HIV-related pain, cancer pain, and pain associated with cancer chemotherapy ( Use of the compound according to any one of 1) to (21) or a pharmaceutically acceptable salt thereof.
- the use according to (35), wherein the pain is inflammatory pain.
- the use according to (35), wherein the pain is postoperative pain.
- the use according to (35), wherein the pain is cancer pain.
- the use according to (35), wherein the pain is pain associated with cancer chemotherapy.
- the use according to (35), wherein the pain is diabetic neuropathic pain. (41) The use according to (35), wherein the pain is HIV-related pain.
- (42) For use in the prevention and / or treatment of pain selected from inflammatory pain, postoperative pain, diabetic neuropathic pain, HIV-related pain, cancer pain, and pain associated with cancer chemotherapy (1) ) To (21) or a pharmaceutically acceptable salt thereof. (43) The agent according to (42), wherein the pain is inflammatory pain. (44) The agent according to (42), wherein the pain is postoperative pain. (45) The agent according to (42), wherein the pain is cancer pain. (46) The agent according to (42), wherein the pain is pain associated with cancer chemotherapy. (47) The agent according to (42), wherein the pain is diabetic neuropathic pain. (48) The agent according to (42), wherein the pain is HIV-related pain.
- a pentadienamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
- An agent for preventing and / or treating pain selected from accompanying pain is provided.
- FIG. 1 shows the improvement rate (%) of hyperalgesia 3% after administration of a test compound in the compound 332 administration group in a rat CFA (rat complete Freundo adjuvant) -induced inflammatory pain model.
- FIG. 2 shows the improvement rate (%) of hyperalgesia in the rat CFA-induced inflammatory pain model in the compound 257 administration group 4 hours after administration of the test compound.
- each group of formula (I) examples include linear or branched alkyl having 1 to 10 carbon atoms, and more specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- Examples include butyl, pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like.
- cycloalkyl examples include cycloalkyl having 3 to 10 carbon atoms, and more specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, noradamantyl, adamantyl, bicyclo [2.2. 1) heptyl, bicyclo [2.2.2] octyl, bicyclo [3.3.0] octyl, bicyclo [3.3.1] nonyl and the like.
- cycloalkenyl examples include cycloalkenyl having 3 to 10 carbon atoms, and more specific examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl and the like.
- aryl examples include aryl having 6 to 14 carbon atoms, and more specifically include phenyl, naphthyl, indenyl, anthryl and the like.
- Aryl is, for example, aryl condensed with a cyclohexyl group, such as 1,2,3,4-tetrahydronaphthalene, or 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquino.
- Ril dihydroquinoxalinyl, tetrahydroquinoxalinyl, dihydrobenzofuranyl, chromanyl, isochromanyl, benzoxazinyl, dihydrobenzoxazinyl, cihydrobenzodioxinyl, 1,3-benzodioxolyl, etc.
- An aryl fused with an alicyclic heterocyclic group may be used.
- aromatic heterocyclic group for example, a 5-membered or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a 3- to 8-membered ring are condensed.
- Examples of the alicyclic heterocyclic group include a 5-membered or 6-membered monocyclic alicyclic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and a 3- to 8-membered ring. And a condensed alicyclic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and more specifically, pyrrolidinyl, pyrrolidonyl, etc.
- the heterocyclic group formed together with the adjacent nitrogen atom includes an aromatic heterocyclic group formed together with the adjacent nitrogen atom or an alicyclic ring formed together with the adjacent nitrogen atom. And a formula heterocyclic group.
- the aromatic heterocyclic group formed together with the adjacent nitrogen atom include a 5-membered or 6-membered monocyclic aromatic heterocyclic group containing at least one nitrogen atom (the monocyclic aromatic group).
- a heterocyclic group may contain other nitrogen, oxygen or sulfur atoms), a bicyclic or tricyclic condensed 3- to 8-membered ring and containing at least one nitrogen atom
- Aromatic heterocyclic group (the condensed aromatic heterocyclic group may contain other nitrogen atom, oxygen atom or sulfur atom) and the like, more specifically pyrrolyl, imidazolyl, indolyl, Indazolyl, carbazolyl, pyrazolyl and the like can be mentioned.
- Examples of the alicyclic heterocyclic group formed together with the adjacent nitrogen atom include a 5- or 6-membered monocyclic alicyclic heterocyclic group containing at least one nitrogen atom (the monocyclic An alicyclic heterocyclic group may contain other nitrogen, oxygen or sulfur atoms), a bicyclic or tricyclic fused 3-8 membered ring and contains at least one nitrogen atom
- a condensed alicyclic heterocyclic group (the condensed alicyclic heterocyclic group may contain other nitrogen, oxygen or sulfur atoms), and more specifically pyrrolidinyl.
