KR20150067188A - 벤즈아미드 - Google Patents
벤즈아미드 Download PDFInfo
- Publication number
- KR20150067188A KR20150067188A KR1020157009187A KR20157009187A KR20150067188A KR 20150067188 A KR20150067188 A KR 20150067188A KR 1020157009187 A KR1020157009187 A KR 1020157009187A KR 20157009187 A KR20157009187 A KR 20157009187A KR 20150067188 A KR20150067188 A KR 20150067188A
- Authority
- KR
- South Korea
- Prior art keywords
- trifluoromethyl
- pyridin
- lcms
- acid
- mmol
- 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.)
- Withdrawn
Links
- 229940054066 benzamide antipsychotics Drugs 0.000 title 1
- 150000003936 benzamides Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 194
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims description 418
- -1 homomorpholinyl Chemical group 0.000 claims description 386
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 161
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 46
- 125000000217 alkyl group Chemical group 0.000 claims description 38
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 33
- 229910052757 nitrogen Inorganic materials 0.000 claims description 26
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 25
- 239000000460 chlorine Substances 0.000 claims description 23
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 19
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 13
- 125000001153 fluoro group Chemical group F* 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000002393 azetidinyl group Chemical group 0.000 claims description 7
- 125000002757 morpholinyl group Chemical group 0.000 claims description 7
- 125000003386 piperidinyl group Chemical group 0.000 claims description 7
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 150000002460 imidazoles Chemical class 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 37
- 201000010099 disease Diseases 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 11
- 102100037602 P2X purinoceptor 7 Human genes 0.000 abstract 1
- 101710189965 P2X purinoceptor 7 Proteins 0.000 abstract 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 399
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 270
- 239000007858 starting material Substances 0.000 description 232
- 239000000203 mixture Substances 0.000 description 176
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 170
- 239000000243 solution Substances 0.000 description 158
- 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 117
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 102
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 91
- QAOJBHRZQQDFHA-UHFFFAOYSA-N 2,3-dichlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1Cl QAOJBHRZQQDFHA-UHFFFAOYSA-N 0.000 description 82
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 79
- 239000012044 organic layer Substances 0.000 description 72
- 238000005481 NMR spectroscopy Methods 0.000 description 71
- 235000019439 ethyl acetate Nutrition 0.000 description 68
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 64
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 62
- 238000006243 chemical reaction Methods 0.000 description 62
- 239000011541 reaction mixture Substances 0.000 description 58
- 239000011734 sodium Substances 0.000 description 53
- IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 description 51
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 51
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 46
- 230000002829 reductive effect Effects 0.000 description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
- 239000012267 brine Substances 0.000 description 45
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 45
