BG108271A - Нови съединения - Google Patents
Нови съединения Download PDFInfo
- Publication number
- BG108271A BG108271A BG108271A BG10827103A BG108271A BG 108271 A BG108271 A BG 108271A BG 108271 A BG108271 A BG 108271A BG 10827103 A BG10827103 A BG 10827103A BG 108271 A BG108271 A BG 108271A
- Authority
- BG
- Bulgaria
- Prior art keywords
- alkyl
- mmol
- methyl
- group
- cyclopropylmethyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 209
- 150000003839 salts Chemical class 0.000 claims abstract description 40
- 208000002193 Pain Diseases 0.000 claims abstract description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 238000002560 therapeutic procedure Methods 0.000 claims abstract 2
- -1 cyano, acetoxymethyl Chemical group 0.000 claims description 200
- 238000000034 method Methods 0.000 claims description 114
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 66
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 65
- 229910052757 nitrogen Inorganic materials 0.000 claims description 56
- 125000000217 alkyl group Chemical group 0.000 claims description 48
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 46
- 239000002904 solvent Substances 0.000 claims description 42
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 32
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 229910052763 palladium Inorganic materials 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- 125000000623 heterocyclic group Chemical group 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 9
- 239000004480 active ingredient Substances 0.000 claims description 9
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 9
- 125000004076 pyridyl group Chemical group 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 5
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 241001465754 Metazoa Species 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 229910052760 oxygen Chemical group 0.000 claims description 4
- 239000001301 oxygen Chemical group 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 2
- DGYIJVNZSDYBOE-UHFFFAOYSA-N [CH2]C1=CC=NC=C1 Chemical group [CH2]C1=CC=NC=C1 DGYIJVNZSDYBOE-UHFFFAOYSA-N 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000003435 aroyl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 125000006592 (C2-C3) alkenyl group Chemical group 0.000 claims 1
- 125000006224 2-tetrahydrofuranylmethyl group Chemical group [H]C([H])(*)C1([H])OC([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 125000005842 heteroatom Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims 1
- 230000001105 regulatory effect Effects 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 366
- 239000000243 solution Substances 0.000 description 218
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 213
- 239000000203 mixture Substances 0.000 description 150
- 235000019439 ethyl acetate Nutrition 0.000 description 122
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 120
- 238000005481 NMR spectroscopy Methods 0.000 description 117
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 101
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 85
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 81
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 78
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 76
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 73
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 73
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 68
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 68
- 239000012043 crude product Substances 0.000 description 63
- 239000011541 reaction mixture Substances 0.000 description 61
- 239000007787 solid Substances 0.000 description 54
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 53
