JP5108878B2 - 置換型カルボキサミド - Google Patents
置換型カルボキサミド Download PDFInfo
- Publication number
- JP5108878B2 JP5108878B2 JP2009514523A JP2009514523A JP5108878B2 JP 5108878 B2 JP5108878 B2 JP 5108878B2 JP 2009514523 A JP2009514523 A JP 2009514523A JP 2009514523 A JP2009514523 A JP 2009514523A JP 5108878 B2 JP5108878 B2 JP 5108878B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- mmol
- preparation
- added
- 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.)
- Expired - Fee Related
Links
- 125000003917 carbamoyl group Chemical class [H]N([H])C(*)=O 0.000 title 1
- -1 carboxamide compound Chemical class 0.000 claims abstract description 46
- 208000002193 Pain Diseases 0.000 claims abstract description 43
- 150000003839 salts Chemical class 0.000 claims abstract description 36
- 230000036407 pain Effects 0.000 claims abstract description 34
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 88
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 17
- 229910052794 bromium Inorganic materials 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 11
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 10
- 239000011737 fluorine Substances 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 9
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 6
- LXZFJIRPRVGCDF-PRHODGIISA-N (1r,2r)-n-[3-(4-chlorophenyl)-4-methyl-1,2-thiazol-5-yl]-2-methylcyclopropane-1-carboxamide Chemical compound C[C@@H]1C[C@H]1C(=O)NC1=C(C)C(C=2C=CC(Cl)=CC=2)=NS1 LXZFJIRPRVGCDF-PRHODGIISA-N 0.000 claims description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000006002 1,1-difluoroethyl group Chemical group 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 230000000144 pharmacologic effect Effects 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 135
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 83
- 238000002360 preparation method Methods 0.000 description 80
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 63
- 235000019439 ethyl acetate Nutrition 0.000 description 57
- 238000000034 method Methods 0.000 description 50
- 239000000243 solution Substances 0.000 description 50
- 239000000203 mixture Substances 0.000 description 41
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 29
- 238000003756 stirring Methods 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 25
- 239000011541 reaction mixture Substances 0.000 description 25
- 239000002253 acid Substances 0.000 description 20
- 239000012074 organic phase Substances 0.000 description 20
- 102000005962 receptors Human genes 0.000 description 19
- 108020003175 receptors Proteins 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 102000016193 Metabotropic glutamate receptors Human genes 0.000 description 18
- 108010010914 Metabotropic glutamate receptors Proteins 0.000 description 18
- 150000001412 amines Chemical class 0.000 description 17
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000012267 brine Substances 0.000 description 15
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 15
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- 230000001684 chronic effect Effects 0.000 description 14
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 14
- AYEGPMGNMOIHDL-QWWZWVQMSA-N (1r,2r)-2-methylcyclopropane-1-carboxylic acid Chemical compound C[C@@H]1C[C@H]1C(O)=O AYEGPMGNMOIHDL-QWWZWVQMSA-N 0.000 description 13
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 13
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 12
- 238000010898 silica gel chromatography Methods 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
- 239000012071 phase Substances 0.000 description 11
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 10
- 230000002757 inflammatory effect Effects 0.000 description 10
- 208000000094 Chronic Pain Diseases 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 9
- 125000001246 bromo group Chemical group Br* 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 208000004296 neuralgia Diseases 0.000 description 9
- 208000021722 neuropathic pain Diseases 0.000 description 9
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 8
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- UEGDTXGDZZESGT-MWLCHTKSSA-N benzyl (1r,2r)-2-methylcyclopropane-1-carboxylate Chemical compound C[C@@H]1C[C@H]1C(=O)OCC1=CC=CC=C1 UEGDTXGDZZESGT-MWLCHTKSSA-N 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 150000002825 nitriles Chemical class 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- AYEGPMGNMOIHDL-UHFFFAOYSA-N 2-methylcyclopropane-1-carboxylic acid Chemical compound CC1CC1C(O)=O AYEGPMGNMOIHDL-UHFFFAOYSA-N 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 230000008878 coupling Effects 0.000 description 7