- the substituents in the substituted alicyclic heterocyclic group formed together with the adjacent nitrogen atom are the same or different, for example, 1 to 3 substituents, more specifically halogen, hydroxy, Amino, hydroxyimino, amidino, hydroxyamidino, nitro, mercapto, cyano, carboxy, methylenedioxy, ethylenedioxy, carbamoyl, sulfamoyl, sulfamoyloxy, lower alkenyl, cycloalkenyl, lower alkynyl, lower alkoxycarbonyl, mono or Di-lower alkylcarbamoyl, lower alkyl Rufinyl, lower alkyls
- Substituted, unsubstituted lower alkanoylamino may be the same or different, for example, more specifically 1 to 3 substituents.
- substituted or unsubstituted lower alkylsulfonyl substituted or unsubstituted lower alkylsulfonyl are the same or different, for example, having 1 to 3 substituents, more specifically, Halogen, hydroxy, cyano and the like
- substituted or unsubstituted lower alkoxy substituted or unsubstituted lower alkoxy [substituents in the substituted lower alkoxy are the same or different, for example, having 1 to 3 substituents, more specifically halogen, amino Mono or di (lower alkyl) amino, hydroxy, cyano, lower alkoxy, lower alkoxycarbonyl, lower alkoxycarbonylamino, lower alkanoyl, cycloalkyl, lower
- Substituted or unsubstituted lower alkanoyl substituted or different and include, for example, 1 to 3 substituents, more specifically halogen, etc.
- substituted or non-substituted Substituted aryl substituted or non-substituted Substituted aryl
- substituted or non-substituted A substituted aralkyl the substituents in the substituted aralkyl are the same or different,
- the number of substituents is 1 to 3, more specifically, halogen, hydroxy, lower alkoxy and the like, and substituted or unsubstituted aromatic heterocyclic groups (substituents in the substituted aromatic heterocyclic groups are the same) Or differently, for example, having 1 to 3 substituents, more specifically,
- a substituted aryl, a substituted aromatic heterocyclic group, a substituted alicyclic heterocyclic group, a substituted aromatic heterocyclic group formed together with an adjacent nitrogen atom, and an adjacent nitrogen atom are formed.
- the substituent in the substituted alicyclic heterocyclic group is a substituted or unsubstituted lower alkyl (the substituents in the substituted lower alkyl are the same or different, for example, 1 to 3 substituents, more specifically halogen Amino, hydroxy, hydroxyimino, cyano, mono- or di-lower alkylamino, aromatic heterocyclic group, alicyclic heterocyclic group, and the like.
- the substituent in the substituted alicyclic heterocyclic group formed together with the substituted lower alkyl, the substituted alicyclic heterocyclic group and the adjacent nitrogen atom may be oxo.
- the substituent in the case where the substituted aryl is an aryl condensed with a substituted alicyclic heterocyclic group includes oxo.
- an alicyclic heterocyclic group, an aromatic heterocyclic group, an aromatic heterocyclic group formed together with an adjacent nitrogen atom, and a substituted alicyclic heterocyclic formed together with an adjacent nitrogen atom When the ring group has a nitrogen atom and / or a sulfur atom in the ring, the nitrogen atom and / or the sulfur atom may be oxidized.
- lower alkyl, cycloalkyl, cycloalkenyl, aryl, aromatic heterocyclic group and alicyclic heterocyclic group have the same meanings as described above.
- the halogen include fluorine, chlorine, bromine, and iodine atoms.
- the lower alkyl-substituted alicyclic heterocyclic group and the lower alkyl moiety of lower alkylthio have the same meaning as the lower alkyl.
- the two lower alkyl moieties in di-lower alkylamino and di-lower alkylcarbamoyl may be the same or different.
- the cycloalkylene moiety in the lower alkyl-substituted cycloalkyl has the same meaning as that obtained by removing one hydrogen atom from the cycloalkyl.
- the cycloalkyl moiety in cycloalkyloxy has the same meaning as the above cycloalkyl.
- alkylene part in aralkyl, aralkyloxy, alicyclic heterocyclic alkyloxy and hydroxyalkyl has the same meaning as that obtained by removing one hydrogen atom from the lower alkyl.
- lower alkenyl include linear or branched alkenyl having 3 to 10 carbon atoms, and more specifically, allyl, 2-butenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, Examples include 6-heptenyl, 6-octenyl, 2,6-octadienyl, 9-decenyl and the like.
- lower alkynyl examples include linear or branched alkynyl having 3 to 6 carbon atoms, and more specifically, propargyl, 3-butynyl, 3-hexynyl, 4-methyl-2-pentynyl and the like. Can be mentioned.
- Examples of the lower alkanoyl part of lower alkanoyl and lower alkanoylamino include linear or branched alkanoyl having 1 to 8 carbon atoms, and more specifically formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl. , Isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl and the like.
- the aryl part of aralkyl, aryloxy, aralkyloxy and aroyl has the same meaning as the above aryl.
- the alicyclic heterocyclic group part in alicyclic heterocyclic oxy and alicyclic heterocyclic alkyloxy is synonymous with the said alicyclic heterocyclic group.
- the alicyclic heterocyclic group moiety in the lower alkyl-substituted alicyclic heterocyclic group has the same meaning as that obtained by removing one hydrogen atom from the alicyclic heterocyclic group.