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 51
- 229920006395 saturated elastomer Polymers 0.000 description 50
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
- 239000000047 product Substances 0.000 description 48
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 47
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 47
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 45
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 42
- 238000000746 purification Methods 0.000 description 41
- 239000012074 organic phase Substances 0.000 description 40
- 238000002360 preparation method Methods 0.000 description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- 238000006243 chemical reaction Methods 0.000 description 34
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 34
- 235000019341 magnesium sulphate Nutrition 0.000 description 34
- 239000000741 silica gel Substances 0.000 description 34
- 229910002027 silica gel Inorganic materials 0.000 description 34
- 239000011780 sodium chloride Substances 0.000 description 32
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 31
- 229910052938 sodium sulfate Inorganic materials 0.000 description 31
- 235000011152 sodium sulphate Nutrition 0.000 description 31
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 238000002955 isolation Methods 0.000 description 29
- 238000003756 stirring Methods 0.000 description 28
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 27
- 229960000583 acetic acid Drugs 0.000 description 27
- 239000012071 phase Substances 0.000 description 22
- 239000007821 HATU Substances 0.000 description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 19
- 238000003818 flash chromatography Methods 0.000 description 19
- 239000008346 aqueous phase Substances 0.000 description 18
- 238000001914 filtration Methods 0.000 description 18
- 238000004128 high performance liquid chromatography Methods 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 17
- DOJYHQGYPJKSPT-UHFFFAOYSA-N 2-(4-ethoxyphenyl)acetyl chloride Chemical compound CCOC1=CC=C(CC(Cl)=O)C=C1 DOJYHQGYPJKSPT-UHFFFAOYSA-N 0.000 description 16
- 102100036214 Cannabinoid receptor 2 Human genes 0.000 description 16
- 239000003921 oil Substances 0.000 description 16
- 235000019198 oils Nutrition 0.000 description 16
- 238000010898 silica gel chromatography Methods 0.000 description 16
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 15
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 14
- 235000017557 sodium bicarbonate Nutrition 0.000 description 14
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 14
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 13
- 238000004587 chromatography analysis Methods 0.000 description 13
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 12
- 238000007429 general method Methods 0.000 description 12
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 11
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 11
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 11
- 238000004007 reversed phase HPLC Methods 0.000 description 11
- ZVVWZNFSMIFGEP-UHFFFAOYSA-N 2-(4-ethoxyphenyl)acetic acid Chemical compound CCOC1=CC=C(CC(O)=O)C=C1 ZVVWZNFSMIFGEP-UHFFFAOYSA-N 0.000 description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 10
- 101710187022 Cannabinoid receptor 2 Proteins 0.000 description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 239000000908 ammonium hydroxide Substances 0.000 description 10
- MRVFZPHNDANYPK-UHFFFAOYSA-N n,n-diethyl-4-fluoro-3-nitrobenzamide Chemical compound CCN(CC)C(=O)C1=CC=C(F)C([N+]([O-])=O)=C1 MRVFZPHNDANYPK-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 9
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 9