- 238000010168 coupling process Methods 0.000 description 7
- 238000005859 coupling reaction Methods 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 238000004817 gas chromatography Methods 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 230000004044 response Effects 0.000 description 7
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 7
- VCSKFTJGUYAXOC-CHDUMGHJSA-N (2s)-2-amino-3-phenylpropan-1-ol;(1r,2r)-2-methylcyclopropane-1-carboxylic acid Chemical compound C[C@@H]1C[C@H]1C(O)=O.OC[C@@H](N)CC1=CC=CC=C1 VCSKFTJGUYAXOC-CHDUMGHJSA-N 0.000 description 6
- BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 6
- STVVMTBJNDTZBF-VIFPVBQESA-N L-phenylalaninol Chemical compound OC[C@@H](N)CC1=CC=CC=C1 STVVMTBJNDTZBF-VIFPVBQESA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- 239000005557 antagonist Substances 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 230000000638 stimulation Effects 0.000 description 6
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 5
- 229960002504 capsaicin Drugs 0.000 description 5
- 235000017663 capsaicin Nutrition 0.000 description 5
- 150000003857 carboxamides Chemical class 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 229930195712 glutamate Natural products 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 230000003040 nociceptive effect Effects 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 230000002085 persistent effect Effects 0.000 description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 210000001032 spinal nerve Anatomy 0.000 description 5
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 5
- HSEURPKENJFQMI-NOZJJQNGSA-N (1r,2r)-n-[3-(4-methoxyphenyl)-4-methyl-1,2-thiazol-5-yl]-2-methylcyclopropane-1-carboxamide Chemical compound C1=CC(OC)=CC=C1C1=NSC(NC(=O)[C@H]2[C@@H](C2)C)=C1C HSEURPKENJFQMI-NOZJJQNGSA-N 0.000 description 4
- MBRXSOUHUFBPQC-RFPWEZLHSA-N (6s,8s,9r,10s,11s,13s,14s,16r,17s)-9-chloro-6,11-difluoro-17-(2-hydroxyacetyl)-10,13,16-trimethyl-7,8,11,12,14,15,16,17-octahydro-6h-cyclopenta[a]phenanthren-3-one Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(Cl)[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)CO)[C@@]2(C)C[C@@H]1F MBRXSOUHUFBPQC-RFPWEZLHSA-N 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 208000004454 Hyperalgesia Diseases 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 230000006399 behavior Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000679 carrageenan Substances 0.000 description 4
- 229940113118 carrageenan Drugs 0.000 description 4
- 235000010418 carrageenan Nutrition 0.000 description 4
- 229920001525 carrageenan Polymers 0.000 description 4
- MJEBFQNRQDMUCQ-PRHODGIISA-N chembl2011880 Chemical compound C[C@@H]1C[C@H]1C(=O)NC1=C(C)C(C=2C=CC(O)=CC=2)=NS1 MJEBFQNRQDMUCQ-PRHODGIISA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000005356 chiral GC Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 206010015037 epilepsy Diseases 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 4
- 229940011051 isopropyl acetate Drugs 0.000 description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical group CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 238000000634 powder X-ray diffraction Methods 0.000 description 4
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 150000003556 thioamides Chemical class 0.000 description 4
- LDHQCZJRKDOVOX-UHFFFAOYSA-N trans-crotonic acid Natural products CC=CC(O)=O LDHQCZJRKDOVOX-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 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 4
- MAUHSBCQDSRPRV-QWWZWVQMSA-N (1r,2r)-n-(3,4-dibromo-1,2-thiazol-5-yl)-2-methylcyclopropane-1-carboxamide Chemical compound C[C@@H]1C[C@H]1C(=O)NC1=C(Br)C(Br)=NS1 MAUHSBCQDSRPRV-QWWZWVQMSA-N 0.000 description 3
- STVVMTBJNDTZBF-UHFFFAOYSA-N -2-Amino-3-phenyl-1-propanol Natural products OCC(N)CC1=CC=CC=C1 STVVMTBJNDTZBF-UHFFFAOYSA-N 0.000 description 3
- UCSVHPBSHQJZJQ-UHFFFAOYSA-N 3,4-dibromo-1,2-thiazol-5-amine Chemical compound NC=1SN=C(Br)C=1Br UCSVHPBSHQJZJQ-UHFFFAOYSA-N 0.000 description 3
- VAIJKTHAHKDKKB-UHFFFAOYSA-N 3-(4-methoxyphenyl)-4-methyl-1,2-thiazol-5-amine Chemical compound C1=CC(OC)=CC=C1C1=NSC(N)=C1C VAIJKTHAHKDKKB-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 101001053401 Arabidopsis thaliana Acid beta-fructofuranosidase 3, vacuolar Proteins 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical group [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 208000019695 Migraine disease Diseases 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 239000012455 biphasic mixture Substances 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 238000004296 chiral HPLC Methods 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 238000001647 drug administration Methods 0.000 description 3
