KR20080080212A - 바닐로이드 수용체 １ (ｖｒｌ) 억제제로서의 신규벤즈이미다졸 유도체 - Google Patents
바닐로이드 수용체 １ (ｖｒｌ) 억제제로서의 신규벤즈이미다졸 유도체 Download PDFInfo
- Publication number
- KR20080080212A KR20080080212A KR1020087017908A KR20087017908A KR20080080212A KR 20080080212 A KR20080080212 A KR 20080080212A KR 1020087017908 A KR1020087017908 A KR 1020087017908A KR 20087017908 A KR20087017908 A KR 20087017908A KR 20080080212 A KR20080080212 A KR 20080080212A
- Authority
- KR
- South Korea
- Prior art keywords
- ethyl
- acetamide
- benzimidazol
- nitro
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 102100029613 Transient receptor potential cation channel subfamily V member 1 Human genes 0.000 title claims description 47
- 108050004388 Transient receptor potential cation channel subfamily V member 1 Proteins 0.000 title claims description 47
- 239000003112 inhibitor Substances 0.000 title description 6
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 title description 2
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 171
- 238000000034 method Methods 0.000 claims abstract description 49
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 239000012453 solvate Substances 0.000 claims abstract description 9
- -1 phenyloxymethyl Chemical group 0.000 claims description 314
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 136
- 208000002193 Pain Diseases 0.000 claims description 44
- 125000001424 substituent group Chemical group 0.000 claims description 43
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 41
- 230000001154 acute effect Effects 0.000 claims description 34
- 208000035475 disorder Diseases 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 29
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 28
- 230000001684 chronic effect Effects 0.000 claims description 27
- 125000001153 fluoro group Chemical group F* 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 20
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 19
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 17
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 125000004791 2-fluoroethoxy group Chemical group FCCO* 0.000 claims description 12
- 206010065390 Inflammatory pain Diseases 0.000 claims description 12
- 208000004296 neuralgia Diseases 0.000 claims description 12
- 208000021722 neuropathic pain Diseases 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- DBVQWDRJFZMDDL-UHFFFAOYSA-N 1-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]ethanamine Chemical compound CC(N)C1=CC=C(OCC(F)(F)F)N=C1 DBVQWDRJFZMDDL-UHFFFAOYSA-N 0.000 claims description 10
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 10
- 208000000094 Chronic Pain Diseases 0.000 claims description 10
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 10
- 208000005298 acute pain Diseases 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 10
- 230000001404 mediated effect Effects 0.000 claims description 10
- 208000023504 respiratory system disease Diseases 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 208000021302 gastroesophageal reflux disease Diseases 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 125000001887 cyclopentyloxy group Chemical group C1(CCCC1)O* 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 7
- 208000008589 Obesity Diseases 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 235000020824 obesity Nutrition 0.000 claims description 7
- 208000024891 symptom Diseases 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- XWOYHZILMRKZMH-UHFFFAOYSA-N 1-(6-tert-butylpyridin-3-yl)ethanamine Chemical compound CC(N)C1=CC=C(C(C)(C)C)N=C1 XWOYHZILMRKZMH-UHFFFAOYSA-N 0.000 claims description 6
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 6
- 208000005615 Interstitial Cystitis Diseases 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 6
- 239000012190 activator Substances 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000002950 monocyclic group Chemical group 0.000 claims description 5
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 4
- JPEGBZFDDUESBF-UHFFFAOYSA-N 1-(6-cyclopentyloxypyridin-3-yl)ethanamine Chemical compound N1=CC(C(N)C)=CC=C1OC1CCCC1 JPEGBZFDDUESBF-UHFFFAOYSA-N 0.000 claims description 4
- OCWSWURUXBXYPL-UHFFFAOYSA-N 1-(6-tert-butyl-2-methylpyridin-3-yl)ethanamine Chemical compound CC(N)C1=CC=C(C(C)(C)C)N=C1C OCWSWURUXBXYPL-UHFFFAOYSA-N 0.000 claims description 4
- MITYSHHPULSAGE-RGURZIINSA-N 1-[4-[(2s)-2-methoxypropoxy]phenyl]ethanamine Chemical compound CO[C@@H](C)COC1=CC=C(C(C)N)C=C1 MITYSHHPULSAGE-RGURZIINSA-N 0.000 claims description 4
- KEDZLCLUXLHIKQ-UHFFFAOYSA-N 1-[6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl]ethanamine Chemical compound CC(N)C1=CC=C(OCC(F)(F)C(F)F)N=C1 KEDZLCLUXLHIKQ-UHFFFAOYSA-N 0.000 claims description 4
- PCGLOQBIDPTHMN-UHFFFAOYSA-N 1-[6-(2,2-difluoroethoxy)pyridin-3-yl]ethanamine Chemical compound CC(N)C1=CC=C(OCC(F)F)N=C1 PCGLOQBIDPTHMN-UHFFFAOYSA-N 0.000 claims description 4
- LIMVSYUTRODGLY-UHFFFAOYSA-N 1-[6-(2-fluoroethoxy)pyridin-3-yl]ethanamine Chemical compound CC(N)C1=CC=C(OCCF)N=C1 LIMVSYUTRODGLY-UHFFFAOYSA-N 0.000 claims description 4
- 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 claims description 4
- UKEQWYSCLIWAHQ-UHFFFAOYSA-N 2-(7-chlorobenzimidazol-1-yl)-n-[1-(6-propan-2-yloxypyridin-3-yl)ethyl]acetamide Chemical compound C1=NC(OC(C)C)=CC=C1C(C)NC(=O)CN1C2=C(Cl)C=CC=C2N=C1 UKEQWYSCLIWAHQ-UHFFFAOYSA-N 0.000 claims description 4