- 238000001704 evaporation Methods 0.000 description 9
- 230000008020 evaporation Effects 0.000 description 9
- 239000000284 extract Substances 0.000 description 9
- 238000000605 extraction Methods 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 239000000556 agonist Substances 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 238000002953 preparative HPLC Methods 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 description 7
- 230000003375 cannabimimetic effect Effects 0.000 description 7
- 230000003197 catalytic effect Effects 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 125000006413 ring segment Chemical group 0.000 description 7
- NWFWDSGJXJHSQK-UHFFFAOYSA-N 3-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]-n-methylimidazo[4,5-b]pyridin-6-amine Chemical compound C1=CC(OCC)=CC=C1CC1=NC2=CC(NC)=CN=C2N1CC1CC1 NWFWDSGJXJHSQK-UHFFFAOYSA-N 0.000 description 6
- 125000004539 5-benzimidazolyl group Chemical group N1=CNC2=C1C=CC(=C2)* 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 108010073376 CB2 Cannabinoid Receptor Proteins 0.000 description 6
- 102000009135 CB2 Cannabinoid Receptor Human genes 0.000 description 6
- 101000875075 Homo sapiens Cannabinoid receptor 2 Proteins 0.000 description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- GCDGCOQSXIVIMI-UHFFFAOYSA-N 1-methylbenzimidazole-5-carboxamide Chemical compound NC(=O)C1=CC=C2N(C)C=NC2=C1 GCDGCOQSXIVIMI-UHFFFAOYSA-N 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical class O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 5
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- 150000001408 amides Chemical class 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 5
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
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- WPUCAQMFSMHQBK-UHFFFAOYSA-N 1-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]benzimidazole-5-carboxylic acid Chemical compound C1=CC(OCC)=CC=C1CC1=NC2=CC(C(O)=O)=CC=C2N1CC1CC1 WPUCAQMFSMHQBK-UHFFFAOYSA-N 0.000 description 4
- MLOFIZGWLGUHLR-UHFFFAOYSA-N 1-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]benzimidazole-5-sulfonyl chloride Chemical compound C1=CC(OCC)=CC=C1CC1=NC2=CC(S(Cl)(=O)=O)=CC=C2N1CC1CC1 MLOFIZGWLGUHLR-UHFFFAOYSA-N 0.000 description 4
- GSLTVFIVJMCNBH-UHFFFAOYSA-N 2-isocyanatopropane Chemical compound CC(C)N=C=O GSLTVFIVJMCNBH-UHFFFAOYSA-N 0.000 description 4
- CVVYLOHQONKUBE-UHFFFAOYSA-N 2-n-(cyclopropylmethyl)-5-nitropyridine-2,3-diamine Chemical compound NC1=CC([N+]([O-])=O)=CN=C1NCC1CC1 CVVYLOHQONKUBE-UHFFFAOYSA-N 0.000 description 4
- CQGPQHZKHPSFFO-UHFFFAOYSA-N 3-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]imidazo[4,5-b]pyridin-6-amine Chemical compound C1=CC(OCC)=CC=C1CC1=NC2=CC(N)=CN=C2N1CC1CC1 CQGPQHZKHPSFFO-UHFFFAOYSA-N 0.000 description 4
- 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 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 4
- 230000027455 binding Effects 0.000 description 4
- GTCAXTIRRLKXRU-UHFFFAOYSA-N carbamic acid methyl ester Natural products COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 4
- 210000003169 central nervous system Anatomy 0.000 description 4
- IGSKHXTUVXSOMB-UHFFFAOYSA-N cyclopropylmethanamine Chemical compound NCC1CC1 IGSKHXTUVXSOMB-UHFFFAOYSA-N 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 231100000673 dose–response relationship Toxicity 0.000 description 4
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- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;o-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000005931 immune cell recruitment Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- BMFVGAAISNGQNM-UHFFFAOYSA-N isopentylamine Chemical compound CC(C)CCN BMFVGAAISNGQNM-UHFFFAOYSA-N 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000003350 kerosene Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 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