- 210000003414 extremity Anatomy 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000007069 methylation reaction Methods 0.000 description 3
- 206010027599 migraine Diseases 0.000 description 3
- 230000001537 neural effect Effects 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000002464 receptor antagonist Substances 0.000 description 3
- 229940044551 receptor antagonist Drugs 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- KNSMKLZZQPGJRN-QWWZWVQMSA-N (1r,2r)-2-methylcyclopropane-1-carbonyl chloride Chemical compound C[C@@H]1C[C@H]1C(Cl)=O KNSMKLZZQPGJRN-QWWZWVQMSA-N 0.000 description 2
- REHRAKWZEXYQAC-PSASIEDQSA-N (1r,2r)-n-(4-bromo-3-phenyl-1,2-thiazol-5-yl)-2-methylcyclopropane-1-carboxamide Chemical compound C[C@@H]1C[C@H]1C(=O)NC1=C(Br)C(C=2C=CC=CC=2)=NS1 REHRAKWZEXYQAC-PSASIEDQSA-N 0.000 description 2
- LRVAFLGRKGZXGK-HTRCEHHLSA-N (1r,2r)-n-[4-bromo-3-(3,4-dichlorophenyl)-1,2-thiazol-5-yl]-2-methylcyclopropane-1-carboxamide Chemical compound C[C@@H]1C[C@H]1C(=O)NC1=C(Br)C(C=2C=C(Cl)C(Cl)=CC=2)=NS1 LRVAFLGRKGZXGK-HTRCEHHLSA-N 0.000 description 2
- JUGQDBWWYFNEET-VXNVDRBHSA-N (1r,2r)-n-[4-bromo-3-(3-fluoro-4-methoxyphenyl)-1,2-thiazol-5-yl]-2-methylcyclopropane-1-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1C1=NSC(NC(=O)[C@H]2[C@@H](C2)C)=C1Br JUGQDBWWYFNEET-VXNVDRBHSA-N 0.000 description 2
- DYSXYKUYJIXXNC-GMSGAONNSA-N (1r,2r)-n-[4-bromo-3-(4-fluorophenyl)-1,2-thiazol-5-yl]-2-methylcyclopropane-1-carboxamide Chemical compound C[C@@H]1C[C@H]1C(=O)NC1=C(Br)C(C=2C=CC(F)=CC=2)=NS1 DYSXYKUYJIXXNC-GMSGAONNSA-N 0.000 description 2
- OFSSUQZMWBSWDZ-LDYMZIIASA-N (1r,2r)-n-[4-bromo-3-(4-methylsulfanylphenyl)-1,2-thiazol-5-yl]-2-methylcyclopropane-1-carboxamide Chemical compound C1=CC(SC)=CC=C1C1=NSC(NC(=O)[C@H]2[C@@H](C2)C)=C1Br OFSSUQZMWBSWDZ-LDYMZIIASA-N 0.000 description 2
- PFJPJQKUSJUVDA-LDYMZIIASA-N (1r,2r)-n-[4-bromo-3-[4-(1,1-difluoroethyl)phenyl]-1,2-thiazol-5-yl]-2-methylcyclopropane-1-carboxamide Chemical compound C[C@@H]1C[C@H]1C(=O)NC1=C(Br)C(C=2C=CC(=CC=2)C(C)(F)F)=NS1 PFJPJQKUSJUVDA-LDYMZIIASA-N 0.000 description 2
- KDVPKCGRSDZCKH-FLIBITNWSA-N (z)-3-amino-3-(4-methoxyphenyl)-2-methylprop-2-enenitrile Chemical compound COC1=CC=C(C(\N)=C(/C)C#N)C=C1 KDVPKCGRSDZCKH-FLIBITNWSA-N 0.000 description 2
- USAKAOWRTVECKR-UHFFFAOYSA-N 3,4-dibromo-1,2-thiazole Chemical compound BrC1=CSN=C1Br USAKAOWRTVECKR-UHFFFAOYSA-N 0.000 description 2
- LINWMMMTASIKET-UHFFFAOYSA-N 3-(3-fluoro-4-methoxyphenyl)-1,2-thiazol-5-amine Chemical compound C1=C(F)C(OC)=CC=C1C1=NSC(N)=C1 LINWMMMTASIKET-UHFFFAOYSA-N 0.000 description 2
- GEXKFHNACZBHFZ-UHFFFAOYSA-N 3-(4-chlorophenyl)-4-methyl-1,2-thiazol-5-amine Chemical compound CC1=C(N)SN=C1C1=CC=C(Cl)C=C1 GEXKFHNACZBHFZ-UHFFFAOYSA-N 0.000 description 2
- HHLOYHLUIKGYNM-UHFFFAOYSA-N 3-[4-(1,1-difluoroethyl)phenyl]-1,2-thiazol-5-amine Chemical compound C1=CC(C(F)(F)C)=CC=C1C1=NSC(N)=C1 HHLOYHLUIKGYNM-UHFFFAOYSA-N 0.000 description 2
- CZCIXBQMUFNEMP-UHFFFAOYSA-N 3-amino-3-(3-fluoro-4-methoxyphenyl)prop-2-enenitrile Chemical compound COC1=CC=C(C(N)=CC#N)C=C1F CZCIXBQMUFNEMP-UHFFFAOYSA-N 0.000 description 2
- SOEDEDJYJMRHRV-UHFFFAOYSA-N 3-amino-3-(3-fluoro-4-methoxyphenyl)prop-2-enethioamide Chemical compound COC1=CC=C(C(N)=CC(N)=S)C=C1F SOEDEDJYJMRHRV-UHFFFAOYSA-N 0.000 description 2
- ZPEYOZZMCMPGOC-UHFFFAOYSA-N 3-amino-3-(4-chlorophenyl)-2-methylprop-2-enenitrile Chemical compound N#CC(C)=C(N)C1=CC=C(Cl)C=C1 ZPEYOZZMCMPGOC-UHFFFAOYSA-N 0.000 description 2
- HURYSNQJWWSELT-UHFFFAOYSA-N 3-amino-3-[4-(1,1-difluoroethyl)phenyl]prop-2-enenitrile Chemical compound CC(F)(F)C1=CC=C(C(N)=CC#N)C=C1 HURYSNQJWWSELT-UHFFFAOYSA-N 0.000 description 2
- UNMRXWBCQGIBQE-UHFFFAOYSA-N 4-(1,1-difluoroethyl)benzonitrile Chemical compound CC(F)(F)C1=CC=C(C#N)C=C1 UNMRXWBCQGIBQE-UHFFFAOYSA-N 0.000 description 2
- YFSYSNCDMBIUDH-UHFFFAOYSA-N 4-(5-amino-4-methyl-1,2-thiazol-3-yl)phenol Chemical compound CC1=C(N)SN=C1C1=CC=C(O)C=C1 YFSYSNCDMBIUDH-UHFFFAOYSA-N 0.000 description 2
- XAGKUQWKQVTDSK-UHFFFAOYSA-N 4-bromo-1,2-thiazole Chemical compound BrC=1C=NSC=1 XAGKUQWKQVTDSK-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 101100459319 Arabidopsis thaliana VIII-2 gene Proteins 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 101150003085 Pdcl gene Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- 102000030621 adenylate cyclase Human genes 0.000 description 2
- 108060000200 adenylate cyclase Proteins 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 238000000540 analysis of variance Methods 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000003542 behavioural effect Effects 0.000 description 2
