JP2015038105A - アゼチジン誘導体 - Google Patents
アゼチジン誘導体 Download PDFInfo
- Publication number
- JP2015038105A JP2015038105A JP2014198461A JP2014198461A JP2015038105A JP 2015038105 A JP2015038105 A JP 2015038105A JP 2014198461 A JP2014198461 A JP 2014198461A JP 2014198461 A JP2014198461 A JP 2014198461A JP 2015038105 A JP2015038105 A JP 2015038105A
- Authority
- JP
- Japan
- Prior art keywords
- phenyl
- yloxy
- azetidine
- carboxylic acid
- pyridin
- 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.)
- Granted
Links
- 150000001539 azetidines Chemical class 0.000 title abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 19
- 201000010099 disease Diseases 0.000 claims abstract description 18
- 208000002193 Pain Diseases 0.000 claims abstract description 17
- 125000006413 ring segment Chemical group 0.000 claims abstract description 16
- 230000036407 pain Effects 0.000 claims abstract description 14
- 206010061218 Inflammation Diseases 0.000 claims abstract description 9
- 230000004054 inflammatory process Effects 0.000 claims abstract description 9
- 208000016285 Movement disease Diseases 0.000 claims abstract description 7
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 104
- -1 chloro, fluoro, bromo, cyclopropyl Chemical group 0.000 claims description 67
- 230000000694 effects Effects 0.000 claims description 33
- 230000005764 inhibitory process Effects 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 16
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 206010010904 Convulsion Diseases 0.000 claims description 10
- 208000010412 Glaucoma Diseases 0.000 claims description 8
- 125000002950 monocyclic group Chemical group 0.000 claims description 8
- 230000036461 convulsion Effects 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 claims description 6
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
- 208000019901 Anxiety disease Diseases 0.000 claims description 6
- 230000036506 anxiety Effects 0.000 claims description 6
- 125000005549 heteroarylene group Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 201000006417 multiple sclerosis Diseases 0.000 claims description 6
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 claims description 6
- KWGBRFMUYCLMJO-UHFFFAOYSA-N 3-[5-[3-(2-phenylmethoxyethoxy)phenyl]pyridin-2-yl]oxy-n-pyridazin-3-ylazetidine-1-carboxamide Chemical compound C1C(OC=2N=CC(=CC=2)C=2C=C(OCCOCC=3C=CC=CC=3)C=CC=2)CN1C(=O)NC1=CC=CN=N1 KWGBRFMUYCLMJO-UHFFFAOYSA-N 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 5
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 5
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 5
- RUVJJFSFPPMCNM-UHFFFAOYSA-N 3-[5-[3-(2-hydroxyethoxy)phenyl]pyridin-2-yl]oxy-n-pyridazin-3-ylazetidine-1-carboxamide Chemical compound OCCOC1=CC=CC(C=2C=NC(OC3CN(C3)C(=O)NC=3N=NC=CC=3)=CC=2)=C1 RUVJJFSFPPMCNM-UHFFFAOYSA-N 0.000 claims description 4
- JKZDNQWCCLHQNS-UHFFFAOYSA-N 3-[5-[3-(2-methoxyethoxy)phenyl]pyridin-2-yl]oxy-n-pyridazin-3-ylazetidine-1-carboxamide Chemical compound COCCOC1=CC=CC(C=2C=NC(OC3CN(C3)C(=O)NC=3N=NC=CC=3)=CC=2)=C1 JKZDNQWCCLHQNS-UHFFFAOYSA-N 0.000 claims description 4
- 208000011688 Generalised anxiety disease Diseases 0.000 claims description 4
- 206010047700 Vomiting Diseases 0.000 claims description 4
- 208000035475 disorder Diseases 0.000 claims description 4
- 208000029364 generalized anxiety disease Diseases 0.000 claims description 4
- 230000004410 intraocular pressure Effects 0.000 claims description 4
- 125000005551 pyridylene group Chemical group 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 208000019116 sleep disease Diseases 0.000 claims description 4
- OJNMDFAPRGQGBO-UHFFFAOYSA-N 3-(4-phenylphenoxy)-n-pyridin-3-ylazetidine-1-carboxamide Chemical compound C1C(OC=2C=CC(=CC=2)C=2C=CC=CC=2)CN1C(=O)NC1=CC=CN=C1 OJNMDFAPRGQGBO-UHFFFAOYSA-N 0.000 claims description 3
- VSQUREFTKYDATG-UHFFFAOYSA-N 3-(5-phenylpyridin-2-yl)oxy-n-pyridazin-3-ylazetidine-1-carboxamide Chemical compound C1C(OC=2N=CC(=CC=2)C=2C=CC=CC=2)CN1C(=O)NC1=CC=CN=N1 VSQUREFTKYDATG-UHFFFAOYSA-N 0.000 claims description 3
- QKAQGMCNRCMETH-UHFFFAOYSA-N 3-[5-(2-fluorophenyl)pyridin-2-yl]oxy-n-(4-methylpyridazin-3-yl)azetidine-1-carboxamide Chemical compound CC1=CC=NN=C1NC(=O)N1CC(OC=2N=CC(=CC=2)C=2C(=CC=CC=2)F)C1 QKAQGMCNRCMETH-UHFFFAOYSA-N 0.000 claims description 3
- LIPUUWBEFCDHSI-UHFFFAOYSA-N 3-[5-(2-fluorophenyl)pyridin-2-yl]oxy-n-pyridazin-3-ylazetidine-1-carboxamide Chemical compound FC1=CC=CC=C1C(C=N1)=CC=C1OC1CN(C(=O)NC=2N=NC=CC=2)C1 LIPUUWBEFCDHSI-UHFFFAOYSA-N 0.000 claims description 3
- IOWKVAJMGCBODV-UHFFFAOYSA-N 3-[5-[2-chloro-5-(2-methoxyethoxy)phenyl]pyridin-2-yl]oxy-n-pyridazin-3-ylazetidine-1-carboxamide Chemical compound COCCOC1=CC=C(Cl)C(C=2C=NC(OC3CN(C3)C(=O)NC=3N=NC=CC=3)=CC=2)=C1 IOWKVAJMGCBODV-UHFFFAOYSA-N 0.000 claims description 3
- PJLSNOYLAQEJLZ-UHFFFAOYSA-N 3-[5-[3-(2-methoxyethoxy)phenyl]pyridin-2-yl]oxy-n-pyrazin-2-ylazetidine-1-carboxamide Chemical compound COCCOC1=CC=CC(C=2C=NC(OC3CN(C3)C(=O)NC=3N=CC=NC=3)=CC=2)=C1 PJLSNOYLAQEJLZ-UHFFFAOYSA-N 0.000 claims description 3
- KUYLWYGIJNQGJB-UHFFFAOYSA-N 3-[5-[3-(2-methoxyethoxy)phenyl]pyridin-2-yl]oxy-n-pyridin-3-ylazetidine-1-carboxamide Chemical compound COCCOC1=CC=CC(C=2C=NC(OC3CN(C3)C(=O)NC=3C=NC=CC=3)=CC=2)=C1 KUYLWYGIJNQGJB-UHFFFAOYSA-N 0.000 claims description 3
- XWQAAAKUKBKZNR-UHFFFAOYSA-N 3-[5-[3-(2-methoxyethoxy)phenyl]pyridin-2-yl]oxy-n-pyrimidin-4-ylazetidine-1-carboxamide Chemical compound COCCOC1=CC=CC(C=2C=NC(OC3CN(C3)C(=O)NC=3N=CN=CC=3)=CC=2)=C1 XWQAAAKUKBKZNR-UHFFFAOYSA-N 0.000 claims description 3
- KAZMCIGKULUUMR-UHFFFAOYSA-N 6-methylpyridazin-3-amine Chemical compound CC1=CC=C(N)N=N1 KAZMCIGKULUUMR-UHFFFAOYSA-N 0.000 claims description 3
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 3
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 3
- 206010015037 epilepsy Diseases 0.000 claims description 3
- 208000027866 inflammatory disease Diseases 0.000 claims description 3
- 230000004770 neurodegeneration Effects 0.000 claims description 3
- 201000001119 neuropathy Diseases 0.000 claims description 3
- 230000007823 neuropathy Effects 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 230000002829 reductive effect Effects 0.000 claims description 3
- 201000000980 schizophrenia Diseases 0.000 claims description 3
- 208000020431 spinal cord injury Diseases 0.000 claims description 3
- 230000035882 stress Effects 0.000 claims description 3
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 230000008673 vomiting Effects 0.000 claims description 3
- JQWUVQIJUMPKBT-UHFFFAOYSA-N 3-[5-(2,5-dimethoxyphenyl)pyridin-2-yl]oxy-n-pyridazin-3-ylazetidine-1-carboxamide Chemical compound COC1=CC=C(OC)C(C=2C=NC(OC3CN(C3)C(=O)NC=3N=NC=CC=3)=CC=2)=C1 JQWUVQIJUMPKBT-UHFFFAOYSA-N 0.000 claims description 2
- KNBDOAMGXZNPNC-UHFFFAOYSA-N 3-[5-(2-fluorophenyl)pyridin-2-yl]oxy-n-(5-methyl-1,3,4-oxadiazol-2-yl)azetidine-1-carboxamide Chemical compound O1C(C)=NN=C1NC(=O)N1CC(OC=2N=CC(=CC=2)C=2C(=CC=CC=2)F)C1 KNBDOAMGXZNPNC-UHFFFAOYSA-N 0.000 claims description 2
- CAOQMJUAAURBJS-UHFFFAOYSA-N 3-[5-(2-fluorophenyl)pyridin-2-yl]oxy-n-(5-methylpyridazin-3-yl)azetidine-1-carboxamide Chemical compound CC1=CN=NC(NC(=O)N2CC(C2)OC=2N=CC(=CC=2)C=2C(=CC=CC=2)F)=C1 CAOQMJUAAURBJS-UHFFFAOYSA-N 0.000 claims description 2
- WDSQRLGJMFXFHS-UHFFFAOYSA-N 3-[5-(2-fluorophenyl)pyridin-2-yl]oxy-n-(6-methoxypyridazin-3-yl)azetidine-1-carboxamide Chemical compound N1=NC(OC)=CC=C1NC(=O)N1CC(OC=2N=CC(=CC=2)C=2C(=CC=CC=2)F)C1 WDSQRLGJMFXFHS-UHFFFAOYSA-N 0.000 claims description 2
- MIFBPPGNFILKGT-UHFFFAOYSA-N 3-[5-(2-fluorophenyl)pyridin-2-yl]oxy-n-pyridazin-4-ylazetidine-1-carboxamide Chemical compound FC1=CC=CC=C1C(C=N1)=CC=C1OC1CN(C(=O)NC=2C=NN=CC=2)C1 MIFBPPGNFILKGT-UHFFFAOYSA-N 0.000 claims description 2
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 2
- 208000002091 Febrile Seizures Diseases 0.000 claims description 2
- 206010020772 Hypertension Diseases 0.000 claims description 2
- 208000007101 Muscle Cramp Diseases 0.000 claims description 2
- 206010028813 Nausea Diseases 0.000 claims description 2
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims description 2
- 206010033892 Paraplegia Diseases 0.000 claims description 2
- 208000028017 Psychotic disease Diseases 0.000 claims description 2
- 208000005392 Spasm Diseases 0.000 claims description 2
- 208000005298 acute pain Diseases 0.000 claims description 2
- 230000032683 aging Effects 0.000 claims description 2
- 208000026935 allergic disease Diseases 0.000 claims description 2
- 210000004556 brain Anatomy 0.000 claims description 2
- 230000001684 chronic effect Effects 0.000 claims description 2
- 206010012601 diabetes mellitus Diseases 0.000 claims description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 230000015654 memory Effects 0.000 claims description 2
- OYKNEKYHRLBMTC-UHFFFAOYSA-N n-(2-fluorophenyl)-3-(4-phenylphenoxy)azetidine-1-carboxamide Chemical compound FC1=CC=CC=C1NC(=O)N1CC(OC=2C=CC(=CC=2)C=2C=CC=CC=2)C1 OYKNEKYHRLBMTC-UHFFFAOYSA-N 0.000 claims description 2
- HFEFMQVTVZOJLC-UHFFFAOYSA-N n-(3-fluorophenyl)-3-(4-phenylphenoxy)azetidine-1-carboxamide Chemical compound FC1=CC=CC(NC(=O)N2CC(C2)OC=2C=CC(=CC=2)C=2C=CC=CC=2)=C1 HFEFMQVTVZOJLC-UHFFFAOYSA-N 0.000 claims description 2
- 230000008693 nausea Effects 0.000 claims description 2
- 230000000926 neurological effect Effects 0.000 claims description 2
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 230000001154 acute effect Effects 0.000 claims 2
- BYDXKBRWKDOLGO-UHFFFAOYSA-N 3-[5-(2,6-difluorophenyl)pyridin-2-yl]oxy-n-pyridazin-3-ylazetidine-1-carboxamide Chemical compound FC1=CC=CC(F)=C1C(C=N1)=CC=C1OC1CN(C(=O)NC=2N=NC=CC=2)C1 BYDXKBRWKDOLGO-UHFFFAOYSA-N 0.000 claims 1
- GQVNLDQKGBHOIC-UHFFFAOYSA-N 3-[5-(2-fluoro-3-methoxyphenyl)pyridin-2-yl]oxy-n-pyridazin-3-ylazetidine-1-carboxamide Chemical compound COC1=CC=CC(C=2C=NC(OC3CN(C3)C(=O)NC=3N=NC=CC=3)=CC=2)=C1F GQVNLDQKGBHOIC-UHFFFAOYSA-N 0.000 claims 1
- MXZUCQMCGWGEFM-UHFFFAOYSA-N 3-[5-(2-fluorophenyl)pyridin-2-yl]oxy-n-pyrazin-2-ylazetidine-1-carboxamide Chemical compound FC1=CC=CC=C1C(C=N1)=CC=C1OC1CN(C(=O)NC=2N=CC=NC=2)C1 MXZUCQMCGWGEFM-UHFFFAOYSA-N 0.000 claims 1