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- IBIKHMZPHNKTHM-RDTXWAMCSA-N merck compound 25 Chemical compound C1C[C@@H](C(O)=O)[C@H](O)CN1C(C1=C(F)C=CC=C11)=NN1C(=O)C1=C(Cl)C=CC=C1C1CC1 IBIKHMZPHNKTHM-RDTXWAMCSA-N 0.000 description 1
- BQPIGGFYSBELGY-UHFFFAOYSA-N mercury(2+) Chemical compound [Hg+2] BQPIGGFYSBELGY-UHFFFAOYSA-N 0.000 description 1
- WZHJKEUHNJHDLS-QTGUNEKASA-N metergoline Chemical compound C([C@H]1CN([C@H]2[C@@H](C=3C=CC=C4N(C)C=C(C=34)C2)C1)C)NC(=O)OCC1=CC=CC=C1 WZHJKEUHNJHDLS-QTGUNEKASA-N 0.000 description 1
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- CPKUCLAIPNVXSA-UHFFFAOYSA-N methyl 5-amino-6-(cyclopropylmethylamino)pyridine-3-carboxylate Chemical compound NC1=CC(C(=O)OC)=CN=C1NCC1CC1 CPKUCLAIPNVXSA-UHFFFAOYSA-N 0.000 description 1
- LMRCFYUILLMSDJ-UHFFFAOYSA-N methyl n-(4-ethoxyphenyl)carbamodithioate Chemical compound CCOC1=CC=C(NC(=S)SC)C=C1 LMRCFYUILLMSDJ-UHFFFAOYSA-N 0.000 description 1
- VOFJVDWBQLUDOI-UHFFFAOYSA-N methyl n-[1-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]benzimidazol-5-yl]carbamate Chemical compound C1=CC(OCC)=CC=C1CC1=NC2=CC(NC(=O)OC)=CC=C2N1CC1CC1 VOFJVDWBQLUDOI-UHFFFAOYSA-N 0.000 description 1
- KZZRMVXJHGWDDD-UHFFFAOYSA-N methyl-(4-nitrophenyl)carbamic acid Chemical compound OC(=O)N(C)C1=CC=C([N+]([O-])=O)C=C1 KZZRMVXJHGWDDD-UHFFFAOYSA-N 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
- VILZUBUMZGHHOR-UHFFFAOYSA-N n,n-diethyl-2-[(4-methoxyphenyl)methyl]-1-(2-morpholin-4-ylethyl)benzimidazole-5-carboxamide Chemical compound C=1C=C(OC)C=CC=1CC1=NC2=CC(C(=O)N(CC)CC)=CC=C2N1CCN1CCOCC1 VILZUBUMZGHHOR-UHFFFAOYSA-N 0.000 description 1
- UDJSYCJLYSNACA-UHFFFAOYSA-N n,n-diethyl-3-fluoro-4-nitrobenzamide Chemical compound CCN(CC)C(=O)C1=CC=C([N+]([O-])=O)C(F)=C1 UDJSYCJLYSNACA-UHFFFAOYSA-N 0.000 description 1
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- UMCYSWWRBSWKDM-UHFFFAOYSA-N n,n-diethyl-4-(methylamino)-3-nitrobenzamide Chemical compound CCN(CC)C(=O)C1=CC=C(NC)C([N+]([O-])=O)=C1 UMCYSWWRBSWKDM-UHFFFAOYSA-N 0.000 description 1
- HAYUGFLFUULMDE-UHFFFAOYSA-N n,n-diethyl-5-nitro-6-(prop-2-enylamino)pyridine-3-carboxamide Chemical compound CCN(CC)C(=O)C1=CN=C(NCC=C)C([N+]([O-])=O)=C1 HAYUGFLFUULMDE-UHFFFAOYSA-N 0.000 description 1
- DAKZISABEDGGSV-UHFFFAOYSA-N n-(2-aminoethyl)acetamide Chemical compound CC(=O)NCCN DAKZISABEDGGSV-UHFFFAOYSA-N 0.000 description 1
- KLHCAOSRFFAKQV-UHFFFAOYSA-N n-(4-fluoro-3-nitrophenyl)acetamide Chemical compound CC(=O)NC1=CC=C(F)C([N+]([O-])=O)=C1 KLHCAOSRFFAKQV-UHFFFAOYSA-N 0.000 description 1
- JGVXAONKPMNAKJ-UHFFFAOYSA-N n-[1-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]benzimidazol-5-yl]-n,5-dimethyl-1,2-oxazole-3-carboxamide Chemical compound C1=CC(OCC)=CC=C1CC1=NC2=CC(N(C)C(=O)C3=NOC(C)=C3)=CC=C2N1CC1CC1 JGVXAONKPMNAKJ-UHFFFAOYSA-N 0.000 description 1
- NZVPBUFTQQUWAK-UHFFFAOYSA-N n-[1-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]benzimidazol-5-yl]-n-methylpiperidine-1-carboxamide Chemical compound C1=CC(OCC)=CC=C1CC1=NC2=CC(N(C)C(=O)N3CCCCC3)=CC=C2N1CC1CC1 NZVPBUFTQQUWAK-UHFFFAOYSA-N 0.000 description 1
- XELDOCUPNFDHOB-UHFFFAOYSA-N n-[1-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]benzimidazol-5-yl]-n-methylpyrrolidine-1-carboxamide Chemical compound C1=CC(OCC)=CC=C1CC1=NC2=CC(N(C)C(=O)N3CCCC3)=CC=C2N1CC1CC1 XELDOCUPNFDHOB-UHFFFAOYSA-N 0.000 description 1
- CBVVRQAZRJZZJO-UHFFFAOYSA-N n-[1-(cyclopropylmethyl)-2-[1-(4-ethoxyphenyl)ethyl]benzimidazol-5-yl]-n,3-dimethylbutanamide Chemical compound C1=CC(OCC)=CC=C1C(C)C1=NC2=CC(N(C)C(=O)CC(C)C)=CC=C2N1CC1CC1 CBVVRQAZRJZZJO-UHFFFAOYSA-N 0.000 description 1