- 238000005452 bending Methods 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 206010008118 cerebral infarction Diseases 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- XTEGARKTQYYJKE-UHFFFAOYSA-N chloric acid Chemical compound OCl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-N 0.000 description 2
- 229940005991 chloric acid Drugs 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000013065 commercial product Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 2
- DKWOHBPRFZIUQL-UHFFFAOYSA-N dimethyl-methylidene-oxo-$l^{6}-sulfane Chemical compound C[S+](C)([CH2-])=O DKWOHBPRFZIUQL-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 229920001971 elastomer Polymers 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 239000001307 helium Substances 0.000 description 2
- 229910052734 helium Inorganic materials 0.000 description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 102000006239 metabotropic receptors Human genes 0.000 description 2
- 108020004083 metabotropic receptors Proteins 0.000 description 2
- 230000001035 methylating effect Effects 0.000 description 2
- 230000011987 methylation Effects 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 239000004090 neuroprotective agent Substances 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 238000005191 phase separation Methods 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000010079 rubber tapping Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000005062 synaptic transmission Effects 0.000 description 2
- 238000012353 t test Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 230000000451 tissue damage Effects 0.000 description 2
- 231100000827 tissue damage Toxicity 0.000 description 2
- BPLKQGGAXWRFOE-UHFFFAOYSA-M trimethylsulfoxonium iodide Chemical compound [I-].C[S+](C)(C)=O BPLKQGGAXWRFOE-UHFFFAOYSA-M 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
- FGCZWAYABREXLD-MWLCHTKSSA-N (1r,2r)-2-methyl-n-(3-phenyl-1,2-thiazol-5-yl)cyclopropane-1-carboxamide Chemical compound C[C@@H]1C[C@H]1C(=O)NC1=CC(C=2C=CC=CC=2)=NS1 FGCZWAYABREXLD-MWLCHTKSSA-N 0.000 description 1
- UTDCZGDLGDVTAF-BXKDBHETSA-N (1r,2r)-2-methyl-n-(4-methyl-3-phenyl-1,2-thiazol-5-yl)cyclopropane-1-carboxamide Chemical compound C[C@@H]1C[C@H]1C(=O)NC1=C(C)C(C=2C=CC=CC=2)=NS1 UTDCZGDLGDVTAF-BXKDBHETSA-N 0.000 description 1
- UGCLAYZYYYGBNB-BXKDBHETSA-N (1r,2r)-2-methyl-n-[3-(4-methylsulfanylphenyl)-1,2-thiazol-5-yl]cyclopropane-1-carboxamide Chemical compound C1=CC(SC)=CC=C1C1=NSC(NC(=O)[C@H]2[C@@H](C2)C)=C1 UGCLAYZYYYGBNB-BXKDBHETSA-N 0.000 description 1
- VMEDFSDYVYJCHY-NOZJJQNGSA-N (1r,2r)-2-methyl-n-[4-methyl-3-(4-methylsulfanylphenyl)-1,2-thiazol-5-yl]cyclopropane-1-carboxamide Chemical compound C1=CC(SC)=CC=C1C1=NSC(NC(=O)[C@H]2[C@@H](C2)C)=C1C VMEDFSDYVYJCHY-NOZJJQNGSA-N 0.000 description 1
- PEADZMCCUXKVRJ-VXNVDRBHSA-N (1r,2r)-n-[3-(3,4-dichlorophenyl)-1,2-thiazol-5-yl]-2-methylcyclopropane-1-carboxamide Chemical compound C[C@@H]1C[C@H]1C(=O)NC1=CC(C=2C=C(Cl)C(Cl)=CC=2)=NS1 PEADZMCCUXKVRJ-VXNVDRBHSA-N 0.000 description 1
- ZSBBASZUYKREPU-PRHODGIISA-N (1r,2r)-n-[3-(4-bromophenyl)-4-methyl-1,2-thiazol-5-yl]-2-methylcyclopropane-1-carboxamide Chemical compound C[C@@H]1C[C@H]1C(=O)NC1=C(C)C(C=2C=CC(Br)=CC=2)=NS1 ZSBBASZUYKREPU-PRHODGIISA-N 0.000 description 1
- MSOYXZGDANCFCO-QMTHXVAHSA-N (1r,2r)-n-[3-(4-ethoxyphenyl)-4-methyl-1,2-thiazol-5-yl]-2-methylcyclopropane-1-carboxamide Chemical compound C1=CC(OCC)=CC=C1C1=NSC(NC(=O)[C@H]2[C@@H](C2)C)=C1C MSOYXZGDANCFCO-QMTHXVAHSA-N 0.000 description 1
- OYDXPFDAFAUMMU-PRHODGIISA-N (1r,2r)-n-[3-(4-fluorophenyl)-4-methyl-1,2-thiazol-5-yl]-2-methylcyclopropane-1-carboxamide Chemical compound C[C@@H]1C[C@H]1C(=O)NC1=C(C)C(C=2C=CC(F)=CC=2)=NS1 OYDXPFDAFAUMMU-PRHODGIISA-N 0.000 description 1
- AJWFAWHWJRCTAQ-BXKDBHETSA-N (1r,2r)-n-[3-(4-methoxyphenyl)-1,2-thiazol-5-yl]-2-methylcyclopropane-1-carboxamide Chemical compound C1=CC(OC)=CC=C1C1=NSC(NC(=O)[C@H]2[C@@H](C2)C)=C1 AJWFAWHWJRCTAQ-BXKDBHETSA-N 0.000 description 1
- VAGHOXREOMUCLL-NOZJJQNGSA-N (1r,2r)-n-[3-[4-(1,1-difluoroethyl)phenyl]-4-methyl-1,2-thiazol-5-yl]-2-methylcyclopropane-1-carboxamide Chemical compound C[C@@H]1C[C@H]1C(=O)NC1=C(C)C(C=2C=CC(=CC=2)C(C)(F)F)=NS1 VAGHOXREOMUCLL-NOZJJQNGSA-N 0.000 description 1
- SNRWVIHFXXODKA-BXKDBHETSA-N (1r,2r)-n-[4-bromo-3-(4-ethoxyphenyl)-1,2-thiazol-5-yl]-2-methylcyclopropane-1-carboxamide Chemical compound C1=CC(OCC)=CC=C1C1=NSC(NC(=O)[C@H]2[C@@H](C2)C)=C1Br SNRWVIHFXXODKA-BXKDBHETSA-N 0.000 description 1
- KDUHKPQYAUUFTD-UHFFFAOYSA-N (4-ethoxyphenoxy)boronic acid Chemical compound CCOC1=CC=C(OB(O)O)C=C1 KDUHKPQYAUUFTD-UHFFFAOYSA-N 0.000 description 1