- UXHHUYMCPZQNPI-UHFFFAOYSA-N 3-[5-(2-methoxyphenyl)pyridin-2-yl]oxyazetidine-1-carboxylic acid;pyridazin-3-amine Chemical compound NC1=CC=CN=N1.COC1=CC=CC=C1C(C=N1)=CC=C1OC1CN(C(O)=O)C1 UXHHUYMCPZQNPI-UHFFFAOYSA-N 0.000 claims 1
- YNZXNGQXSSMPCL-UHFFFAOYSA-N 3-[5-[2-methoxy-5-(2-methoxyethoxy)phenyl]pyridin-2-yl]oxy-n-pyridazin-3-ylazetidine-1-carboxamide Chemical compound COCCOC1=CC=C(OC)C(C=2C=NC(OC3CN(C3)C(=O)NC=3N=NC=CC=3)=CC=2)=C1 YNZXNGQXSSMPCL-UHFFFAOYSA-N 0.000 claims 1
- 208000000094 Chronic Pain Diseases 0.000 claims 1
- 208000030814 Eating disease Diseases 0.000 claims 1
- 102100027297 Fatty acid 2-hydroxylase Human genes 0.000 claims 1
- 208000019454 Feeding and Eating disease Diseases 0.000 claims 1
- 208000018522 Gastrointestinal disease Diseases 0.000 claims 1
- 101000937693 Homo sapiens Fatty acid 2-hydroxylase Proteins 0.000 claims 1
- 101000918494 Homo sapiens Fatty-acid amide hydrolase 1 Proteins 0.000 claims 1
- 208000019693 Lung disease Diseases 0.000 claims 1
- 206010029350 Neurotoxicity Diseases 0.000 claims 1
- 208000022873 Ocular disease Diseases 0.000 claims 1
- 208000001132 Osteoporosis Diseases 0.000 claims 1
- 206010038910 Retinitis Diseases 0.000 claims 1
- 206010044221 Toxic encephalopathy Diseases 0.000 claims 1
- 208000030886 Traumatic Brain injury Diseases 0.000 claims 1
- 206010046543 Urinary incontinence Diseases 0.000 claims 1
- 208000022362 bacterial infectious disease Diseases 0.000 claims 1
- 208000010643 digestive system disease Diseases 0.000 claims 1
- 235000014632 disordered eating Nutrition 0.000 claims 1
- 208000018685 gastrointestinal system disease Diseases 0.000 claims 1
- 208000026278 immune system disease Diseases 0.000 claims 1
- PQSZLQWHLSSGQC-UHFFFAOYSA-N n-phenyl-3-(4-phenylphenoxy)azetidine-1-carboxamide Chemical compound C1C(OC=2C=CC(=CC=2)C=2C=CC=CC=2)CN1C(=O)NC1=CC=CC=C1 PQSZLQWHLSSGQC-UHFFFAOYSA-N 0.000 claims 1
- 208000015122 neurodegenerative disease Diseases 0.000 claims 1
- 230000007135 neurotoxicity Effects 0.000 claims 1
- 231100000228 neurotoxicity Toxicity 0.000 claims 1
- 244000045947 parasite Species 0.000 claims 1
- 230000001314 paroxysmal effect Effects 0.000 claims 1
- 208000020685 sleep-wake disease Diseases 0.000 claims 1
- 230000009529 traumatic brain injury Effects 0.000 claims 1
- 230000003612 virological effect Effects 0.000 claims 1
- 108010046094 fatty-acid amide hydrolase Proteins 0.000 abstract description 48
- 102100029111 Fatty-acid amide hydrolase 1 Human genes 0.000 abstract description 39
- 230000007958 sleep Effects 0.000 abstract description 7
- 239000003112 inhibitor Substances 0.000 abstract description 6
- 206010056677 Nerve degeneration Diseases 0.000 abstract 1
- 235000012054 meals Nutrition 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 135
- 238000000034 method Methods 0.000 description 81
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 70
- 239000002904 solvent Substances 0.000 description 62
- 239000000243 solution Substances 0.000 description 59
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 54
- 239000000203 mixture Substances 0.000 description 54
- 235000019439 ethyl acetate Nutrition 0.000 description 51
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 48
- 239000007787 solid Substances 0.000 description 43
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 40
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- 239000011541 reaction mixture Substances 0.000 description 33
- 229920006395 saturated elastomer Polymers 0.000 description 32
- 238000005481 NMR spectroscopy Methods 0.000 description 29
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- 239000002253 acid Substances 0.000 description 24
- 238000001914 filtration Methods 0.000 description 21
- 238000003818 flash chromatography Methods 0.000 description 21
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
- 239000011780 sodium chloride Substances 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 14
- 241000700159 Rattus Species 0.000 description 13
- 229910052938 sodium sulfate Inorganic materials 0.000 description 13
- 235000011152 sodium sulphate Nutrition 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 239000012299 nitrogen atmosphere Substances 0.000 description 11
- 230000008569 process Effects 0.000 description 11
- LETVJWLLIMJADE-UHFFFAOYSA-N pyridazin-3-amine Chemical compound NC1=CC=CN=N1 LETVJWLLIMJADE-UHFFFAOYSA-N 0.000 description 11
- 239000012043 crude product Substances 0.000 description 10
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- 235000019341 magnesium sulphate Nutrition 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 238000004809 thin layer chromatography Methods 0.000 description 10
- XYZLQUMFZDMMFN-UHFFFAOYSA-N 3-(5-iodopyridin-2-yl)oxy-n-pyridazin-3-ylazetidine-1-carboxamide Chemical compound N1=CC(I)=CC=C1OC1CN(C(=O)NC=2N=NC=CC=2)C1 XYZLQUMFZDMMFN-UHFFFAOYSA-N 0.000 description 9
- 239000003940 fatty acid amidase inhibitor Substances 0.000 description 9
- 230000014759 maintenance of location Effects 0.000 description 9
- 239000002480 mineral oil Substances 0.000 description 9
- 235000010446 mineral oil Nutrition 0.000 description 9
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 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 8
- GCUVBACNBHGZRS-UHFFFAOYSA-N cyclopenta-1,3-diene cyclopenta-2,4-dien-1-yl(diphenyl)phosphane iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.c1cc[c-](c1)P(c1ccccc1)c1ccccc1 GCUVBACNBHGZRS-UHFFFAOYSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 235000019253 formic acid Nutrition 0.000 description 8
- 125000001072 heteroaryl group Chemical group 0.000 description 8
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 239000003981 vehicle Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 238000002953 preparative HPLC Methods 0.000 description 7
- 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 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 6
- 238000007792 addition Methods 0.000 description 6
- LGEQQWMQCRIYKG-DOFZRALJSA-N anandamide Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)NCCO LGEQQWMQCRIYKG-DOFZRALJSA-N 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 239000000679 carrageenan Substances 0.000 description 6
- 235000010418 carrageenan Nutrition 0.000 description 6
- 229920001525 carrageenan Polymers 0.000 description 6
- 229940113118 carrageenan Drugs 0.000 description 6
- 229910001873 dinitrogen Inorganic materials 0.000 description 6
- 231100000673 dose–response relationship Toxicity 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- 206010065390 Inflammatory pain Diseases 0.000 description 5
- 229930003827 cannabinoid Natural products 0.000 description 5
- 239000003557 cannabinoid Substances 0.000 description 5
- 229940065144 cannabinoids Drugs 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- FEKGWIHDBVDVSM-UHFFFAOYSA-N 1,1,1,2-tetrachloropropane Chemical compound CC(Cl)C(Cl)(Cl)Cl FEKGWIHDBVDVSM-UHFFFAOYSA-N 0.000 description 4
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 4
- 239000005695 Ammonium acetate Substances 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 description 4
- 235000019257 ammonium acetate Nutrition 0.000 description 4
- 229940043376 ammonium acetate Drugs 0.000 description 4
- 239000012131 assay buffer Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000010779 crude oil Substances 0.000 description 4
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 229960004242 dronabinol Drugs 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 150000004665 fatty acids Chemical class 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 229960000905 indomethacin Drugs 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- 239000006188 syrup Substances 0.000 description 4
- 235000020357 syrup Nutrition 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- ZCODYHRHSDXJLQ-UHFFFAOYSA-N (4-nitrophenyl) 3-(5-bromopyridin-2-yl)oxyazetidine-1-carboxylate Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC(=O)N1CC(OC=2N=CC(Br)=CC=2)C1 ZCODYHRHSDXJLQ-UHFFFAOYSA-N 0.000 description 3
- MMAJXKGUZYDTHV-UHFFFAOYSA-N 1-benzhydrylazetidin-3-ol Chemical compound C1C(O)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 MMAJXKGUZYDTHV-UHFFFAOYSA-N 0.000 description 3
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 description 3
- APFVZKRXHVQHRQ-UHFFFAOYSA-N 2-(1-benzhydrylazetidin-3-yl)oxy-5-iodopyridine Chemical compound N1=CC(I)=CC=C1OC1CN(C(C=2C=CC=CC=2)C=2C=CC=CC=2)C1 APFVZKRXHVQHRQ-UHFFFAOYSA-N 0.000 description 3
- ZHWQXKJDSUFMTH-UHFFFAOYSA-N 2-(azetidin-3-yloxy)-5-bromopyridine;hydrochloride Chemical compound Cl.N1=CC(Br)=CC=C1OC1CNC1 ZHWQXKJDSUFMTH-UHFFFAOYSA-N 0.000 description 3
- FIKKYGSZXTVIEA-UHFFFAOYSA-N 3-(5-bromopyridin-2-yl)oxy-n-pyrazin-2-ylazetidine-1-carboxamide Chemical compound N1=CC(Br)=CC=C1OC1CN(C(=O)NC=2N=CC=NC=2)C1 FIKKYGSZXTVIEA-UHFFFAOYSA-N 0.000 description 3
- CKTJAGNZSZBHQP-UHFFFAOYSA-N 3-[5-(3-hydroxyphenyl)pyridin-2-yl]oxy-n-pyridin-3-ylazetidine-1-carboxamide Chemical compound OC1=CC=CC(C=2C=NC(OC3CN(C3)C(=O)NC=3C=NC=CC=3)=CC=2)=C1 CKTJAGNZSZBHQP-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 230000036592 analgesia Effects 0.000 description 3
- LGEQQWMQCRIYKG-UHFFFAOYSA-N arachidonic acid ethanolamide Natural products CCCCCC=CCC=CCC=CCC=CCCCC(=O)NCCO LGEQQWMQCRIYKG-UHFFFAOYSA-N 0.000 description 3
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 3
- 230000005587 bubbling Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000004202 carbamide Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 206010061428 decreased appetite Diseases 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 210000002683 foot Anatomy 0.000 description 3
- 125000002541 furyl group Chemical group 0.000 description 3
- 125000002883 imidazolyl group Chemical group 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 125000000842 isoxazolyl group Chemical group 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 239000006199 nebulizer Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 125000002971 oxazolyl group Chemical group 0.000 description 3
- 229950007031 palmidrol Drugs 0.000 description 3
- HXYVTAGFYLMHSO-UHFFFAOYSA-N palmitoyl ethanolamide Chemical compound CCCCCCCCCCCCCCCC(=O)NCCO HXYVTAGFYLMHSO-UHFFFAOYSA-N 0.000 description 3