- aromatic heterocyclic group moiety in the aromatic heterocyclic aminosulfonyl has the same meaning as the aromatic heterocyclic group.
- compound (I) or a pharmaceutically acceptable salt thereof can be used as the preventive and / or therapeutic agent for pain of the present invention.
- R 5 , R 6 and R 7 are each hydrogen.
- Compound (I) which is an atom or a pharmaceutically acceptable salt thereof, (ii) Compound (I) wherein R 1 and R 2 are substituted or unsubstituted aryl, or a pharmaceutically acceptable salt thereof (iii) ) Compound (I), wherein R 3 is a hydrogen atom and R 4 is substituted or unsubstituted tetrahydroquinolyl, or a pharmaceutically acceptable salt thereof can be used. More preferably, the compound of the aspect which combined two or three said (i), (ii) and (iii) can be used. More preferably, a compound selected from compounds 188, 191, 229, 240, 257, 270, 310, 314 and 332 can be used.
- Examples of the pharmaceutically acceptable salt of compound (I) include pharmaceutically acceptable metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, acid addition salts, and the like.
- Examples of the pharmaceutically acceptable metal salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt and zinc salt, and the like.
- Examples of ammonium salts include ammonium and tetramethylammonium salts
- pharmaceutically acceptable organic amine addition salts include addition salts such as morpholine and piperidine, which are pharmaceutically acceptable.
- Examples of amino acid addition salts include addition salts of amino acids such as lysine, glycine, and phenylalanine.
- Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloride, sulfate, and phosphate, Examples thereof include organic acid salts such as acetate, maleate, fumarate, tartrate and citrate.
- Compound (I) and a pharmaceutically acceptable salt thereof in the present invention may exist in the form of an adduct with water or various solvents, and these adducts are also used for the prevention of pain and / or the present invention. Can be used for therapeutic agents.
- the compound (I) may be purified as it is when it is obtained in the form of a salt. It may be isolated or purified by dissolving or suspending in an appropriate solvent and adding an acid or base to form a salt.
- Some compounds (I) in the present invention may have various stereoisomers, positional isomers, tautomers, enantiomers and the like. All the possible isomers and mixtures thereof can be used for the preventive and / or therapeutic agent for pain of the present invention, and the mixing ratio may be any ratio. Next, the manufacturing method of the compound used by this invention is demonstrated. Compound (I) or a pharmaceutically acceptable salt thereof can be produced, for example, by the method described in WO2008 / 007780. Specific examples of the compounds used in the present invention are shown in Tables 1 to 6, but the compounds used for the preventive and / or therapeutic agents for pain of the present invention are not limited thereto.
- Intermediates and target compounds in the above production method are isolated and purified by subjecting them to separation and purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. Can do.
- the intermediate can be subjected to the next reaction without any particular purification.
- Compound (I) or a pharmaceutically acceptable salt thereof can be used for the prevention and / or treatment of inflammatory pain, and preferably can be used for the prevention and / or treatment of chronic inflammatory pain, More preferably, it can be used for the prevention and / or treatment of pain associated with arthritis such as osteoarthritis and rheumatoid arthritis.
- postoperative pain include chest thoracotomy, pain after laparotomy, pain after mastectomy, pain after orthopedic surgery, pain after tooth extraction, and the like.
- Compound (I) or a pharmaceutically acceptable salt thereof can be used for the prevention and / or treatment of postoperative pain.
- Cancer pain is a symptom that appears as cancer progresses, and the causes of the pain are known to be inflammation around the cancer, nerve compression due to cancer, bone metastasis, and the like.
- Cancer pain includes, for example, pain associated with various cancers such as breast cancer, prostate cancer, ovarian cancer, uterine cancer, lung cancer, bone cancer, esophageal cancer, stomach cancer, liver cancer, pancreatic cancer, colon cancer, skin cancer, and tongue cancer. Is mentioned.
- Compound (I) or a pharmaceutically acceptable salt thereof can be used for the prevention and / or treatment of cancer pain, and preferably used for the prevention and / or treatment of cancer pain associated with bone metastasis. Can do.
- Neuropathic pain includes postherpetic neuralgia, diabetic neuropathic pain, HIV-related pain, trigeminal neuralgia, pain associated with cancer chemotherapy, fibromyalgia and the like.
- vinca alkaloid preparations such as vincristine used in chemotherapy, taxane preparations such as paclitaxel, and platinum complex preparations such as cisplatin, as side effects, damage the axon function of nerve cells, causing pain and numbness.
- peripheral neuropathy such as sensory disorder
- pain associated with these neuropathies is classified as pain associated with cancer chemotherapy.
- Compound (I) or a pharmaceutically acceptable salt thereof can be used for the prevention and / or treatment of neuropathic pain, and preferably used for the prevention and / or treatment of pain associated with cancer chemotherapy. Can do.