- PHBVXHIVWULVNF-UHFFFAOYSA-N (4-fluorophenoxy)boronic acid Chemical compound OB(O)OC1=CC=C(F)C=C1 PHBVXHIVWULVNF-UHFFFAOYSA-N 0.000 description 1
- KFSQJVOLYQRELE-HWKANZROSA-N (e)-2-ethylbut-2-enoic acid Chemical compound CC\C(=C/C)C(O)=O KFSQJVOLYQRELE-HWKANZROSA-N 0.000 description 1
- GDJDODGBGRBEAN-TWGQIWQCSA-N (z)-3-amino-3-phenylprop-2-enenitrile Chemical compound N#C\C=C(/N)C1=CC=CC=C1 GDJDODGBGRBEAN-TWGQIWQCSA-N 0.000 description 1
- 0 *C(Nc1c(*)c(*)n[s]1)=O Chemical compound *C(Nc1c(*)c(*)n[s]1)=O 0.000 description 1
- GKZNVLJEHYUFIC-UHFFFAOYSA-N 1,2-thiazol-5-amine Chemical compound NC1=CC=NS1 GKZNVLJEHYUFIC-UHFFFAOYSA-N 0.000 description 1
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 1
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 description 1
- BHPYMZQTCPRLNR-UHFFFAOYSA-N 2-cyanoethanethioamide Chemical compound NC(=S)CC#N BHPYMZQTCPRLNR-UHFFFAOYSA-N 0.000 description 1
- KAKCLWUKLSECEM-UHFFFAOYSA-N 2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound C1=NC(CC)=CC=C1B1OC(C)(C)C(C)(C)O1 KAKCLWUKLSECEM-UHFFFAOYSA-N 0.000 description 1
- APOYTRAZFJURPB-UHFFFAOYSA-N 2-methoxy-n-(2-methoxyethyl)-n-(trifluoro-$l^{4}-sulfanyl)ethanamine Chemical compound COCCN(S(F)(F)F)CCOC APOYTRAZFJURPB-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- AJGQBMYDBNTQSW-UHFFFAOYSA-N 2-triethylphosphaniumylacetate Chemical compound CC[P+](CC)(CC)CC([O-])=O AJGQBMYDBNTQSW-UHFFFAOYSA-N 0.000 description 1
- KUWBYWUSERRVQP-UHFFFAOYSA-N 3,4-dichlorobenzonitrile Chemical compound ClC1=CC=C(C#N)C=C1Cl KUWBYWUSERRVQP-UHFFFAOYSA-N 0.000 description 1
- ZJIKPUJNSSMNBC-UHFFFAOYSA-N 3-(3,4-dichlorophenyl)-1,2-thiazol-5-amine Chemical compound S1C(N)=CC(C=2C=C(Cl)C(Cl)=CC=2)=N1 ZJIKPUJNSSMNBC-UHFFFAOYSA-N 0.000 description 1
- GUFUTTLYPPNHPE-UHFFFAOYSA-N 3-(3,4-dichlorophenyl)prop-2-enenitrile Chemical compound ClC1=CC=C(C=CC#N)C=C1Cl GUFUTTLYPPNHPE-UHFFFAOYSA-N 0.000 description 1
- ALIUUWWLXNBJJC-UHFFFAOYSA-N 3-(4-bromophenyl)-4-methyl-1,2-thiazol-5-amine Chemical compound CC1=C(N)SN=C1C1=CC=C(Br)C=C1 ALIUUWWLXNBJJC-UHFFFAOYSA-N 0.000 description 1
- MYSVJRIBRLABRU-UHFFFAOYSA-N 3-(4-methoxyphenyl)-1,2-thiazol-5-amine Chemical compound C1=CC(OC)=CC=C1C1=NSC(N)=C1 MYSVJRIBRLABRU-UHFFFAOYSA-N 0.000 description 1
- BTWALZSTGHHMJH-UHFFFAOYSA-N 3-(4-methylsulfanylphenyl)-1,2-thiazol-5-amine Chemical compound C1=CC(SC)=CC=C1C1=NSC(N)=C1 BTWALZSTGHHMJH-UHFFFAOYSA-N 0.000 description 1
- CPBJUFSZBCMFHX-UHFFFAOYSA-N 3-(4-methylsulfanylphenyl)prop-2-enenitrile Chemical compound CSC1=CC=C(C=CC#N)C=C1 CPBJUFSZBCMFHX-UHFFFAOYSA-N 0.000 description 1
- GYWNMIWWNZZOKY-UHFFFAOYSA-N 3-amino-3-(3,4-dichlorophenyl)prop-2-enethioamide Chemical compound NC(=S)C=C(N)C1=CC=C(Cl)C(Cl)=C1 GYWNMIWWNZZOKY-UHFFFAOYSA-N 0.000 description 1
- KEOSVJWZERWSCZ-UHFFFAOYSA-N 3-amino-3-(4-bromophenyl)-2-methylprop-2-enenitrile Chemical compound N#CC(C)=C(N)C1=CC=C(Br)C=C1 KEOSVJWZERWSCZ-UHFFFAOYSA-N 0.000 description 1
- XLXKORDXCFLAMC-UHFFFAOYSA-N 3-amino-3-(4-bromophenyl)-2-methylprop-2-enethioamide Chemical compound NC(=S)C(C)=C(N)C1=CC=C(Br)C=C1 XLXKORDXCFLAMC-UHFFFAOYSA-N 0.000 description 1
- DIZJBZGPIQUYSM-UHFFFAOYSA-N 3-amino-3-(4-chlorophenyl)-2-methylprop-2-enethioamide Chemical compound NC(=S)C(C)=C(N)C1=CC=C(Cl)C=C1 DIZJBZGPIQUYSM-UHFFFAOYSA-N 0.000 description 1
- RVSBIAFYHQQXMR-UHFFFAOYSA-N 3-amino-3-(4-methoxyphenyl)-2-methylprop-2-enethioamide Chemical compound COC1=CC=C(C(N)=C(C)C(N)=S)C=C1 RVSBIAFYHQQXMR-UHFFFAOYSA-N 0.000 description 1
- XAVHLMLFGRPINF-UHFFFAOYSA-N 3-amino-3-(4-methylsulfanylphenyl)prop-2-enethioamide Chemical compound CSC1=CC=C(C(N)=CC(N)=S)C=C1 XAVHLMLFGRPINF-UHFFFAOYSA-N 0.000 description 1
- SBKOUDOEOMZGOD-UHFFFAOYSA-N 3-amino-3-[4-(1,1-difluoroethyl)phenyl]prop-2-enethioamide Chemical compound CC(F)(F)C1=CC=C(C(N)=CC(N)=S)C=C1 SBKOUDOEOMZGOD-UHFFFAOYSA-N 0.000 description 1
- PBDPEETVZXFWHX-UHFFFAOYSA-N 3-amino-3-phenylprop-2-enethioamide Chemical compound NC(=S)C=C(N)C1=CC=CC=C1 PBDPEETVZXFWHX-UHFFFAOYSA-N 0.000 description 1
- FEEOVAOEPGQDTJ-UHFFFAOYSA-N 3-fluoro-4-methoxybenzonitrile Chemical compound COC1=CC=C(C#N)C=C1F FEEOVAOEPGQDTJ-UHFFFAOYSA-N 0.000 description 1
- DHGKYVMNSHRALD-UHFFFAOYSA-N 3-phenyl-1,2-thiazol-5-amine Chemical compound S1C(N)=CC(C=2C=CC=CC=2)=N1 DHGKYVMNSHRALD-UHFFFAOYSA-N 0.000 description 1
- NLPHXWGWBKZSJC-UHFFFAOYSA-N 4-acetylbenzonitrile Chemical compound CC(=O)C1=CC=C(C#N)C=C1 NLPHXWGWBKZSJC-UHFFFAOYSA-N 0.000 description 1
- GJNGXPDXRVXSEH-UHFFFAOYSA-N 4-chlorobenzonitrile Chemical compound ClC1=CC=C(C#N)C=C1 GJNGXPDXRVXSEH-UHFFFAOYSA-N 0.000 description 1