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 3
- 125000000168 pyrrolyl group Chemical group 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 125000001113 thiadiazolyl group Chemical group 0.000 description 3
- 125000000335 thiazolyl group Chemical group 0.000 description 3
- 125000001544 thienyl group Chemical group 0.000 description 3
- 125000001425 triazolyl group Chemical group 0.000 description 3
- QOZLFNQLIKOGDR-UHFFFAOYSA-N (2,5-dimethoxyphenyl)boronic acid Chemical compound COC1=CC=C(OC)C(B(O)O)=C1 QOZLFNQLIKOGDR-UHFFFAOYSA-N 0.000 description 2
- YLZGWUSCGVXOIY-UHFFFAOYSA-N (3-bromo-4-methoxyphenyl) acetate Chemical compound COC1=CC=C(OC(C)=O)C=C1Br YLZGWUSCGVXOIY-UHFFFAOYSA-N 0.000 description 2
- YAPCNXGBNRDBIW-UHFFFAOYSA-N (4-methoxyphenyl) acetate Chemical compound COC1=CC=C(OC(C)=O)C=C1 YAPCNXGBNRDBIW-UHFFFAOYSA-N 0.000 description 2
- KJTONRFPKXUHEU-UHFFFAOYSA-N (4-nitrophenyl) 3-(5-iodopyridin-2-yl)oxyazetidine-1-carboxylate Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC(=O)N1CC(OC=2N=CC(I)=CC=2)C1 KJTONRFPKXUHEU-UHFFFAOYSA-N 0.000 description 2
- OKDHBYVKNGPSNZ-UHFFFAOYSA-N (4-nitrophenyl) 3-[5-(2-fluorophenyl)pyridin-2-yl]oxyazetidine-1-carboxylate Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC(=O)N1CC(OC=2N=CC(=CC=2)C=2C(=CC=CC=2)F)C1 OKDHBYVKNGPSNZ-UHFFFAOYSA-N 0.000 description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- AXVCRZHDBMSXJO-UHFFFAOYSA-N 1-benzhydryl-3-(4-phenylphenoxy)azetidine Chemical compound C1C(OC=2C=CC(=CC=2)C=2C=CC=CC=2)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 AXVCRZHDBMSXJO-UHFFFAOYSA-N 0.000 description 2
- ZNUKSRFJVSGOTL-UHFFFAOYSA-N 1-nitro-4-(trichloromethyl)benzene Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)(Cl)Cl)C=C1 ZNUKSRFJVSGOTL-UHFFFAOYSA-N 0.000 description 2
- TXFZBPGKAVFBKW-UHFFFAOYSA-N 2-(azetidin-3-yloxy)-5-iodopyridine;hydrochloride Chemical compound Cl.N1=CC(I)=CC=C1OC1CNC1 TXFZBPGKAVFBKW-UHFFFAOYSA-N 0.000 description 2
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 2
- WWVRGGSYMUIJJQ-UHFFFAOYSA-N 2-[3-(2-methoxyethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound COCCOC1=CC=CC(B2OC(C)(C)C(C)(C)O2)=C1 WWVRGGSYMUIJJQ-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- LYEKTLKTMUOVCV-UHFFFAOYSA-N 2-bromo-1-methoxy-4-(2-methoxyethoxy)benzene Chemical compound COCCOC1=CC=C(OC)C(Br)=C1 LYEKTLKTMUOVCV-UHFFFAOYSA-N 0.000 description 2
- MUKIFYQKIZOYKT-UHFFFAOYSA-N 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=CC(O)=C1 MUKIFYQKIZOYKT-UHFFFAOYSA-N 0.000 description 2
- CVNOVPANGOZXQW-UHFFFAOYSA-N 3-(4-phenylphenoxy)azetidine;hydrochloride Chemical compound Cl.C1NCC1OC1=CC=C(C=2C=CC=CC=2)C=C1 CVNOVPANGOZXQW-UHFFFAOYSA-N 0.000 description 2
- ZFVRJYJTQCZHNV-UHFFFAOYSA-N 3-(5-bromopyridin-2-yl)oxy-n-pyridazin-3-ylazetidine-1-carboxamide Chemical compound N1=CC(Br)=CC=C1OC1CN(C(=O)NC=2N=NC=CC=2)C1 ZFVRJYJTQCZHNV-UHFFFAOYSA-N 0.000 description 2
- GTXKGDRBYHAVJF-UHFFFAOYSA-N 3-(5-iodopyridin-2-yl)oxy-n-pyridin-3-ylazetidine-1-carboxamide Chemical compound N1=CC(I)=CC=C1OC1CN(C(=O)NC=2C=NC=CC=2)C1 GTXKGDRBYHAVJF-UHFFFAOYSA-N 0.000 description 2
- IQXVTOJBOKMQPB-UHFFFAOYSA-N 3-(5-iodopyridin-2-yl)oxy-n-pyrimidin-4-ylazetidine-1-carboxamide Chemical compound N1=CC(I)=CC=C1OC1CN(C(=O)NC=2N=CN=CC=2)C1 IQXVTOJBOKMQPB-UHFFFAOYSA-N 0.000 description 2
- PKIUXJLUOPGTQF-UHFFFAOYSA-N 3-[5-(2-fluorophenyl)pyridin-2-yl]oxy-n-(6-methylpyridazin-3-yl)azetidine-1-carboxamide Chemical compound N1=NC(C)=CC=C1NC(=O)N1CC(OC=2N=CC(=CC=2)C=2C(=CC=CC=2)F)C1 PKIUXJLUOPGTQF-UHFFFAOYSA-N 0.000 description 2
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 2
- NOJOUQQJSGRBMN-UHFFFAOYSA-N 3-bromo-4-methoxyphenol Chemical compound COC1=CC=C(O)C=C1Br NOJOUQQJSGRBMN-UHFFFAOYSA-N 0.000 description 2
- SHVVSKCXWMEDRW-UHFFFAOYSA-N 3-isocyanatopyridine Chemical compound O=C=NC1=CC=CN=C1 SHVVSKCXWMEDRW-UHFFFAOYSA-N 0.000 description 2
- AIJGXXDEKCWZBF-UHFFFAOYSA-N 4,4,5,5-tetramethyl-2-[3-(2-phenylmethoxyethoxy)phenyl]-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=CC(OCCOCC=2C=CC=CC=2)=C1 AIJGXXDEKCWZBF-UHFFFAOYSA-N 0.000 description 2
- MTZMRMZJCYVKSJ-UHFFFAOYSA-N 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC(O)=CC=C1Cl MTZMRMZJCYVKSJ-UHFFFAOYSA-N 0.000 description 2
- XPXWYVCQCNFIIJ-UHFFFAOYSA-N 5-methyl-1,3,4-oxadiazol-2-amine Chemical compound CC1=NN=C(N)O1 XPXWYVCQCNFIIJ-UHFFFAOYSA-N 0.000 description 2
- HSAHCMOZFNSMLH-UHFFFAOYSA-N 6-chloro-4-methylpyridazin-3-amine Chemical compound CC1=CC(Cl)=NN=C1N HSAHCMOZFNSMLH-UHFFFAOYSA-N 0.000 description 2
- UWDLNRUFHRYMSE-UHFFFAOYSA-N 6-chloro-5-methylpyridazin-3-amine Chemical compound CC1=CC(N)=NN=C1Cl UWDLNRUFHRYMSE-UHFFFAOYSA-N 0.000 description 2
- PFTBPWVKBKBTIF-UHFFFAOYSA-N 7-amino-N-[(5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoyl]-4-methyl-2-oxochromene-3-carboxamide Chemical compound NC1=CC=C2C(=C(C(OC2=C1)=O)C(=O)NC(CCCC=C/CC=C/CC=C/CC=C/CCCCC)=O)C PFTBPWVKBKBTIF-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical group C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 description 2
- 0 CCCC(C)(CCC)C(C)*C(*1)C(*)*(C)C1=C Chemical compound CCCC(C)(CCC)C(C)*C(*1)C(*)*(C)C1=C 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 208000004454 Hyperalgesia Diseases 0.000 description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- 208000001145 Metabolic Syndrome Diseases 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 150000001200 N-acyl ethanolamides Chemical class 0.000 description 2
- 208000001294 Nociceptive Pain Diseases 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 229920002684 Sepharose Polymers 0.000 description 2
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- QHMBSVQNZZTUGM-UHFFFAOYSA-N Trans-Cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-UHFFFAOYSA-N 0.000 description 2
- 229920004890 Triton X-100 Polymers 0.000 description 2
- 239000013504 Triton X-100 Substances 0.000 description 2
- ROFVXGGUISEHAM-UHFFFAOYSA-N URB597 Chemical compound NC(=O)C1=CC=CC(C=2C=C(OC(=O)NC3CCCCC3)C=CC=2)=C1 ROFVXGGUISEHAM-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 208000022531 anorexia Diseases 0.000 description 2
- 230000036528 appetite Effects 0.000 description 2
- 235000019789 appetite Nutrition 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- YXVFYQXJAXKLAK-UHFFFAOYSA-N biphenyl-4-ol Chemical compound C1=CC(O)=CC=C1C1=CC=CC=C1 YXVFYQXJAXKLAK-UHFFFAOYSA-N 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- QHMBSVQNZZTUGM-ZWKOTPCHSA-N cannabidiol Chemical compound OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-ZWKOTPCHSA-N 0.000 description 2
- 229950011318 cannabidiol Drugs 0.000 description 2
- ZTGXAWYVTLUPDT-UHFFFAOYSA-N cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CC=C(C)C1 ZTGXAWYVTLUPDT-UHFFFAOYSA-N 0.000 description 2
- 206010009887 colitis Diseases 0.000 description 2
- GLNDAGDHSLMOKX-UHFFFAOYSA-N coumarin 120 Chemical compound C1=C(N)C=CC2=C1OC(=O)C=C2C GLNDAGDHSLMOKX-UHFFFAOYSA-N 0.000 description 2
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 239000008157 edible vegetable oil Substances 0.000 description 2
- 239000002621 endocannabinoid Substances 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 206010022437 insomnia Diseases 0.000 description 2
- 208000028867 ischemia Diseases 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 240000004308 marijuana Species 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- 208000004296 neuralgia Diseases 0.000 description 2
- 230000004112 neuroprotection Effects 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- FATBGEAMYMYZAF-KTKRTIGZSA-N oleamide Chemical compound CCCCCCCC\C=C/CCCCCCCC(N)=O FATBGEAMYMYZAF-KTKRTIGZSA-N 0.000 description 2
- FATBGEAMYMYZAF-UHFFFAOYSA-N oleicacidamide-heptaglycolether Natural products CCCCCCCCC=CCCCCCCCC(N)=O FATBGEAMYMYZAF-UHFFFAOYSA-N 0.000 description 2
- BOWVQLFMWHZBEF-KTKRTIGZSA-N oleoyl ethanolamide Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)NCCO BOWVQLFMWHZBEF-KTKRTIGZSA-N 0.000 description 2
- 230000010355 oscillation Effects 0.000 description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 description 2
- NWVVVBRKAWDGAB-UHFFFAOYSA-N p-methoxyphenol Chemical compound COC1=CC=C(O)C=C1 NWVVVBRKAWDGAB-UHFFFAOYSA-N 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- XFTQRUTUGRCSGO-UHFFFAOYSA-N pyrazin-2-amine Chemical compound NC1=CN=CC=N1 XFTQRUTUGRCSGO-UHFFFAOYSA-N 0.000 description 2
- 125000005550 pyrazinylene group Chemical group 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- LUCGBEPEAUHERV-UHFFFAOYSA-N pyridazin-4-amine Chemical compound NC1=CC=NN=C1 LUCGBEPEAUHERV-UHFFFAOYSA-N 0.000 description 2
- 125000005576 pyrimidinylene group Chemical group 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000020341 sensory perception of pain Effects 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 230000008536 thermal pain sensitivity Effects 0.000 description 2
- 125000005557 thiazolylene group Chemical group 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
- 230000000472 traumatic effect Effects 0.000 description 2
- 125000004306 triazinyl group Chemical group 0.000 description 2
- 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 2
- SLAPQAZQRNMJLC-UHFFFAOYSA-N (2-chloro-5-hydroxyphenyl)boronic acid Chemical compound OB(O)C1=CC(O)=CC=C1Cl SLAPQAZQRNMJLC-UHFFFAOYSA-N 0.000 description 1
- JCKZNMSBFBPDPM-UHFFFAOYSA-N (2-fluoro-3-methoxyphenyl)boronic acid Chemical compound COC1=CC=CC(B(O)O)=C1F JCKZNMSBFBPDPM-UHFFFAOYSA-N 0.000 description 1
- ROEQGIFOWRQYHD-UHFFFAOYSA-N (2-methoxyphenyl)boronic acid Chemical compound COC1=CC=CC=C1B(O)O ROEQGIFOWRQYHD-UHFFFAOYSA-N 0.000 description 1
- WFWQWTPAPNEOFE-UHFFFAOYSA-N (3-hydroxyphenyl)boronic acid Chemical compound OB(O)C1=CC=CC(O)=C1 WFWQWTPAPNEOFE-UHFFFAOYSA-N 0.000 description 1
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 1
- 125000002733 (C1-C6) fluoroalkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical group C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- 125000001989 1,3-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([H])C([*:2])=C1[H] 0.000 description 1
- VZNCSZQPNIEEMN-UHFFFAOYSA-N 1-fluoro-2-isocyanatobenzene Chemical compound FC1=CC=CC=C1N=C=O VZNCSZQPNIEEMN-UHFFFAOYSA-N 0.000 description 1