- WYPURNGWBNDAKY-UHFFFAOYSA-N n-[3-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]imidazo[4,5-b]pyridin-6-yl]-n-methylbenzenesulfonamide Chemical compound C1=CC(OCC)=CC=C1CC1=NC2=CC(N(C)S(=O)(=O)C=3C=CC=CC=3)=CN=C2N1CC1CC1 WYPURNGWBNDAKY-UHFFFAOYSA-N 0.000 description 1
- QNTPHKKMTHUHRU-UHFFFAOYSA-N n-[3-[[2-(4-ethoxyphenyl)acetyl]amino]-4-nitrophenyl]-n,3-dimethylbutanamide Chemical compound C1=CC(OCC)=CC=C1CC(=O)NC1=CC(N(C)C(=O)CC(C)C)=CC=C1[N+]([O-])=O QNTPHKKMTHUHRU-UHFFFAOYSA-N 0.000 description 1
- RWIVICVCHVMHMU-UHFFFAOYSA-N n-aminoethylmorpholine Chemical compound NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 description 1
- OOPCLAAGKDFZQT-UHFFFAOYSA-N n-cyclopentyl-1-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]benzimidazole-5-sulfonamide Chemical compound C1=CC(OCC)=CC=C1CC1=NC2=CC(S(=O)(=O)NC3CCCC3)=CC=C2N1CC1CC1 OOPCLAAGKDFZQT-UHFFFAOYSA-N 0.000 description 1
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- UHHKSVZZTYJVEG-UHFFFAOYSA-N oxepane Chemical compound C1CCCOCC1 UHHKSVZZTYJVEG-UHFFFAOYSA-N 0.000 description 1
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- 230000020477 pH reduction Effects 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 125000003395 phenylethylamino group Chemical group [H]N(*)C([H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 1
- BIFDXOOJPDHKJH-UHFFFAOYSA-N piperidine-1-carbonyl chloride Chemical compound ClC(=O)N1CCCCC1 BIFDXOOJPDHKJH-UHFFFAOYSA-N 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 239000001120 potassium sulphate Substances 0.000 description 1
- 235000011151 potassium sulphates Nutrition 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- ALDITMKAAPLVJK-UHFFFAOYSA-N prop-1-ene;hydrate Chemical group O.CC=C ALDITMKAAPLVJK-UHFFFAOYSA-N 0.000 description 1
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- TXQWFIVRZNOPCK-UHFFFAOYSA-N pyridin-4-ylmethanamine Chemical compound NCC1=CC=NC=C1 TXQWFIVRZNOPCK-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- XACWJIQLDLUFSR-UHFFFAOYSA-N pyrrolidine-1-carbonyl chloride Chemical compound ClC(=O)N1CCCC1 XACWJIQLDLUFSR-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- ADRDEXBBJTUCND-UHFFFAOYSA-N pyrrolizidine Chemical compound C1CCN2CCCC21 ADRDEXBBJTUCND-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000005956 quaternization reaction Methods 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000007885 tablet disintegrant Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- AOCSUUGBCMTKJH-UHFFFAOYSA-N tert-butyl n-(2-aminoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCN AOCSUUGBCMTKJH-UHFFFAOYSA-N 0.000 description 1
- OWXUXIKLDXRQEY-UHFFFAOYSA-N tert-butyl n-(3-amino-4-nitrophenyl)-n-methylcarbamate Chemical compound CC(C)(C)OC(=O)N(C)C1=CC=C([N+]([O-])=O)C(N)=C1 OWXUXIKLDXRQEY-UHFFFAOYSA-N 0.000 description 1
- AOGLJTALRZBRON-UHFFFAOYSA-N tert-butyl n-[2-[2-amino-4-(diethylcarbamoyl)anilino]ethyl]carbamate Chemical compound CCN(CC)C(=O)C1=CC=C(NCCNC(=O)OC(C)(C)C)C(N)=C1 AOGLJTALRZBRON-UHFFFAOYSA-N 0.000 description 1
- JHLVEBNWCCKSGY-UHFFFAOYSA-N tert-butyl n-methylcarbamate Chemical compound CNC(=O)OC(C)(C)C JHLVEBNWCCKSGY-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- VNNLHYZDXIBHKZ-UHFFFAOYSA-N thiophene-2-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CS1 VNNLHYZDXIBHKZ-UHFFFAOYSA-N 0.000 description 1
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 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
- 238000005809 transesterification reaction Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- HQVHOQAKMCMIIM-UHFFFAOYSA-N win 55,212-2 Chemical compound C=12N3C(C)=C(C(=O)C=4C5=CC=CC=C5C=CC=4)C2=CC=CC=1OCC3CN1CCOCC1 HQVHOQAKMCMIIM-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