- XDJAAZYHCCRJOK-UHFFFAOYSA-N 4-methoxybenzonitrile Chemical compound COC1=CC=C(C#N)C=C1 XDJAAZYHCCRJOK-UHFFFAOYSA-N 0.000 description 1
- GAESTZKQSOXSNU-UHFFFAOYSA-N 4-methyl-1,2-thiazol-5-amine Chemical group CC=1C=NSC=1N GAESTZKQSOXSNU-UHFFFAOYSA-N 0.000 description 1
- RPVGEEHGKIFQFO-UHFFFAOYSA-N 4-methylsulfanylbenzonitrile Chemical compound CSC1=CC=C(C#N)C=C1 RPVGEEHGKIFQFO-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- 101001053395 Arabidopsis thaliana Acid beta-fructofuranosidase 4, vacuolar Proteins 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- ICPRIIYIVHKDKT-VKKIDBQXSA-N C(CC)O.C[C@H]1[C@@H](C1)C(=O)O Chemical compound C(CC)O.C[C@H]1[C@@H](C1)C(=O)O ICPRIIYIVHKDKT-VKKIDBQXSA-N 0.000 description 1
- 206010064012 Central pain syndrome Diseases 0.000 description 1
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- OZLGRUXZXMRXGP-UHFFFAOYSA-N Fluo-3 Chemical compound CC1=CC=C(N(CC(O)=O)CC(O)=O)C(OCCOC=2C(=CC=C(C=2)C2=C3C=C(Cl)C(=O)C=C3OC3=CC(O)=C(Cl)C=C32)N(CC(O)=O)CC(O)=O)=C1 OZLGRUXZXMRXGP-UHFFFAOYSA-N 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 102000018899 Glutamate Receptors Human genes 0.000 description 1
- 108010027915 Glutamate Receptors Proteins 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- 229930195714 L-glutamate Natural products 0.000 description 1
- 102000004086 Ligand-Gated Ion Channels Human genes 0.000 description 1
- 108090000543 Ligand-Gated Ion Channels Proteins 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000000114 Pain Threshold Diseases 0.000 description 1
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 101100388546 Rattus norvegicus Slc1a3 gene Proteins 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- IVOMOUWHDPKRLL-UHFFFAOYSA-N UNPD107823 Natural products O1C2COP(O)(=O)OC2C(O)C1N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-UHFFFAOYSA-N 0.000 description 1
- INKDAKMSOSCDGL-UHFFFAOYSA-N [O].OC1=CC=CC=C1 Chemical compound [O].OC1=CC=CC=C1 INKDAKMSOSCDGL-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- GLRAHDCHUZLKKC-UHFFFAOYSA-N acetonitrile;2,2,2-trifluoroacetic acid;hydrate Chemical compound O.CC#N.OC(=O)C(F)(F)F GLRAHDCHUZLKKC-UHFFFAOYSA-N 0.000 description 1
- PTPUOMXKXCCSEN-UHFFFAOYSA-N acetyloxymethyl 2-[2-[2-[5-[3-(acetyloxymethoxy)-2,7-dichloro-6-oxoxanthen-9-yl]-2-[bis[2-(acetyloxymethoxy)-2-oxoethyl]amino]phenoxy]ethoxy]-n-[2-(acetyloxymethoxy)-2-oxoethyl]-4-methylanilino]acetate Chemical compound CC(=O)OCOC(=O)CN(CC(=O)OCOC(C)=O)C1=CC=C(C)C=C1OCCOC1=CC(C2=C3C=C(Cl)C(=O)C=C3OC3=CC(OCOC(C)=O)=C(Cl)C=C32)=CC=C1N(CC(=O)OCOC(C)=O)CC(=O)OCOC(C)=O PTPUOMXKXCCSEN-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000001174 ascending effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000009227 behaviour therapy Methods 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].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 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 1
- 230000009460 calcium influx Effects 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 229940095074 cyclic amp Drugs 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- CLUOCCWZZAGLPM-UHFFFAOYSA-N diphenyl-sulfanyl-sulfanylidene-$l^{5}-phosphane Chemical compound C=1C=CC=CC=1P(=S)(S)C1=CC=CC=C1 CLUOCCWZZAGLPM-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 1
- JWYSLVLBKXDZCW-PHDIDXHHSA-N ethyl (1r,2r)-2-methylcyclopropane-1-carboxylate Chemical compound CCOC(=O)[C@@H]1C[C@H]1C JWYSLVLBKXDZCW-PHDIDXHHSA-N 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 230000002461 excitatory amino acid Effects 0.000 description 1
- 239000003257 excitatory amino acid Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 229960004279 formaldehyde Drugs 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-L glutamate group Chemical group N[C@@H](CCC(=O)[O-])C(=O)[O-] WHUUTDBJXJRKMK-VKHMYHEASA-L 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000012750 in vivo screening Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 230000001057 ionotropic effect Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000004501 isothiazol-5-yl group Chemical group S1N=CC=C1* 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 238000002514 liquid chromatography mass spectrum Methods 0.000 description 1
- CETVQRFGPOGIQJ-UHFFFAOYSA-N lithium;hexane Chemical compound [Li+].CCCCC[CH2-] CETVQRFGPOGIQJ-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000004682 monohydrates Chemical group 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000007243 oxidative cyclization reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 230000008058 pain sensation Effects 0.000 description 1