- Test Example 1 Analgesic effect in rat model of complete Freund's adjuvant (CFA) -induced inflammatory pain Crl: CD (SD) rats (male, 5 weeks old, Charles River, Japan) Freund's adjuvant (CFA) (DIFCO Laboratories) 100 ⁇ L was subcutaneously administered to induce inflammatory pain.
- Compound 332 was evaluated 24 hours after CFA administration, and compound 257 was evaluated 7 days after CFA administration.
- Hot / Cold® Plate® 35100® manufactured by Ugo® Basile
- Rats were placed on a hot plate maintained at a temperature of 48 ° C., and the time (latency) until a pain reaction such as licking, biting, or shaking of the treated side was measured.
- the rats were left in the laboratory for about 1 hour, and the latency before drug administration was measured.
- the latency of normal rats was about 30 seconds, but the latency of CFA-induced inflammatory pain rats with CFA was about 15 seconds, confirming a reduction in latency that was recognized as hyperalgesia.
- the test compound was administered to this CFA-induced inflammatory pain model according to the following procedure, the latency was measured, and the improvement rate was calculated from the following formula.
- Compound 332 was suspended in 0.5% methylcellulose (0.5% MC) aqueous solution at concentrations of 0.6 and 2 mg / mL, and doses of 3 and 10 mg / kg were orally administered.
- Compound 257 was suspended in 0.5% aqueous MC solution at concentrations of 2 and 6 mg / mL, and doses of 10 and 30 mg / kg were orally administered.
- 0.5% MC aqueous solution was orally administered to a CFA-induced inflammatory pain model. The test was conducted with 8 animals in each group. For Compound 332, the improvement rate 3 hours after its administration was calculated, and for Compound 257, the improvement rate 4 hours after its administration was calculated.
- Crl CD (SD) rats (male, 5 weeks old, Charles River Japan, Inc.) were anesthetized with pentobarbital (50 mg / kg, intraperitoneal administration) and the sole of the left hind limb was disinfected with popidone iodine. Thereafter, the skin and fascia were incised approximately 1 cm from a position 0.5 mm from the heel. Thereafter, the plantar muscle was lifted with tweezers, and an incision was made about 1 cm. After compression and hemostasis with absorbent cotton, the skin was sutured with two nylon sutures. For evaluation of pain, a plantar test apparatus (manufactured by Ugo Basile) was used.
- the rat was placed in an acrylic cage (width 390 mm ⁇ depth 210 mm ⁇ height 145 mm, rat 4-chamber cage, manufactured by Ugo Basile) for about 20 minutes to get used to the surrounding environment. Thereafter, radiant heat was applied to the left hind limb incision of the rat, and the time (latency) until an escape reaction (lifting the foot) before drug administration was measured was measured.
- the latency of normal rats was about 17-19 seconds, but the postoperative pain model rats had a latency of about 7-9 seconds on the surgical foot, confirming a shortened latency that was recognized as hyperalgesia. .
- test compound was administered to the postoperative pain model according to the following procedure, the latency was measured 3 hours after administration, and the improvement rate was calculated in the same manner as in Test Example 1.
- Compound 332 was suspended in an aqueous 0.5% methylcellulose (0.5% MC) solution at a concentration of 2 mg / mL, and a dose of 10 mg / kg was orally administered.
- Compound 257 was suspended in 0.5% MC aqueous solution at a concentration of 6 mg / mL, and was orally administered at a dose of 30 mg / kg.
- a solvent administration group a group in which 0.5 mL MC aqueous solution was orally administered to a postoperative pain model was provided. The test was conducted with 8 animals in each group.
- the improvement rate of the compound 332 administration group was 63.0 ⁇ 11.4%, which was significantly higher than the improvement rate of the solvent administration group ( ⁇ 5.9 ⁇ 8.0%). That is, it has been clarified that Compound 332 exhibits a pain suppressing effect in an animal model of postoperative pain.
- the improvement rate of the compound 257 administration group was 81.7 ⁇ 21.2%, which was significantly higher than the improvement rate of the solvent administration group (3.9 ⁇ 20.4%). That is, it has been clarified that Compound 257 exhibits a pain suppressing effect in an animal model of postoperative pain.
- Test Example 3 Analgesic effect in mouse cancer pain model A report by Honore et al. [Neuroscience, 2000, Vol. 98, p.585] was used to prepare a cancer pain model.
- C3H / He mice male, 4 weeks old, Nippon Charles River
- pentobarbital 50-60 mg / kg, intraperitoneal administration
- the skin of the left knee joint was about 5
- An incision was made, and a 26-gauge injection needle was inserted into the bone marrow cavity from the distal end of the femur to open a hole for cell implantation.
- 10 ⁇ L of a cell solution containing 2.5 ⁇ 10 4 tumor cells (NCTC 2472 osteolytic sarcoma cell, purchased from American Type Culture Collection) was injected into the bone marrow cavity. Thereafter, the skin was sutured. Pain assessment was performed 2-3 weeks after the creation of the cancer pain model.