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- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/30—Nitrogen atoms not forming part of a nitro radical
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- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Neurology (AREA)
- Neurosurgery (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyridine Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Publications (1)
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| BG108271A true BG108271A (bg) | 2004-12-30 |
Family
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| US7465815B2 (en) * | 2003-06-26 | 2008-12-16 | Takeda Pharmaceutical Company Limited | Cannabinoid receptor modulator |
| US7157471B2 (en) * | 2003-08-25 | 2007-01-02 | Boehringer Ingelheim International Gmbh | Haloalkyl- and piperidine-substituted benzimidazole-derivatives |
| WO2005021547A2 (en) * | 2003-08-28 | 2005-03-10 | Pharmaxis Pty Ltd. | Heterocyclic cannabinoid cb2 receptor antagonists |
| SE0302570D0 (sv) * | 2003-09-26 | 2003-09-26 | Astrazeneca Ab | Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof |
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| SE0302571D0 (sv) * | 2003-09-26 | 2003-09-26 | Astrazeneca Ab | Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof |
| EP1675822A2 (en) | 2003-10-16 | 2006-07-05 | Cara Therapeutics, Inc. | Amide or thioamide derivatives and their use in the treatment of pain |
| UA87327C2 (ru) * | 2004-09-24 | 2009-07-10 | Астразенека Аб | Производные бензимидазола, композиция, которая их содержит, их получение и применение |
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| RU2374234C2 (ru) * | 2004-09-24 | 2009-11-27 | Астразенека Аб | Бензимидазольные производные, содержащие их композиции, их получение и применение |
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| WO2006033632A1 (en) * | 2004-09-24 | 2006-03-30 | Astrazeneca Ab | Benzimidazole derivatives and their use as cannabinoid receptor ligands I |
| JP2008514591A (ja) * | 2004-09-24 | 2008-05-08 | アストラゼネカ・アクチエボラーグ | ベンゾイミダゾール誘導体及びカンナビノイド受容体リガンドとしてのその使用 |
| EP1797074A4 (en) * | 2004-09-24 | 2009-04-01 | Astrazeneca Ab | COMPOUNDS, COMPOSITIONS CONTAINING THEM, PREPARATION THEREOF AND APPLICATIONS THEREOF IIII |
| JP2008514590A (ja) * | 2004-09-24 | 2008-05-08 | アストラゼネカ・アクチエボラーグ | ベンゾイミダゾール誘導体、それを含む組成物、その製造方法及びその使用 |
| CA2585030A1 (en) | 2004-10-27 | 2006-05-04 | F. Hoffmann-La Roche Ag | New indole or benzimidazole derivatives |
| ES2318556T3 (es) * | 2004-11-02 | 2009-05-01 | Pfizer, Inc. | Derivados de sulfonil bencimidazol. |
| SE0402762D0 (sv) * | 2004-11-11 | 2004-11-11 | Astrazeneca Ab | Indazole sulphonamide derivatives |
| SE0402763D0 (sv) * | 2004-11-11 | 2004-11-11 | Astrazeneca Ab | Nitro indazole derivatives |
| DE602006019213D1 (de) | 2005-03-15 | 2011-02-10 | Pfizer | Benzimidazolonderivate als cb2-rezeptor-liganden |
| WO2006116399A2 (en) | 2005-04-28 | 2006-11-02 | Ferring B.V. | Use of novel compounds for ibd treatment |
| UY30048A1 (es) | 2005-12-23 | 2007-07-31 | Astrazeneca Ab | Derivados sustituidos de la n,2-(1h-benzimidazol-1-il) acetamida, composiciones farmacéuticas conteniéndolos, procesos de preparación y aplicaciones |
| WO2007091950A1 (en) * | 2006-02-07 | 2007-08-16 | Astrazeneca Ab | Benzimidazoles and imidazopyridines useful in the treatment of diseases or disorders associated with cannabinoid receptor 2 (cb2) such as pain |
| JP2009536918A (ja) * | 2006-03-06 | 2009-10-22 | ファイザー株式会社 | スルホニルベンゾイミダゾール誘導体 |
| TW200745049A (en) | 2006-03-23 | 2007-12-16 | Astrazeneca Ab | New crystalline forms |
| TW200808769A (en) | 2006-04-18 | 2008-02-16 | Astrazeneca Ab | Therapeutic compounds |
| TW200808772A (en) * | 2006-06-13 | 2008-02-16 | Astrazeneca Ab | Therapeutic compounds |