- 230000037040 pain threshold Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 150000003109 potassium Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000003518 presynaptic effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000013014 purified material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 230000003238 somatosensory effect Effects 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- VXKWYPOMXBVZSJ-UHFFFAOYSA-N tetramethyltin Chemical compound C[Sn](C)(C)C VXKWYPOMXBVZSJ-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000006478 transmetalation reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
- C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
-
- 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
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Rheumatology (AREA)
- Epidemiology (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US81183906P | 2006-06-08 | 2006-06-08 | |
| US60/811,839 | 2006-06-08 | ||
| PCT/US2007/070572 WO2008103185A2 (en) | 2006-06-08 | 2007-06-07 | Substituted carboxamides as group i metabotropic receptor antagonists |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2009539874A JP2009539874A (ja) | 2009-11-19 |
| JP2009539874A5 JP2009539874A5 (enExample) | 2010-07-01 |
| JP5108878B2 true JP5108878B2 (ja) | 2012-12-26 |
Family
ID=39673278
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2009514523A Expired - Fee Related JP5108878B2 (ja) | 2006-06-08 | 2007-06-07 | 置換型カルボキサミド |
Country Status (30)
| Country | Link |
|---|---|
| US (1) | US7960419B2 (enExample) |
| EP (1) | EP2076502B1 (enExample) |
| JP (1) | JP5108878B2 (enExample) |
| KR (1) | KR101051559B1 (enExample) |
| CN (1) | CN101466691B (enExample) |
| AT (1) | ATE509921T1 (enExample) |
| AU (1) | AU2007347428B2 (enExample) |
| BR (1) | BRPI0712862A2 (enExample) |
| CA (1) | CA2652074C (enExample) |
| CR (1) | CR10410A (enExample) |
| CY (1) | CY1111588T1 (enExample) |
| DK (1) | DK2076502T3 (enExample) |
| EA (1) | EA014233B1 (enExample) |
| EC (1) | ECSP088939A (enExample) |
| ES (1) | ES2362949T3 (enExample) |
| HR (1) | HRP20110436T1 (enExample) |
| IL (1) | IL195632A (enExample) |
| MA (1) | MA30620B1 (enExample) |
| MX (1) | MX2008015485A (enExample) |
| MY (1) | MY148084A (enExample) |
| NO (1) | NO341474B1 (enExample) |
| NZ (1) | NZ573352A (enExample) |
| PL (1) | PL2076502T3 (enExample) |
| PT (1) | PT2076502E (enExample) |
| RS (1) | RS51818B (enExample) |
| SI (1) | SI2076502T1 (enExample) |
| TN (1) | TNSN08506A1 (enExample) |
| UA (1) | UA95480C2 (enExample) |
| WO (1) | WO2008103185A2 (enExample) |
| ZA (1) | ZA200809111B (enExample) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0804685D0 (en) | 2008-03-13 | 2008-04-16 | Univ Edinburgh | Therapeutic compounds and their use |
| JO2775B1 (en) | 2008-04-04 | 2014-03-15 | ايلي ليلي اند كومباني | 3-indazolil 4-pyridyl isothiazole |
| US20120095046A1 (en) * | 2009-06-15 | 2012-04-19 | The University Of Edinburgh | Amido-Isothiazole Compounds and Their Use as Inhibitors of 11Beta-HSD1 for the Treatment of Metabolic Syndrome and Related Disorders |
| ES2540547T3 (es) | 2009-09-16 | 2015-07-10 | The University Of Edinburgh | Compuestos de (4-fenil-piperidin-1-il)-[5-(1H-pirazol-4-il)-tiofen-3-il]-metanona y su uso |
| ES2543692T3 (es) | 2010-04-29 | 2015-08-21 | The University Of Edinburgh | (8-aza-biciclo[3.2.1biciclo[oct-8-il)-[5-(1H-pirazol-4-il)-tiofeno-3-il]-metanonas 3,3-disustituidas como inhibidores de 11beta-HSD1 |
| ES2641469T3 (es) | 2012-11-13 | 2017-11-10 | Nissan Chemical Industries, Ltd. | Compuesto de 2-piridona |
| KR20190053242A (ko) | 2016-09-23 | 2019-05-17 | 바이엘 악티엔게젤샤프트 | N3-시클릭 치환된 티에노우라실 및 그의 용도 |
| CN117567266B (zh) * | 2023-11-07 | 2024-06-14 | 康龙化成手性医药技术(宁波)有限公司 | 一种制备2-甲基环丙羧酸的方法 |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL72091A0 (en) * | 1983-06-20 | 1984-10-31 | Lilly Co Eli | N'-substituted(3-aryl 5-isothiazolyl)urea derivatives |
| DE4328425A1 (de) * | 1993-08-24 | 1995-03-02 | Basf Ag | Acylamino-substituierte Isoxazol- bzw. Isothiazolderivate, Verfahren zu deren Herstellung und ihre Verwendung |
| DK124393D0 (da) * | 1993-11-03 | 1993-11-03 | Lundbeck & Co As H | Compounds |
| DE19542372A1 (de) * | 1995-11-14 | 1997-05-15 | Bayer Ag | Acylierte 5-Aminoisothiazole |
| UA60365C2 (uk) * | 1998-06-04 | 2003-10-15 | Пфайзер Продактс Інк. | Похідні ізотіазолу, спосіб їх одержання, фармацевтична композиція та спосіб лікування гіперпроліферативного захворювання у ссавця |
| JP3411262B2 (ja) * | 1999-08-20 | 2003-05-26 | 萬有製薬株式会社 | 新規スピロ化合物 |
| AU2002342607B2 (en) * | 2001-08-06 | 2006-10-19 | Pharmacia Italia S.P.A. | Aminoisoxazole derivatives active as kinase inhibitors |