- RIKWVZGZRYDACA-UHFFFAOYSA-N 1-fluoro-3-isocyanatobenzene Chemical compound FC1=CC=CC(N=C=O)=C1 RIKWVZGZRYDACA-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- IKBFIJAQGOOLJX-UHFFFAOYSA-N 2-(1-benzhydrylazetidin-3-yl)oxy-5-bromopyridine Chemical compound N1=CC(Br)=CC=C1OC1CN(C(C=2C=CC=CC=2)C=2C=CC=CC=2)C1 IKBFIJAQGOOLJX-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- RCRCTBLIHCHWDZ-DOFZRALJSA-N 2-arachidonoylglycerol Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)OC(CO)CO RCRCTBLIHCHWDZ-DOFZRALJSA-N 0.000 description 1
- FWOHDAGPWDEWIB-UHFFFAOYSA-N 2-bromoethoxymethylbenzene Chemical compound BrCCOCC1=CC=CC=C1 FWOHDAGPWDEWIB-UHFFFAOYSA-N 0.000 description 1
- QWLGCWXSNYKKDO-UHFFFAOYSA-N 2-chloro-5-iodopyridine Chemical compound ClC1=CC=C(I)C=N1 QWLGCWXSNYKKDO-UHFFFAOYSA-N 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- ROYHWGZNGMXQEU-UHFFFAOYSA-N 3,6-dichloro-4-methylpyridazine Chemical compound CC1=CC(Cl)=NN=C1Cl ROYHWGZNGMXQEU-UHFFFAOYSA-N 0.000 description 1
- AIZRKFAOIQGVHS-UHFFFAOYSA-N 3-[5-(2-methoxyphenyl)pyridin-2-yl]oxy-n-pyridazin-3-ylazetidine-1-carboxamide Chemical compound COC1=CC=CC=C1C(C=N1)=CC=C1OC1CN(C(=O)NC=2N=NC=CC=2)C1 AIZRKFAOIQGVHS-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 description 1
- LBUNNMJLXWQQBY-UHFFFAOYSA-N 4-fluorophenylboronic acid Chemical compound OB(O)C1=CC=C(F)C=C1 LBUNNMJLXWQQBY-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical compound [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- PEAOEIWYQVXZMB-UHFFFAOYSA-N 5-bromo-2-chloropyridine Chemical compound ClC1=CC=C(Br)C=N1 PEAOEIWYQVXZMB-UHFFFAOYSA-N 0.000 description 1
- NDPKVJZZCMFBIO-UHFFFAOYSA-N 5-methylpyridazin-3-amine Chemical compound CC1=CN=NC(N)=C1 NDPKVJZZCMFBIO-UHFFFAOYSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- YPWBPONDYDVMLX-UHFFFAOYSA-N 6-methoxypyridazin-3-amine Chemical compound COC1=CC=C(N)N=N1 YPWBPONDYDVMLX-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 206010000234 Abortion spontaneous Diseases 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- 206010006811 Bursitis Diseases 0.000 description 1
- 102000009132 CB1 Cannabinoid Receptor Human genes 0.000 description 1
- 108010073366 CB1 Cannabinoid Receptor Proteins 0.000 description 1
- 102000009135 CB2 Cannabinoid Receptor Human genes 0.000 description 1
- 108010073376 CB2 Cannabinoid Receptor Proteins 0.000 description 1
- BETWATDZFVZRJV-UHFFFAOYSA-N CC(C)=C/N=C(/C)\O Chemical compound CC(C)=C/N=C(/C)\O BETWATDZFVZRJV-UHFFFAOYSA-N 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- 102100036214 Cannabinoid receptor 2 Human genes 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 235000012766 Cannabis sativa ssp. sativa var. sativa Nutrition 0.000 description 1
- 235000012765 Cannabis sativa ssp. sativa var. spontanea Nutrition 0.000 description 1
- RVDCWVITIURHRY-UHFFFAOYSA-N Cc(ccc(-c(cn1)ccc1OC(C1)CN1C(Nc1c(C)nccc1)=O)c1)c1OCCOC Chemical compound Cc(ccc(-c(cn1)ccc1OC(C1)CN1C(Nc1c(C)nccc1)=O)c1)c1OCCOC RVDCWVITIURHRY-UHFFFAOYSA-N 0.000 description 1
- SDXAWLJRERMRKF-UHFFFAOYSA-N Cc1cc(C)n[nH]1 Chemical compound Cc1cc(C)n[nH]1 SDXAWLJRERMRKF-UHFFFAOYSA-N 0.000 description 1
- RHOOLJLEYYXKTK-UHFFFAOYSA-N Cc1cnc(C)nc1 Chemical compound Cc1cnc(C)nc1 RHOOLJLEYYXKTK-UHFFFAOYSA-N 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 208000019888 Circadian rhythm sleep disease Diseases 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 206010010144 Completed suicide Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 206010011793 Cystitis haemorrhagic Diseases 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 241000400611 Eucalyptus deanei Species 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 101100334124 Homo sapiens FAAH gene Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000035154 Hyperesthesia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 208000031773 Insulin resistance syndrome Diseases 0.000 description 1
- 208000001456 Jet Lag Syndrome Diseases 0.000 description 1
- 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 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 208000008238 Muscle Spasticity Diseases 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 206010028817 Nausea and vomiting symptoms Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- QYAYBPUCOYFANP-UHFFFAOYSA-N O=C(Nc1nnccc1)N(C1)CC1Oc(nc1)ccc1C1=CCCC(OCCOCc2ccccc2)=C1 Chemical compound O=C(Nc1nnccc1)N(C1)CC1Oc(nc1)ccc1C1=CCCC(OCCOCc2ccccc2)=C1 QYAYBPUCOYFANP-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 208000027089 Parkinsonian disease Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- 240000006711 Pistacia vera Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 1
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 206010066218 Stress Urinary Incontinence Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 238000003639 Student–Newman–Keuls (SNK) method Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 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
- 206010057040 Temperature intolerance Diseases 0.000 description 1
- 208000000491 Tendinopathy Diseases 0.000 description 1
- 206010043255 Tendonitis Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 208000010399 Wasting Syndrome Diseases 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 239000002830 appetite depressant Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000002639 bone cement Substances 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 230000008993 bowel inflammation Effects 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940112822 chewing gum Drugs 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000004122 cyclic group Chemical group 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
- 230000002950 deficient Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000011903 deuterated solvents Substances 0.000 description 1
- 125000002720 diazolyl group Chemical group 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- PCXRACLQFPRCBB-ZWKOTPCHSA-N dihydrocannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)C)CCC(C)=C1 PCXRACLQFPRCBB-ZWKOTPCHSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- MYIRARNXCGWFHI-UHFFFAOYSA-N ethoxyethane;2-methylpentane Chemical compound CCOCC.CCCC(C)C MYIRARNXCGWFHI-UHFFFAOYSA-N 0.000 description 1
- 239000004060 excitotoxin Substances 0.000 description 1
- 238000002270 exclusion chromatography Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 208000010706 fatty liver disease Diseases 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000004428 fluoroalkoxy group Chemical group 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- ZHOGHWVKKXUAPI-UHFFFAOYSA-N fluorooxy(phenyl)borinic acid Chemical compound FOB(O)C1=CC=CC=C1 ZHOGHWVKKXUAPI-UHFFFAOYSA-N 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 230000002518 glial effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000008543 heat sensitivity Effects 0.000 description 1
- 201000002802 hemorrhagic cystitis Diseases 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 208000009326 ileitis Diseases 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000004245 indazol-3-yl group Chemical group [H]N1N=C(*)C2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 208000028774 intestinal disease Diseases 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 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
- 150000002513 isocyanates Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 208000033915 jet lag type circadian rhythm sleep disease Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 235000011475 lollipops Nutrition 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 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
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 208000015994 miscarriage Diseases 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 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
- 239000007922 nasal spray Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 239000002581 neurotoxin Substances 0.000 description 1
- 231100000618 neurotoxin Toxicity 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 210000000929 nociceptor Anatomy 0.000 description 1
- 108091008700 nociceptors Proteins 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 210000000056 organ Anatomy 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
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000005564 oxazolylene group Chemical group 0.000 description 1
- 230000008533 pain sensitivity Effects 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000010149 post-hoc-test Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 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 1
- 239000003380 propellant Substances 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000001107 psychogenic effect Effects 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 229960004889 salicylic acid Drugs 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
- 230000035945 sensitivity Effects 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 208000000995 spontaneous abortion Diseases 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 125000005650 substituted phenylene group Chemical group 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 201000004415 tendinitis Diseases 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 description 1
- 125000005556 thienylene group Chemical group 0.000 description 1
- 206010043778 thyroiditis Diseases 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 125000005558 triazinylene group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- PBIMIGNDTBRRPI-UHFFFAOYSA-N trifluoro borate Chemical compound FOB(OF)OF PBIMIGNDTBRRPI-UHFFFAOYSA-N 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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
- A61K31/495—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
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
-
- 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
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines 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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- 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