- YFDDTRRLUSZGFV-UHFFFAOYSA-N 6-tert-butyl-2-methylpyridine-3-carbonitrile Chemical compound CC1=NC(C(C)(C)C)=CC=C1C#N YFDDTRRLUSZGFV-UHFFFAOYSA-N 0.000 claims description 4
- AALSACTXRRHVGH-UHFFFAOYSA-N 6-tert-butyl-4-methylpyridine-3-carbonitrile Chemical compound CC1=CC(C(C)(C)C)=NC=C1C#N AALSACTXRRHVGH-UHFFFAOYSA-N 0.000 claims description 4
- 208000008035 Back Pain Diseases 0.000 claims description 4
- 206010011224 Cough Diseases 0.000 claims description 4
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 4
- 206010020853 Hypertonic bladder Diseases 0.000 claims description 4
- FGOOFBXONCYYFU-UHFFFAOYSA-N N-(7-cyanobenzimidazol-1-yl)acetamide Chemical compound C(C)(=O)NN1C=NC2=C1C(=CC=C2)C#N FGOOFBXONCYYFU-UHFFFAOYSA-N 0.000 claims description 4
- HRQVDFYSVVIRIK-UHFFFAOYSA-N N-(7-nitrobenzimidazol-1-yl)acetamide Chemical compound CC(=O)Nn1cnc2cccc([N+]([O-])=O)c12 HRQVDFYSVVIRIK-UHFFFAOYSA-N 0.000 claims description 4
- 208000009722 Overactive Urinary Bladder Diseases 0.000 claims description 4
- 206010033645 Pancreatitis Diseases 0.000 claims description 4
- 208000000450 Pelvic Pain Diseases 0.000 claims description 4
- 208000004550 Postoperative Pain Diseases 0.000 claims description 4
- 201000004681 Psoriasis Diseases 0.000 claims description 4
- 208000008765 Sciatica Diseases 0.000 claims description 4
- 206010047700 Vomiting Diseases 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 206010003246 arthritis Diseases 0.000 claims description 4
- 208000006673 asthma Diseases 0.000 claims description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 4
- 201000003146 cystitis Diseases 0.000 claims description 4
- 208000028867 ischemia Diseases 0.000 claims description 4
- 201000006417 multiple sclerosis Diseases 0.000 claims description 4
- 201000001119 neuropathy Diseases 0.000 claims description 4
- 230000007823 neuropathy Effects 0.000 claims description 4
- 208000020629 overactive bladder Diseases 0.000 claims description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 4
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- 208000009935 visceral pain Diseases 0.000 claims description 4
- 230000008673 vomiting Effects 0.000 claims description 4
- JFJPJOTYLAFMDE-UHFFFAOYSA-N 1-(6-tert-butyl-2-chloropyridin-3-yl)ethanamine Chemical compound CC(N)C1=CC=C(C(C)(C)C)N=C1Cl JFJPJOTYLAFMDE-UHFFFAOYSA-N 0.000 claims description 3
- AALOSQGYSQQSAF-UHFFFAOYSA-N 1-(6-tert-butyl-2-methoxypyridin-3-yl)ethanamine Chemical compound COC1=NC(C(C)(C)C)=CC=C1C(C)N AALOSQGYSQQSAF-UHFFFAOYSA-N 0.000 claims description 3
- BRTYBKBWWHXCNW-UHFFFAOYSA-N 1-(6-tert-butyl-4-methylpyridin-3-yl)ethanamine Chemical compound CC(N)C1=CN=C(C(C)(C)C)C=C1C BRTYBKBWWHXCNW-UHFFFAOYSA-N 0.000 claims description 3
- CBYHRTAEBJGIOT-UHFFFAOYSA-N 1-[4-(1-methylpiperidin-4-yl)oxy-3-(trifluoromethyl)phenyl]ethanamine Chemical compound FC(F)(F)C1=CC(C(N)C)=CC=C1OC1CCN(C)CC1 CBYHRTAEBJGIOT-UHFFFAOYSA-N 0.000 claims description 3
- ZARTWYNUPAMSJI-UHFFFAOYSA-N 1-[4-(2,2,2-trifluoroethoxy)phenyl]ethanamine Chemical compound CC(N)C1=CC=C(OCC(F)(F)F)C=C1 ZARTWYNUPAMSJI-UHFFFAOYSA-N 0.000 claims description 3
- LWFFJCCIYJNXRN-IENPIDJESA-N 1-[4-[(2s)-2-methoxypropoxy]-3-(trifluoromethyl)phenyl]ethanamine Chemical compound CO[C@@H](C)COC1=CC=C(C(C)N)C=C1C(F)(F)F LWFFJCCIYJNXRN-IENPIDJESA-N 0.000 claims description 3
- CRBPTRTYTRYTND-UHFFFAOYSA-N 2-(7-nitrobenzimidazol-1-yl)acetamide Chemical compound C1=CC([N+]([O-])=O)=C2N(CC(=O)N)C=NC2=C1 CRBPTRTYTRYTND-UHFFFAOYSA-N 0.000 claims description 3
- 206010014561 Emphysema Diseases 0.000 claims description 3
- 208000029523 Interstitial Lung disease Diseases 0.000 claims description 3
- 208000019695 Migraine disease Diseases 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- KTJLVUWPOQLDMN-NSHDSACASA-N n-[(1s)-1-(4-hydroxyphenyl)ethyl]-2-(7-nitrobenzimidazol-1-yl)acetamide Chemical compound C1([C@@H](NC(=O)CN2C3=C([N+]([O-])=O)C=CC=C3N=C2)C)=CC=C(O)C=C1 KTJLVUWPOQLDMN-NSHDSACASA-N 0.000 claims description 3
- CFSFMRBQOICZBR-UHFFFAOYSA-N n-[1-(6-tert-butyl-2-chloropyridin-3-yl)ethyl]-2-(7-cyanobenzimidazol-1-yl)acetamide Chemical compound C1=NC2=CC=CC(C#N)=C2N1CC(=O)NC(C)C1=CC=C(C(C)(C)C)N=C1Cl CFSFMRBQOICZBR-UHFFFAOYSA-N 0.000 claims description 3
- KVIWZGDQZSWRMU-UHFFFAOYSA-N n-[1-(6-tert-butyl-2-methoxypyridin-3-yl)ethyl]-2-(7-cyanobenzimidazol-1-yl)acetamide Chemical compound COC1=NC(C(C)(C)C)=CC=C1C(C)NC(=O)CN1C2=C(C#N)C=CC=C2N=C1 KVIWZGDQZSWRMU-UHFFFAOYSA-N 0.000 claims description 3
- GXSVWIPFOKAMDC-UHFFFAOYSA-N n-[1-(6-tert-butyl-2-methylpyridin-3-yl)ethyl]-2-(6,7-difluorobenzimidazol-1-yl)acetamide Chemical compound C1=NC2=CC=C(F)C(F)=C2N1CC(=O)NC(C)C1=CC=C(C(C)(C)C)N=C1C GXSVWIPFOKAMDC-UHFFFAOYSA-N 0.000 claims description 3
- YBWAPUVFZKXKIE-UHFFFAOYSA-N n-[1-(6-tert-butyl-4-methylpyridin-3-yl)ethyl]-2-(7-cyanobenzimidazol-1-yl)acetamide Chemical compound C1=NC2=CC=CC(C#N)=C2N1CC(=O)NC(C)C1=CN=C(C(C)(C)C)C=C1C YBWAPUVFZKXKIE-UHFFFAOYSA-N 0.000 claims description 3
- CFERFOIUABURIX-UHFFFAOYSA-N n-[1-(6-tert-butylpyridin-3-yl)ethyl]-2-(7-cyanobenzimidazol-1-yl)acetamide Chemical compound C1=NC2=CC=CC(C#N)=C2N1CC(=O)NC(C)C1=CC=C(C(C)(C)C)N=C1 CFERFOIUABURIX-UHFFFAOYSA-N 0.000 claims description 3
- 201000008482 osteoarthritis Diseases 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 2