- the time for guarding behavior was measured according to the report of Honore et al. That is, the mouse was allowed to walk freely on the observation wire mesh, and the time during which the left hind limb was raised (guarding behavior) out of the observation time of 2 minutes was measured and used as an index of pain behavior. Normal animals did not show guarding behavior, but a guarding behavior of about 10 seconds was observed in the cancer pain model.
- the test compound was administered to the above cancer pain model animal according to the following procedure, and the guarding time in the observation period of 2 minutes was measured 3 hours later.
- Compound 332 was suspended in an aqueous 0.5% methylcellulose (0.5% MC) solution at a concentration of 2 mg / mL, and a dose of 10 mg / kg was orally administered.
- Compound 257 was suspended in 0.5% MC aqueous solution at a concentration of 6 mg / mL, and a dose of 30 mg / kg was orally administered.
- a solvent administration group a group in which 0.5 mL MC aqueous solution was orally administered to cancer pain mice was provided. Using 10 animals in each group, the average value of guarding action time ⁇ standard error was obtained.
- the guarding action time per observation time of 2 minutes was 9.3 ⁇ 1.0 seconds in the solvent administration group and 5.7 ⁇ 1.0 seconds in the compound 332 administration group. Compared to the solvent-administered group, the guarding action time was significantly shortened in the compound 332-administered group. That is, Compound 332 showed a pain suppressing effect in an animal model of cancer pain.
- the guarding behavior time per observation time of 2 minutes was 11.0 ⁇ 1.1 seconds in the solvent administration group and 5.1 ⁇ 0.7 seconds in the compound 257 administration group. Compared to the solvent-administered group, the guarding action time was significantly shortened in the compound 257-administered group. That is, Compound 257 showed a pain suppressing effect in an animal model of cancer pain.
- Compound (I) or a pharmaceutically acceptable salt thereof suppresses pain behavior in a cancer pain model. Therefore, Compound (I) or a pharmaceutically acceptable salt thereof is effective for the prevention and / or treatment of cancer pain. That is, compound (I) or a pharmaceutically acceptable salt thereof is, for example, breast cancer, prostate cancer, ovarian cancer, uterine cancer, lung cancer, bone cancer, esophageal cancer, stomach cancer, liver cancer, pancreatic cancer, colon cancer, skin It became clear that it is useful for the treatment and prevention of pain associated with various cancers such as cancer and tongue cancer.
- Test Example 4 Paclitaxel with reference to the report of the analgesic effect of Flatters et al.
- the pain was evaluated according to the report of Flatters et al. Place the rat in a transparent acrylic cage (390 mm wide x 210 mm deep x 145 mm high, 4 rat cage, manufactured by Ugo Basile) with a metal mesh on the bottom, and leave the surrounding environment for about 20 minutes. After habituation, the von Frey filament (von Frey filament (trade name: touch test ⁇ sensory evaluator, manufactured by Muromachi Kikai Co., Ltd.)) with a bending pressure of 10 g is vertically placed in the middle of the sole of the hind limb until the filament bends 5 Pressed for 2 seconds and observed for escape behavior (withdrawal of foot).
- von Frey filament Japanese Frey filament (trade name: touch test ⁇ sensory evaluator, manufactured by Muromachi Kikai Co., Ltd.)
- a bending pressure of 10 g is vertically placed in the middle of the sole of the hind limb until the filament bends 5 Pressed for 2 seconds and observed for escape behavior (
- Compound 332 or compound 257 was administered to the above-mentioned paclitaxel-induced painful neuropathy model animal by the following procedure, and the response rate of escape behavior was measured 3 hours after administration of compound 332 and 1 hour after administration of compound 257. .
- Compound 332 was suspended in an aqueous solution of 0.5% methylcellulose (0.5% MC) at a concentration of 2 mg / mL, and a dose of 10 mg / kg was orally administered.
- Compound 257 was suspended in a 0.5% aqueous MC solution at a concentration of 6 mg / mL, and a dose of 30 mg / kg was orally administered.
- a solvent administration group a group in which 0.5% MC aqueous solution was orally administered to a paclitaxel-induced painful neuropathy model was provided. The test was conducted with 8 animals in each group.
- the response rate of escape behavior 3 hours after administration was 72.5 ⁇ 5.3% in the solvent administration group and 42.5 ⁇ 3.7% in the Compound 332 administration group.
- the compound 332 administration group showed a marked decrease in the response rate of escape behavior. That is, Compound 332 showed a pain-suppressing effect in an animal model of paclitaxel-induced neuropathic pain.
- the response rate of the escape behavior 1 hour after administration was 67.5 ⁇ 5.6% in the solvent administration group and 45.0 ⁇ 8.2% in the Compound 257 administration group.
- the compound 257-administered group showed a marked decrease in the response rate of escape behavior. That is, Compound 257 showed a pain-suppressing effect in an animal model of paclitaxel-induced neuropathic pain.
- Test Example 5 An analgesic effect experiment in a rat streptozotocin-induced diabetic pain model was performed by the method of Calcutt et al. [British Journal of Pharmacology, 1997, Vol. 122, p.1478]. According to the same procedure. Streptozotocin (60 mg / kg) was intraperitoneally administered to male SD rats to develop diabetes.