-
- 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
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- 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
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- 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
- A61P17/04—Antipruritics
-
- 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
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Immunology (AREA)
- Pain & Pain Management (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Ophthalmology & Optometry (AREA)
- Heart & Thoracic Surgery (AREA)
- Psychiatry (AREA)
- Urology & Nephrology (AREA)
- Cardiology (AREA)
- Hospice & Palliative Care (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pulmonology (AREA)
- Diabetes (AREA)
- Child & Adolescent Psychology (AREA)
- Anesthesiology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Tropical Medicine & Parasitology (AREA)
- Virology (AREA)
Abstract
Description
いくつかの外因性カンナビノイド類の効果に対する研究の結果は、FAAH阻害剤が種々の状態、疾病、障害又は症状を治療するために有用であり得ることも示唆している。
承認された適応症と異なり、カンナビノイドを使用することにより多くの注目を受けた治療分野は、鎮痛、即ち疼痛の治療である。5つの小さな無作為の対照臨床試験により、テトラヒドロカンナビノールTHCが、容量依存性の無痛を生じることで、プラセボより優れていることが示された(Robson, Br. J. Psychiatry 2001, 178, 107-115)。
カンナビノイド類は、眼内圧力の容量関連減少を生じ、それゆえ緑内障の症状を軽減できるかもしれない。眼科科学者は、緑内障の患者にカンナビス類を処方しており、他の薬で眼内圧を適切に制御していない(Robson, 2001 supra)。
AEA及び他のエンドカンナビノイド類でのFAAH阻害剤の効果の付加において、他の脂質調製物質のFAAHのカタボリズムの阻害剤は、他の治療の徴候を治療するために使用し得る。例えば、PEAは、炎症、免疫抑制、鎮痛及び神経保護の動物モデルで生物学上の効果が証明されている(Ueda, J. Biol. Chem. 2001, 276(38), 35552)。FAAH以外の物質として、オレアミドは睡眠を誘発している(Boger, Proc. Natl. Acad. Sci. USA 2000, 97(10), 5044; Mendelson, Neuropsychopharmacology 2001, 25, S36)。
FAAH阻害剤は、アルツハイマー症、精神分裂症、うつ病、アルコール中毒、中毒、自殺、パーキンソン病、ハチングトン病、脳卒中、嘔吐、流産、胚移植、エンドトキシンショック、肝硬変、アテローム性動脈硬化症、癌、外傷性頭部障害、緑内障及び骨セメント移植シンドロームの治療に潜在的に有用であると考えられている。
FAAH活性の阻害から潜在的に有用である他の疾病及び医学的状態は、例えば、インスリン抵抗症候群、糖尿病、高脂血症、脂肪肝疾患、肥満、アテローム性動脈硬化症及び動脈硬化症を限定されずに含む、種々のメタボリックシンドローム、疾病、疾患及び/又は状態を含む。
FAAH活性の阻害は、炎症を含む種々の状態の治療にも潜在的に有用である。これら状態は、限定されないが、関節炎(リュウマチ性関節炎、肩腱炎又は滑液嚢炎、尿酸性関節炎、リュウマチ性多発性筋痛(aolymyalgia rheumatica)、臓器特異性炎症性疾患(甲状腺炎、肝炎、炎症性腸疾患等)、喘息、他の自己免疫性疾患(多発性硬化症等)、慢性閉塞性肺疾患(COPD)、アレルギー性鼻炎、及び心臓血管系疾患を含む。
FAAH阻害剤は、神経変性を避けるため又は神経保護に潜在的に有用である。
本発明は、FAAH阻害活性を有する以下に十分に規定及び記載する、アゼチジン誘導体のクラスを利用可能にする。本発明の化合物は、FAAH活性の阻害から恩恵を得る疾病の治療又は医学的状態に有用である。そのような疾病又は状態は、上記されている。特に、本発明の化合物は、不安、うつ病、疼痛、炎症、睡眠障害又は運動障害の治療に使用し得る。
1つの観点において、本発明は、式(I)
Ar2 は、任意に置換されたフェニル、任意に置換された5又は6個の環原子を有するモノサイクリックヘテロアリール又は任意に置換された個々の縮合環中に5又は6個の環原子を有する縮合ビサイクリックへテロアリールである;及び
Ar3は、任意に置換されたフェニレン及び任意に置換された5又は6個の環原子を有するモノサイクリックヘテロアリーレン基からなる群から選択された二価の基である)の化合物又はその薬学的に受容な塩を提供する。
(a)1以上の薬学的に受容な担体及び/又は賦形剤と共に、上記式(I)又はその薬学的に受容な塩を含む医薬組成物;
(b)FAAH活性の阻害から恩恵を得る疾病又は医学的状態の治療用の、上記式(I)又はその薬学的に受容な塩を含む医薬組成物の使用;
(c)疾病や状態等で苦しんでいる対象者に、上記式(I)又はその薬学的に受容な塩の効果量を投与することを含むFAAH活性の阻害から恩恵を得る疾病又は医学的状態の治療方法
を提供する。
FAAH活性の阻害から恩恵を得る疾病又は医学的状態は、上記で参照されるものを含み、特に、不安、うつ病、疼痛(特に、侵害、ニューロパシー、内臓、術後の疼痛及び癌に由来する疼痛)、炎症、睡眠障害及び運動障害を含む。
ここで使用される用語“(Ca-Cb)アルキル”(a及びbは整数)は、aからbの炭素原子を有する直鎖又は分岐鎖アルキル基を示す。従って、例えば、aが1でbが6の場合、この用語は、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、sec-ブチル、t-ブチル、n-ペンチル及びn-ヘキシルを含む。
ここで使用される用語“(Ca-Cb)フルオロアルキル”(a及びbは整数)は、1つ以上の水素原子がフッ素原子で置換されたaからbの炭素原子を有する直鎖又は分岐鎖アルキル基を示す。モノ−、ジ−及びトリ−フルオロメチルがこの用語に包含される。
ここで使用される制限されない用語“ヘテロアリール”は、S、N及びOから選択される1つ以上のヘテロ原子を含むモノサイクリック又は縮合ビシクロ芳香基を示す。
それが存在する文中で特定されない限り、フェニル又はヘテロアリール成分に使用される用語“置換された”は、例えば、(C1-C6)アルキル、(C1-C6)フルオロアルキル、(C1-C6)アルコキシ(芳香族環の隣接する炭素原子上のメチレンジオキシ及びエチレンジオキシ置換分を含む)、(C1-C6)フルオロアルコキシ、(C1-C6)アルコキシ-(C1-C6)アルキル、ベンジルオキシ-(C1-C6)アルキル、(C1-C6)アルコキシ-(C1-C6)アルコキシ、ベンジルオキシ-(C1-C6)アルコキシ、ヒドロキシ、ヒドロキシ(C1-C6)アルキル、ヒドロキシ(C1-C6)アルコキシ、メルカプト、メルカプト(C1-C6)アルキル、(C1-C6)アルキルチオ、シクロプロピル、ハロ(フルオロ及びクロロを含む)、ニトロ、ニトリル(シアノ)、-COOH、テロラゾールイル、 -COORA、-CORA、-SO2RA、-CONH2、-SO2NH2、-CONHRA、-SO2NHRA、-CONRARB、-SO2NRARB、-NH2、-NHRA、-NRARB、-OCONH2、-OCONHRA、-OCONRARB、-NHCORA、-NHCOORA、-NRBCOORA、-NHSO2ORA、-NRBSO2ORA、-NHCONH2、-NRACONH2、-NHCONHRB、-NRACONHRB、-NHCONRARB、又は-NRACONRARB(RA及びRBは、独立に、(C1-C4)アルキル基、又はRA及びRBは、同じ窒素に付加している場合、窒素原子と共に、モルフィニル、ピペリジニル又はピペラジニル基のようなサイクリックアミノ基である)から選択される少なくとも置換基、を意味する。“任意の置換基”は、上記記載に含まれる置換基の1つでもよい。
好適な塩のレビューとして、Stahl及びWermuthによるHandbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, Weinheim, Germany, 2002)が参照される。
そのような水和物及び溶媒和物は、本発明の活性化合物の単なる特定の物理化学形態の過程であり、それゆえ本発明の部分を形成する。式(I)に含まれる限定的でなく関連するいかなる化合物も、水和物又は溶媒和物を形成するかしないかどうかに関係なく、そのような化合物に関連するとして解釈されうる。用語“溶媒和物”は、本発明の化合物と1以上の薬学的に受容な溶媒分子、例えばエタノール、の量論量との分子複合体を表現するためにここで使用される。用語“水和物”は、溶媒が水である場合に使用される。
本発明の化合物において:
Ar1は、任意に置換されたフェニルであるか、又は例えば、ピリジル、チエニル、フリル、ピロールイル、イミダゾールイル、オキサゾールイル、イソキサゾールイル、チアゾールイル、イソチアゾールイル、ピラゾールイル、トリアゾールイル、オキサジアゾールイル、チアジアゾールイル、ピリダジニル、ピリミジニル、ピラジニル、テトラゾールイル、及びトリアジンイル、任意に置換されたこれらのいずれかからなるモノサイクリックヘテロアリール基類の群から選択し得る。特定の場合、Ar1は、フェニル、2-, 4-又は5-オキサゾールイル、2-, 4-又は5-チアゾールイル、[1,3,4]チアジアゾール-2-イル、[1,3,4]オキサジアゾール-2-イル、[1,2,3]オキサジアゾール-4-イル、1-, 4-ピラゾールイル、又は[1,2,4]トリアゾール-3-イル、任意に置換されたいずれかである。特定の場合、Ar1は、例えば、フェニル、2-フルオロフェニル、3-(2-メトキシ-エトキシ)-フェニル、又は2-メトキシ-5-(2-メトキシ-エトキシ)-フェニルであり得る。
Ar3は、例えば、1,4-フェニレン基のような、任意に置換されたフェニレン基でもよく、例えば、二価の、ピリジニレン、チエニレン、フリレン、ピロリレン、イミダゾリレン、オキサゾリレン、イソキサゾリレン、チアゾリレン、イソチアゾリレン、ピラゾリレン、チアゾリレン、ピリダジニレン、ピリミジニレン、ピラジニレン、トリアジニレン、チアジアゾリレン基、任意に置換されたこれらのいずれかからなる群から選択されてもよい。
現時点で好ましいAr3基は、任意に置換された二価の、1,4-フェニレン又は式
の2,5-ピリジニレン基のようなフェニレン又はピリジニレン基を含む。
の二価の基、任意に置換されたこれらのいずれかを含む。
Ar1、Ar2及びAr3の任意の置換基は、例えば、クロロ、フルオロ、ブロモ、シクロプロピル、メチル、モノ-、ジ-又はトリ-メチル、トリフルオロメチル、ジフルオロメチル、モノフルオロメチル、メトキシ、エトキシ、プロポキシ、ブトキシ、ペントキシ、2-メトキシエトキシ、2-ベンジルオキシ-エトキシ、2-ヒドロキシ-エトキシ、モノ-、ジ-又はトリ-フルオロメトキシ、シアノ、ヒドロキシ、CO2R1又は-SO2R1(R1は水素、メチル又はエチル)テトラゾールイル、-NR2R3、-CH2NR2R3及び-C(=O)NR2R3(R2及びR3は独立に水素、メチル又はエチル)から独立に選択し得る。
本発明のいくつかの化合物において、Ar1-Ar3-基は、4-フェニルフェニル、具体的にはビフェニル-4-イル基である。
本発明の他のいくつかの化合物において、Ar2は、2-又は3-フルオロフェニル、又は3-ピリジルである。
Ar2が3-ピリジル、ピリミジン-4-イル、ピラジン-2-イル又はピリダジン-3-イルであり;
Ar3が、任意に置換されている二価の、1,4-フェニレン又は式
の2,5-ピリジニレン基であり;
Ar1が任意に置換されたフェニルである。
経口投与後、良好で本質的なFAAH阻害能力と、高及び長期血漿濃度との組み合わせに対して、現時点で好ましい本発明の化合物は、実験ラットでの試験での検証で、
3-(ビフェニル-4-イルオキシ)-アゼチジン-1-カルボキシリックアシッドピリジン-3-イルアミド;
3-[5-(2-フルオロ-フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド;
3-[5-[3-(2-メトキシ-エトキシ)-フェニル]-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド;
3-(5-フェニル-ピリジン-2-イルオキシ)-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド;
3-[5-(2-メトキシ-フェニル)-ピリジン-2-イルオキシ]- アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド;
及びそれらの薬学的需要な塩である。
本発明が関する化合物(I)の合成のために多数の合成戦略があるが、しかし全てが、合成有機化学者に知られている公知の化学に頼る。よって、式(I)による化合物は、標準的な文献に記載され、かつ当業者に周知の方法に従って合成され得る。代表的な文献の出典は、“Advanced organic chemistry”, 第4版(Wiley), J March,“Comprehensive Organic Transformation”, 第2版(Wiley), R.C. Larock,“Handbook of Heterocyclic Chemistry”, 第2版(Pergamon), A.R. Katritzky)や、“Synthesis”、“Acc. Chem. Res.”、“Chem. Rev”に見られるような総説であり、又はオンラインの標準文献サーチによる一次文献出典又は“Chemical Abstracts”や“Beilstein”のような2次出典から確認された一次文献出典である。そのような文献の方法は、本明細書中の製造実施例のもの及びそれらに類似の方法を含む。
Ar1, Ar2又はAr3 中の任意の反応性置換基は、反応の間保護され、その後脱保護されてもよい。
上記したように、本発明の化合物は、FAAH活性の阻害から恩恵を得る疾病又は医学的状態の治療に有用であり、そのような疾病及び状態の例示は上記している。
任意の特定の患者についての具体的な用量レベルが、用いられる具体的な化合物の活性、年齢、体重、全身の健康状態、性別、食餌、投与の時間、投与経路、排出経路、薬物の組み合わせ及び原因の機構並びに療法を受ける特定の疾患の重篤度を含む様々な因子に依存することが理解されるだろう。一般に、経口投与可能な製剤の適切な用量は、通常、0.1〜3000mgの範囲で、1日あたりに1、2もしくは3回であり、又は注入、吸入、点滴もしくはその他の経路により投与される等価な1日量であろう。しかし、最適な用量レベル及び投与頻度は、当該技術において通常行われているように、臨床試験により決定される。
有効成分は、吸引用、例えば、鼻スプレー、又は乾燥粉末やエアロゾル吸入剤のような剤型を有してもよい。吸引によるデリバリーのために、活性化合物がマイクロ粒子の形態であることが好ましい。それは、スプレードライ、フリーズドライ及び微小化を含む種々の技術により製造し得る。エアロゾル発生は、例えば、圧推進ジェット噴霧器又は超音波噴霧器を使用すること、好ましくは微細化活性化合物、例えば、吸引カプセルや他の“乾燥粉末”デリバリーシステムの噴霧剤推進規制噴霧器又は無噴霧剤投与を使用することで、実行し得る。
本発明の化合物は、他のクラスの薬学的な活性薬物と共に投与し得る。
パートA:実施例1〜4
1H (400 MHz)及び13C (100 MHz)核磁気共鳴(NMR)分析は、Bruker DPX-400 MHz NMR分光計を使用して実行した。分光リファレンスは、公知のサンプル溶媒の化学シフトとした。1H nmrデータは、化学シフト(δ)、多重度(s,シングレット; d, ダブレット; t, トリプレット; q, カルテット; m, マルチプレット; dd, ダブルダブレット; br, ブロード; app, 見かけ等)、積分(例えば1H)、Hzでのカップリング定数(J)を示していることを報告している。13Cデータは、化学シフト(δ)を示していることを報告している。重水素化溶媒は、Sigma-Aldrich Chemical Company又はFluorochemから入手された。
溶媒A:HPLCグレード水+10mM酢酸アンモニウム+0.08% v/vギ酸
溶媒B:95% v/v HPLCグレード水+5% v/v 溶媒 A +0.08% v/vギ酸
グラジエント:95:5 溶媒A : 溶媒B, 0.00から0.25 mins.; 95 : 5から5 : 95溶媒A : 溶媒B, 0.25 から2.50 mins.; 5 : 95溶媒A : 溶媒 B, 2.50 から3.75 mins.
を使用し、温度22℃で、2 mL min-1の流量で、Luna 3 μM, C18(2), Phenomenexからの30 mm × 4.6 mm i.d.カラムを備えたHP1100装置により行った。
3-(ビフェニル-4-イルオキシ)-アゼチジン-1-カルボキシリックアシッドフェニルアミド
1-ベンズヒドリル-3-(ビフェニル-4-イルオキシ)アゼチジン
3-(ビフェニル-4-イルオキシ)アゼチジンヒドロクロライド
3-(ビフェニル-4-イルオキシ)-アゼチジン-1-カルボキシリックアシッドフェニルアミド
ジクロロメタン(2.5mL)中の3-(1,1'-ビフェニル-4-イルオキシ)アゼチジンヒドロクロライド(100mg,382μmol)懸濁液に、トリエチルアミン(63μL,48mg,478μmol)に続いてフェニルイソシアネート(35μL,38mg,320μmol)を添加して、反応物を室温で2.5時間攪拌した。混合物を、プレパック(pre-packed)された2gSCX-2カートリッジに直接装填して、生成物を1:1のジクロロメタン:メタノール(15mL)で溶出させた。溶媒を蒸発させて、白色粉末状の尿素(urea)(113mg,100%)を得た。LCMS保持時間2.57分,m/z345.2[M+H]+;1Hnmr(400MHz;DMSO-d6)δ8.54(s,1H),7.62(d,4H,J=7.6Hz),7.50(d,2H,J=8.0Hz),7.44(t,2H,J=7.6Hz),7.32(t,1H,J=7.2Hz),7.23(t,2H,J=7.8Hz),7.98-7.91(m,3H),5.09(m,1H),4.46-4.42(m,2H)及び3.95-3.91(m,2H).
3-(ビフェニル-4-イルオキシ)-アゼチジン-1-カルボキシリックアシッド(3-フルオロ-フェニル)-アミド
3-(ビフェニル-4-イルオキシ)-アゼチジン-1-カルボキシリックアシッド(2-フルオロ-フェニル)-アミド
3-(ビフェニル-4-イルオキシ)-アゼチジン-1-カルボキシリックアシッドピリジン-3-イルアミド
一般手順
市販されている全ての試薬は、これ以上精製することなく用いた。無水溶媒は、市販されているものを用い、更に乾燥させなかった。フラッシュクロマトグラフィーは、シリカゲルカートリッジを予め装填して用いる(Strata SI-1;61Å, Phenomenex,Cheshire UK又はIST Flash II, 54Å,Argonaut,Hengoed,UK)。薄層クロマトグラフィー(TLC)は、メルク社(Merck)製60F254シリカゲルで被膜(塗装)された5×10cmプレート(板)で行った。UV下で可視すると、個々のスポットの保持価(Rf)を、溶媒により移動した全距離による生成物の移動した距離を適切に区分することにより、規定できる。
溶媒B:95%v/vHPLCグレードのアセトニトリル+溶媒A5%v/v+蟻酸0.08%v/v
pH9:溶媒A:HPLCグレードの水+アンモニウムアセテート10mM+アンモニア溶液0.08%v/v
溶媒B:95%v/vHPLCグレードのアセトニトリル+溶媒A5%v/v+アンモニア溶液0.08%v/v
1H(400MHz)及び13C(100MHz)核磁気共鳴器(MNR)分析を、Brucker DPX-400MHz NMR分光計で行った。分光リファレンスは、公知のサンプル溶媒の化学シフトとした。1H nmrデータは、以下のように報告される:化学シフト(δ)、多重度(s=シングレット、d=ダブレット、t=トリプレット、q=カルテット、m=マルチプレット、dd=ダブルダブレット、br=ブロード、app=アパレント等)、積分(例えば、1H)、カップリング定数)(J)Hz。13Cデータは、化学シフト(δ)を示して報告される。重水素化溶媒は、シグマ-アルドリッチ化学社又はフルオロケミカルから得られる。
IUPAC化学名は、AutoNomスタンダードを用いて行う。
3-[5-[3-(2-メトキシ-エトキシ)-フェニル]-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリミジン-4-イルアミド
2-(1-ベンズヒドリル-アゼチジン-3-イルオキシ)-5-ヨードピリジン
LCMS(方法A)RT=2.19min;m/z=443[M+H]+
2-(アゼチジン-3-イルオキシ)-5-ヨードピリジンヒドロクロライド
LCMS(方法A)RT=1.24min;m/z=277[M+H]+
(中間物5)
3-(5-ヨードピリジン-2-イルオキシ)-アゼチジン-1-カルボキシリックアシッド4-ニトロ−フェニルエステル
LCMS(方法A)RT=2.54min;m/z=442[M+H]+.1H NMR:(400MHz,DMSO-d6)δ3.95-4.04(m,1H,4.16-4.24(m,1H),4.36-4.44(m,1H),4.56-4.74(m,1H),5.35-5.40*m,1H),6.84(d,1H,J=8.5Hz),7.43-7.47(m,2H),8.07(dd,1H,J=8.5,2.2Hz),8.26-8.29(m,2H),8.38(d,1H,J=2.1Hz).
3-(5-ヨードピリジン-2-イルオキシ)-アゼチジン-1-カルボキシリックアシッドピリミジン-4-イルアミド
LCMS(方法A)RT=1.89min;m/z=398[M+H]+.