- 208000001640 Fibromyalgia Diseases 0.000 claims description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 2
- 206010046543 Urinary incontinence Diseases 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 claims description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 2
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims 1
- BXAQGGSZBDFEBV-UHFFFAOYSA-N [F].[F].[F].[F].[F].[F].N1=NN(C2=NC=CC=C21)OC(N(C)C)=[N+](C)C Chemical compound [F].[F].[F].[F].[F].[F].N1=NN(C2=NC=CC=C21)OC(N(C)C)=[N+](C)C BXAQGGSZBDFEBV-UHFFFAOYSA-N 0.000 claims 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims 1
- 206010027599 migraine Diseases 0.000 claims 1
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims 1
- 229940124597 therapeutic agent Drugs 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 99
- 238000003786 synthesis reaction Methods 0.000 description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 235000019439 ethyl acetate Nutrition 0.000 description 33
- 230000015572 biosynthetic process Effects 0.000 description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 26
- 210000004027 cell Anatomy 0.000 description 26
- 239000000243 solution Substances 0.000 description 25
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 20
- 239000000203 mixture Substances 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 150000001412 amines Chemical class 0.000 description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 235000017663 capsaicin Nutrition 0.000 description 13
- 229960002504 capsaicin Drugs 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 238000000746 purification Methods 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 125000000623 heterocyclic group Chemical group 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- JRYYVMDEUJQWRO-UHFFFAOYSA-N 2-methylnicotinamide Chemical compound CC1=NC=CC=C1C(N)=O JRYYVMDEUJQWRO-UHFFFAOYSA-N 0.000 description 7
- JHHURKBLEGFPPB-UHFFFAOYSA-N 6-tert-butylpyridine-3-carbonitrile Chemical compound CC(C)(C)C1=CC=C(C#N)C=N1 JHHURKBLEGFPPB-UHFFFAOYSA-N 0.000 description 7
- 239000007821 HATU Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- CTMUOPMCEIJFPH-UHFFFAOYSA-N 2-(7-cyanobenzimidazol-1-yl)acetic acid Chemical compound C1=CC(C#N)=C2N(CC(=O)O)C=NC2=C1 CTMUOPMCEIJFPH-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 208000004454 Hyperalgesia Diseases 0.000 description 6
- 208000035154 Hyperesthesia Diseases 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 238000007429 general method Methods 0.000 description 6
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 5
- 101710134784 Agnoprotein Proteins 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 239000000679 carrageenan Substances 0.000 description 5
- 229920001525 carrageenan Polymers 0.000 description 5
- 235000010418 carrageenan Nutrition 0.000 description 5
- 229940113118 carrageenan Drugs 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 5
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 5
- 239000003039 volatile agent Substances 0.000 description 5
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 5
- LJYFETXSAWJLNA-UHFFFAOYSA-N 1h-benzimidazole-4-carbonitrile Chemical compound N#CC1=CC=CC2=C1NC=N2 LJYFETXSAWJLNA-UHFFFAOYSA-N 0.000 description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 4
- AIVDGNMSAJOGES-UHFFFAOYSA-N 2-(6,7-difluorobenzimidazol-1-yl)acetic acid Chemical compound C1=C(F)C(F)=C2N(CC(=O)O)C=NC2=C1 AIVDGNMSAJOGES-UHFFFAOYSA-N 0.000 description 4
- 239000007995 HEPES buffer Substances 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 description 4
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 150000002825 nitriles Chemical class 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- LLGJRTUJOWVXOD-UHFFFAOYSA-N 2-(2,3-difluoro-6-nitroanilino)ethanol Chemical compound OCCNC1=C(F)C(F)=CC=C1[N+]([O-])=O LLGJRTUJOWVXOD-UHFFFAOYSA-N 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 3
- JCCWYJAWPPUERF-UHFFFAOYSA-N 6-(2,2,2-trifluoroethoxy)pyridine-3-carbonitrile Chemical compound FC(F)(F)COC1=CC=C(C#N)C=N1 JCCWYJAWPPUERF-UHFFFAOYSA-N 0.000 description 3
- 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 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 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 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 108010025083 TRPV1 receptor Proteins 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000013058 crude material Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 229960001031 glucose Drugs 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 3
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 210000000929 nociceptor Anatomy 0.000 description 3
- 108091008700 nociceptors Proteins 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- YTTFFPATQICAQN-BYPYZUCNSA-N (2s)-2-methoxypropan-1-ol Chemical compound CO[C@@H](C)CO YTTFFPATQICAQN-BYPYZUCNSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- GFTPLFVZKMIYAP-UHFFFAOYSA-N 2-(1h-benzimidazol-1-ium-2-yl)acetate Chemical compound C1=CC=C2NC(CC(=O)O)=NC2=C1 GFTPLFVZKMIYAP-UHFFFAOYSA-N 0.000 description 2
- MXZKEULCPQUUFK-UHFFFAOYSA-N 2-(6,7-difluorobenzimidazol-1-yl)ethanol Chemical compound C1=C(F)C(F)=C2N(CCO)C=NC2=C1 MXZKEULCPQUUFK-UHFFFAOYSA-N 0.000 description 2
- FUCXOIWSEFJHCP-UHFFFAOYSA-N 2-(6-amino-2,3-difluoroanilino)ethanol Chemical compound NC1=CC=C(F)C(F)=C1NCCO FUCXOIWSEFJHCP-UHFFFAOYSA-N 0.000 description 2