- the rat is placed in a cage made of metal mesh on the bottom and made of acrylic (width 390 mm ⁇ depth 210 mm ⁇ height 145 mm, rat quadruple cage, Ugo Basile, Comerio, VA, Italy)
- the pain threshold was measured after acclimatization to the surrounding environment for 20 minutes.
- von Frey filament trade name: touch test sensory evaluator, model number: model 58011, manufactured by Muromachi Kikai Co., Ltd.
- Pain threshold is based on Dixon's up-down method [Annual Review of Pharmacology and Toxicology, 1980, Volume 20, p.411] Calculated.
- diabetic rats having a pain threshold of less than 4 g were used.
- Compound 332 was suspended in an aqueous solution of 0.5% methylcellulose (0.5% MC) at a concentration of 2 mg / mL, and a dose of 10 mg / kg was orally administered.
- Compound 257 was suspended in 0.5% aqueous MC solution at a concentration of 6 mg / mL and orally administered at a dose of 30 mg / kg.
- 0.5% MC aqueous solution was orally administered at 5 mL / kg.
- the solvent administration group and drug administration group were 6 cases, and the normal animal group was 10 cases.
- the pain threshold for normal rats was around 10 g.
- the pain threshold was measured 3 hours after administration of the test compound (Compound 332 or Compound 257) and the solvent, and the improvement rate was calculated from the following formula.
- the improvement rate of the compound 332 administration group was 74.0 ⁇ 22.6%, which was significantly higher than the improvement rate of the solvent administration group ( ⁇ 5.8 ⁇ 5.5%). That is, Compound 332 showed a pain suppressing effect in an animal model of diabetic pain.
- the improvement rate of the compound 257 administration group was 75.7 ⁇ 22.4%, which was significantly higher than the improvement rate of the solvent administration group ( ⁇ 0.2 ⁇ 3.1%). That is, Compound 257 showed a pain suppressing effect in an animal model of diabetic pain.
- Test Example 6 Analgesic inhibitory effect in mouse gp120-induced pain model (HIV-related pain model) A ddY male mouse is placed in a cage made of a metal mesh on the bottom and made of acrylic (width 390 mm x depth 210 mm x height 145 mm, 8-mouse cage, Ugo Basile, Comerio, VA, Italy), 120 The pain threshold was measured after acclimatization to the surrounding environment for a minute.
- von Frey filament (trade name: touch test sensory evaluator, model number: model 58011, manufactured by Muromachi Kikai Co., Ltd.) was used. Pain threshold is based on Dixon's up-down method [Annual Review of Pharmacology and Toxicology, 1980, Volume 20, p.411] Calculated. Evaluate mice whose pain threshold is less than 0.5 g after 1 hour administration of 5 ⁇ L of gp120 solution (2 pg / ⁇ L, dissolved in phosphate buffer) into the medullary canal of mice with a pain threshold of 0.9 g or more Used for. Compound 332 was administered 1.5 hours after administration of the gp120 solution, and the pain threshold was measured 1 hour later.
- Compound 332 was suspended in an aqueous 0.5% methylcellulose (0.5% MC) solution at a concentration of 1 mg / mL, and a dose of 10 mg / kg was orally administered.
- the solvent administration group was orally administered with a 0.5% MC aqueous solution at 10 mL / kg.
- the test was conducted in 7 cases in each group.
- the improvement rate of the compound 332 administration group was 51.3 ⁇ 12.9%, which was significantly higher than the improvement rate of the solvent administration group (4.0 ⁇ 2.5%). That is, Compound 332 showed a pain suppressing effect in an HIV-related pain animal model.
- Step 2 (2E, 4Z) -N-[(3R) -3-Hydroxy-2-oxo-1,2,3,4-tetrahydro-5-quinolyl] -5- (4-isopropoxyphenyl) -5
- 5- [4- (Trifluoromethyl) phenyl] -2,4-pentadienoic acid (6.00 g, 16.0 mmol) is dissolved in dimethylformamide (DMF, 120 mL), and compound a (3.21 g, 18.0 mmol), 1 -Ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) hydrochloride (6.14 g, 32.0
- Compound (I) or a pharmaceutically acceptable salt thereof can be administered alone as it is, but it is usually desirable to provide it as various pharmaceutical preparations. These pharmaceutical preparations are used for animals or humans.
- the pharmaceutical preparation according to the present invention can contain Compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient alone or as a mixture with any other active ingredient for treatment.
- These pharmaceutical preparations are well known in the technical field of pharmaceutics by mixing the active ingredient together with one or more pharmaceutically acceptable carriers (eg, diluents, solvents, excipients, etc.). It is formulated by any method.
- the administration route it is desirable to use one that is most effective in the treatment, and can be oral or parenteral, such as intravenous.
- the dosage form include tablets and injections.
- tablets suitable for oral administration can be produced using excipients such as lactose, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, and the like.