- 239000012043 crude product Substances 0.000 description 40
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 39
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 37
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 36
- WJYAYXKXZNITAZ-UHFFFAOYSA-N 2-chloro-3-fluorobenzoic acid Chemical compound OC(=O)C1=CC=CC(F)=C1Cl WJYAYXKXZNITAZ-UHFFFAOYSA-N 0.000 description 34
- 229920006395 saturated elastomer Polymers 0.000 description 31
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- 239000000741 silica gel Substances 0.000 description 28
- 229910002027 silica gel Inorganic materials 0.000 description 28
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 27
- 208000035475 disorder Diseases 0.000 description 26
- 239000003208 petroleum Substances 0.000 description 26
- 238000004440 column chromatography Methods 0.000 description 25
- XNTIGDVFBDJLTQ-UHFFFAOYSA-N 2-chloro-6-fluorobenzoic acid Chemical compound OC(=O)C1=C(F)C=CC=C1Cl XNTIGDVFBDJLTQ-UHFFFAOYSA-N 0.000 description 23
- 210000004027 cell Anatomy 0.000 description 23
- 239000000543 intermediate Substances 0.000 description 23
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- 238000003818 flash chromatography Methods 0.000 description 21
- 239000010410 layer Substances 0.000 description 21
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- 238000000746 purification Methods 0.000 description 19
- 102000005962 receptors Human genes 0.000 description 19
- 108020003175 receptors Proteins 0.000 description 19
- ATCRIUVQKHMXSH-UHFFFAOYSA-N 2,4-dichlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1Cl ATCRIUVQKHMXSH-UHFFFAOYSA-N 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 17
- 229910052938 sodium sulfate Inorganic materials 0.000 description 17
- 235000011152 sodium sulphate Nutrition 0.000 description 17
- QRCVHNPXCMDFNV-UHFFFAOYSA-N [4,4-difluoro-1-(6-fluoropyridin-3-yl)cyclohexyl]methanamine Chemical compound C=1C=C(F)N=CC=1C1(CN)CCC(F)(F)CC1 QRCVHNPXCMDFNV-UHFFFAOYSA-N 0.000 description 16
- MIPUNIMXSFJARK-UHFFFAOYSA-N [4,4-difluoro-1-[6-(trifluoromethyl)pyridin-3-yl]cyclohexyl]methanamine Chemical compound C=1C=C(C(F)(F)F)N=CC=1C1(CN)CCC(F)(F)CC1 MIPUNIMXSFJARK-UHFFFAOYSA-N 0.000 description 16
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 description 16
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- MRUDNSFOFOQZDA-UHFFFAOYSA-N 2,6-dichlorobenzoic acid Chemical compound OC(=O)C1=C(Cl)C=CC=C1Cl MRUDNSFOFOQZDA-UHFFFAOYSA-N 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 14
- UGXUGTRUDUHPAC-UHFFFAOYSA-N 3-cyclopropyl-2-[6-(trifluoromethyl)pyridin-3-yl]propan-1-amine Chemical compound C=1C=C(C(F)(F)F)N=CC=1C(CN)CC1CC1 UGXUGTRUDUHPAC-UHFFFAOYSA-N 0.000 description 13
- ARKFJLXRPCTJJC-UHFFFAOYSA-N 4-(4-chlorophenyl)-n-methyloxan-4-amine Chemical compound C=1C=C(Cl)C=CC=1C1(NC)CCOCC1 ARKFJLXRPCTJJC-UHFFFAOYSA-N 0.000 description 13
- 208000002193 Pain Diseases 0.000 description 13
- 208000027534 Emotional disease Diseases 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- BQDJLAWUTBCDHK-UHFFFAOYSA-N 2-(trifluoromethyl)pyrimidine Chemical compound FC(F)(F)C1=NC=CC=N1 BQDJLAWUTBCDHK-UHFFFAOYSA-N 0.000 description 11
- VIUDWLLKFANPLX-UHFFFAOYSA-N 2-chloro-3-methoxybenzoic acid Chemical compound COC1=CC=CC(C(O)=O)=C1Cl VIUDWLLKFANPLX-UHFFFAOYSA-N 0.000 description 11
- 238000001816 cooling Methods 0.000 description 11
- 208000015122 neurodegenerative disease Diseases 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- 239000003643 water by type Substances 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- KUHSAAHTEMAJTF-UHFFFAOYSA-N 2-(difluoromethyl)pyridine Chemical compound FC(F)C1=CC=CC=N1 KUHSAAHTEMAJTF-UHFFFAOYSA-N 0.000 description 10