- LVVHTRTZAYLIMQ-UHFFFAOYSA-N 2-(7-acetylbenzimidazol-1-yl)acetic acid Chemical compound CC(=O)C1=CC=CC2=C1N(CC(O)=O)C=N2 LVVHTRTZAYLIMQ-UHFFFAOYSA-N 0.000 description 2
- MWRXEWAYZFDWAZ-UHFFFAOYSA-N 2-(7-nitrobenzimidazol-1-yl)acetic acid Chemical compound C1=CC([N+]([O-])=O)=C2N(CC(=O)O)C=NC2=C1 MWRXEWAYZFDWAZ-UHFFFAOYSA-N 0.000 description 2
- UBKKNWJGYLSDSJ-UHFFFAOYSA-N 2-methylpyridine-3-carbonitrile Chemical compound CC1=NC=CC=C1C#N UBKKNWJGYLSDSJ-UHFFFAOYSA-N 0.000 description 2
- GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 description 2
- ZASLPMVTITVAGX-UHFFFAOYSA-N 4-(1-methylpiperidin-4-yl)oxy-3-(trifluoromethyl)benzonitrile Chemical compound C1CN(C)CCC1OC1=CC=C(C#N)C=C1C(F)(F)F ZASLPMVTITVAGX-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- CQZQCORFYSSCFY-UHFFFAOYSA-N 4-fluoro-3-(trifluoromethyl)benzonitrile Chemical compound FC1=CC=C(C#N)C=C1C(F)(F)F CQZQCORFYSSCFY-UHFFFAOYSA-N 0.000 description 2
- ZGAPRXSQJGVERK-UHFFFAOYSA-N 6-tert-butyl-2-chloropyridine-3-carbonitrile Chemical compound CC(C)(C)C1=CC=C(C#N)C(Cl)=N1 ZGAPRXSQJGVERK-UHFFFAOYSA-N 0.000 description 2
- WDYIUBSUHVOGHP-UHFFFAOYSA-N 6-tert-butyl-2-methoxypyridine-3-carbonitrile Chemical compound COC1=NC(C(C)(C)C)=CC=C1C#N WDYIUBSUHVOGHP-UHFFFAOYSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- PCBZRNYXXCIELG-WYFCWLEVSA-N COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 Chemical compound COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 PCBZRNYXXCIELG-WYFCWLEVSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical class CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- OUVXYXNWSVIOSJ-UHFFFAOYSA-N Fluo-4 Chemical compound CC1=CC=C(N(CC(O)=O)CC(O)=O)C(OCCOC=2C(=CC=C(C=2)C2=C3C=C(F)C(=O)C=C3OC3=CC(O)=C(F)C=C32)N(CC(O)=O)CC(O)=O)=C1 OUVXYXNWSVIOSJ-UHFFFAOYSA-N 0.000 description 2
- 208000003098 Ganglion Cysts Diseases 0.000 description 2
- 239000012981 Hank's balanced salt solution Substances 0.000 description 2
- 206010021639 Incontinence Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- 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 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 208000005400 Synovial Cyst Diseases 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 230000003042 antagnostic effect Effects 0.000 description 2
- 239000012131 assay buffer Substances 0.000 description 2
- 239000007844 bleaching agent Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 210000002683 foot Anatomy 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- IMACFCSSMIZSPP-UHFFFAOYSA-N phenacyl chloride Chemical compound ClCC(=O)C1=CC=CC=C1 IMACFCSSMIZSPP-UHFFFAOYSA-N 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 2
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 2
- 238000007423 screening assay Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 239000003491 tear gas Substances 0.000 description 2
- LTCGADYUJGMDCF-UHFFFAOYSA-N tert-butyl n-[1-(4-hydroxyphenyl)ethyl]carbamate Chemical compound CC(C)(C)OC(=O)NC(C)C1=CC=C(O)C=C1 LTCGADYUJGMDCF-UHFFFAOYSA-N 0.000 description 2
- UTDAAMOVDAQYAS-UEWDXFNNSA-N tert-butyl n-[1-[4-[(2s)-2-methoxypropoxy]phenyl]ethyl]carbamate Chemical compound CO[C@@H](C)COC1=CC=C(C(C)NC(=O)OC(C)(C)C)C=C1 UTDAAMOVDAQYAS-UEWDXFNNSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical group CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
- ARCACZWMYGILNI-UHFFFAOYSA-N 1,2,3-trifluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C(F)=C1F ARCACZWMYGILNI-UHFFFAOYSA-N 0.000 description 1
- QACMXJJLQXUOPQ-UHFFFAOYSA-N 1,2-dichloroethane;3-(ethyliminomethylideneamino)-n,n-dimethylpropan-1-amine Chemical compound ClCCCl.CCN=C=NCCCN(C)C QACMXJJLQXUOPQ-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- WVZSBXKYGWAOCK-UHFFFAOYSA-N 1-(5-tert-butylpyridin-2-yl)ethanamine Chemical compound CC(N)C1=CC=C(C(C)(C)C)C=N1 WVZSBXKYGWAOCK-UHFFFAOYSA-N 0.000 description 1
- FFDQOLNELGLDQN-UHFFFAOYSA-N 1-(5-tert-butylpyridin-2-yl)ethanone Chemical compound CC(=O)C1=CC=C(C(C)(C)C)C=N1 FFDQOLNELGLDQN-UHFFFAOYSA-N 0.000 description 1
- AHABAANUAYYPCC-UHFFFAOYSA-N 1-(5-tert-butylthiophen-2-yl)ethanone Chemical compound CC(=O)C1=CC=C(C(C)(C)C)S1 AHABAANUAYYPCC-UHFFFAOYSA-N 0.000 description 1
- CDQPLIAKRDYOCB-UHFFFAOYSA-N 1-(p-Hydroxyphenyl)ethylamine Chemical compound CC(N)C1=CC=C(O)C=C1 CDQPLIAKRDYOCB-UHFFFAOYSA-N 0.000 description 1
- ZOODBAVWYLUHCI-UHFFFAOYSA-N 1-[3-(2-hydroxyethyl)benzimidazol-4-yl]ethanone Chemical compound CC(=O)C1=CC=CC2=C1N(CCO)C=N2 ZOODBAVWYLUHCI-UHFFFAOYSA-N 0.000 description 1
- BAUWRHPMUVYFOD-UHFFFAOYSA-N 1-methylpiperidin-4-ol Chemical compound CN1CCC(O)CC1 BAUWRHPMUVYFOD-UHFFFAOYSA-N 0.000 description 1
- NBUKAOOFKZFCGD-UHFFFAOYSA-N 2,2,3,3-tetrafluoropropan-1-ol Chemical compound OCC(F)(F)C(F)F NBUKAOOFKZFCGD-UHFFFAOYSA-N 0.000 description 1
- VOGSDFLJZPNWHY-UHFFFAOYSA-N 2,2-difluoroethanol Chemical compound OCC(F)F VOGSDFLJZPNWHY-UHFFFAOYSA-N 0.000 description 1
- ADUBONMXVUWYCF-UHFFFAOYSA-N 2-(5-tert-butylthiophen-2-yl)ethanamine Chemical compound CC(C)(C)C1=CC=C(CCN)S1 ADUBONMXVUWYCF-UHFFFAOYSA-N 0.000 description 1
- WKHRGYGWUZSFLP-UHFFFAOYSA-N 2-(7-chlorobenzimidazol-1-yl)acetic acid Chemical compound C1=CC(Cl)=C2N(CC(=O)O)C=NC2=C1 WKHRGYGWUZSFLP-UHFFFAOYSA-N 0.000 description 1