- an injection suitable for parenteral administration can be produced using a diluent or a solvent such as a salt solution, a glucose solution, or a mixed solution of a saline solution and a glucose solution.
- the dose and frequency of administration of compound (I) or a pharmaceutically acceptable salt thereof vary depending on the administration form, patient age, body weight, nature or severity of symptoms to be treated, etc.
- the dose is 0.01 to 1000 mg, preferably 0.05 to 100 mg per adult, once to several times a day.
- parenteral administration such as intravenous administration
- 0.001 to 1000 mg preferably 0.01 to 100 mg per adult is usually administered once to several times a day.
- the dose and the number of doses vary depending on the various conditions described above.
- Formulation Example 1 Tablet A tablet having the following composition is prepared by a conventional method. 40 g of Compound 257, 286.8 g of lactose and 60 g of potato starch are mixed, and 120 g of a 10% aqueous solution of hydroxypropylcellulose is added thereto. The obtained mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. To this, 1.2 g of magnesium stearate is added and mixed, and tableting is performed with a tableting machine having a 8 mm diameter punch to obtain tablets (containing 20 mg of active ingredient per tablet).
- Formula Compound 257 20 mg Lactose 143.4 mg
- Formulation Example 2 Tablets As in Example 1, tablets are prepared with the following formulation.
- Formula Compound 332 20 mg Lactose 143.4 mg
- Potato starch 30 mg Hydroxypropylcellulose 6 mg
- Magnesium stearate 0.6 mg 200 mg
- Formulation example 3 Injection The injection which consists of the following compositions is prepared by a conventional method. 1 mg of Compound 257 is added to and mixed with distilled water for injection, and further, hydrochloric acid and aqueous sodium hydroxide solution are added to adjust the pH to 7. Then, the total volume is made up to 1000 mL with distilled water for injection. The obtained mixed solution is aseptically filled into glass vials by 2 mL to obtain an injection (containing 2 ⁇ g of active ingredient per vial).
- Formulation Compound 257 2 ⁇ g Hydrochloric acid appropriate amount Sodium hydroxide aqueous solution appropriate amount distilled water for injection appropriate amount 2.00 mL
- Formulation Example 4 Injection An injection is prepared according to the following formulation in the same manner as in Example 3.
- Formula Compound 332 2 ⁇ g Hydrochloric acid appropriate amount Sodium hydroxide aqueous solution appropriate amount distilled water for injection appropriate amount 2.00 mL
- a pentadienamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
- a prophylactic and / or therapeutic agent for pain selected from accompanying pain can be provided.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Pain & Pain Management (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Rheumatology (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
La présente invention concerne un agent prophylactique et/ou thérapeutique contre la douleur choisie parmi une douleur induite par une inflammation, une douleur post-opératoire, une douleur neurogène du diabète, une douleur associée au VIH, une douleur cancéreuse et une douleur neurogène associée à une chimiothérapie cancéreuse. Ledit agent comprend un dérivé de pentadiénamide représenté par la formule générale (I) [dans laquelle R1 représente un groupe aryle substitué ou non substitué ou un groupe hétérocyclique aromatique substitué ou non substitué ; R2 représente un groupe aryle substitué ou non substitué, un groupe hétérocyclique aromatique substitué ou non substitué, ou analogue ; R3 représente un atome d’hydrogène ou analogue ; R4 représente un groupe alkyle inférieur substitué ou non substitué, un groupe aryle substitué ou non substitué ou un groupe hétérocyclique alicyclique substitué, ou non substitué ou analogue ; et R5, R6 et R7 représentent indépendamment un atome d’hydrogène ou analogue] ou un sel pharmaceutiquement acceptable de celui-ci en tant que principe actif ; et d’autres.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2010528760A JPWO2010029995A1 (ja) | 2008-09-11 | 2009-09-11 | 疼痛治療剤 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2008-233397 | 2008-09-11 | ||
JP2008233397 | 2008-09-11 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2010029995A1 true WO2010029995A1 (fr) | 2010-03-18 |
Family
ID=42005245
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2009/065911 WO2010029995A1 (fr) | 2008-09-11 | 2009-09-11 | Agent thérapeutique contre la douleur |