| BRPI0714199A2 (pt) | 2006-07-04 | 2012-12-25 | Janssen Pharmaceutica Nv | agonistas de canabinàide de benzimidazol que transportam um grupo heterocÍclico substituÍdo |
| TWI433839B (zh) | 2006-08-11 | 2014-04-11 | Neomed Inst | 新穎的苯并咪唑衍生物290 |
| FR2907784B1 (fr) * | 2006-10-27 | 2009-02-13 | Sod Conseils Rech Applic | Derives phenyliques et leur utilisation comme medicament |
| WO2009116074A2 (en) * | 2008-02-13 | 2009-09-24 | Cadila Healthcare Limited | Substituted benzimidazoles as cannabinoid modulator |
| WO2011009883A1 (en) | 2009-07-23 | 2011-01-27 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Selective cb2 receptor agonists for use in the prevention or treatment of alcoholic liver disease |
| US20110086853A1 (en) * | 2009-10-08 | 2011-04-14 | William Brown | Therapeutic Compounds |
| US8759535B2 (en) | 2010-02-18 | 2014-06-24 | High Point Pharmaceuticals, Llc | Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof |
| EA201290808A1 (ru) | 2010-02-18 | 2013-03-29 | ХАЙ ПОЙНТ ФАРМАСЬЮТИКАЛЗ, ЭлЭлСи | Замещенные конденсированные производные имидазола, фармацевтические композиции и способы их применения |
| JP6162694B2 (ja) | 2011-07-18 | 2017-07-12 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングMerck Patent Gesellschaft mit beschraenkter Haftung | ベンズアミド類 |
| CN102977056B (zh) * | 2012-11-28 | 2014-11-26 | 深圳万乐药业有限公司 | N-苄氧羰基-3-氟-4-吗啉基苯胺的合成方法 |
| WO2016089648A1 (en) | 2014-12-01 | 2016-06-09 | Vtv Therapeutics Llc | Bach 1 inhibitors in combination with nrf2 activators and pharmaceutical compositions thereof |
| WO2017157332A1 (zh) * | 2016-03-18 | 2017-09-21 | 江苏恒瑞医药股份有限公司 | 芳香酰胺类衍生物、其制备方法及其在医药上的应用 |
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| US2945044A (en) * | 1957-07-12 | 1960-07-12 | Ciba Pharm Prod Inc | Certain 1-(diethyl-aminoethyl), 5-amino, 2-benzyl or substituted benzyl, benzimidazoles |
| FR1481049A (fr) | 1965-11-25 | 1967-05-19 | France Ministre Des Armees | Nouveaux dialkylaminoalkyl-1 p-alkoxyphényl alkyl-2 benzimidazoles 5-substitués |
| IL112235A (en) * | 1994-01-03 | 2000-06-29 | Acea Pharm Inc | 1,4-dihydro-pyrido¬2,3-b¾pyrazine-2,3-dione (5 or 8) oxide derivatives and pharmaceutical compositions containing them |
| NZ288608A (en) * | 1994-06-10 | 1999-01-28 | Byk Gulden Lomberg Chem Fab | Substituted pyridinylmethyl-thio(or sulphinyl)-benzimidazole(or 1h-imidazo-[2,3-b]-pyridine) and medicaments to combat heliobacter bacteria |
| SE0203070D0 (en) * | 2002-10-16 | 2002-10-16 | Astrazeneca Ab | Novel compounds |
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Also Published As
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|---|---|
| MY134568A (en) | 2007-12-31 |
| NO20034665L (no) | 2003-12-10 |
| SE0101387D0 (sv) | 2001-04-20 |
| WO2002085866A1 (en) | 2002-10-31 |
| IL158142A0 (en) | 2004-03-28 |
| RU2003129638A (ru) | 2005-04-10 |
| RU2312864C2 (ru) | 2007-12-20 |
| AR035959A1 (es) | 2004-07-28 |
| CZ20032833A3 (en) | 2004-05-12 |
| BR0208907A (pt) | 2004-04-20 |
| MXPA03009558A (es) | 2004-02-12 |
| HUP0303825A2 (hu) | 2004-03-01 |
| PL366517A1 (en) | 2005-02-07 |
| CN1250531C (zh) | 2006-04-12 |
| US7030139B2 (en) | 2006-04-18 |
| CA2444381A1 (en) | 2002-10-31 |
| EE200300524A (et) | 2004-02-16 |
| UA76743C2 (uk) | 2006-09-15 |
| HUP0303825A3 (en) | 2005-06-28 |
| US20060135554A1 (en) | 2006-06-22 |
| NZ528403A (en) | 2005-05-27 |
| NO20034665D0 (no) | 2003-10-17 |
| IS6971A (is) | 2003-09-29 |
| US20040116465A1 (en) | 2004-06-17 |
| KR20040022421A (ko) | 2004-03-12 |
| EP1390350A1 (en) | 2004-02-25 |
| JP2004528334A (ja) | 2004-09-16 |
| SK13032003A3 (sk) | 2005-01-03 |
| ZA200307752B (en) | 2005-01-03 |
| CN1503787A (zh) | 2004-06-09 |
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