- AFHSZBKDUTWXDX-UHFFFAOYSA-N 2-(benzimidazol-1-yl)acetic acid Chemical class C1=CC=C2N(CC(=O)O)C=NC2=C1 AFHSZBKDUTWXDX-UHFFFAOYSA-N 0.000 description 1
- JAUPUQRPBNDMDT-UHFFFAOYSA-N 2-chloropyridine-3-carbonitrile Chemical compound ClC1=NC=CC=C1C#N JAUPUQRPBNDMDT-UHFFFAOYSA-N 0.000 description 1
- GGDYAKVUZMZKRV-UHFFFAOYSA-N 2-fluoroethanol Chemical compound OCCF GGDYAKVUZMZKRV-UHFFFAOYSA-N 0.000 description 1
- IHWZCGMZILLKFD-UHFFFAOYSA-N 2-methoxypyridine-3-carbonitrile Chemical compound COC1=NC=CC=C1C#N IHWZCGMZILLKFD-UHFFFAOYSA-N 0.000 description 1
- HNTZKNJGAFJMHQ-UHFFFAOYSA-N 2-methylpyridine-3-carboxylic acid Chemical compound CC1=NC=CC=C1C(O)=O HNTZKNJGAFJMHQ-UHFFFAOYSA-N 0.000 description 1
- LYDZBCFIIYATHV-UHFFFAOYSA-N 3-(2-hydroxyethyl)benzimidazole-4-carbonitrile Chemical compound C1=CC(C#N)=C2N(CCO)C=NC2=C1 LYDZBCFIIYATHV-UHFFFAOYSA-N 0.000 description 1
- CDQPLIAKRDYOCB-LURJTMIESA-N 4-[(1s)-1-aminoethyl]phenol Chemical compound C[C@H](N)C1=CC=C(O)C=C1 CDQPLIAKRDYOCB-LURJTMIESA-N 0.000 description 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- XLAPHZHNODDMDD-UHFFFAOYSA-N 4-methylpyridine-3-carbonitrile Chemical compound CC1=CC=NC=C1C#N XLAPHZHNODDMDD-UHFFFAOYSA-N 0.000 description 1
- NEJMFSBXFBFELK-UHFFFAOYSA-N 4-nitro-1h-benzimidazole Chemical compound [O-][N+](=O)C1=CC=CC2=C1N=CN2 NEJMFSBXFBFELK-UHFFFAOYSA-N 0.000 description 1
- XPEZHOPSQNRNDD-UHFFFAOYSA-N 6-(2,2,3,3-tetrafluoropropoxy)pyridine-3-carbonitrile Chemical compound FC(F)C(F)(F)COC1=CC=C(C#N)C=N1 XPEZHOPSQNRNDD-UHFFFAOYSA-N 0.000 description 1
- OZYSXUHCBUCOJY-UHFFFAOYSA-N 6-(2,2-difluoroethoxy)pyridine-3-carbonitrile Chemical compound FC(F)COC1=CC=C(C#N)C=N1 OZYSXUHCBUCOJY-UHFFFAOYSA-N 0.000 description 1
- LNDXQUOODQMNDU-UHFFFAOYSA-N 6-(2-fluoroethoxy)pyridine-3-carbonitrile Chemical compound FCCOC1=CC=C(C#N)C=N1 LNDXQUOODQMNDU-UHFFFAOYSA-N 0.000 description 1
- ORIQLMBUPMABDV-UHFFFAOYSA-N 6-chloropyridine-3-carbonitrile Chemical compound ClC1=CC=C(C#N)C=N1 ORIQLMBUPMABDV-UHFFFAOYSA-N 0.000 description 1
- CPMLUNYPHAGCDE-UHFFFAOYSA-N 6-cyclopentyloxypyridine-3-carbonitrile Chemical compound N1=CC(C#N)=CC=C1OC1CCCC1 CPMLUNYPHAGCDE-UHFFFAOYSA-N 0.000 description 1
- 208000030090 Acute Disease Diseases 0.000 description 1
- 241000349731 Afzelia bipindensis Species 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 240000004160 Capsicum annuum Species 0.000 description 1
- 235000008534 Capsicum annuum var annuum Nutrition 0.000 description 1
- 235000007862 Capsicum baccatum Nutrition 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 241000694440 Colpidium aqueous Species 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 241000195493 Cryptophyta Species 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 208000002705 Glucose Intolerance Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010021033 Hypomenorrhoea Diseases 0.000 description 1
- 206010021113 Hypothermia Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 206010027603 Migraine headaches Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 108010052185 Myotonin-Protein Kinase Proteins 0.000 description 1
- 102100022437 Myotonin-protein kinase Human genes 0.000 description 1
- 229910019093 NaOCl Inorganic materials 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 208000010886 Peripheral nerve injury Diseases 0.000 description 1
- 229920005372 Plexiglas® Polymers 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 108010062740 TRPV Cation Channels Proteins 0.000 description 1
- 102000011040 TRPV Cation Channels Human genes 0.000 description 1
- 102000003566 TRPV1 Human genes 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- 101150016206 Trpv1 gene Proteins 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- LUXUAZKGQZPOBZ-SAXJAHGMSA-N [(3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] (Z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O LUXUAZKGQZPOBZ-SAXJAHGMSA-N 0.000 description 1
- WXIONIWNXBAHRU-UHFFFAOYSA-N [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium Chemical compound C1=CN=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 WXIONIWNXBAHRU-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000007825 activation reagent Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- GZCGUPFRVQAUEE-SLPGGIOYSA-N aldehydo-D-glucose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O GZCGUPFRVQAUEE-SLPGGIOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000001147 anti-toxic effect Effects 0.000 description 1
- 108010054176 apotransferrin Proteins 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000001728 capsicum frutescens Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 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
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- ZFTFAPZRGNKQPU-UHFFFAOYSA-N dicarbonic acid Chemical compound OC(=O)OC(O)=O ZFTFAPZRGNKQPU-UHFFFAOYSA-N 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 108010007093 dispase Proteins 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000013213 extrapolation Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002390 heteroarenes Chemical class 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 1
- 230000002631 hypothermal effect Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- UEXQBEVWFZKHNB-UHFFFAOYSA-N intermediate 29 Natural products C1=CC(N)=CC=C1NC1=NC=CC=N1 UEXQBEVWFZKHNB-UHFFFAOYSA-N 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 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