Country Status (2)
Country | Link |
---|---|
JP (1) | JPWO2010029995A1 (fr) |
WO (1) | WO2010029995A1 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2014111592A (ja) * | 2012-11-08 | 2014-06-19 | Kao Corp | 体感温度低減用外用剤 |
JPWO2013022080A1 (ja) * | 2011-08-10 | 2015-03-05 | 国立大学法人富山大学 | 動物を用いた痺れ又は自発痛の評価方法 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH05230069A (ja) * | 1992-02-20 | 1993-09-07 | Yamanouchi Pharmaceut Co Ltd | 新規なピロロチアゾ−ル誘導体 |
WO2005044786A1 (fr) * | 2003-11-08 | 2005-05-19 | Bayer Healthcare Ag | Derives bicycliques d'amide, de carbamate ou d'uree tel que recepteur modulateurs vanilloïde |
WO2008007780A1 (fr) * | 2006-07-13 | 2008-01-17 | Kyowa Hakko Kirin Co., Ltd. | Dérivé du pentadiènamide |
WO2008096755A1 (fr) * | 2007-02-07 | 2008-08-14 | Nippon Suisan Kaisha, Ltd. | Inhibiteur du récepteur vanilloïde (vr1) et son utilisation |
JP2008533177A (ja) * | 2005-03-24 | 2008-08-21 | ノボジェン リサーチ ピーティーワイ リミテッド | 抗炎症治療法 |
-
2009
- 2009-09-11 WO PCT/JP2009/065911 patent/WO2010029995A1/fr active Application Filing
- 2009-09-11 JP JP2010528760A patent/JPWO2010029995A1/ja not_active Withdrawn
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH05230069A (ja) * | 1992-02-20 | 1993-09-07 | Yamanouchi Pharmaceut Co Ltd | 新規なピロロチアゾ−ル誘導体 |
WO2005044786A1 (fr) * | 2003-11-08 | 2005-05-19 | Bayer Healthcare Ag | Derives bicycliques d'amide, de carbamate ou d'uree tel que recepteur modulateurs vanilloïde |
JP2008533177A (ja) * | 2005-03-24 | 2008-08-21 | ノボジェン リサーチ ピーティーワイ リミテッド | 抗炎症治療法 |
WO2008007780A1 (fr) * | 2006-07-13 | 2008-01-17 | Kyowa Hakko Kirin Co., Ltd. | Dérivé du pentadiènamide |
WO2008096755A1 (fr) * | 2007-02-07 | 2008-08-14 | Nippon Suisan Kaisha, Ltd. | Inhibiteur du récepteur vanilloïde (vr1) et son utilisation |
Non-Patent Citations (1)
Title |
---|
WALKER, KATHARINE M ET AL.: "The VR1 antagonist Capsazepine reverses mechanical hyperalgesia in models of inflammatory and neuropathic pain", THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 304, no. 1, 2003, pages 56 - 62 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPWO2013022080A1 (ja) * | 2011-08-10 | 2015-03-05 | 国立大学法人富山大学 | 動物を用いた痺れ又は自発痛の評価方法 |
JP2014111592A (ja) * | 2012-11-08 | 2014-06-19 | Kao Corp | 体感温度低減用外用剤 |
Also Published As
Publication number | Publication date |
---|---|
JPWO2010029995A1 (ja) | 2012-02-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
RU2650895C2 (ru) | Соединения замещенных пиразолонов и способы использования | |
US20090042883A1 (en) | Antitumor agent | |
TW200307535A (en) | Therapeutic agent for cancer | |
BR112019020691A2 (pt) | Composição farmacêutica contendo agonista do mor e agonista do kor, e usos da mesma | |
US20150297581A1 (en) | Rho kinase inhibitors | |
US8178529B2 (en) | Imidazole substituted pyrimidines | |
AU2014214326B2 (en) | Substituted quinoxaline derivatives and their use as positive allosteric modulators of mGluR4 | |
BR112014023460B1 (pt) | Composto, formulação farmacêutica, uso de um composto | |
US20110212973A1 (en) | Carbamate compound or salt thereof | |
BR112013022552B1 (pt) | Compostos de quinazolina substituídos com alcino, seu uso, composição farmacêutica, e kit | |
JP6155026B2 (ja) | プロテインキナーゼ阻害のための新規化合物及びその治療的使用 | |
MX2015003276A (es) | Profarmacos de aminoquinazolina inhibidora de cinasa. | |
JP6521995B2 (ja) | 選択的マトリックスメタロプロテイナーゼ阻害剤 | |
AU2015269449A1 (en) | 2-acylaminothiazole derivative or salt thereof | |
AU2015218775C1 (en) | Antimitotic amides for the treatment of cancer and proliferative disorders | |
AU2016298962A1 (en) | Compounds and pharmaceutical composition associated with ubiquitination-proteasome system | |
KR20030085005A (ko) | 진양제 | |
WO2010029995A1 (fr) | Agent thérapeutique contre la douleur | |
KR101704386B1 (ko) | 티에노[3,2-d]피리미딘 유도체의 T315I-Bcr-Abl 점돌연변이종의 저해 활성 | |
EP2631233A1 (fr) | Antagoniste du récepteur muté des androgènes | |
US9642851B2 (en) | Indolinone derivative as tyrosine kinase inhibitor | |
JPWO2006132192A1 (ja) | 新規2−キノロン誘導体 | |
CN108473504B (zh) | 新型二氢吡喃并嘧啶酮衍生物及其用途 | |
TW201925208A (zh) | 對於蛋白激酶具抑制活性之噻吩并[3,2-d]嘧啶化合物 | |
WO2016206551A1 (fr) | Application d'inhibiteur de la protéine src dans un médicament pour la prévention et/ou le traitement de la maladie d'alzheimer |
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: 09813141 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2010528760 Country of ref document: JP |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 09813141 Country of ref document: EP Kind code of ref document: A1 |