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- ATRQECRSCHYSNP-UHFFFAOYSA-N 2-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CC=CC=N1 ATRQECRSCHYSNP-UHFFFAOYSA-N 0.000 description 9
- MUURVYOEMFYHRI-UHFFFAOYSA-N 2-[6-(trifluoromethyl)pyridin-3-yl]acetonitrile Chemical compound FC(F)(F)C1=CC=C(CC#N)C=N1 MUURVYOEMFYHRI-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 9
- 230000036407 pain Effects 0.000 description 9
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- 125000006420 1-fluorocyclopropyl group Chemical group [H]C1([H])C([H])([H])C1(F)* 0.000 description 8
- AZYKQNQXVATDRT-UHFFFAOYSA-N 2-(difluoromethyl)pyrimidine Chemical compound FC(F)C1=NC=CC=N1 AZYKQNQXVATDRT-UHFFFAOYSA-N 0.000 description 8
- UENGBOCGGKLVJJ-UHFFFAOYSA-N 2-chloro-1-(2,4-difluorophenyl)ethanone Chemical compound FC1=CC=C(C(=O)CCl)C(F)=C1 UENGBOCGGKLVJJ-UHFFFAOYSA-N 0.000 description 8
- LNJMHEJAYSYZKK-UHFFFAOYSA-N 2-methylpyrimidine Chemical compound CC1=NC=CC=N1 LNJMHEJAYSYZKK-UHFFFAOYSA-N 0.000 description 8
- DUGHICZXRJUMHK-UHFFFAOYSA-N 3-cyclopropyl-2-[4-(trifluoromethyl)-2h-pyrimidin-1-yl]propan-1-amine Chemical compound C1N=C(C(F)(F)F)C=CN1C(CN)CC1CC1 DUGHICZXRJUMHK-UHFFFAOYSA-N 0.000 description 8
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 8
- YYMONMOJCASXKN-UHFFFAOYSA-N N-[3-cyclopropyl-2-[2-(difluoromethyl)pyrimidin-5-yl]propyl]benzamide Chemical compound C(C1=CC=CC=C1)(=O)NCC(CC1CC1)C=1C=NC(=NC=1)C(F)F YYMONMOJCASXKN-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 238000000132 electrospray ionisation Methods 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 208000024714 major depressive disease Diseases 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- LEBWXJZAWTVKFL-UHFFFAOYSA-N 2-chloro-5-methylbenzoic acid Chemical compound CC1=CC=C(Cl)C(C(O)=O)=C1 LEBWXJZAWTVKFL-UHFFFAOYSA-N 0.000 description 7
- HBTYYGDIGVIQSH-UHFFFAOYSA-N 2-phenyl-2-[6-(trifluoromethyl)pyridin-3-yl]ethanamine Chemical compound C=1C=C(C(F)(F)F)N=CC=1C(CN)C1=CC=CC=C1 HBTYYGDIGVIQSH-UHFFFAOYSA-N 0.000 description 7
- 239000007868 Raney catalyst Substances 0.000 description 7
- 229910000564 Raney nickel Inorganic materials 0.000 description 7
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 238000010828 elution Methods 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- FEWQGNVIIFBGFC-UHFFFAOYSA-N 2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethanamine Chemical compound C1=NC(C)=NC=C1C(CN)C1CCC(F)(F)CC1 FEWQGNVIIFBGFC-UHFFFAOYSA-N 0.000 description 6
- AZGXXQCVPPEMBV-UHFFFAOYSA-N 3-[1-(trifluoromethyl)cyclopropyl]-2-[6-(trifluoromethyl)pyridin-3-yl]propan-1-amine Chemical compound C=1C=C(C(F)(F)F)N=CC=1C(CN)CC1(C(F)(F)F)CC1 AZGXXQCVPPEMBV-UHFFFAOYSA-N 0.000 description 6
- VVWJDHLQAUZEBO-UHFFFAOYSA-N 3-cyclopropyl-2-[6-(difluoromethyl)pyridin-3-yl]propan-1-amine Chemical compound C=1C=C(C(F)F)N=CC=1C(CN)CC1CC1 VVWJDHLQAUZEBO-UHFFFAOYSA-N 0.000 description 6
- HAUPNGKRMKQZBS-UHFFFAOYSA-N 3-cyclopropyl-2-methyl-2-[2-(trifluoromethyl)pyrimidin-5-yl]propan-1-amine Chemical compound C=1N=C(C(F)(F)F)N=CC=1C(CN)(C)CC1CC1 HAUPNGKRMKQZBS-UHFFFAOYSA-N 0.000 description 6
- KKWPALCYWRJQSM-UHFFFAOYSA-N C1N=C(C(F)F)C=CN1C(CN)CC1CC1 Chemical compound C1N=C(C(F)F)C=CN1C(CN)CC1CC1 KKWPALCYWRJQSM-UHFFFAOYSA-N 0.000 description 6
- 206010061218 Inflammation Diseases 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- YWLQOJHSDYQBRR-UHFFFAOYSA-N [4,4-difluoro-1-[2-(trifluoromethyl)pyrimidin-5-yl]cyclohexyl]methanamine Chemical compound C=1N=C(C(F)(F)F)N=CC=1C1(CN)CCC(F)(F)CC1 YWLQOJHSDYQBRR-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 230000004054 inflammatory process Effects 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- VIKFTRZVEVXPFI-UHFFFAOYSA-N (1-pyridin-3-ylcyclopentyl)methanamine Chemical compound C=1C=CN=CC=1C1(CN)CCCC1 VIKFTRZVEVXPFI-UHFFFAOYSA-N 0.000 description 5