- ZFSLODLOARCGLH-UHFFFAOYSA-N isocyanuric acid Chemical compound OC1=NC(O)=NC(O)=N1 ZFSLODLOARCGLH-UHFFFAOYSA-N 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- FGNGTWFJQFTFGN-UHFFFAOYSA-N n,n,n',n'-tetramethylethane-1,2-diamine Chemical compound CN(C)CCN(C)C.CN(C)CCN(C)C FGNGTWFJQFTFGN-UHFFFAOYSA-N 0.000 description 1
- LLYKPZOWCPVRPD-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine;n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=CC=N1 LLYKPZOWCPVRPD-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 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
- 210000002241 neurite Anatomy 0.000 description 1
- 231100000189 neurotoxic Toxicity 0.000 description 1
- 230000002887 neurotoxic effect Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 230000008533 pain sensitivity Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 201000009104 prediabetes syndrome Diseases 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 229960003081 probenecid Drugs 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 235000008160 pyridoxine Nutrition 0.000 description 1
- 239000011677 pyridoxine Substances 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 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
- 210000001044 sensory neuron Anatomy 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 229940011671 vitamin b6 Drugs 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Diabetes (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Pulmonology (AREA)
- Pain & Pain Management (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Child & Adolescent Psychology (AREA)
- Cardiology (AREA)
- Emergency Medicine (AREA)
- Dermatology (AREA)
- Immunology (AREA)
- Endocrinology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US75360405P | 2005-12-23 | 2005-12-23 | |
| US60/753,604 | 2005-12-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20080080212A true KR20080080212A (ko) | 2008-09-02 |
Family
ID=38189102
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020087017908A Abandoned KR20080080212A (ko) | 2005-12-23 | 2006-12-21 | 바닐로이드 수용체 １ (ｖｒｌ) 억제제로서의 신규벤즈이미다졸 유도체 |
Country Status (21)
| Country | Link |
|---|---|
| US (2) | US7618993B2 (enExample) |
| EP (1) | EP1966156B1 (enExample) |
| JP (1) | JP2009521431A (enExample) |
| KR (1) | KR20080080212A (enExample) |
| CN (1) | CN101389610B (enExample) |
| AR (1) | AR058705A1 (enExample) |
| AT (1) | ATE538101T1 (enExample) |
| AU (1) | AU2006327320B2 (enExample) |
| BR (1) | BRPI0620410A2 (enExample) |
| CA (1) | CA2634804A1 (enExample) |
| EC (1) | ECSP088584A (enExample) |
| ES (1) | ES2377661T3 (enExample) |
| IL (1) | IL191753A0 (enExample) |
| NO (1) | NO20083246L (enExample) |
| NZ (1) | NZ569923A (enExample) |
| RU (1) | RU2427573C2 (enExample) |
| TW (1) | TW200736227A (enExample) |
| UA (1) | UA96277C2 (enExample) |
| UY (1) | UY30048A1 (enExample) |
| WO (1) | WO2007073303A2 (enExample) |
| ZA (1) | ZA200805162B (enExample) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE0301446D0 (sv) | 2003-05-16 | 2003-05-16 | Astrazeneca Ab | New Compounds |
| UY30048A1 (es) * | 2005-12-23 | 2007-07-31 | Astrazeneca Ab | Derivados sustituidos de la n,2-(1h-benzimidazol-1-il) acetamida, composiciones farmacéuticas conteniéndolos, procesos de preparación y aplicaciones |
| TWI433839B (zh) | 2006-08-11 | 2014-04-11 | Neomed Inst | 新穎的苯并咪唑衍生物290 |
| WO2009054983A1 (en) * | 2007-10-24 | 2009-04-30 | Merck & Co., Inc. | Heterocycle amide t-type calcium channel antagonists |
| NZ587771A (en) | 2008-04-18 | 2011-05-27 | Dae Woong Pharma | Novel benzoxazine benzimidazole derivatives, pharmaceutical composition comprising same, and a use thereof |
| DE112011102008B4 (de) | 2010-06-15 | 2022-04-21 | Merck Patent Gmbh | Metallkomplexe |
| KR101293384B1 (ko) | 2010-10-13 | 2013-08-05 | 주식회사 대웅제약 | 신규 피리딜 벤조옥사진 유도체, 이를 포함하는 약학 조성물 및 이의 용도 |
| WO2016055582A1 (en) * | 2014-10-08 | 2016-04-14 | Thomas Helledays Stiftelse För Medicinsk Forskning | Heterocyclic compounds as dctpp1 modulators |
| JO3719B1 (ar) | 2014-11-20 | 2021-01-31 | Takeda Pharmaceuticals Co | 4- أوكسو-4،3- داي هيدرو-3،2،1- بنزوترايازينات كمواد ضابطة لأجل gpr139 |
| JP2018052817A (ja) * | 2015-01-21 | 2018-04-05 | 大日本住友製薬株式会社 | 新規ベンズイミダゾール誘導体およびその医薬用途 |
| US11186564B2 (en) | 2016-08-04 | 2021-11-30 | Sunovion Pharmaceuticals Inc. | Dual NAV1.2/5HT2a inhibitors for treating CNS disorders |
| EP3908574A4 (en) * | 2019-01-08 | 2022-10-26 | Neomed Institute | CRYSTALLINE FORMS OF (S)-2-(7-CYANO-1H-BENZIMIDAZOL-1YL)-N-{1-[4-(1-CYANO-1-METHYLETHYL)PHENYL]ETHYL}ACETAMIDE |
| CR20220160A (es) | 2019-09-16 | 2022-06-16 | Takeda Pharmaceuticals Co | Derivados de piridazin-3(2h)-ona fusionados con azol |
| CA3218090A1 (en) | 2021-05-10 | 2022-11-17 | Magnus HALLDIN | New formulations and uses |
| GB202217159D0 (en) | 2022-11-16 | 2022-12-28 | AlzeCure Pharma AB | New use |
Family Cites Families (44)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1186504A (en) | 1966-10-15 | 1970-04-02 | Fisons Pest Control Ltd | Substituted Heterocyclic Compounds |
| IT1036004B (it) * | 1968-05-21 | 1979-10-30 | Abc Ist Biolog Chem Spa | Acidt 3 indolil adetoidrossamici |
| BE793718A (fr) | 1972-01-07 | 1973-07-05 | Merck & Co Inc | Aminobenzimidazoles |