| EP1667983A4 (en) * | 2003-09-23 | 2010-07-21 | Merck Sharp & Dohme | PYRAZOL MODULATORS OF METABOTROPIC GLUTAMATE RECEPTORS |
| CN1984899B (zh) * | 2004-05-12 | 2011-07-27 | 先灵公司 | Cxcr1和cxcr2趋化因子拮抗剂 |
| EP1794156A2 (en) * | 2004-09-23 | 2007-06-13 | Pfizer Products Incorporated | Trombopoietin receptor agonists |
-
2007
- 2007-06-07 UA UAA200813907A patent/UA95480C2/uk unknown
- 2007-06-07 CN CN2007800211890A patent/CN101466691B/zh not_active Expired - Fee Related
- 2007-06-07 JP JP2009514523A patent/JP5108878B2/ja not_active Expired - Fee Related
- 2007-06-07 AU AU2007347428A patent/AU2007347428B2/en not_active Ceased
- 2007-06-07 HR HR20110436T patent/HRP20110436T1/hr unknown
- 2007-06-07 MY MYPI20084973A patent/MY148084A/en unknown
- 2007-06-07 KR KR1020087029772A patent/KR101051559B1/ko not_active Expired - Fee Related
- 2007-06-07 PL PL07873705T patent/PL2076502T3/pl unknown
- 2007-06-07 BR BRPI0712862-2A patent/BRPI0712862A2/pt not_active IP Right Cessation
- 2007-06-07 ES ES07873705T patent/ES2362949T3/es active Active
- 2007-06-07 EP EP07873705A patent/EP2076502B1/en active Active
- 2007-06-07 AT AT07873705T patent/ATE509921T1/de active
- 2007-06-07 EA EA200870516A patent/EA014233B1/ru not_active IP Right Cessation
- 2007-06-07 SI SI200730695T patent/SI2076502T1/sl unknown
- 2007-06-07 WO PCT/US2007/070572 patent/WO2008103185A2/en not_active Ceased
- 2007-06-07 PT PT07873705T patent/PT2076502E/pt unknown
- 2007-06-07 DK DK07873705.3T patent/DK2076502T3/da active
- 2007-06-07 MX MX2008015485A patent/MX2008015485A/es active IP Right Grant
- 2007-06-07 CA CA2652074A patent/CA2652074C/en not_active Expired - Fee Related
- 2007-06-07 RS RS20110336A patent/RS51818B/sr unknown
- 2007-06-07 US US12/300,415 patent/US7960419B2/en active Active
- 2007-06-07 NZ NZ573352A patent/NZ573352A/en not_active IP Right Cessation
- 2007-10-29 CR CR10410A patent/CR10410A/es unknown
-
2008
- 2008-10-23 ZA ZA200809111A patent/ZA200809111B/xx unknown
- 2008-12-01 IL IL195632A patent/IL195632A/en not_active IP Right Cessation
- 2008-12-02 NO NO20085028A patent/NO341474B1/no not_active IP Right Cessation
- 2008-12-03 EC EC2008008939A patent/ECSP088939A/es unknown
- 2008-12-05 TN TNP2008000506A patent/TNSN08506A1/en unknown
-
2009
- 2009-01-06 MA MA31553A patent/MA30620B1/fr unknown
-
2011
- 2011-06-24 CY CY20111100600T patent/CY1111588T1/el unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5108878B2 (ja) | 置換型カルボキサミド | |
| EP2330894B1 (en) | Compositions including 6-aminohexanoic acid derivatives as hdac inhibitors | |
| JP7434278B2 (ja) | ラニフィブラノールの重水素化誘導体 | |
| KR101198057B1 (ko) | 신규한 ｎ-(2-아미노-페닐)-아미드 유도체 | |
| KR102764121B1 (ko) | 항-염증제, 면역조절제 및 항-증식제로서의 신규한 칼슘 염 다형체 | |
| US5843988A (en) | Cyclopropachromencarboxylic acid derivatives | |
| US20130109672A1 (en) | Activators of human pyruvate kinase | |
| WO2010118354A1 (en) | Substituted di-arylhydantoin and di-arylthiohydantoin compounds and methods for use thereof | |
| HUE034362T2 (en) | N-prop-2-ynyl carboxamide derivatives and their use as trpa1 antagonists | |
| JP2016507544A (ja) | Ｅｐ４受容体に対する活性を伴う置換ベンズアミド | |
| CA2683653A1 (en) | Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof | |
| JP2016516716A (ja) | Ｈｄａｃ阻害剤 | |
| US20160229848A1 (en) | Benzazepine Ketone Compounds as Glycogen Phosphorylase Inhibitor, Preparation Method therefor, and Medical Uses | |
| CN101309909B (zh) | 作为钙和/或钠通道调节剂的2-苯基乙基氨基衍生物 | |
| JP7142406B2 (ja) | インドリジン誘導体及びその医学的応用 | |
| CN108623537B (zh) | 含胺基侧链的芳香胺类乙酰胆碱酯酶抑制剂合成与用途 | |
| KR100187952B1 (ko) | 알콕시페닐알킬아민 유도체 | |
| JPH06329535A (ja) | シグマ受容体拮抗薬 | |
| HK1131984B (en) | Substituted carboxamides as group i metabotropic receptor antagonists | |
| RU2155748C2 (ru) | Производные циклогексадиена, смесь их изомеров или отдельные изомеры и их соли и фармацевтическая композиция с избирательным модулирующим действием на зависимые от кальция калиевые канальцы высокой проводимости | |
| HK40110761B (en) | Therapeutic uses of deuterated derivatives of lanifibranor | |
| HK40110761A (en) | Therapeutic uses of deuterated derivatives of lanifibranor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20100513 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20100513 |
|
| TRDD | Decision of grant or rejection written | ||
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20120918 |
|
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20120925 |
|
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20121005 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 5108878 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20151012 Year of fee payment: 3 |
|
| 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 |
|
| LAPS | Cancellation because of no payment of annual fees |