2-[3-(2-メトキシ-エトキシ)-フェニル]-4,4,5,5-テトラメチル-[1,3,2]ジオキサボロラン
LCMS(方法A)RT=1.42min;m/z=非イオン化
3-[5-[3-(2-メトキシ-エトキシ)-フェニル]-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリミジン-4-イルアミド
LCMS:(方法A)RT=1.97min;m/z=422[M+H]+.
TLC:RF=0.39(100%EtOAc).1HNMR:(400MHz,DMSO-d6)δ3.32(s,3H),3.68(m,2H),4.03(brm,2H),4.17(m,2H),4.48(brm,2H),5.38(m,1H),6.95(dd,1H,J=8.1,2.5Hz),6.99(d,1H,J=8.6Hz),7.20-7.26(m,2H),7.37(dd,1H,J=8.3,8.3Hz),7.92(dd,1H,J=5.7,1.2Hz),8.08(dd,1H,J=8.6,2.5Hz),8.48-8.54(m,2H),8.57(m,1H),9.86(brs,1H).
3-[5-[3-(2-メトキシ-エトキシ)-フェニル]-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピラジン-2-イルアミド
2-(1-ベンズヒドリル-アゼチジン-3-イルオキシ)-5-ブロモピリジン
2-(アゼチジン-3-イルオキシ)-5-ブロモピリジンヒドロクロライド
3-(5-ブロモピリジン-2-イルオキシ)-アゼチジン-1-カルボキシリックアシッド4-ニトロ−フェニルエステル
LCMS:(方法A)RT=2.50min;m/z=396[M+H]+.
3-(5-ブロモピリジン-2-イルオキシ)-アゼチジン-1-カルボキシリックアシッドピラジン-2-イルアミド
LCMS:(方法A)RT=1.86min;m/z=352[M+H]+.
3-[5-[3-(2-メトキシ-エトキシ)-フェニル]-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピラジン-2-イルアミド
LCMS:(方法A)RT=2.01min;m/z=422[M+H]+.
TLC:Rf=0.51(100% EtOAc)
1H NMR:(400MHz,DMSO-d6)δ3.32(s,3H),3.68(m,2H),4.03(m,2H),4.17(m,2H),4.48(m,2H),5.39(m,1H),6.95(m,1H),6.99(d,1H,J=8.6Hz),7.21-7.25(m,2H),7.37(dd,1H,J=8.3,8.3Hz),8.09(dd,1H,J=8.5,2.5Hz),8.22(d,1H,J=2.5Hz),8.29(m,1H)8.49(d,1H,J=2.0Hz),9.17(d,1H,J=1.5Hz),9.65(brs,1H)
3-[5-[3-(2-メトキシ-エトキシ)-フェニル]-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド
3-(5-ヨードピリジン-2-イルオキシ)-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド
LCMS:(方法A)RT=1.84min;m/z=398[M+H]+.
3-[5-[3-(2-メトキシ-エトキシ)-フェニル]-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド
LCMS:(方法A)RT=1.18min;m/z=422[M+H]+.
1H NMR:(400MHz,DMSO-d6)δ3.32(s,3H),3.68(m,2H),4.04(brm,2H),4.17(m,2H),4.49(brm,2H),5.40(m,1H),6.95(m,1H),6.99(d,1H,J=8.9Hz),7.21-7.25(m,2H),7.37(dd,1H,J=8.3,8.3Hz),7.59(dd,1H,J=9.1,4.5Hz),8.09(dd,1H,J=8.6,2.6Hz),8.15(dd,1H,J=9.1,1.4Hz),8.50(d,1H,J=4.5,1.4Hz),8.85(dd,1H,J=4.5,1.4Hz),9.97(s,1H).
3-[5-[3-(2-メトキシ-エトキシ)-フェニル]-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリジン-3-イルアミド
3-(5-ヨードピリジン-2-イルオキシ)-アゼチジン-1-カルボキシリックアシッドピリジン-3-イルアミド
LCMS:(方法A)RT=1.04min;m/z=397[M+H]+
3-[5-(3-ヒドロキシ-フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリジン-3-イルアミド
LCMS:(方法A)RT=0.97min;m/z=363[M+H]+.
3-[5-[3-(2-メトキシ-エトキシ)-フェニル]-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリジン-3-イルアミド
LCMS:(方法A)RT=1.11min;m/z=421[M+H]+.
1H NMR:(400MHz,DMSO-d6)δ3.32(s,3H),3.68(m,2H),3.99(m,2H),4.17(m,2H),4.44(m,2H),5.39(m,1H),6.92-6.97(m,1H),7.00(d,1H,J=8.6Hz),7.21-7.25(m,2H),7.27(dd,1H,J=8.3,4.8Hz),7.37(dd,1H,J=8.1,8.1Hz),7.93(dm,1H),8.09(dd,1H,J=8.6,2.6Hz),8.15(dd,1H,J=4.5,1.6Hz),8.49(d,1H,J=2.1Hz),8.66(d,1H,J=2.1Hz),8.75(s,1H)
3-[5-[3-(2-ベンジルオキシ-エトキシ)-フェニル]-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド
2-[3-(2-ベンジルオキシ-エトキシ)-フェニル]-4,4,5,5-テトラメチル-[1,3,2]ジオキサボロラン
3-[5-[3-(2-ベンジルオキシ-エトキシ)-フェニル]-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド
LCMS:(方法B)RT=1.37min;m/z=498[M+H]+.
1H NMR:(400MHz,DMSO-d6)δ3.80(m,2H),4.04(m,2H),4.23(m,2H),4.49(m,2H),4.57(s,2H),5.40(m,1H),6.96(m,1H),6.99(d,1H,J=8.6Hz),7.21-7.25(m,2H),7.29(m,1H),7.33-7.39(m,5H),7.59(dd,1H,J=9.1,4.8Hz),8.08(dd,1H,J=8.6,2.5Hz),8.15(dd,1H,J=9.1,1.3Hz),8.49(d,1H,J=2.5Hz),8.84(dd,1H,J=4.5,1.3Hz),9.97(brs,1H).
3-[5-[3-(2-ヒドロキシ-エトキシ)-フェニル]-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド
3-[5-[3-(2-ヒドロキシ-エトキシ)-フェニル]-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド
LCMS:(方法B)RT=1.05min;m/z=408[M+H]+.
1HNMR:(400MHz,DMSO-d6)δ3.73(m,2H),4.00-4.09(m,4H),4.49(m,2H),4.89(t,1H,J=5.5Hz),5.40(m,1H),6.94(dm,1H),7.00(d,1H,J=8.6Hz),7.20-7.25(m,2H),7.37(dd,1H,J=8.1,8.1Hz),7.58(dd,1H,J=9.1,4.8Hz),8.08(dd,1H,J=8.6,2.8Hz),8.15(dd,1H,J=8.8,1.2Hz),8.49(d,H,J=1.7Hz),8.84(dd, 1H,J=4.8,1.7Hz),9.97(brs,1H).
3-[5-[2-メトキシ-5-(2-メトキシ-エトキシ)-フェニル]-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド
酢酸4-メトキシ−フェニルエステル
LCMS:(方法A)RT=1.88min;非イオン化
TLC:Rf=0.72(7:3EtOAc:ヘキサン)
酢酸3-ブロモ4-メトキシ−フェニル−エステル
LCMS:(方法A)RT=2.11min;非イオン化
TLC:Rf=0.20(1:9EtOAc:ヘキサン)
3-ブロモ4-メトキシ-フェノール
LCMS:(方法A)RT=2.11min;非イオン化
TLC:Rf=0.28(1:4EtOAc:ヘキサン)
2-ブロモ1-メトキシ-4(2-メトキシ-エトキシ)ベンゼン
LCMS:(方法A)RT=2.12min;非イオン化
TLC:Rf=0.34(1:4EtOAc:ヘキサン)
3-[5-[2-メトキシ-5-(2-メトキシ-エトキシ)-フェニル]-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド
LCMS:(方法A)RT=1.94min;m/z=450[M-H]-(非イオン化).
TLC:Rf=0.21(100%EtOAc)
1H NMR:(400MHz,CDCl3)δ3.45(s,3H),3.75(m,2H),3.77(s,3H),4.12(m,2H),4.21(m,2H),4.56(m,2H),5.48(m,1H),6.83(d,1H,J=8.6Hz),6.91(m,3H),7.42(dd,1H,J=9.1,4.8Hz),7.47(brs,1H),7.82(dd,1H,J=8.6,2.5Hz),8.25(d,1H,J=2.3Hz)8.38(dd,1H,J=9.1,1.3Hz),8.84(dd,1H,J=4.5,1.3Hz).
3-[5-(2,5-ジメトキシ-フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド
LCMS:(方法B)RT=1.19min;m/z=408[M+H]+.
1H NMR:(400MHz,DMSO-d6)δ3.72(s,3H),3.75(s,3H),4.00-4.08(m,2H),4.46-4.51(m,2H),5.36-5.41(m,1H),6.91-6.97(m,3H),7.04-7.06(m,1H),7.58(dd,1H,J=4.5,9.1Hz)7.89(dd,1H,J=2.3,8.6Hz),8.15(dd,1H,J=1.5,9.1Hz),8.27(d,1H,J=1.7Hz),8.85(dd,1H,J=1.4,4.6Hz),9.96(s,1H).
3-(5-フェニル-ピリジン-2-イルオキシ)-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド
mp201-202℃;RF0.17(EtOAc);LCMS rt1.19mins[方法B],m/z348([M+H]+,100%);δH(399MHz;DMSO-d6)9.97(1H,br s),8.85(1H,dd,J=4.5及び1.3Hz),8.48(1H,dd,J=2.5及び0.5Hz),8.15(1H,dd,J=9.1及び1.5Hz),8.08(1H,dd,J=8.6,2.5Hz),7.68-7.66(2H,m),7.59(1H,dd,J=9.1及び4.5Hz),7.49-7.45(2H,m),7.39-7.36(1H,m),7.01(1H,dd,J=8.6及び0.5Hz),5.40(1H,tt,J=6.6及び4.0Hz),4.48(2H,dd,J=8.6及び6.6Hz)及び4.04(2H,dd,J=9.6及び3.0Hz).
3-[5-(2,6-ジフルオロ-フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド
LCMS:(方法B)RT=1.2min;m/z=384[M+H]+
1H NMR:(400MHz,CDCl3)δ4.06(m,2H),4.50(m,2H),5.41(m,1H),7.07(dd,1H,J=8.6,0.5Hz),7.26(m,2H),7.51(m,1H),7.59(dd,1H,J=4.5Hz),7.89(m,1H),8.15(dd,1H,J=9.0,1.5Hz)8.28(m,1H),8.85(dd,1H,J=4.5,1.3Hz),9.97(bs,1H).
3-[5-[2-クロロ-5-(2-メトキシ-エトキシ)-フェニル]-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド
4-クロロ-3-(4,4,5,5-テトラメチル-[1,3,2]ジオキサボロラン-2-イル)-フェノール
LCMS:(方法A)RT=2.35min;m/z=253[M-H]-.
3-[5-[2-クロロ-5-(2-メトキシ-エトキシ)-フェニル]-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド
LCMS:(方法B)RT=1.28min;m/z=456[M+H]+
1H NMR:(400MHz,CDCl3)δ3.30(s,3H),3.65(m,2H),4.05(m,2H),4.15(m,2H),4.50(m,2H),5.41(m,1H),7.01(m,3H),7.47(d,1H,J=8.8Hz),7.59(dd,1H,J=4.5Hz),7.89(dd,1H,J=8.6,2.5Hz),8.15(dd,1H,J=9.1,1.5Hz)8.25(d,1H,J=2.5Hz),8.85(dd,1H,J=4.5,1.5Hz),9.97(bs,1H).
3-[5-(2-フルオロ−フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピラジン-2-イルアミド
LCMS:(方法A)RT=2.09min;m/z=366.1[M+H]+.
TLC:Rf=0.16(EtOAc/ヘキサン,1:1)
1H NMR: (400MHz,DMSO-d6)δ4.00-4.07(m,2H),4.44-4.57(m,2H),5.37-5.43(m,1H),7.03(d,1H,J=8.6Hz),7.29-7.37(m,2H),7.40-7.48(m,1H),7.54-7.60(m,1H),7.95-7.99(m,1H),8.22(d,1H,J=2.5Hz),8.29-8.31(m,1H),8.34-8.36(brm,1H),9.17(d,1H,J=1.6Hz),9.65(s,1H).
3-[5-(2-メトキシ-フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミン
LCMS:(方法A)RT=2.04min;m/z=378[M+H]+.
1H NMR:(400MHz,DMSO-d6)δ3.78(s,3H),4.04(brm,2H),4.49(brm,2H),5.39(m,1H),6.96(d,1H,J=8.6Hz),7.04(m,1H),7.13(d,1H,J=8.2Hz),7.33(dd,1H,J=7.5,1.6Hz),7.37(m,1H),7.59(dd,1H,J=9.1,4.7Hz),7.88(dd,1H,J=8.6,2.5Hz),8.16(dd,1H,J=9.1,1.4Hz),8.25(d,1H,J=2.5Hz),8.85(dd,1H,J=4.7,1.4Hz),9.96(s,1H).
3-[5-(2-フルオロ-フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド
LCMS:(方法B)RT=1.20min;m/z=366[M+H]+.
1H NMR:(400MHz,DMSO-d6)δ4.05(brm,2H),4.50(brm,2H),5.41(m,1H),7.04(d,1H,J=8.6Hz),7.29-7.38(m,2H),7.45(m,1H),7.54-7.62(m,2H),7.97(m,1H),8.15(dd,1H,J=9.1,1.4Hz),8.36(app s,1H),8.85(dd,1H,J=4.6,1.4Hz),9.97(s,1H).