| US4136189A (en) * | 1975-09-16 | 1979-01-23 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara R.T. | 2-(5-nitro-furfurylidene)-amino-benzimidoles and fungicidal compositions containing the same |
| DE3347290A1 (de) * | 1983-12-28 | 1985-07-11 | Dr. Karl Thomae Gmbh, 7950 Biberach | Neue 2-phenyl-imidazole, ihre herstellung und diese verbindungen enthaltende arzneimittel |
| US4738981A (en) * | 1984-11-13 | 1988-04-19 | Warner-Lambert | Substituted trans-1,2-diaminocyclohexyl amide compounds |
| JPH06759B2 (ja) | 1989-09-22 | 1994-01-05 | ファイザー製薬株式会社 | 新規なベンゾイミダゾール化合物 |
| DE4309969A1 (de) | 1993-03-26 | 1994-09-29 | Bayer Ag | Substituierte heteroanellierte Imidazole |
| US5403851A (en) | 1994-04-05 | 1995-04-04 | Interneuron Pharmaceuticals, Inc. | Substituted tryptamines, phenalkylamines and related compounds |
| EA002357B1 (ru) | 1995-12-28 | 2002-04-25 | Фудзисава Фармасьютикал Ко., Лтд. | Производные бензимидазола |
| GB9713484D0 (en) | 1997-06-27 | 1997-09-03 | Smithkline Beecham Plc | Neuroprotective vanilloid compounds |
| JP2000095767A (ja) | 1998-09-28 | 2000-04-04 | Takeda Chem Ind Ltd | 性腺刺激ホルモン放出ホルモン拮抗剤 |
| BR0013143A (pt) | 1999-08-12 | 2002-06-11 | Pharmacia Italia Spa | Derivados de 3 (5) amino pirazol, processo para sua preparação e uso dos mesmos como agentes antitumorais |
| US6534651B2 (en) * | 2000-04-06 | 2003-03-18 | Inotek Pharmaceuticals Corp. | 7-Substituted isoindolinone inhibitors of inflammation and reperfusion injury and methods of use thereof |
| EP1278744A1 (en) | 2000-05-05 | 2003-01-29 | Millenium Pharmaceuticals, Inc. | Heterobicyclic sulfonamides and their use as platelet adp receptor inhibitors |
| MXPA02010763A (es) | 2000-06-14 | 2003-03-10 | Warner Lambert Co | Heterociclicos biciclos-6,5 fusionados. |
| US6448281B1 (en) * | 2000-07-06 | 2002-09-10 | Boehringer Ingelheim (Canada) Ltd. | Viral polymerase inhibitors |
| JP4929472B2 (ja) | 2000-08-22 | 2012-05-09 | 小野薬品工業株式会社 | カルボン酸誘導体、それらの製造方法およびそれらを有効成分として含有する薬剤 |
| GB0031315D0 (en) * | 2000-12-21 | 2001-02-07 | Glaxo Group Ltd | Indole derivatives |
| ITTO20010110A1 (it) | 2001-02-08 | 2002-08-08 | Rotta Research Lab | Nuovi derivati benzamidinici dotati di attivita' anti-infiammatoria ed immunosoppressiva. |
| GB0105895D0 (en) | 2001-03-09 | 2001-04-25 | Smithkline Beecham Plc | Novel compounds |
| SE0101387D0 (sv) | 2001-04-20 | 2001-04-20 | Astrazeneca Ab | Novel compounds |
| GB0110901D0 (en) | 2001-05-02 | 2001-06-27 | Smithkline Beecham Plc | Novel Compounds |
| TWI239942B (en) | 2001-06-11 | 2005-09-21 | Dainippon Pharmaceutical Co | N-arylphenylacetamide derivative and pharmaceutical composition containing the same |
| CA2445653A1 (en) | 2001-06-11 | 2002-12-19 | Biovitrum Ab | Substituted sulfonamide compounds, process for their use as medicament for the treatment of cns disorders, obesity and type ii diabetes |
| AU2002325381A1 (en) | 2001-07-31 | 2003-02-24 | Bayer Healthcare Ag | Naphthylurea and naphthylacetamide derivatives as vanilloid receptor 1 (vr1) antagonists |
| TWI283665B (en) | 2001-09-13 | 2007-07-11 | Smithkline Beecham Plc | Novel urea compound, pharmaceutical composition containing the same and its use |
| TWI231757B (en) | 2001-09-21 | 2005-05-01 | Solvay Pharm Bv | 1H-Imidazole derivatives having CB1 agonistic, CB1 partial agonistic or CB1-antagonistic activity |
| PL373484A1 (en) | 2001-12-10 | 2005-09-05 | Amgen Inc. | Vanilloid receptor ligands and their use in treatments |
| GB0130550D0 (en) | 2001-12-20 | 2002-02-06 | Smithkline Beecham Plc | Novel compounds |
| EP2033953A1 (en) | 2002-02-15 | 2009-03-11 | Glaxo Group Limited | Vanilloid receptor modulators |
| US20030158188A1 (en) * | 2002-02-20 | 2003-08-21 | Chih-Hung Lee | Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor |
| NZ552283A (en) | 2002-06-20 | 2008-07-31 | Biovitrum Ab Publ | New compounds useful for the treatment of obesity, type II diabetes and CNS disorders |
| GB0221157D0 (en) | 2002-09-12 | 2002-10-23 | Glaxo Group Ltd | Novel treatment |
| WO2004024710A1 (en) | 2002-09-13 | 2004-03-25 | Glaxo Group Limited | Urea compounds active as vanilloid receptor antagonists for the treatment of pain |
| US7582761B2 (en) * | 2002-10-17 | 2009-09-01 | Amgen Inc. | Vanilloid receptor ligands and their use in treatments |
| SE0301446D0 (sv) * | 2003-05-16 | 2003-05-16 | Astrazeneca Ab | New Compounds |
| SE0301701D0 (sv) | 2003-06-10 | 2003-06-10 | Astrazeneca Ab | Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof |
| OA13248A (en) | 2003-09-03 | 2007-01-31 | Pfizer | Benzimidazolone coumpounds having 5-HT4 receptor agonistic activity. |
| EP1736465A4 (en) * | 2004-03-31 | 2009-06-17 | Ajinomoto Kk | ANILINE DERIVATIVES |
| SE0402284D0 (sv) * | 2004-09-21 | 2004-09-21 | Astrazeneca Ab | New heterocyclic amides |
| UY30048A1 (es) * | 2005-12-23 | 2007-07-31 | Astrazeneca Ab | Derivados sustituidos de la n,2-(1h-benzimidazol-1-il) acetamida, composiciones farmacéuticas conteniéndolos, procesos de preparación y aplicaciones |
| RU2424233C2 (ru) * | 2006-06-29 | 2011-07-20 | Ф.Хоффманн-Ля Рош Аг | Производные бензимидазола, методы их получения, применение их в качестве агонистов фарнезоид-х-рецептора (fxr) и содержащие их фармацевтические препараты |
| TWI433839B (zh) | 2006-08-11 | 2014-04-11 | Neomed Inst | 新穎的苯并咪唑衍生物290 |
-
2006
- 2006-12-20 UY UY30048A patent/UY30048A1/es unknown
- 2006-12-20 AR ARP060105673A patent/AR058705A1/es not_active Application Discontinuation