- JXFDVKDUAZFNQJ-UHFFFAOYSA-N 2-(2-methylpyrimidin-5-yl)-2-(oxan-4-yl)ethanamine Chemical compound C1=NC(C)=NC=C1C(CN)C1CCOCC1 JXFDVKDUAZFNQJ-UHFFFAOYSA-N 0.000 description 5
- ZXIOMYHPVISDLH-UHFFFAOYSA-N 2-(2-methylpyrimidin-5-yl)-2-pyridin-4-ylethanamine Chemical compound C1=NC(C)=NC=C1C(CN)C1=CC=NC=C1 ZXIOMYHPVISDLH-UHFFFAOYSA-N 0.000 description 5
- HLLIGPMLEFXSPO-UHFFFAOYSA-N 2-(2-methylpyrimidin-5-yl)acetonitrile Chemical compound CC1=NC=C(CC#N)C=N1 HLLIGPMLEFXSPO-UHFFFAOYSA-N 0.000 description 5
- CXCZPHUOZMSYCT-UHFFFAOYSA-N 2-(4,4-difluorocyclohexyl)-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethanamine Chemical compound C=1N=C(C(F)(F)F)N=CC=1C(CN)C1CCC(F)(F)CC1 CXCZPHUOZMSYCT-UHFFFAOYSA-N 0.000 description 5
- IVAFQTOHKXKDJG-UHFFFAOYSA-N 2-(4-chlorophenyl)-2-(oxan-4-yl)ethanamine Chemical compound C=1C=C(Cl)C=CC=1C(CN)C1CCOCC1 IVAFQTOHKXKDJG-UHFFFAOYSA-N 0.000 description 5
- HIFAECYAJZMISZ-UHFFFAOYSA-N 2-(4-fluorophenyl)-2-[6-(trifluoromethyl)pyridin-3-yl]ethanamine Chemical compound C=1C=C(C(F)(F)F)N=CC=1C(CN)C1=CC=C(F)C=C1 HIFAECYAJZMISZ-UHFFFAOYSA-N 0.000 description 5
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000003572 second messenger assay Methods 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- YZUAOVCUGSBIPP-UHFFFAOYSA-N tert-butyl N-[1-([1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl]carbamate Chemical compound C1=CC=CN2C(C(NC(=O)OC(C)(C)C)C)=NN=C21 YZUAOVCUGSBIPP-UHFFFAOYSA-N 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
- 229960000278 theophylline Drugs 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- 229950002929 trinitrophenol Drugs 0.000 description 1
Classifications
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- 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
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- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
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- C07C2601/00—Systems containing only non-condensed rings
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- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Applications Claiming Priority (3)
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|---|---|---|---|
| US201261713113P | 2012-10-12 | 2012-10-12 | |
| US61/713,113 | 2012-10-12 | ||
| PCT/EP2013/071247 WO2014057078A1 (en) | 2012-10-12 | 2013-10-11 | Benzamides |
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| KR20150067188A true KR20150067188A (ko) | 2015-06-17 |
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| TWI598325B (zh) | 2012-10-12 | 2017-09-11 | H 朗德貝克公司 | 苯甲醯胺類 |
| TW201427947A (zh) * | 2012-10-12 | 2014-07-16 | Lundbeck & Co As H | 環狀胺 |
| AR093921A1 (es) | 2012-12-12 | 2015-06-24 | Actelion Pharmaceuticals Ltd | Derivados de indol carboxamida como antagonistas del receptor p2x7 |
| KR102232744B1 (ko) | 2012-12-18 | 2021-03-26 | 이도르시아 파마슈티컬스 리미티드 | P2x7 수용체 길항제로서의 인돌 카르복사미드 유도체 |
| ES2616883T3 (es) | 2013-01-22 | 2017-06-14 | Actelion Pharmaceuticals Ltd. | Derivados amida heterocíclicos como antagonistas del receptor P2X7 |
| KR102222220B1 (ko) | 2013-01-22 | 2021-03-03 | 이도르시아 파마슈티컬스 리미티드 | P2x7 수용체 길항제로서의 헤테로시클릭 아미드 유도체 |
| CN105503787A (zh) * | 2015-12-31 | 2016-04-20 | 阜阳欣奕华材料科技有限公司 | 一种索非布韦中间体的纯化方法 |
| CN106366056B (zh) * | 2016-08-26 | 2018-12-11 | 常州市阳光药业有限公司 | 3-氨甲基四氢呋喃的制备方法 |
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