3-[5-(2-フルオロ-3-メトキシ-フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド
3-(5-ブロモピリジン-2-イルオキシ)-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミドの合成
LCMS:(方法A)RT=1.81min;m/z=352[M+H]+
3-[5-(2-フルオロ-3-メトキシ-フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド
LCMS:(方法B)RT=1.18min;m/z=408[M+H]+.
1H NMR:(400MHz,DMSO-d6)δ3.88(s,3H),4.05(brm,2H),4.49(brm,2H),5.41(m,1H),7.03(d,1H,J=8.6Hz),7.08(m,1H),7.17-7.26(m,2H),7.59(dd,1H,J=9.1,4.6Hz),7.94(m,1H),8.15(dd,1H,J=9.1,1.4Hz),8.33(app s,1H),8.85(dd,1H,J=4.6,1.4Hz),9.96(s,1H)
3-[5-(2-フルオロ-フェニル)-ピリジン-2-イルオキシ]-アセチジン-1-カルボキシリックアシッド(6-メチル-ピリダジン-3-イル)-アミド
2-(1-ベンズヒドリル-アセチジン-3-イルオキシ)-5-(2-フルオロ-フェニル)-ピリジン
反応混合物を真空で濃縮し、エチルアセテート(400mL)で希釈し、セライトで濾過して、炭酸水素ナトリウム飽和水溶液(3x150mL)及び塩化ナトリウム飽和水溶液(150mL)で洗浄した。混合物を硫酸マグネシウムで乾燥させ、濾過した。濾過溶媒を真空で除去し、残留物をフラッシュクロマトグラフィー(4%DCM中のメタノール)で精製して標題の化合物(2.18g,67%)を得た。
LCMS:(方法A)RT=2.54min;m/z=411[M+H]+.
1H NMR:(400MHz,CDCl3)δ3.12-3.20(m,2H),3.74-3.80(m,2H),4.45(s,1H),5.27-5.33(m,1H),6.81(d,1H,J8.6),7.11-7.22(m,4H),7.28-7.40(m,6H),7.43-7.46(m,4H),7.75-7.78(m,1H),8.21-8.28(m,1H).
3-[5-(2-フルオロ-フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッド4-ニトロ−フェニルエステル
LCMS:(方法A)RT=2.46min;m/z=410[M+H]+.
1H NMR:(400MHz,CDCl3)δ4.20-4.26(m,1H),4,26-4.34(m,1H),4.52-4.60(m,1H),4.60-4.72(m,1H),5.46-5.52(m,1H),6.90(d,1H,J8.6),7.15-7.25(m,2H),7.33(d,2H,J9.4),7.31-7.43(m,3H),7.82-7.86(m,1H),8.25(d,2H,J9.1),8.28-8.32(m,1H).
3-[5-(2-フルオロ−フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッド(6-メチル-ピリダジン-3-イル)-アミド
LCMS:(方法A)RT=1.86min;m/z=380[M+H]+.
1H NMR:(400MHz,CDCl3)δ2.60(s,3H),4.19-4.23(m,2H),4.54-4.58(m,2H),5.45-5.50(m,1H),6.88(d,1H,J8.6),7.14-7.24(m,2H),7.27-7.41(m,3H),7.80-7.84(m,1H),8.25-8.30(m,2H).
3-[5-(2-フルオロ-フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッド(6-メトキシ-ピリダジン-3-イル)-アミド
LCMS:(方法A)RT=1.97min;m/z=396[M+H]+.
1H NMR:(400MHz,CDCl3)δ4.03(s,3H),4.21-4.25(m,2H),4.55-4.59(m,2H),5.45-5.50(m,1H),6.88(d,1H,J8.6),7.02(d,1H,J9.6),7.15-7.25(m,2H),7.31-7.42(m,2H),7.81-7.84(m,1H),8.28(bs,1H),8.35(d,1H,J9.3).
3-[5-(2-フルオロ-フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッド(5-メチル-[1,3,4]オキサジアゾール-2-イル)-アミド
LCMS:(方法A)RT=1.77min;m/z=370[M+H]+.
1H NMR:(400MHz,CD3OD)δ2.34(s,3H),3.96-4.00(m,2H),4.36-4.40(m,2H),5.33-5.39(m,1H),6.94(d,1H,J8.8),7.18-7.29(m,2H),7.36-7.41(m,1H),7.46-7.50(m,1H),7.88-7.91(m,1H),8.29(bs,1H).
3-[5-(2-フルオロ-フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-4-イルアミド
1H NMR:(400MHz,CD3OD)δ4.15-4.18(m,2H),4.56-4.61(m,2H),5.46-5.51(m,1H),6.98(d,1H,J8.6),7.19-7.29(m,2H),7.37-7.42(m,1H),7.46-7.50(m,1H),7.91-7.94(m,1H),7.95-7.98(m,1H),8.31(bs,1H),8.87(d,1H,J6.1),9.26-9.28(m,1H).
6-クロロ-4-メチル-ピリダジン-3-イルアミン及び6-クロロ-5-メチル-ピリダジン-3-イルアミン
LCMS:(方法A)RT=0.45min;m/z=144[M+H]+.
1H NMR:(400MHz,DMSO-d6)δ2.07(s,3H),2.18(s,3H),6.47(bs,2H),6.49(bs,2H),6.74(s,1H),7.31(s,1H).
3-[5-(2-フルオロ-フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッド(5-メチル-ピリダジン-3-イル)-アミド及び3-[5-(2-フルオロ-フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッド(4-メチル-ピリダジン-3-イル)-アミド
3-[5-(2-フルオロ-フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッド(5-メチル-ピリダジン-3-イル)-アミド(24mg,6%).
LCMS:(方法A)RT=1.91min;m/z=380[M+H]+.
1H NMR:(400MHz,CD3OD)δ2.38(s,3H),4.15-4.18(m,2H),4.56-4.61(m,2H),5.45-5.51(m,1H),6.98(d,1H,J8.6),7.19-7.29(m,2H),7.37-7.41(m,1H),7.46-7.50(m,1H),7.90-7.93(m,1H),8.12(bs,1H),8.31(bs,1H),8.69(bs,1H).
3-[5-(2-フルオロ-フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッド(4メチル-ピリダジン-3-イル)-アミド(11mg,3%)
LCMS:(方法A)RT=1.82min;m/z=380[M+H]+.
パートA
ラットFAAH阻害アッセイ
活性ラットFAAHプロテイン(30-579)を文献に記載されているように分離した。ラットFAAHのアミノ酸30-579のコーディングシーケンスを、N-ターミナルHis-tagとして提供されるイクスプレッションベクターpET28aにクローンした。続くイクスプレッションにおいて、His-tagged FAAH (30-579)をPatricelli et al., 1998; Biochemistry vol 37, p 15177に基づくキレート性セファロース、ヘパリンセファロース及び立体排除クロマトグラフィの組み合わせによる方法を使用して分離した。
FAAH活性を、FAAHによるアラキドノイル7-アミノ, 4-メチルクマリンアミド(AAMCA)での基板の加水分解の間に生じる高い蛍光性の7-アミノ, 4-メチルクマリン(AMC)の遊離を測定することにより規定した。FAAH活性の阻害を、化合物の非存在下で測定した蛍光のパーセンテージ減算により測定した。
以下の表1に、上記ラットFAAH阻害アッセイ中のここでの実施例1〜4の化合物を試験した3-時間インキュベーション結果を示す。
ヒトFAAH 1アッセイ
ヒトFAAH 1活性を、FAAHによるアラキドノイル7-アミノ, 4-メチルクマリンアミド(AAMCA)での基板の加水分解の間に生じる高い蛍光性の7-アミノ, 4-メチルクマリン(AMC)の遊離を測定することにより規定した。ヒトFAAH 1活性の阻害を、化合物の非存在下で測定した蛍光のパーセンテージ減算により測定した。
アッセイを、黒色壁、透明底、384-ウエルプレートで行った。27.5μlのヒトFAAH 1プロティン(FAAHアッセイバッファ中: 50 mM Hepes, 0.01 % Triton X-100, 1 mM EDTA, 0.5 mg/ml BSA (脂肪酸なし), pH 8.2)を、10nMで、室温、1時間、化合物(100 % DMSO中2.5μl)の濃度を増加させつつ、プレインキュベートした。2.5μlのDMSOを“トータル”コントロール(100 % FAAH活性)のために添加し、2.5μlのURB-597、公知のFAAH活性阻害剤(最終で飽和し、10μMの濃度)、を“非特異性”コントロール(0 % FAAH活性)のために添加した。次いで、20μlの7.5μM AAMCA基板(FAAHアッセイバッファ中)を全てのウエルに添加し、室温で更に4時間インキュベートした。蛍光を、Flexstation plate reader (Molecular Devices, UK)を用いて、励起波長355nm及び発振波長460nmで測定した。化合物によるヒトFAAH 1活性の阻害を、“非特異性”コントロールを減算した“トータル”コントロールと比較した相対蛍光単位(RFU)中のパーセンテージ減算により測定した。IC50値を、10-ポイントドーズレスポンス曲線から、4-Parameter Logistic Model (Sigmoidal Dose-Response Model)を使用するXL-Fit中で、測定した。
表2に、上記ヒトFAAH阻害アッセイ中のここでの実施例5〜19の化合物を試験した1時間インキュベーション結果を示す。
炎症性疼痛のラットカラギーナン誘導熱痛覚過敏モデル
オスのウィスターラットの熱疼痛感受性を、カラギーナンの局所イントラプランター前後、集束形光ビームを後ろ足に照射し、足を引っ込める時間を記録することにより評価した。3時間後、熱疼痛感受性を、試験化合物又は賦形剤をドーズする前に、処理後ろ足及び未処理後ろ足で再評価した。インドメタシンを陽性対象として 投与した。
手順
オスのスプラーグダウレイラットをテールマークし、3つの分割期間(試験日前6、5及び1日)においてプランターボックスにそれぞれの期間において少なくとも5分間馴化させた。予備試験日において、ラットを試験前少なくとも30分間試験室に馴らした。ラットをハーグリーヴスプランターボックスに入れ、約3-5分間かけて落ち着かせ、移動放射熱源で刺激した。熱源から 左と右の両後ろ足を引っ込める潜在時間を2期間(3分違い)と規定した。2回の刺激による平均を、個々の動物のベースラインとして記録した。ラット18と30を、極めて高いベースライン読みを示すため、研究に使用せず、61と63に置き換えた。次いで、ラットを医薬処理に付して、ベースライン潜在時間がグループによりバランスしていることを確認した。
ラットは、t = 0でインタープランターカラギーナンを投与され;t = 2hで実施例13の化合物(1, 3及び10 mg/kg経口的)又は媒体(5% EtOH: 95% (水中1%メチルセルロース))を投与され;t = 2.5h でインドメタシン(10mg/kg腹膜内)又は媒体を投与され及びt = 3hで熱感応性を測定した。よって、全てのラットは経口及び腹膜内投与の両方を受けた。
実施例13の化合物(1, 3, 10mg/kg経口的)は、カラギーナン−誘導熱過敏症の用量依存阻害を生じ、3及び10mg/kgの投与量で、統計上有意量に達した(媒体/カラナギーナン群; 1回 ANOVAに続くNewman-Keuls post hoc tests参照)。化合物は、以下の通常のレベルに疼痛感受性を下げられず、熱疼痛へ対側性足感受性の効果を有していなかった。化合物の最大効果は、陽性対照であるインドメタシンのそれと同様であった。
Hargreaves, K., Dubner, R., Brown, F., Flores, C., Joris, J., (1988). A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain, 32, 77-88.
Hedo, G., Laird, J.M.A., Lopez-Garcia, J.A., (1999). Time course of spinal sensitization following carrageenan-induced inflammation in the young rat: a comparative electrophysiological and behavioural study in vitro and in vivo. Neuroscience, 92, 309-318
Morris, C.J., (2003). Carrageenan-induced paw edema in the rat and mouse. Methods in Mol Biol., 225, 115-121.