- 2006-12-20 TW TW095148018A patent/TW200736227A/zh unknown
- 2006-12-21 EP EP06835882A patent/EP1966156B1/en active Active
- 2006-12-21 CN CN2006800533688A patent/CN101389610B/zh not_active Expired - Fee Related
- 2006-12-21 JP JP2008547169A patent/JP2009521431A/ja active Pending
- 2006-12-21 US US11/614,346 patent/US7618993B2/en active Active
- 2006-12-21 WO PCT/SE2006/001467 patent/WO2007073303A2/en not_active Ceased
- 2006-12-21 RU RU2008122404/04A patent/RU2427573C2/ru not_active IP Right Cessation
- 2006-12-21 ES ES06835882T patent/ES2377661T3/es active Active
- 2006-12-21 AT AT06835882T patent/ATE538101T1/de active
- 2006-12-21 UA UAA200807385A patent/UA96277C2/ru unknown
- 2006-12-21 KR KR1020087017908A patent/KR20080080212A/ko not_active Abandoned
- 2006-12-21 BR BRPI0620410-4A patent/BRPI0620410A2/pt not_active IP Right Cessation
- 2006-12-21 AU AU2006327320A patent/AU2006327320B2/en not_active Ceased
- 2006-12-21 NZ NZ569923A patent/NZ569923A/en unknown
- 2006-12-21 CA CA002634804A patent/CA2634804A1/en not_active Abandoned
-
2008
- 2008-05-27 IL IL191753A patent/IL191753A0/en unknown
- 2008-06-12 ZA ZA200805162A patent/ZA200805162B/xx unknown
- 2008-06-27 EC EC2008008584A patent/ECSP088584A/es unknown
- 2008-07-22 NO NO20083246A patent/NO20083246L/no not_active Application Discontinuation
-
2009
- 2009-10-14 US US12/578,730 patent/US8168668B2/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN101389610A (zh) | 2009-03-18 |
| EP1966156B1 (en) | 2011-12-21 |
| ECSP088584A (es) | 2008-07-30 |
| IL191753A0 (en) | 2008-12-29 |
| WO2007073303A3 (en) | 2007-08-30 |
| UY30048A1 (es) | 2007-07-31 |
| US7618993B2 (en) | 2009-11-17 |
| WO2007073303A2 (en) | 2007-06-28 |
| CA2634804A1 (en) | 2007-06-28 |
| RU2427573C2 (ru) | 2011-08-27 |
| BRPI0620410A2 (pt) | 2011-11-08 |
| NZ569923A (en) | 2011-04-29 |
| RU2008122404A (ru) | 2010-01-27 |
| AU2006327320B2 (en) | 2009-12-10 |
| US20080171770A1 (en) | 2008-07-17 |
| CN101389610B (zh) | 2011-12-07 |
| JP2009521431A (ja) | 2009-06-04 |
| NO20083246L (no) | 2008-09-11 |
| ATE538101T1 (de) | 2012-01-15 |
| US8168668B2 (en) | 2012-05-01 |
| ES2377661T3 (es) | 2012-03-29 |
| AU2006327320A1 (en) | 2007-06-28 |
| AR058705A1 (es) | 2008-02-20 |
| US20100286202A1 (en) | 2010-11-11 |
| HK1121755A1 (en) | 2009-04-30 |
| UA96277C2 (en) | 2011-10-25 |
| TW200736227A (en) | 2007-10-01 |
| ZA200805162B (en) | 2009-11-25 |
| EP1966156A2 (en) | 2008-09-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US8168668B2 (en) | Compounds | |
| JP5433708B2 (ja) | 抗炎症剤としての３ｈ−イミダゾ［４，５−ｃ］ピリジン−６−カルボキサミド | |
| JP5608655B2 (ja) | Ｐ２ｘ３受容体活性のモジュレーター | |
| DE60222396T2 (de) | N-(2-arylethyl) benzylamine als 5-ht6 rezeptor-antagoniste | |
| KR101754940B1 (ko) | 3-치환된 1ｈ-피롤 및 방향족 및 헤테로 방향족 스페이서에 동시에 기반한 신규한 히스톤 디아세틸라아제 저해제 | |
| KR101110404B1 (ko) | 신규 벤즈이미다졸 유도체 | |
| JP2007525482A (ja) | イオンチャネルリガンドとしてのアミド化合物およびその使用 | |
| US20130023522A1 (en) | Benzamides | |
| US20080306107A1 (en) | Compounds | |
| JP2006524687A (ja) | バニロイド受容体で阻害活性を示す新規複素環アミド | |
| US20080015222A1 (en) | New Heterocyclic Amides | |
| HK1121755B (en) | New compounds iii |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PA0105 | International application |
Patent event date: 20080722 Patent event code: PA01051R01D Comment text: International Patent Application |
|
| PG1501 | Laying open of application | ||
| A201 | Request for examination | ||
| AMND | Amendment | ||
| PA0201 | Request for examination |
Patent event code: PA02012R01D Patent event date: 20111221 Comment text: Request for Examination of Application |
|
| E902 | Notification of reason for refusal | ||
| PE0902 | Notice of grounds for rejection |
Comment text: Notification of reason for refusal Patent event date: 20130828 Patent event code: PE09021S01D |
|
| E601 | Decision to refuse application | ||
| PE0601 | Decision on rejection of patent |
Patent event date: 20131230 Comment text: Decision to Refuse Application Patent event code: PE06012S01D Patent event date: 20130828 Comment text: Notification of reason for refusal Patent event code: PE06011S01I |
|
| AMND | Amendment | ||
| J201 | Request for trial against refusal decision | ||
| PJ0201 | Trial against decision of rejection |
Patent event date: 20140129 Comment text: Request for Trial against Decision on Refusal Patent event code: PJ02012R01D Patent event date: 20131230 Comment text: Decision to Refuse Application Patent event code: PJ02011S01I Appeal kind category: Appeal against decision to decline refusal Decision date: 20140327 Appeal identifier: 2014101000603 Request date: 20140129 |
|
| PB0901 | Examination by re-examination before a trial |
Comment text: Amendment to Specification, etc. Patent event date: 20140129 Patent event code: PB09011R02I Comment text: Request for Trial against Decision on Refusal Patent event date: 20140129 Patent event code: PB09011R01I Comment text: Amendment to Specification, etc. Patent event date: 20111221 Patent event code: PB09011R02I |
|
| B701 | Decision to grant | ||
| PB0701 | Decision of registration after re-examination before a trial |
Patent event date: 20140327 Comment text: Decision to Grant Registration Patent event code: PB07012S01D Patent event date: 20140303 Comment text: Transfer of Trial File for Re-examination before a Trial Patent event code: PB07011S01I |
|
| PC1904 | Unpaid initial registration fee |