Claims (10)
Ar1は、任意に置換されたフェニル又は任意に置換された5又は6個の環原子を有するモノサイクリックヘテロアリールである;
Ar2は、任意に置換されたフェニル、任意に置換された5又は6個の環原子を有するモノサイクリックヘテロアリール又は任意に置換された個々の縮合環中に5又は6個の環原子を有する縮合ビサイクリックへテロアリールである;及び
Ar3は、任意に置換されたフェニレン及び任意に置換された5又は6個の環原子を有するモノサイクリックヘテロアリーレン基からなる群から選択された二価の基である;
ここで、Ar1、Ar2及びAr3における任意の置換基は、クロロ、フルオロ、ブロモ、シクロプロピル、メチル、モノ-、ジ-又はトリ-メチル、トリフルオロメチル、ジフルオロメチル、モノフルオロメチル、メトキシ、エトキシ、プロポキシ、ブトキシ、ペントキシ、2-メトキシエトキシ、2-ベンジルオキシ-エトキシ、2-ヒドロキシ-エトキシ、モノ-、ジ-又はトリ-フルオロメトキシ、シアノ、ヒドロキシ、-CO2R1及び-SO2R1(R1は水素、メチル又はエチル)、テトラゾールイル、-NR2R3、-CH2NR2R3及び-C(=O)NR2R3(R2及びR3は独立に水素、メチル又はエチル)から独立に選択される)の化合物又はその薬学的に受容な塩の有効量を含む、急性又は慢性疼痛;目眩;嘔吐;吐き気;摂食障害;発作、熱性発作、発作性障害、神経毒性、外傷性脳傷害、脳卒中、運動障害、運動異常、ニューロパチー、痙攣、筋痙縮、多発性硬化症関連疼痛及び痙攣、脊髄損傷に伴う対麻痺における疼痛性痙攣、注意欠陥過多動性障害、ストレス、記憶、老化、うつ病、不安、全般性不安障害(GAD)、強迫神経症、精神分裂症、精神病から選択される神経科及び精神科の病状;急性又は慢性神経変性疾患;てんかん;睡眠障害;心血管疾患;腎虚血;ガン;免疫系疾患;アレルギー性疾患;寄生虫による、ウィルスによる又はバクテリアによる伝染性疾患;炎症性疾患;炎症;骨粗しょう症;網膜炎、緑内障、緑内障における眼圧減少から選択される眼疾患;肺疾患;消化器疾患;緑内障関連高血圧;尿失禁;及び痒疹の中から選択される、FAAH活性の阻害から恩恵を得る疾病又は医学的状態の治療用医薬組成物。
3-(ビフェニル-4-イルオキシ)-アゼチジン-1-カルボキシリックアシッドフェニルアミド、
3-(ビフェニル-4-イルオキシ)-アゼチジン-1-カルボキシリックアシッド(3-フルオロ-フェニル)-アミド、
3-(ビフェニル-4-イルオキシ)-アゼチジン-1-カルボキシリックアシッド(2-フルオロ-フェニル)-アミド、
3-(ビフェニル-4-イルオキシ)-アゼチジン-1-カルボキシリックアシッドピリジン-3-イルアミド、
3-[5-[3-(2-メトキシ-エトキシ)-フェニル]-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリミジン-4-イルアミド、
3-[5-[3-(2-メトキシ-エトキシ)-フェニル]-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピラジン-2-イルアミド、
3-[5-[3-(2-メトキシ-エトキシ)-フェニル]-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド、
3-[5-[3-(2-メトキシ-エトキシ)-フェニル]-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリジン-3-イルアミド、
3-[5-[3-(2-ベンジルオキシ-エトキシ)-フェニル]-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド、
3-[5-[3-(2-ヒドロキシ-エトキシ)-フェニル]-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド、
3-[5-[2-メトキシ-5-(2-メトキシ-エトキシ)-フェニル]-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド、
3-[5-(2,5-ジメトキシ-フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド、
3-(5-フェニル-ピリジン-2-イルオキシ)-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド、
3-[5-(2,6-ジフルオロ-フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド、
3-[5-[2-クロロ-5-(2-メトキシ-エトキシ)-フェニル]-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド、
3-[5-(2-フルオロ−フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピラジン-2-イルアミド、
3-[5-(2-メトキシ-フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミン、
3-[5-(2-フルオロ-フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド、
3-[5-(2-フルオロ-3-メトキシ-フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-3-イルアミド、
3-[5-(2-フルオロ-フェニル)-ピリジン-2-イルオキシ]-アセチジン-1-カルボキシリックアシッド(6-メチル-ピリダジン-3-イル)-アミド、
3-[5-(2-フルオロ-フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッド(6-メトキシ-ピリダジン-3-イル)-アミド、
3-[5-(2-フルオロ-フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッド(5-メチル-[1,3,4]オキサジアゾール-2-イル)-アミド、
3-[5-(2-フルオロ-フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッドピリダジン-4-イルアミド、
3-[5-(2-フルオロ-フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッド(5-メチル-ピリダジン-3-イル)-アミド又は
3-[5-(2-フルオロ-フェニル)-ピリジン-2-イルオキシ]-アゼチジン-1-カルボキシリックアシッド(4-メチル-ピリダジン-3-イル)-アミド
である請求項1〜9のいずれか1つに記載の医薬組成物。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0804006.5A GB0804006D0 (en) | 2008-03-04 | 2008-03-04 | Azetidine derivatives |
GB0804006.5 | 2008-04-05 | ||
GB0821694.7 | 2008-11-27 | ||
GBGB0821694.7A GB0821694D0 (en) | 2008-11-27 | 2008-11-27 | Azetidine derivatives |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2010549188A Division JP5624894B2 (ja) | 2008-03-04 | 2009-02-27 | アゼチジン誘導体 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2015038105A true JP2015038105A (ja) | 2015-02-26 |
JP5986163B2 JP5986163B2 (ja) | 2016-09-06 |
Family
ID=40613126
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2010549188A Active JP5624894B2 (ja) | 2008-03-04 | 2009-02-27 | アゼチジン誘導体 |
JP2014198461A Active JP5986163B2 (ja) | 2008-03-04 | 2014-09-29 | アゼチジン誘導体 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2010549188A Active JP5624894B2 (ja) | 2008-03-04 | 2009-02-27 | アゼチジン誘導体 |
Country Status (18)
Country | Link |
---|---|
US (6) | US8450346B2 (ja) |
EP (1) | EP2265578B1 (ja) |
JP (2) | JP5624894B2 (ja) |
CN (1) | CN102015635B (ja) |
AU (1) | AU2009220974B2 (ja) |
BR (1) | BRPI0909782B8 (ja) |
CA (1) | CA2717750C (ja) |
DK (1) | DK2265578T3 (ja) |
EA (1) | EA017842B1 (ja) |
ES (1) | ES2550367T3 (ja) |
HU (1) | HUE025411T2 (ja) |
IL (1) | IL207768A (ja) |
MX (1) | MX2010009658A (ja) |
NZ (1) | NZ587532A (ja) |
PL (1) | PL2265578T3 (ja) |
PT (1) | PT2265578E (ja) |
WO (1) | WO2009109743A1 (ja) |
ZA (1) | ZA201006270B (ja) |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PL2265578T3 (pl) | 2008-03-04 | 2015-12-31 | Vernalis R&D Ltd | Pochodne azetydyny |
WO2011085216A2 (en) | 2010-01-08 | 2011-07-14 | Ironwood Pharmaceuticals, Inc. | Use of faah inhibitors for treating parkinson's disease and restless legs syndrome |
WO2011123719A2 (en) | 2010-03-31 | 2011-10-06 | Ironwood Pharmaceuticals, Inc. | Use of faah inhibitors for treating abdominal, visceral and pelvic pain |
KR101273566B1 (ko) * | 2011-09-05 | 2013-06-11 | 한국과학기술연구원 | 신규한 아제티딘 유도체 및 이를 함유하는 항우울제 조성물 |
PT2800738T (pt) * | 2012-01-06 | 2020-06-23 | Novartis Ag | Compostos heterocíclicos e métodos para a utilização dos mesmos |
US10570146B2 (en) * | 2014-07-25 | 2020-02-25 | Northeastern University | Urea/carbamates FAAH MAGL or dual FAAH/MAGL inhibitors and uses thereof |
JOP20190072A1 (ar) | 2016-10-13 | 2019-04-07 | Glaxosmithkline Ip Dev Ltd | مشتقات 1، 3 سيكلوبوتان ثنائي الاستبدال أو آزيتيدين كمثبطات للإنزيم المخلق للبروستاجلاندين d المكون للدم |
AU2018277981B2 (en) * | 2017-06-02 | 2021-04-08 | Fujifilm Toyama Chemical Co., Ltd. | Agent for preventing or treating spinocerebellar ataxia |
MX2019014306A (es) | 2017-06-02 | 2022-06-09 | Fujifilm Toyama Chemical Co Ltd | Agente para reducir la cantidad de proteina beta amiloide. |
CN116492335A (zh) * | 2017-06-02 | 2023-07-28 | 富士胶片富山化学株式会社 | 脑萎缩预防或治疗剂 |
SG11201911520UA (en) * | 2017-06-02 | 2020-01-30 | Fujifilm Toyama Chemical Co Ltd | Agent for preventing or treating tauopathy |
US11541033B2 (en) | 2017-06-02 | 2023-01-03 | Fujifilm Toyama Chemical Co., Ltd. | Agent for preventing or treating Alzheimer's disease |
US11548878B2 (en) | 2017-10-30 | 2023-01-10 | Fujifilm Toyama Chemical Co., Ltd. | Emopamil binding protein binding agent and use thereof |
US20240180905A1 (en) * | 2020-07-21 | 2024-06-06 | Neuritek Ltd. | Uses of fatty acid amide hydrolase inhibitors in treatment of trauma related psychiatric disorders |
CN112374984A (zh) * | 2020-11-06 | 2021-02-19 | 苏州求索生物科技有限公司 | 一种2-溴-4-羟基苯甲醚的制备工艺 |
US11141404B1 (en) | 2020-11-18 | 2021-10-12 | Anebulo Pharmaceuticals, Inc. | Formulations and methods for treating acute cannabinoid overdose |
WO2023064225A1 (en) | 2021-10-11 | 2023-04-20 | Anebulo Pharmaceuticals, Inc. | Crystalline forms of a cannabinoid receptor type 1 (cb1) modulator and methods of use and preparation thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS61205254A (ja) * | 1985-02-28 | 1986-09-11 | エイ・エイチ・ロビンス・カンパニー・インコーポレーテッド | 筋弛緩薬および抗不安薬としての3‐アリールオキシアゼチジンカルボキサミド含有組成物 |
JP2002501047A (ja) * | 1998-01-23 | 2002-01-15 | バーナリス リサーチ リミテッド | Cns障害を処置するためのアゼチジンカルボキサミド誘導体 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5183902A (en) * | 1985-02-28 | 1993-02-02 | A. H. Robins Company, Incorporated | Method of treating muscular tension, muscle spasticity and anxiety with 3-aryloxy and 3-arylthioazetidinecarboxamides |
US6335445B1 (en) * | 1997-03-24 | 2002-01-01 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Derivatives of 2-(iminomethyl)amino-phenyl, their preparation, their use as medicaments and the pharmaceutical compositions containing them |
FR2866884B1 (fr) * | 2004-02-26 | 2007-08-31 | Sanofi Synthelabo | Derives d'aryl-et d'heteroaryl-piperidinecarboxylates, leur preparation et leur application en therapeutique |
PL2265578T3 (pl) * | 2008-03-04 | 2015-12-31 | Vernalis R&D Ltd | Pochodne azetydyny |
-
2009
- 2009-02-27 PL PL09716712T patent/PL2265578T3/pl unknown
- 2009-02-27 WO PCT/GB2009/000568 patent/WO2009109743A1/en active Application Filing
- 2009-02-27 ES ES09716712.6T patent/ES2550367T3/es active Active
- 2009-02-27 HU HUE09716712A patent/HUE025411T2/en unknown
- 2009-02-27 BR BRPI0909782A patent/BRPI0909782B8/pt active IP Right Grant
- 2009-02-27 JP JP2010549188A patent/JP5624894B2/ja active Active
- 2009-02-27 AU AU2009220974A patent/AU2009220974B2/en active Active
- 2009-02-27 EA EA201001414A patent/EA017842B1/ru not_active IP Right Cessation
- 2009-02-27 CA CA2717750A patent/CA2717750C/en active Active
- 2009-02-27 EP EP09716712.6A patent/EP2265578B1/en active Active
- 2009-02-27 PT PT97167126T patent/PT2265578E/pt unknown
- 2009-02-27 MX MX2010009658A patent/MX2010009658A/es active IP Right Grant
- 2009-02-27 DK DK09716712.6T patent/DK2265578T3/en active
- 2009-02-27 CN CN2009801079287A patent/CN102015635B/zh active Active
- 2009-02-27 NZ NZ587532A patent/NZ587532A/en unknown
- 2009-02-27 US US12/920,181 patent/US8450346B2/en active Active
-
2010
- 2010-08-24 IL IL207768A patent/IL207768A/en active IP Right Grant
- 2010-09-01 ZA ZA2010/06270A patent/ZA201006270B/en unknown
-
2013
- 2013-04-19 US US13/866,059 patent/US9006269B2/en active Active
-
2014
- 2014-09-29 JP JP2014198461A patent/JP5986163B2/ja active Active
-
2015
- 2015-03-09 US US14/641,783 patent/US9475800B2/en active Active
-
2016
- 2016-09-28 US US15/278,386 patent/US10383871B2/en active Active
-
2019
- 2019-07-09 US US16/506,225 patent/US10918640B2/en active Active
-
2021
- 2021-01-14 US US17/148,785 patent/US20210267974A1/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS61205254A (ja) * | 1985-02-28 | 1986-09-11 | エイ・エイチ・ロビンス・カンパニー・インコーポレーテッド | 筋弛緩薬および抗不安薬としての3‐アリールオキシアゼチジンカルボキサミド含有組成物 |
JP2002501047A (ja) * | 1998-01-23 | 2002-01-15 | バーナリス リサーチ リミテッド | Cns障害を処置するためのアゼチジンカルボキサミド誘導体 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5986163B2 (ja) | アゼチジン誘導体 | |
TWI421074B (zh) | 嘧啶基吲哚啉化合物、含有其之醫藥組成物及嘧啶基吲哚啉化合物之使用 | |
US9604940B2 (en) | 2-aminopyrazine derivatives as CSF-1R kinase inhibitors | |
CN103974953B (zh) | 激酶抑制剂 | |
CN103987708B (zh) | 4-羟基-1,2,3,4-四氢萘-1-基脲的衍生物及其在呼吸道疾病治疗中的用途 | |
JP2008208129A (ja) | Pparアゴニスト活性を有する誘導体 | |
TW200539872A (en) | Therapeutic agents | |
CN112920124A (zh) | 一种嘧啶-2,4-二胺类化合物及其制备方法与应用 | |
CN101918352A (zh) | 17β-羟基类固醇脱氢酶的抑制剂 | |
JP5704924B2 (ja) | 新規複素環化合物 | |
WO2011162267A1 (ja) | 新規チオフェンカルボキサミド誘導体及びその医薬用途 | |
US20230295110A1 (en) | Phd inhibitor compounds, compositions, and methods of use | |
WO2013026587A1 (en) | 1,4 disubstituted pyrrolidine - 3 - yl -amine derivatives and their use for the treatment of metabolic disorders | |
US8648099B2 (en) | 3-pyridine carboxylic acid hydrazides | |
JP2009504719A (ja) | 結核症の治療のためのピラゾロン誘導体 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20150818 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20151111 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20160216 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20160712 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20160804 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5986163 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |