TW201542543A - 用於治療脊髓性肌肉萎縮症之化合物 - Google Patents
用於治療脊髓性肌肉萎縮症之化合物 Download PDFInfo
- Publication number
- TW201542543A TW201542543A TW103121679A TW103121679A TW201542543A TW 201542543 A TW201542543 A TW 201542543A TW 103121679 A TW103121679 A TW 103121679A TW 103121679 A TW103121679 A TW 103121679A TW 201542543 A TW201542543 A TW 201542543A
- Authority
- TW
- Taiwan
- Prior art keywords
- fluoro
- pyridin
- methylimidazo
- compound
- benzamide
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 232
- 208000002320 spinal muscular atrophy Diseases 0.000 title claims description 92
- 150000003839 salts Chemical class 0.000 claims abstract description 48
- 239000003814 drug Substances 0.000 claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 claims abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- -1 imidazo[1,2-a]pyrazin-2-yl Chemical group 0.000 claims description 145
- 150000001408 amides Chemical class 0.000 claims description 118
- 239000001257 hydrogen Substances 0.000 claims description 57
- 229910052739 hydrogen Inorganic materials 0.000 claims description 57
- 238000000034 method Methods 0.000 claims description 48
- 238000002360 preparation method Methods 0.000 claims description 45
- 125000005843 halogen group Chemical group 0.000 claims description 35
- 125000000217 alkyl group Chemical group 0.000 claims description 34
- 150000002431 hydrogen Chemical class 0.000 claims description 33
- 229910052757 nitrogen Inorganic materials 0.000 claims description 31
- 238000011282 treatment Methods 0.000 claims description 27
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 25
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
- 125000001188 haloalkyl group Chemical group 0.000 claims description 22
- 125000001153 fluoro group Chemical group F* 0.000 claims description 21
- 125000003545 alkoxy group Chemical group 0.000 claims description 20
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 239000002585 base Substances 0.000 claims description 17
- 230000002265 prevention Effects 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 13
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 13
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
- 125000004429 atom Chemical group 0.000 claims description 11
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- 125000002619 bicyclic group Chemical group 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 235000005152 nicotinamide Nutrition 0.000 claims description 9
- 239000011570 nicotinamide Substances 0.000 claims description 9
- 229960003966 nicotinamide Drugs 0.000 claims description 9
- 229960002715 nicotine Drugs 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 229920006395 saturated elastomer Polymers 0.000 claims description 9
- 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 125000002950 monocyclic group Chemical group 0.000 claims description 8
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 claims description 8
- IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 claims description 7
- 125000006242 amine protecting group Chemical group 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 5
- YJLUPSHULWHEFR-UHFFFAOYSA-N 2,6-difluoro-n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide Chemical compound C1CNC(C)CN1C(C=C1F)=CC(F)=C1C(=O)NC1=CN2C=C(C)N=C2C(F)=C1 YJLUPSHULWHEFR-UHFFFAOYSA-N 0.000 claims description 5
- WXDSFKVEUQARAL-UHFFFAOYSA-N 2-fluoro-n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide Chemical compound C1=C(F)C2=NC(C)=CN2C=C1NC(=O)C(C(=C1)F)=CC=C1C1=CCNCC1 WXDSFKVEUQARAL-UHFFFAOYSA-N 0.000 claims description 5
- BEEFXPXLOVUQJM-LBPRGKRZSA-N 2-fluoro-n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-[(3s)-3-methylpiperazin-1-yl]benzamide Chemical compound C1CN[C@@H](C)CN1C(C=C1F)=CC=C1C(=O)NC1=CN2C=C(C)N=C2C(F)=C1 BEEFXPXLOVUQJM-LBPRGKRZSA-N 0.000 claims description 5
- KKIJUDRQFQKRMV-UHFFFAOYSA-N 6-(3,4-dimethylpiperazin-1-yl)-n-(2-methylimidazo[1,2-a]pyridin-6-yl)pyridine-3-carboxamide Chemical compound C1CN(C)C(C)CN1C1=CC=C(C(=O)NC2=CN3C=C(C)N=C3C=C2)C=N1 KKIJUDRQFQKRMV-UHFFFAOYSA-N 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- QUJOVOYZKLBJOP-UHFFFAOYSA-N n-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-4-(3-methylpiperazin-1-yl)benzamide Chemical compound C1CNC(C)CN1C1=CC=C(C(=O)NC=2C=C3OC(C)=NC3=C(F)C=2)C=C1 QUJOVOYZKLBJOP-UHFFFAOYSA-N 0.000 claims description 5
- QNMLZXPESKFTCH-UHFFFAOYSA-N n-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-4-piperazin-1-ylbenzamide Chemical compound C1=C2OC(C)=NC2=C(F)C=C1NC(=O)C(C=C1)=CC=C1N1CCNCC1 QNMLZXPESKFTCH-UHFFFAOYSA-N 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims description 4
- ONYFYCFGMPJTJH-UHFFFAOYSA-N 2-ethoxy-n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-piperazin-1-ylpyridine-3-carboxamide Chemical compound C=1C=C(C(=O)NC2=CN3C=C(C)N=C3C(F)=C2)C(OCC)=NC=1N1CCNCC1 ONYFYCFGMPJTJH-UHFFFAOYSA-N 0.000 claims description 4
- CDFYPSURDFQWHV-UHFFFAOYSA-N 2-fluoro-n-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide Chemical compound C1CNC(C)CN1C(C=C1F)=CC=C1C(=O)NC1=CN2C=C(C)N=C2C=C1 CDFYPSURDFQWHV-UHFFFAOYSA-N 0.000 claims description 4
- VGQGGSXEFWCYFA-UHFFFAOYSA-N 2-fluoro-n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-piperazin-1-ylbenzamide Chemical compound C1=C(F)C2=NC(C)=CN2C=C1NC(=O)C(C(=C1)F)=CC=C1N1CCNCC1 VGQGGSXEFWCYFA-UHFFFAOYSA-N 0.000 claims description 4
- FYDXFOSDKWKKCU-UHFFFAOYSA-N 4-(3,5-dimethylpiperazin-1-yl)-n-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)benzamide Chemical compound C1C(C)NC(C)CN1C1=CC=C(C(=O)NC=2C=C3OC(C)=NC3=C(F)C=2)C=C1 FYDXFOSDKWKKCU-UHFFFAOYSA-N 0.000 claims description 4
- 239000013543 active substance Substances 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- ZKLAQRFKZCJHJW-UHFFFAOYSA-N n-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide Chemical compound C1CNC(C)CN1C(C=C1F)=CC=C1C(=O)NC1=CN(C=C(C)N=C2C)C2=N1 ZKLAQRFKZCJHJW-UHFFFAOYSA-N 0.000 claims description 4
- YTYYMBZTLZDAMO-UHFFFAOYSA-N n-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-(3-methylpiperazin-1-yl)benzamide Chemical compound C1CNC(C)CN1C1=CC=C(C(=O)NC=2N=C3C(C)=NC(C)=CN3C=2)C=C1 YTYYMBZTLZDAMO-UHFFFAOYSA-N 0.000 claims description 4
- RKDSASAFBWZLDW-UHFFFAOYSA-N n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-methyl-6-piperazin-1-ylpyridine-3-carboxamide Chemical compound C1=C(F)C2=NC(C)=CN2C=C1NC(=O)C(C=C1C)=CN=C1N1CCNCC1 RKDSASAFBWZLDW-UHFFFAOYSA-N 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 claims description 4
- 125000003652 trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims description 4
- HFOKVKNPEMHSJN-UHFFFAOYSA-N 2,5-difluoro-n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide Chemical compound C1CNC(C)CN1C1=CC(F)=C(C(=O)NC2=CN3C=C(C)N=C3C(F)=C2)C=C1F HFOKVKNPEMHSJN-UHFFFAOYSA-N 0.000 claims description 3
- RPMHUCKFZNXWHV-UHFFFAOYSA-N 2-fluoro-n-(2-methyl-1,3-benzoxazol-6-yl)-4-(3-methylpiperazin-1-yl)benzamide Chemical compound C1CNC(C)CN1C(C=C1F)=CC=C1C(=O)NC1=CC=C(N=C(C)O2)C2=C1 RPMHUCKFZNXWHV-UHFFFAOYSA-N 0.000 claims description 3
- BEEFXPXLOVUQJM-UHFFFAOYSA-N 2-fluoro-n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide Chemical compound C1CNC(C)CN1C(C=C1F)=CC=C1C(=O)NC1=CN2C=C(C)N=C2C(F)=C1 BEEFXPXLOVUQJM-UHFFFAOYSA-N 0.000 claims description 3
- STIYQLJDPISHDQ-UHFFFAOYSA-N 2-fluoro-n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-piperidin-4-ylbenzamide Chemical compound C1=C(F)C2=NC(C)=CN2C=C1NC(=O)C(C(=C1)F)=CC=C1C1CCNCC1 STIYQLJDPISHDQ-UHFFFAOYSA-N 0.000 claims description 3
- OARKCOYNBVFPCR-UHFFFAOYSA-N 4-fluoro-n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-piperazin-1-ylpyridine-3-carboxamide Chemical compound C1=C(F)C2=NC(C)=CN2C=C1NC(=O)C(C(=C1)F)=CN=C1N1CCNCC1 OARKCOYNBVFPCR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 3
- LMAVPIIJOYURAF-UHFFFAOYSA-N benzene guanidine Chemical compound NC(=N)N.C1=CC=CC=C1.C1=CC=CC=C1 LMAVPIIJOYURAF-UHFFFAOYSA-N 0.000 claims description 3
- 125000005605 benzo group Chemical group 0.000 claims description 3
- XRUFCZNZLGDUTC-UHFFFAOYSA-N n-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-2,6-difluoro-4-(3-methylpiperazin-1-yl)benzamide Chemical compound C1CNC(C)CN1C(C=C1F)=CC(F)=C1C(=O)NC1=CN2C=C(C)N=C2C(Cl)=C1 XRUFCZNZLGDUTC-UHFFFAOYSA-N 0.000 claims description 3
- BHDBXXZOKWKFSQ-UHFFFAOYSA-N n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-methoxy-6-piperazin-1-ylpyridine-3-carboxamide Chemical compound N=1C=C(C(=O)NC2=CN3C=C(C)N=C3C(F)=C2)C(OC)=CC=1N1CCNCC1 BHDBXXZOKWKFSQ-UHFFFAOYSA-N 0.000 claims description 3
- GBESJSDFWIKMFD-UHFFFAOYSA-N n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-piperazin-1-ylpyridine-3-carboxamide Chemical compound C1=C(F)C2=NC(C)=CN2C=C1NC(=O)C(C=N1)=CC=C1N1CCNCC1 GBESJSDFWIKMFD-UHFFFAOYSA-N 0.000 claims description 3
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
- 125000005943 1,2,3,6-tetrahydropyridyl group Chemical group 0.000 claims description 2
- UVDCWTFXXKSREY-UHFFFAOYSA-N 2-fluoro-n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-piperazin-1-ylpyridine-3-carboxamide Chemical compound C1=C(F)C2=NC(C)=CN2C=C1NC(=O)C(C(=N1)F)=CC=C1N1CCNCC1 UVDCWTFXXKSREY-UHFFFAOYSA-N 0.000 claims description 2
- LZPWAYBEOJRFAX-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1,3,2$l^{2}-dioxaborolane Chemical group CC1(C)O[B]OC1(C)C LZPWAYBEOJRFAX-UHFFFAOYSA-N 0.000 claims description 2
- ZMPLZLGTBIDFOX-KRWDZBQOSA-N 4-[(8as)-3,4,6,7,8,8a-hexahydro-1h-pyrrolo[1,2-a]pyrazin-2-yl]-2-fluoro-n-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]benzamide Chemical compound C1CN2CCC[C@H]2CN1C(C=C1F)=CC=C1C(=O)NC1=CN2C=C(C)N=C2C(C(F)(F)F)=C1 ZMPLZLGTBIDFOX-KRWDZBQOSA-N 0.000 claims description 2
- BFPGTMZIXCKHHF-UHFFFAOYSA-N 4-ethoxy-n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-piperazin-1-ylpyridine-3-carboxamide Chemical compound N=1C=C(C(=O)NC2=CN3C=C(C)N=C3C(F)=C2)C(OCC)=CC=1N1CCNCC1 BFPGTMZIXCKHHF-UHFFFAOYSA-N 0.000 claims description 2
- XEDWNPCVJMUMGH-UHFFFAOYSA-N 5-fluoro-n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)pyridine-3-carboxamide Chemical compound C1CNC(C)CN1C1=NC=C(C(=O)NC2=CN3C=C(C)N=C3C(F)=C2)C=C1F XEDWNPCVJMUMGH-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 claims description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-O Imidazolium Chemical compound C1=C[NH+]=CN1 RAXXELZNTBOGNW-UHFFFAOYSA-O 0.000 claims description 2
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 claims description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 2
- 238000007112 amidation reaction Methods 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Chemical group 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims description 2
- 230000008878 coupling Effects 0.000 claims description 2
- 238000010168 coupling process Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 239000003446 ligand Substances 0.000 claims description 2
- YDWAWZDNPJFPGN-UHFFFAOYSA-N n-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-fluoro-4-(4-methylpiperazin-1-yl)benzamide Chemical compound C1CN(C)CCN1C(C=C1F)=CC=C1C(=O)NC1=CN(C=C(C)N=C2C)C2=N1 YDWAWZDNPJFPGN-UHFFFAOYSA-N 0.000 claims description 2
- PIXNAEMAWWVCJF-UHFFFAOYSA-N n-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-piperazin-1-ylbenzamide Chemical compound N1=C2C(C)=NC(C)=CN2C=C1NC(=O)C(C=C1)=CC=C1N1CCNCC1 PIXNAEMAWWVCJF-UHFFFAOYSA-N 0.000 claims description 2
- SYUXCXOGZKDFGD-UHFFFAOYSA-N n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-piperazin-1-ylbenzamide Chemical compound C1=C(F)C2=NC(C)=CN2C=C1NC(=O)C(C=C1)=CC=C1N1CCNCC1 SYUXCXOGZKDFGD-UHFFFAOYSA-N 0.000 claims description 2
- WDGNYBSYPUWDTA-UHFFFAOYSA-N n-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-6-piperazin-1-ylpyridine-3-carboxamide Chemical compound C1=C(C(F)(F)F)C2=NC(C)=CN2C=C1NC(=O)C(C=N1)=CC=C1N1CCNCC1 WDGNYBSYPUWDTA-UHFFFAOYSA-N 0.000 claims description 2
- 235000001968 nicotinic acid Nutrition 0.000 claims description 2
- 239000011664 nicotinic acid Substances 0.000 claims description 2
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 claims description 2
- 150000003512 tertiary amines Chemical class 0.000 claims description 2
- YKYIFUROKBDHCY-ONEGZZNKSA-N (e)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one Chemical group CCO\C=C\C(=O)C(F)(F)F YKYIFUROKBDHCY-ONEGZZNKSA-N 0.000 claims 1
- 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 claims 1
- OCHQWZXDTMGOLV-UHFFFAOYSA-N 2-pyrazin-2-ylbenzamide Chemical compound NC(=O)C1=CC=CC=C1C1=CN=CC=N1 OCHQWZXDTMGOLV-UHFFFAOYSA-N 0.000 claims 1
- OUSHEUFKULRBIA-UHFFFAOYSA-N 6-(3,5-dimethylpiperazin-1-yl)-n-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)pyridine-3-carboxamide Chemical compound C1C(C)NC(C)CN1C1=CC=C(C(=O)NC=2C=C3OC(C)=NC3=C(F)C=2)C=N1 OUSHEUFKULRBIA-UHFFFAOYSA-N 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical group 0.000 claims 1
- KBDRCBZOMWOGER-UHFFFAOYSA-N n-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(4-methylpiperazin-1-yl)pyridine-3-carboxamide Chemical compound C1CN(C)CCN1C1=CC=C(C(=O)NC=2N=C3C(C)=NC(C)=CN3C=2)C=N1 KBDRCBZOMWOGER-UHFFFAOYSA-N 0.000 claims 1
- 125000004430 oxygen atom Chemical group O* 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 185
- 235000019439 ethyl acetate Nutrition 0.000 description 83
- 102100021947 Survival motor neuron protein Human genes 0.000 description 82
- 239000000203 mixture Substances 0.000 description 45
- 239000000243 solution Substances 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 101000617738 Homo sapiens Survival motor neuron protein Proteins 0.000 description 37
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- 108020004999 messenger RNA Proteins 0.000 description 30
- 238000003786 synthesis reaction Methods 0.000 description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- 230000015572 biosynthetic process Effects 0.000 description 26
- 101150081851 SMN1 gene Proteins 0.000 description 25
- 108090000623 proteins and genes Proteins 0.000 description 23
- 239000011541 reaction mixture Substances 0.000 description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 201000010099 disease Diseases 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 17
- 238000012360 testing method Methods 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 239000002253 acid Substances 0.000 description 16
- 125000001424 substituent group Chemical group 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 14
- 239000000523 sample Substances 0.000 description 14
- 239000000725 suspension Substances 0.000 description 14
- 208000024891 symptom Diseases 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 230000006870 function Effects 0.000 description 13
- 230000035772 mutation Effects 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- 101150015954 SMN2 gene Proteins 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 238000003818 flash chromatography Methods 0.000 description 11
- 239000010410 layer Substances 0.000 description 11
- 125000006413 ring segment Chemical group 0.000 description 11
- 229910052938 sodium sulfate Inorganic materials 0.000 description 11
- 235000011152 sodium sulphate Nutrition 0.000 description 11
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 10
- 239000002773 nucleotide Substances 0.000 description 10
- 125000003729 nucleotide group Chemical group 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- 210000002161 motor neuron Anatomy 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 238000012217 deletion Methods 0.000 description 8
- 230000037430 deletion Effects 0.000 description 8
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 8
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 8
- 239000003981 vehicle Substances 0.000 description 8
- JOMNTHCQHJPVAZ-UHFFFAOYSA-N 2-methylpiperazine Chemical compound CC1CNCCN1 JOMNTHCQHJPVAZ-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 230000007812 deficiency Effects 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 230000002779 inactivation Effects 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 239000010779 crude oil Substances 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 230000014509 gene expression Effects 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000003381 stabilizer Substances 0.000 description 6
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 5
- 208000010428 Muscle Weakness Diseases 0.000 description 5
- 206010028372 Muscular weakness Diseases 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 229910052763 palladium Inorganic materials 0.000 description 5
- 230000002441 reversible effect Effects 0.000 description 5
- 229910052717 sulfur Inorganic materials 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- YSPXWEDKEUHKNX-SFHVURJKSA-N 4-[(8as)-3,4,6,7,8,8a-hexahydro-1h-pyrrolo[1,2-a]pyrazin-2-yl]-2-fluoro-n-(2-methylimidazo[1,2-a]pyridin-6-yl)benzamide Chemical compound C1CN2CCC[C@H]2CN1C(C=C1F)=CC=C1C(=O)NC1=CN2C=C(C)N=C2C=C1 YSPXWEDKEUHKNX-SFHVURJKSA-N 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 210000000349 chromosome Anatomy 0.000 description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 150000002430 hydrocarbons Chemical group 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- DLILIUSWDLJMCE-UHFFFAOYSA-N methyl 4-bromo-2-fluorobenzoate Chemical compound COC(=O)C1=CC=C(Br)C=C1F DLILIUSWDLJMCE-UHFFFAOYSA-N 0.000 description 4
- 210000003205 muscle Anatomy 0.000 description 4
- 230000004770 neurodegeneration Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- TVSSATKGQVGHAW-UHFFFAOYSA-N 2,3-difluoro-n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide Chemical compound C1CNC(C)CN1C(C(=C1F)F)=CC=C1C(=O)NC1=CN2C=C(C)N=C2C(F)=C1 TVSSATKGQVGHAW-UHFFFAOYSA-N 0.000 description 3
- DQACBNCZMGSGSC-UHFFFAOYSA-N 2-fluoro-n-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide Chemical compound C1=CC2=NC(C)=CN2C=C1NC(=O)C(C(=C1)F)=CC=C1C1=CCNCC1 DQACBNCZMGSGSC-UHFFFAOYSA-N 0.000 description 3
- LMBQTUOSZJXFRB-UHFFFAOYSA-N 2-fluoro-n-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-piperazin-1-ylbenzamide Chemical compound C1=CC2=NC(C)=CN2C=C1NC(=O)C(C(=C1)F)=CC=C1N1CCNCC1 LMBQTUOSZJXFRB-UHFFFAOYSA-N 0.000 description 3
- BEEFXPXLOVUQJM-GFCCVEGCSA-N 2-fluoro-n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-[(3r)-3-methylpiperazin-1-yl]benzamide Chemical compound C1CN[C@H](C)CN1C(C=C1F)=CC=C1C(=O)NC1=CN2C=C(C)N=C2C(F)=C1 BEEFXPXLOVUQJM-GFCCVEGCSA-N 0.000 description 3
- DALGKDKNTBRGJC-MRXNPFEDSA-N 4-[(8ar)-3,4,6,7,8,8a-hexahydro-1h-pyrrolo[1,2-a]pyrazin-2-yl]-2-fluoro-n-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)benzamide Chemical compound C1CN2CCC[C@@H]2CN1C(C=C1F)=CC=C1C(=O)NC1=CC(F)=C2N=C(C)OC2=C1 DALGKDKNTBRGJC-MRXNPFEDSA-N 0.000 description 3
- ARRIUUTVEGHTPL-UHFFFAOYSA-N 6,8-dimethylimidazo[1,2-a]pyrazin-2-amine trihydrochloride Chemical compound Cl.Cl.Cl.Cc1cn2cc(N)nc2c(C)n1 ARRIUUTVEGHTPL-UHFFFAOYSA-N 0.000 description 3
- SPQKFZPMRYIWMX-UHFFFAOYSA-N Cl.Cc1cn2cc(N)cc(F)c2n1 Chemical compound Cl.Cc1cn2cc(N)cc(F)c2n1 SPQKFZPMRYIWMX-UHFFFAOYSA-N 0.000 description 3
- UJVZYWOFLYFUEY-UHFFFAOYSA-N Cl.Cc1cn2cc(N)cc(c2n1)C(F)(F)F Chemical compound Cl.Cc1cn2cc(N)cc(c2n1)C(F)(F)F UJVZYWOFLYFUEY-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- ISRRHMHXDZATDJ-NSHDSACASA-N FC1=C(C(=O)O)C=CC(=C1)N1C[C@H]2N(CC1)CCC2 Chemical compound FC1=C(C(=O)O)C=CC(=C1)N1C[C@H]2N(CC1)CCC2 ISRRHMHXDZATDJ-NSHDSACASA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 206010057190 Respiratory tract infections Diseases 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 210000004748 cultured cell Anatomy 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000007659 motor function Effects 0.000 description 3
- 238000010172 mouse model Methods 0.000 description 3
- PPAJLPPPZFCQSD-UHFFFAOYSA-N n-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide Chemical compound C1CNC(C)CN1C(C=C1F)=CC=C1C(=O)NC(C(=C1)C)=CN2C1=NC(C)=C2 PPAJLPPPZFCQSD-UHFFFAOYSA-N 0.000 description 3
- YTYYMBZTLZDAMO-ZDUSSCGKSA-N n-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-[(3s)-3-methylpiperazin-1-yl]benzamide Chemical compound C1CN[C@@H](C)CN1C1=CC=C(C(=O)NC=2N=C3C(C)=NC(C)=CN3C=2)C=C1 YTYYMBZTLZDAMO-ZDUSSCGKSA-N 0.000 description 3
- OLFWQPDYWBDNQG-UHFFFAOYSA-N n-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(4-ethylpiperazin-1-yl)pyridine-3-carboxamide Chemical compound C1CN(CC)CCN1C1=CC=C(C(=O)NC=2N=C3C(C)=NC(C)=CN3C=2)C=N1 OLFWQPDYWBDNQG-UHFFFAOYSA-N 0.000 description 3
- RQHFSKWVTQJVKJ-UHFFFAOYSA-N n-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)pyridine-3-carboxamide Chemical compound C1CNC(C)CN1C1=CC=C(C(=O)NC2=CN3C=C(C)N=C3C(Cl)=C2)C=N1 RQHFSKWVTQJVKJ-UHFFFAOYSA-N 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000000241 respiratory effect Effects 0.000 description 3
- 230000029058 respiratory gaseous exchange Effects 0.000 description 3
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 230000009747 swallowing Effects 0.000 description 3
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- AEIHRRMIARXQBG-UHFFFAOYSA-N 2-chloro-4-(2,2,2-trifluoroethoxy)pyridine Chemical compound FC(F)(F)COC1=CC=NC(Cl)=C1 AEIHRRMIARXQBG-UHFFFAOYSA-N 0.000 description 2
- PMTPFBWHUOWTNN-UHFFFAOYSA-N 2-chloro-4-methoxypyridine Chemical compound COC1=CC=NC(Cl)=C1 PMTPFBWHUOWTNN-UHFFFAOYSA-N 0.000 description 2
- ZWYDVEGLPZWOPF-UHFFFAOYSA-N 2-fluoro-n-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-4-piperazin-1-ylbenzamide Chemical compound C1=C2OC(C)=NC2=C(F)C=C1NC(=O)C(C(=C1)F)=CC=C1N1CCNCC1 ZWYDVEGLPZWOPF-UHFFFAOYSA-N 0.000 description 2
- DOZCJJMCZAHHMK-UHFFFAOYSA-N 2-fluoro-n-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-4-piperazin-1-ylbenzamide Chemical compound C1=C(C(F)(F)F)C2=NC(C)=CN2C=C1NC(=O)C(C(=C1)F)=CC=C1N1CCNCC1 DOZCJJMCZAHHMK-UHFFFAOYSA-N 0.000 description 2
- QUYZBNHTYCLZLW-UHFFFAOYSA-N 5-bromo-3-(trifluoromethyl)pyridin-2-amine Chemical compound NC1=NC=C(Br)C=C1C(F)(F)F QUYZBNHTYCLZLW-UHFFFAOYSA-N 0.000 description 2
- VXCUGLKQXLPHKI-UHFFFAOYSA-N 5-bromo-3-chloropyridin-2-amine Chemical compound NC1=NC=C(Br)C=C1Cl VXCUGLKQXLPHKI-UHFFFAOYSA-N 0.000 description 2
- QLXASFJHUCKEHU-UHFFFAOYSA-N 5-bromo-3-fluoropyridin-2-amine Chemical compound NC1=NC=C(Br)C=C1F QLXASFJHUCKEHU-UHFFFAOYSA-N 0.000 description 2
- UAWMVMPAYRWUFX-UHFFFAOYSA-N 6-Chloronicotinic acid Chemical compound OC(=O)C1=CC=C(Cl)N=C1 UAWMVMPAYRWUFX-UHFFFAOYSA-N 0.000 description 2
- YRIIBJDQDIQTAG-UHFFFAOYSA-N 6-bromo-4-fluoro-2-methyl-1,3-benzoxazole Chemical compound C1=C(Br)C=C2OC(C)=NC2=C1F YRIIBJDQDIQTAG-UHFFFAOYSA-N 0.000 description 2
- 208000035657 Abasia Diseases 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- GCWYHXDDULFIQW-UHFFFAOYSA-N Br.CCOC(=O)c1cn2cc(C)nc(C)c2n1 Chemical compound Br.CCOC(=O)c1cn2cc(C)nc(C)c2n1 GCWYHXDDULFIQW-UHFFFAOYSA-N 0.000 description 2
- IGXOMDRMQBUEJJ-UHFFFAOYSA-N CC(C)(C)OC(=O)N1CCN(CC1)c1cc(F)c(I)cn1 Chemical compound CC(C)(C)OC(=O)N1CCN(CC1)c1cc(F)c(I)cn1 IGXOMDRMQBUEJJ-UHFFFAOYSA-N 0.000 description 2
- BRVDAGZZEASUMZ-UHFFFAOYSA-N CC(C)(C)OC(=O)N1CCN(CC1)c1cc(F)ccn1 Chemical compound CC(C)(C)OC(=O)N1CCN(CC1)c1cc(F)ccn1 BRVDAGZZEASUMZ-UHFFFAOYSA-N 0.000 description 2
- BPGOIZKYNDXJMK-UHFFFAOYSA-N CC1CN(CCN1C(=O)OC(C)(C)C)c1ccc(C(O)=O)c(F)c1 Chemical compound CC1CN(CCN1C(=O)OC(C)(C)C)c1ccc(C(O)=O)c(F)c1 BPGOIZKYNDXJMK-UHFFFAOYSA-N 0.000 description 2
- CMNUDLPFXACRKJ-UHFFFAOYSA-N COc1nc(ccc1C(O)=O)N1CCN(CC1)C(=O)OC(C)(C)C Chemical compound COc1nc(ccc1C(O)=O)N1CCN(CC1)C(=O)OC(C)(C)C CMNUDLPFXACRKJ-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- XRLUKCWQMWWGNM-UHFFFAOYSA-N Cc1cn2cc(Br)cc(c2n1)C(F)(F)F Chemical compound Cc1cn2cc(Br)cc(c2n1)C(F)(F)F XRLUKCWQMWWGNM-UHFFFAOYSA-N 0.000 description 2
- KRGGJWSDJPQVDF-UHFFFAOYSA-N Cc1cn2cc(NC(=O)c3ccc(F)cc3)nc2c(C)n1 Chemical compound Cc1cn2cc(NC(=O)c3ccc(F)cc3)nc2c(C)n1 KRGGJWSDJPQVDF-UHFFFAOYSA-N 0.000 description 2
- HRSFUSUIYWRCMU-UHFFFAOYSA-N Cc1cn2cc(cc(c2n1)C(F)(F)F)N=C(c1ccccc1)c1ccccc1 Chemical compound Cc1cn2cc(cc(c2n1)C(F)(F)F)N=C(c1ccccc1)c1ccccc1 HRSFUSUIYWRCMU-UHFFFAOYSA-N 0.000 description 2
- MQHHTULMERTHHH-UHFFFAOYSA-N Cl.Cc1cn2cc(nc2c(C)n1)C(O)=O Chemical compound Cl.Cc1cn2cc(nc2c(C)n1)C(O)=O MQHHTULMERTHHH-UHFFFAOYSA-N 0.000 description 2
- FRPFHPLKGQOOLZ-UHFFFAOYSA-N Cl.Cc1nc2c(F)cc(N)cc2o1 Chemical compound Cl.Cc1nc2c(F)cc(N)cc2o1 FRPFHPLKGQOOLZ-UHFFFAOYSA-N 0.000 description 2
- QZTXMHRQBHZCIN-UHFFFAOYSA-N Cl.Cl.C(CCCCCCCCC)N.N1=CC=CC(=C1)C1N(C)CCC1 Chemical compound Cl.Cl.C(CCCCCCCCC)N.N1=CC=CC(=C1)C1N(C)CCC1 QZTXMHRQBHZCIN-UHFFFAOYSA-N 0.000 description 2
- 206010011469 Crying Diseases 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- ILRFEGNRSQTCIW-LBPRGKRZSA-N FC1=C(C(=O)OC)C=CC(=C1)N1C[C@H]2N(CC1)CCC2 Chemical compound FC1=C(C(=O)OC)C=CC(=C1)N1C[C@H]2N(CC1)CCC2 ILRFEGNRSQTCIW-LBPRGKRZSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 102000003964 Histone deacetylase Human genes 0.000 description 2
- 108090000353 Histone deacetylase Proteins 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 206010028289 Muscle atrophy Diseases 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 235000019502 Orange oil Nutrition 0.000 description 2
- 101150003085 Pdcl gene Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 101150113275 Smn gene Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 208000003954 Spinal Muscular Atrophies of Childhood Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 238000012937 correction Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 230000004199 lung function Effects 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- 239000012139 lysis buffer Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000000873 masking effect Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 230000020763 muscle atrophy Effects 0.000 description 2
- 201000000585 muscular atrophy Diseases 0.000 description 2
- RPUUTKDRBOMSQB-UHFFFAOYSA-N n-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide Chemical compound C1CNC(C)CN1C(C=C1F)=CC=C1C(=O)NC1=CN2C=C(C)N=C2C(C)=C1 RPUUTKDRBOMSQB-UHFFFAOYSA-N 0.000 description 2
- ZXPNEDWJSSFQJE-UHFFFAOYSA-N n-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-piperazin-1-ylpyridine-3-carboxamide Chemical compound C1=CC2=NC(C)=CN2C=C1NC(=O)C(C=N1)=CC=C1N1CCNCC1 ZXPNEDWJSSFQJE-UHFFFAOYSA-N 0.000 description 2
- OXMOETOVMNVVOM-UHFFFAOYSA-N n-(4-bromo-2,6-difluorophenyl)acetamide Chemical compound CC(=O)NC1=C(F)C=C(Br)C=C1F OXMOETOVMNVVOM-UHFFFAOYSA-N 0.000 description 2
- NLPPFOABWIWXNS-UHFFFAOYSA-N n-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-6-(4-methylpiperazin-1-yl)pyridine-3-carboxamide Chemical compound C1CN(C)CCN1C1=CC=C(C(=O)NC=2C=C3OC(C)=NC3=C(F)C=2)C=N1 NLPPFOABWIWXNS-UHFFFAOYSA-N 0.000 description 2
- PRBNMVWBWGWHNR-UHFFFAOYSA-N n-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide Chemical compound C1CNC(C)CN1C(C=C1F)=CC=C1C(=O)NC1=CN2C=C(C)N=C2C(Cl)=C1 PRBNMVWBWGWHNR-UHFFFAOYSA-N 0.000 description 2
- RYUGODUJAWWBFU-UHFFFAOYSA-N n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridine-3-carboxamide Chemical compound C1=C(F)C2=NC(C)=CN2C=C1NC(=O)C(C=N1)=CC=C1C1=CCNCC1 RYUGODUJAWWBFU-UHFFFAOYSA-N 0.000 description 2
- PDNBINYXFWGAQJ-UHFFFAOYSA-N n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1-methylpiperidin-4-yl)pyridine-3-carboxamide Chemical compound C1CN(C)CCC1C1=CC=C(C(=O)NC2=CN3C=C(C)N=C3C(F)=C2)C=N1 PDNBINYXFWGAQJ-UHFFFAOYSA-N 0.000 description 2
- WZVHDYFAOYQHBH-UHFFFAOYSA-N n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)pyridine-3-carboxamide Chemical compound C1CNC(C)CN1C1=CC=C(C(=O)NC2=CN3C=C(C)N=C3C(F)=C2)C=N1 WZVHDYFAOYQHBH-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 239000010502 orange oil Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 230000007310 pathophysiology Effects 0.000 description 2
- 229940127557 pharmaceutical product Drugs 0.000 description 2
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 238000003753 real-time PCR Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000003757 reverse transcription PCR Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 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 2
- XTDXZSGSIMLARD-UHFFFAOYSA-N tert-butyl 2h-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC=CC=C1 XTDXZSGSIMLARD-UHFFFAOYSA-N 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 239000012929 tonicity agent Substances 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- MMIWDPMBWOTICQ-RXMQYKEDSA-N (2r)-2-methylpiperazine-1-carboxylic acid Chemical compound C[C@@H]1CNCCN1C(O)=O MMIWDPMBWOTICQ-RXMQYKEDSA-N 0.000 description 1
- MMIWDPMBWOTICQ-YFKPBYRVSA-N (2s)-2-methylpiperazine-1-carboxylic acid Chemical compound C[C@H]1CNCCN1C(O)=O MMIWDPMBWOTICQ-YFKPBYRVSA-N 0.000 description 1
- HAJKHJOABGFIGP-MRVPVSSYSA-N (8ar)-1,2,3,5,6,7,8,8a-octahydroindolizine Chemical compound C1CCCN2CCC[C@H]21 HAJKHJOABGFIGP-MRVPVSSYSA-N 0.000 description 1
- FTTATHOUSOIFOQ-ZETCQYMHSA-N (8as)-1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine Chemical compound C1NCCN2CCC[C@H]21 FTTATHOUSOIFOQ-ZETCQYMHSA-N 0.000 description 1
- 239000001211 (E)-4-phenylbut-3-en-2-one Substances 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 101150084750 1 gene Proteins 0.000 description 1
- RHUYHJGZWVXEHW-UHFFFAOYSA-N 1,1-Dimethyhydrazine Chemical compound CN(C)N RHUYHJGZWVXEHW-UHFFFAOYSA-N 0.000 description 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- ANQSHZQPHXOOPB-UHFFFAOYSA-N 1,2,3-benzothiadiazole 2H-benzotriazole Chemical compound N1N=NC2=C1C=CC=C2.S2N=NC1=C2C=CC=C1 ANQSHZQPHXOOPB-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical class C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- ZTEHOZMYMCEYRM-UHFFFAOYSA-N 1-chlorodecane Chemical class CCCCCCCCCCCl ZTEHOZMYMCEYRM-UHFFFAOYSA-N 0.000 description 1
- ZDZHCHYQNPQSGG-UHFFFAOYSA-N 1-naphthalen-1-ylnaphthalene Chemical group C1=CC=C2C(C=3C4=CC=CC=C4C=CC=3)=CC=CC2=C1 ZDZHCHYQNPQSGG-UHFFFAOYSA-N 0.000 description 1
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- IEVMFAWRTJEFCF-UHFFFAOYSA-N 2,6-difluoropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=C(F)N=C1F IEVMFAWRTJEFCF-UHFFFAOYSA-N 0.000 description 1
- OFHQTZYEMRJMCT-UHFFFAOYSA-N 2-chloro-4-ethoxypyridine Chemical compound CCOC1=CC=NC(Cl)=C1 OFHQTZYEMRJMCT-UHFFFAOYSA-N 0.000 description 1
- FGSAQRJRWCZLOB-UHFFFAOYSA-N 2-chloro-4-fluoropyridine Chemical compound FC1=CC=NC(Cl)=C1 FGSAQRJRWCZLOB-UHFFFAOYSA-N 0.000 description 1
- LIEPVGBDUYKPLC-UHFFFAOYSA-N 2-chloro-4-nitropyridine Chemical compound [O-][N+](=O)C1=CC=NC(Cl)=C1 LIEPVGBDUYKPLC-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- RWEYGBUDAZUPEH-UHFFFAOYSA-N 2-methylimidazo[1,2-a]pyridin-6-amine;hydrobromide Chemical compound Br.C1=C(N)C=CC2=NC(C)=CN21 RWEYGBUDAZUPEH-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- GZZRWBRYYZGTNW-UHFFFAOYSA-N 3,5-dimethylpyrazin-2-amine Chemical compound CC1=CN=C(N)C(C)=N1 GZZRWBRYYZGTNW-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- JOPXYTZNVRZGJB-UHFFFAOYSA-N 4-(3-fluoro-4-methoxycarbonylphenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid Chemical compound FC=1C=C(C=CC1C(=O)OC)C1=CCN(CC1)C(=O)O JOPXYTZNVRZGJB-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ZQQSRVPOAHYHEL-UHFFFAOYSA-M 4-bromo-2-fluorobenzoate Chemical compound [O-]C(=O)C1=CC=C(Br)C=C1F ZQQSRVPOAHYHEL-UHFFFAOYSA-M 0.000 description 1
- NQSPBOCZLLKJEG-UHFFFAOYSA-N 5-[1-[(2-methylpropan-2-yl)oxycarbonyl]-3,6-dihydro-2h-pyridin-4-yl]pyridine-2-carboxylic acid Chemical compound C1N(C(=O)OC(C)(C)C)CCC(C=2C=NC(=CC=2)C(O)=O)=C1 NQSPBOCZLLKJEG-UHFFFAOYSA-N 0.000 description 1
- JTKFIIQGMVKDNZ-UHFFFAOYSA-N 5-fluoropyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(F)C=N1 JTKFIIQGMVKDNZ-UHFFFAOYSA-N 0.000 description 1
- KDALBLYTIRMBDX-UHFFFAOYSA-N 6-(2,6-diazaspiro[3.3]heptan-2-yl)-n-(2-methylimidazo[1,2-a]pyridin-6-yl)pyridine-3-carboxamide Chemical compound C1=CC2=NC(C)=CN2C=C1NC(=O)C(C=N1)=CC=C1N(C1)CC21CNC2 KDALBLYTIRMBDX-UHFFFAOYSA-N 0.000 description 1
- ICCWBBALBHDANM-UHFFFAOYSA-N 6-(3,3-dimethylpiperazin-1-yl)-n-(2-methylimidazo[1,2-a]pyridin-6-yl)pyridine-3-carboxamide Chemical compound C1=CC2=NC(C)=CN2C=C1NC(=O)C(C=N1)=CC=C1N1CCNC(C)(C)C1 ICCWBBALBHDANM-UHFFFAOYSA-N 0.000 description 1
- KNHQMKOYHWRBCO-UHFFFAOYSA-N 6-(3-methylpiperazin-1-yl)-n-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]pyridine-3-carboxamide Chemical compound C1CNC(C)CN1C1=CC=C(C(=O)NC2=CN3C=C(C)N=C3C(=C2)C(F)(F)F)C=N1 KNHQMKOYHWRBCO-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 108091093088 Amplicon Proteins 0.000 description 1
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- ZYCDVJAXUHSPGD-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCN(CC1)C1=NC=C(C(=O)O)C(=C1)OC Chemical compound C(C)(C)(C)OC(=O)N1CCN(CC1)C1=NC=C(C(=O)O)C(=C1)OC ZYCDVJAXUHSPGD-UHFFFAOYSA-N 0.000 description 1
- YQPKWKHTSCDVAY-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCN(CC1)C1=NC=C(C(=O)O)C(=C1)OCC Chemical compound C(C)(C)(C)OC(=O)N1CCN(CC1)C1=NC=C(C(=O)O)C(=C1)OCC YQPKWKHTSCDVAY-UHFFFAOYSA-N 0.000 description 1
- USXGFPWAWRLVHV-UHFFFAOYSA-N C(C)[S+](CC)CC.[Na+] Chemical compound C(C)[S+](CC)CC.[Na+] USXGFPWAWRLVHV-UHFFFAOYSA-N 0.000 description 1
- WDRNCZFWROPPSH-UHFFFAOYSA-N C(CCCCCCCCC)N.N1=CC=CC(=C1)C1N(C)CCC1 Chemical compound C(CCCCCCCCC)N.N1=CC=CC(=C1)C1N(C)CCC1 WDRNCZFWROPPSH-UHFFFAOYSA-N 0.000 description 1
- KAKOSLAMBFDEJJ-UHFFFAOYSA-N CC(C)(C)OC(=O)N1CCC(=CC1)c1ccc(C(O)=O)c(F)c1 Chemical compound CC(C)(C)OC(=O)N1CCC(=CC1)c1ccc(C(O)=O)c(F)c1 KAKOSLAMBFDEJJ-UHFFFAOYSA-N 0.000 description 1
- XWDRLPHSQUFTDJ-UHFFFAOYSA-N CC(C)(C)OC(=O)N1CCC(=CC1)c1ccc(cn1)C(O)=O Chemical compound CC(C)(C)OC(=O)N1CCC(=CC1)c1ccc(cn1)C(O)=O XWDRLPHSQUFTDJ-UHFFFAOYSA-N 0.000 description 1
- ZSXLBPHAAGNZSK-UHFFFAOYSA-N CC(C)(C)OC(=O)N1CCN(CC1)c1cc(F)c(cn1)C(O)=O Chemical compound CC(C)(C)OC(=O)N1CCN(CC1)c1cc(F)c(cn1)C(O)=O ZSXLBPHAAGNZSK-UHFFFAOYSA-N 0.000 description 1
- GMYSZZBSYJZRQK-UHFFFAOYSA-N CC(C)(C)OC(=O)N1CCN(CC1)c1cc(OCC(F)(F)F)c(cn1)C(O)=O Chemical compound CC(C)(C)OC(=O)N1CCN(CC1)c1cc(OCC(F)(F)F)c(cn1)C(O)=O GMYSZZBSYJZRQK-UHFFFAOYSA-N 0.000 description 1
- RDMAXPDDDMFFMD-UHFFFAOYSA-N CC(C)(C)OC(=O)N1CCN(CC1)c1ccc(C(O)=O)c(F)n1 Chemical compound CC(C)(C)OC(=O)N1CCN(CC1)c1ccc(C(O)=O)c(F)n1 RDMAXPDDDMFFMD-UHFFFAOYSA-N 0.000 description 1
- OCIKBVMZKHJBLH-UHFFFAOYSA-N CC(C)(C)OC(=O)N1CCN(CC1)c1ccc(C(O)=O)c(OCC(F)(F)F)n1 Chemical compound CC(C)(C)OC(=O)N1CCN(CC1)c1ccc(C(O)=O)c(OCC(F)(F)F)n1 OCIKBVMZKHJBLH-UHFFFAOYSA-N 0.000 description 1
- LSUYOXGXTYWMGP-UHFFFAOYSA-N CC1CN(CCN1)c1ccc(cn1)C(=O)Nc1cc(F)c2nc(C)oc2c1 Chemical compound CC1CN(CCN1)c1ccc(cn1)C(=O)Nc1cc(F)c2nc(C)oc2c1 LSUYOXGXTYWMGP-UHFFFAOYSA-N 0.000 description 1
- OUWWIYGNBQWFST-UHFFFAOYSA-N CC1CN(CCN1C(=O)OC(C)(C)C)c1cc(F)c(C(O)=O)c(F)c1 Chemical compound CC1CN(CCN1C(=O)OC(C)(C)C)c1cc(F)c(C(O)=O)c(F)c1 OUWWIYGNBQWFST-UHFFFAOYSA-N 0.000 description 1
- KJHPKBFDHLQMSO-UHFFFAOYSA-N CC1CN(CCN1C(=O)OC(C)(C)C)c1cc(F)c(cc1F)C(O)=O Chemical compound CC1CN(CCN1C(=O)OC(C)(C)C)c1cc(F)c(cc1F)C(O)=O KJHPKBFDHLQMSO-UHFFFAOYSA-N 0.000 description 1
- RXJUMKRKFQJUAW-UHFFFAOYSA-N CC1CN(CCN1C(=O)OC(C)(C)C)c1ccc(C(O)=O)c(F)c1F Chemical compound CC1CN(CCN1C(=O)OC(C)(C)C)c1ccc(C(O)=O)c(F)c1F RXJUMKRKFQJUAW-UHFFFAOYSA-N 0.000 description 1
- NYADMRVWNZQLKH-UHFFFAOYSA-N CC1CN(CCN1C(=O)OC(C)(C)C)c1cnc(C(O)=O)c(F)c1 Chemical compound CC1CN(CCN1C(=O)OC(C)(C)C)c1cnc(C(O)=O)c(F)c1 NYADMRVWNZQLKH-UHFFFAOYSA-N 0.000 description 1
- MDUSXQWICXUPTO-UHFFFAOYSA-N CC1CN(CCN1C(=O)OC(C)(C)C)c1ncc(cc1F)C(O)=O Chemical compound CC1CN(CCN1C(=O)OC(C)(C)C)c1ncc(cc1F)C(O)=O MDUSXQWICXUPTO-UHFFFAOYSA-N 0.000 description 1
- CHPNOUCHEIGHAJ-UHFFFAOYSA-N CCOC(=O)c1ccc(cc1F)N1CCN(C(C)C1)C(=O)OC(C)(C)C Chemical compound CCOC(=O)c1ccc(cc1F)N1CCN(C(C)C1)C(=O)OC(C)(C)C CHPNOUCHEIGHAJ-UHFFFAOYSA-N 0.000 description 1
- LILIELWUGAKQBW-UHFFFAOYSA-N CCOc1nc(ccc1C(O)=O)N1CCN(CC1)C(=O)OC(C)(C)C Chemical compound CCOc1nc(ccc1C(O)=O)N1CCN(CC1)C(=O)OC(C)(C)C LILIELWUGAKQBW-UHFFFAOYSA-N 0.000 description 1
- UBZKWDSKABLFJO-UHFFFAOYSA-N COC(=O)c1ccc(nc1F)N1CCN(CC1)C(=O)OC(C)(C)C Chemical compound COC(=O)c1ccc(nc1F)N1CCN(CC1)C(=O)OC(C)(C)C UBZKWDSKABLFJO-UHFFFAOYSA-N 0.000 description 1
- BYTXTDCRRMAILC-UHFFFAOYSA-N COc1cc(ncc1C(O)=O)N1CCN(C(C)C1)C(=O)OC(C)(C)C Chemical compound COc1cc(ncc1C(O)=O)N1CCN(C(C)C1)C(=O)OC(C)(C)C BYTXTDCRRMAILC-UHFFFAOYSA-N 0.000 description 1
- ASHJCIRDIITQQB-UHFFFAOYSA-N COc1nc(ccc1C(O)=O)N1CCN(C(=O)OC(C)(C)C)C(C)(C)C1 Chemical compound COc1nc(ccc1C(O)=O)N1CCN(C(=O)OC(C)(C)C)C(C)(C)C1 ASHJCIRDIITQQB-UHFFFAOYSA-N 0.000 description 1
- ARAGGUUONWOFHH-UHFFFAOYSA-N COc1nc(ccc1C(O)=O)N1CCN(C(C)C1)C(=O)OC(C)(C)C Chemical compound COc1nc(ccc1C(O)=O)N1CCN(C(C)C1)C(=O)OC(C)(C)C ARAGGUUONWOFHH-UHFFFAOYSA-N 0.000 description 1
- BPGOIZKYNDXJMK-LLVKDONJSA-N C[C@@H]1CN(CCN1C(=O)OC(C)(C)C)c1ccc(C(O)=O)c(F)c1 Chemical compound C[C@@H]1CN(CCN1C(=O)OC(C)(C)C)c1ccc(C(O)=O)c(F)c1 BPGOIZKYNDXJMK-LLVKDONJSA-N 0.000 description 1
- BPGOIZKYNDXJMK-NSHDSACASA-N C[C@H]1CN(CCN1C(=O)OC(C)(C)C)c1ccc(C(O)=O)c(F)c1 Chemical compound C[C@H]1CN(CCN1C(=O)OC(C)(C)C)c1ccc(C(O)=O)c(F)c1 BPGOIZKYNDXJMK-NSHDSACASA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- LQPKAVFECXTSLT-UHFFFAOYSA-N Cc1cn2cc(NC(=O)c3ccc(nc3)C3CCNCC3)ccc2n1 Chemical compound Cc1cn2cc(NC(=O)c3ccc(nc3)C3CCNCC3)ccc2n1 LQPKAVFECXTSLT-UHFFFAOYSA-N 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- VYBGHSRLPWWYRQ-UHFFFAOYSA-N Cl.CC1CN(CCN1)c1cc(F)c(C(=O)Nc2cc(F)c3nc(C)cn3c2)c(F)c1 Chemical compound Cl.CC1CN(CCN1)c1cc(F)c(C(=O)Nc2cc(F)c3nc(C)cn3c2)c(F)c1 VYBGHSRLPWWYRQ-UHFFFAOYSA-N 0.000 description 1
- XMYWQWRQCOZRHZ-UTONKHPSSA-N Cl.C[C@@H]1CN(CCN1)c1ccc(C(=O)Nc2cc(F)c3nc(C)cn3c2)c(F)c1 Chemical compound Cl.C[C@@H]1CN(CCN1)c1ccc(C(=O)Nc2cc(F)c3nc(C)cn3c2)c(F)c1 XMYWQWRQCOZRHZ-UTONKHPSSA-N 0.000 description 1
- ZKEUHGUANUKJOV-UHFFFAOYSA-N Cl.Cc1cn2cc(N)cc(Cl)c2n1 Chemical compound Cl.Cc1cn2cc(N)cc(Cl)c2n1 ZKEUHGUANUKJOV-UHFFFAOYSA-N 0.000 description 1
- GRENQABYOPDUMS-UHFFFAOYSA-N Cl.Cc1cn2cc(NC(=O)c3ccc(cc3)N3CCNCC3)cc(F)c2n1 Chemical compound Cl.Cc1cn2cc(NC(=O)c3ccc(cc3)N3CCNCC3)cc(F)c2n1 GRENQABYOPDUMS-UHFFFAOYSA-N 0.000 description 1
- ODXSLCUFVJOFEQ-UHFFFAOYSA-N Cl.Cc1cn2cc(NC(=O)c3ccc(cc3F)C3=CCNCC3)ccc2n1 Chemical compound Cl.Cc1cn2cc(NC(=O)c3ccc(cc3F)C3=CCNCC3)ccc2n1 ODXSLCUFVJOFEQ-UHFFFAOYSA-N 0.000 description 1
- IKQYDEIONVCTTD-UHFFFAOYSA-N Cl.Cc1cn2cc(NC(=O)c3ccc(cc3F)C3CCNCC3)cc(F)c2n1 Chemical compound Cl.Cc1cn2cc(NC(=O)c3ccc(cc3F)C3CCNCC3)cc(F)c2n1 IKQYDEIONVCTTD-UHFFFAOYSA-N 0.000 description 1
- ALHJLBHACOVDPG-UHFFFAOYSA-N Cl.Cc1cn2cc(NC(=O)c3ccc(nc3)C3=CCNCC3)ccc2n1 Chemical compound Cl.Cc1cn2cc(NC(=O)c3ccc(nc3)C3=CCNCC3)ccc2n1 ALHJLBHACOVDPG-UHFFFAOYSA-N 0.000 description 1
- QTMLHTVDHWHMQM-UHFFFAOYSA-N ClC1=NC=C(C(=O)NC=2C=C(C=3N(C=2)C=C(N=3)C)C(F)(F)F)C=C1 Chemical compound ClC1=NC=C(C(=O)NC=2C=C(C=3N(C=2)C=C(N=3)C)C(F)(F)F)C=C1 QTMLHTVDHWHMQM-UHFFFAOYSA-N 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- MHZGKXUYDGKKIU-UHFFFAOYSA-N Decylamine Chemical compound CCCCCCCCCCN MHZGKXUYDGKKIU-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- YQYJSBFKSSDGFO-UHFFFAOYSA-N Epihygromycin Natural products OC1C(O)C(C(=O)C)OC1OC(C(=C1)O)=CC=C1C=C(C)C(=O)NC1C(O)C(O)C2OCOC2C1O YQYJSBFKSSDGFO-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- ISRRHMHXDZATDJ-LLVKDONJSA-N FC1=C(C(=O)O)C=CC(=C1)N1C[C@@H]2N(CC1)CCC2 Chemical compound FC1=C(C(=O)O)C=CC(=C1)N1C[C@@H]2N(CC1)CCC2 ISRRHMHXDZATDJ-LLVKDONJSA-N 0.000 description 1
- KDQZFBGQTRKRAK-UHFFFAOYSA-N FC=1C=2N(C=C(C1)NC(C1=C(N=C(C=C1)N1CCCCC1)OC)=O)C=C(N2)C Chemical compound FC=1C=2N(C=C(C1)NC(C1=C(N=C(C=C1)N1CCCCC1)OC)=O)C=C(N2)C KDQZFBGQTRKRAK-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108090000331 Firefly luciferases Proteins 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 101710088172 HTH-type transcriptional regulator RipA Proteins 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- WURCPZDERCBZQX-UHFFFAOYSA-N INC(CCC)N Chemical compound INC(CCC)N WURCPZDERCBZQX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- NMMIHXMBOZYNET-UHFFFAOYSA-N Methyl picolinate Chemical compound COC(=O)C1=CC=CC=N1 NMMIHXMBOZYNET-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 208000007379 Muscle Hypotonia Diseases 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000006057 Non-nutritive feed additive Substances 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 208000032225 Proximal spinal muscular atrophy type 1 Diseases 0.000 description 1
- 208000033526 Proximal spinal muscular atrophy type 3 Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 102000004598 Small Nuclear Ribonucleoproteins Human genes 0.000 description 1
- 108010003165 Small Nuclear Ribonucleoproteins Proteins 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000026481 Werdnig-Hoffmann disease Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- XRNLDNHTFMNHKA-UHFFFAOYSA-M [Cl-].C(C)(C)[Mg+].Cl Chemical compound [Cl-].C(C)(C)[Mg+].Cl XRNLDNHTFMNHKA-UHFFFAOYSA-M 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 1
- 229960004176 aclarubicin Drugs 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 229960004977 anhydrous lactose Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
- 210000002226 anterior horn cell Anatomy 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000000712 assembly Effects 0.000 description 1
- 238000000429 assembly Methods 0.000 description 1
- PXWLUICTRPHECG-UHFFFAOYSA-N azane;trihydrochloride Chemical compound N.Cl.Cl.Cl PXWLUICTRPHECG-UHFFFAOYSA-N 0.000 description 1
- 125000003725 azepanyl group Chemical group 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 238000005452 bending Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- SNIABFMMCKVXSY-UHFFFAOYSA-N benzoylazanium;chloride Chemical compound Cl.NC(=O)C1=CC=CC=C1 SNIABFMMCKVXSY-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 229930008407 benzylideneacetone Natural products 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000006727 cell loss Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 239000013553 cell monolayer Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- CETPSERCERDGAM-UHFFFAOYSA-N ceric oxide Chemical compound O=[Ce]=O CETPSERCERDGAM-UHFFFAOYSA-N 0.000 description 1
- 229910000422 cerium(IV) oxide Inorganic materials 0.000 description 1
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 208000018697 congenital contractures Diseases 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- USVZFSNDGFNNJT-UHFFFAOYSA-N cyclopenta-1,4-dien-1-yl(diphenyl)phosphane (2,3-dichlorocyclopenta-1,4-dien-1-yl)-diphenylphosphane iron(2+) Chemical compound [Fe++].c1cc[c-](c1)P(c1ccccc1)c1ccccc1.Clc1c(cc[c-]1Cl)P(c1ccccc1)c1ccccc1 USVZFSNDGFNNJT-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 1
- 150000001983 dialkylethers Chemical class 0.000 description 1
- RAABOESOVLLHRU-UHFFFAOYSA-O diazenium Chemical compound [NH2+]=N RAABOESOVLLHRU-UHFFFAOYSA-O 0.000 description 1
- 125000005959 diazepanyl group Chemical group 0.000 description 1
- BSHICDXRSZQYBP-UHFFFAOYSA-N dichloromethane;palladium(2+) Chemical compound [Pd+2].ClCCl BSHICDXRSZQYBP-UHFFFAOYSA-N 0.000 description 1
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000005050 dihydrooxazolyl group Chemical group O1C(NC=C1)* 0.000 description 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- DXPIZCZNFUTPEI-UHFFFAOYSA-O diphenylphosphanium;azide Chemical compound [N-]=[N+]=[N-].C=1C=CC=CC=1[PH2+]C1=CC=CC=C1 DXPIZCZNFUTPEI-UHFFFAOYSA-O 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000002567 electromyography Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- MLANUBGYWOMWLZ-UHFFFAOYSA-N ethyl 2,3,4-trifluorobenzoate Chemical compound CCOC(=O)C1=CC=C(F)C(F)=C1F MLANUBGYWOMWLZ-UHFFFAOYSA-N 0.000 description 1
- OPQFYGPAOVCNEQ-UHFFFAOYSA-N ethyl 2,4-difluorobenzoate Chemical compound CCOC(=O)C1=CC=C(F)C=C1F OPQFYGPAOVCNEQ-UHFFFAOYSA-N 0.000 description 1
- VICYTAYPKBLQFB-UHFFFAOYSA-N ethyl 3-bromo-2-oxopropanoate Chemical compound CCOC(=O)C(=O)CBr VICYTAYPKBLQFB-UHFFFAOYSA-N 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000030279 gene silencing Effects 0.000 description 1
- 229940121390 gene splicing modulator Drugs 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- ATBKVKDEMSGMTQ-UHFFFAOYSA-N hydrazine triphenylphosphane Chemical compound NN.C1(=CC=CC=C1)P(C1=CC=CC=C1)C1=CC=CC=C1 ATBKVKDEMSGMTQ-UHFFFAOYSA-N 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- PXZQEOJJUGGUIB-UHFFFAOYSA-N isoindolin-1-one Chemical class C1=CC=C2C(=O)NCC2=C1 PXZQEOJJUGGUIB-UHFFFAOYSA-N 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 201000004815 juvenile spinal muscular atrophy Diseases 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- WHJMGBFVYCLTFS-UHFFFAOYSA-N methyl 2,4,5-trifluorobenzoate Chemical compound COC(=O)C1=CC(F)=C(F)C=C1F WHJMGBFVYCLTFS-UHFFFAOYSA-N 0.000 description 1
- FTFGRVXYRDOUJN-UHFFFAOYSA-N methyl 2,6-difluoropyridine-3-carboxylate Chemical compound COC(=O)C1=CC=C(F)N=C1F FTFGRVXYRDOUJN-UHFFFAOYSA-N 0.000 description 1
- IYJHSWYHTRMPJE-UHFFFAOYSA-N methyl 3,5-difluoropyridine-2-carboxylate Chemical compound COC(=O)C1=NC=C(F)C=C1F IYJHSWYHTRMPJE-UHFFFAOYSA-N 0.000 description 1
- LKLUUOBGNQFJQA-UHFFFAOYSA-N methyl 5-[1-[(2-methylpropan-2-yl)oxycarbonyl]-3,6-dihydro-2h-pyridin-4-yl]pyridine-2-carboxylate Chemical compound C1=NC(C(=O)OC)=CC=C1C1=CCN(C(=O)OC(C)(C)C)CC1 LKLUUOBGNQFJQA-UHFFFAOYSA-N 0.000 description 1
- JEURNBCYNWNADN-UHFFFAOYSA-N methyl 5-bromopyridine-2-carboxylate Chemical compound COC(=O)C1=CC=C(Br)C=N1 JEURNBCYNWNADN-UHFFFAOYSA-N 0.000 description 1
- KDMTVIVGDHCOAH-UHFFFAOYSA-N methyl 6-chloro-5-fluoropyridine-3-carboxylate Chemical compound COC(=O)C1=CN=C(Cl)C(F)=C1 KDMTVIVGDHCOAH-UHFFFAOYSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 238000001964 muscle biopsy Methods 0.000 description 1
- PFNADGUGHHKORB-UHFFFAOYSA-N n-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-fluoro-6-(3-methylpiperazin-1-yl)pyridine-3-carboxamide Chemical compound C1CNC(C)CN1C1=NC=C(C(=O)NC2=CN3C=C(C)N=C3C(Cl)=C2)C=C1F PFNADGUGHHKORB-UHFFFAOYSA-N 0.000 description 1
- GNHGIDUPJIFMBG-UHFFFAOYSA-N n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-piperazin-1-ylpyridine-3-carboxamide Chemical compound C=1C=C(C(=O)NC2=CN3C=C(C)N=C3C(F)=C2)C(OC)=NC=1N1CCNCC1 GNHGIDUPJIFMBG-UHFFFAOYSA-N 0.000 description 1
- VJLRSDBVFYMLMW-UHFFFAOYSA-N n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-methyl-4-piperazin-1-ylbenzamide Chemical compound C1=C(F)C2=NC(C)=CN2C=C1NC(=O)C(C=C1C)=CC=C1N1CCNCC1 VJLRSDBVFYMLMW-UHFFFAOYSA-N 0.000 description 1
- GGVPNCKDWACDPB-UHFFFAOYSA-N n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-piperazin-1-yl-2-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide Chemical compound C1=C(F)C2=NC(C)=CN2C=C1NC(=O)C(C(=N1)OCC(F)(F)F)=CC=C1N1CCNCC1 GGVPNCKDWACDPB-UHFFFAOYSA-N 0.000 description 1
- IKACCJUGROOZFB-UHFFFAOYSA-N n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-piperazin-1-yl-4-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide Chemical compound C1=C(F)C2=NC(C)=CN2C=C1NC(=O)C(C(=C1)OCC(F)(F)F)=CN=C1N1CCNCC1 IKACCJUGROOZFB-UHFFFAOYSA-N 0.000 description 1
- IITCZUPNJSGXIM-UHFFFAOYSA-N n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-piperidin-4-ylpyridine-3-carboxamide Chemical compound C1=C(F)C2=NC(C)=CN2C=C1NC(=O)C(C=N1)=CC=C1C1CCNCC1 IITCZUPNJSGXIM-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000032405 negative regulation of neuron apoptotic process Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 239000004090 neuroprotective agent Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- QNTASHOAVRSLMD-FCARAQADSA-N olesoxime Chemical compound C1CC2=C\C(=N/O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 QNTASHOAVRSLMD-FCARAQADSA-N 0.000 description 1
- 229950001051 olesoxime Drugs 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 1
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 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
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 1
- 108091007054 readthrough proteins Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000009291 secondary effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000003319 supportive effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000035900 sweating Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- DVMUNQAGXAMHOR-UHFFFAOYSA-N tert-butyl 2,2-dimethylpiperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1(C)C DVMUNQAGXAMHOR-UHFFFAOYSA-N 0.000 description 1
- DATRVIMZZZVHMP-UHFFFAOYSA-N tert-butyl 2-methylpiperazine-1-carboxylate Chemical compound CC1CNCCN1C(=O)OC(C)(C)C DATRVIMZZZVHMP-UHFFFAOYSA-N 0.000 description 1
- XQEPHVNQECRREI-UHFFFAOYSA-N tert-butyl 4-(3-fluoro-4-methoxycarbonylphenyl)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1=C(F)C(C(=O)OC)=CC=C1C1=CCN(C(=O)OC(C)(C)C)CC1 XQEPHVNQECRREI-UHFFFAOYSA-N 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 125000005942 tetrahydropyridyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 231100000440 toxicity profile Toxicity 0.000 description 1
- BWHOZHOGCMHOBV-BQYQJAHWSA-N trans-benzylideneacetone Chemical compound CC(=O)\C=C\C1=CC=CC=C1 BWHOZHOGCMHOBV-BQYQJAHWSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 108091006106 transcriptional activators Proteins 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000012863 translational readthrough Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- 208000032471 type 1 spinal muscular atrophy Diseases 0.000 description 1
- 208000032527 type III spinal muscular atrophy Diseases 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 235000001892 vitamin D2 Nutrition 0.000 description 1
- 230000036266 weeks of gestation Effects 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
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- 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
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Epidemiology (AREA)
- Psychiatry (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP13173487 | 2013-06-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TW201542543A true TW201542543A (zh) | 2015-11-16 |
Family
ID=48669815
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW103121679A TW201542543A (zh) | 2013-06-25 | 2014-06-24 | 用於治療脊髓性肌肉萎縮症之化合物 |
Country Status (12)
| Country | Link |
|---|---|
| US (2) | US20160145270A1 (enExample) |
| EP (1) | EP3013345B1 (enExample) |
| JP (1) | JP6492071B2 (enExample) |
| KR (1) | KR102314290B1 (enExample) |
| CN (1) | CN105358151B (enExample) |
| AR (1) | AR096684A1 (enExample) |
| BR (1) | BR112015030288B1 (enExample) |
| CA (1) | CA2913785C (enExample) |
| MX (1) | MX363456B (enExample) |
| RU (1) | RU2673542C2 (enExample) |
| TW (1) | TW201542543A (enExample) |
| WO (1) | WO2014209841A2 (enExample) |
Families Citing this family (41)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2915764A1 (en) | 2013-08-19 | 2015-02-26 | F. Hoffmann-La Roche Ag | Screening method |
| GB201410693D0 (en) | 2014-06-16 | 2014-07-30 | Univ Southampton | Splicing modulation |
| MX375925B (es) * | 2014-06-25 | 2025-03-07 | Hoffmann La Roche | Compuestos imidazo[1,2-a]pirazin-1-il-benzamida para tratar atrofia muscular espinal. |
| CN107109411B (zh) | 2014-10-03 | 2022-07-01 | 冷泉港实验室 | 核基因输出的定向增加 |
| WO2016161572A1 (en) * | 2015-04-08 | 2016-10-13 | Merck Sharp & Dohme Corp. | TrkA KINASE INHIBITORS, COMPOSITIONS AND METHODS THEREOF |
| CN108603230A (zh) | 2015-10-09 | 2018-09-28 | 南安普敦大学 | 基因表达的调节与蛋白质表达失调的筛选 |
| AU2016353961B2 (en) | 2015-11-12 | 2019-08-29 | F. Hoffmann-La Roche Ag | Compositions for treating spinal muscular atrophy |
| EP3386978B1 (en) | 2015-12-10 | 2021-01-27 | H. Hoffnabb-La Roche Ag | Bridged piperidine derivatives |
| CA3119019C (en) | 2015-12-10 | 2024-06-11 | Ptc Therapeutics, Inc. | Compounds and methods for treating huntington's disease |
| US11096956B2 (en) | 2015-12-14 | 2021-08-24 | Stoke Therapeutics, Inc. | Antisense oligomers and uses thereof |
| CN116059236A (zh) | 2015-12-14 | 2023-05-05 | 冷泉港实验室 | 用于治疗常染色体显性精神发育迟滞5型和Dravet综合征的反义寡聚体 |
| EP4151627A1 (en) | 2017-06-05 | 2023-03-22 | PTC Therapeutics, Inc. | Compounds for treating huntington's disease |
| CN111182898B (zh) | 2017-06-28 | 2024-04-16 | Ptc医疗公司 | 用于治疗亨廷顿氏病的方法 |
| CN111163838B (zh) | 2017-06-28 | 2023-03-28 | Ptc医疗公司 | 用于治疗亨廷顿氏病的方法 |
| MX2020001425A (es) | 2017-08-04 | 2020-08-06 | Skyhawk Therapeutics Inc | Metodos y composiciones para modular el empalme. |
| KR20260009385A (ko) | 2017-08-25 | 2026-01-19 | 스톡 테라퓨틱스, 인크. | 병태 및 질환 치료용 안티센스 올리고머 |
| LT3700570T (lt) | 2017-10-23 | 2025-04-10 | Stoke Therapeutics, Inc. | Priešprasmiai oligomerai, skirti būklių ir ligų, pagrįstų nonsens kodono nulemta mrnr degradacija, gydymui |
| BR112020019373A2 (pt) | 2018-03-27 | 2020-12-29 | Ptc Therapeutics, Inc. | Compostos para o tratamento da doença de hutington |
| JP2021523227A (ja) | 2018-05-04 | 2021-09-02 | ストーク セラピューティクス，インク． | コレステリルエステル蓄積症の処置のための方法及び組成物 |
| WO2020005882A1 (en) | 2018-06-27 | 2020-01-02 | Ptc Therapeutics, Inc. | Heteroaryl compounds for treating huntington's disease |
| KR20210038845A (ko) | 2018-06-27 | 2021-04-08 | 피티씨 테라퓨틱스, 인크. | 헌팅턴병 치료를 위한 헤테로아릴 화합물 |
| IL279688B2 (en) | 2018-06-27 | 2025-01-01 | Ptc Therapeutics Inc | Heterocyclic and heteroaryl compounds for the treatment of Huntington's disease |
| WO2020004594A1 (ja) | 2018-06-27 | 2020-01-02 | 株式会社リボルナバイオサイエンス | 脊髄性筋萎縮症の予防または治療剤 |
| GEAP202315648A (en) | 2018-11-02 | 2023-07-25 | Merck Sharp & Dohme Llc | 2-amino-n-heteroaryl-nicotinamides as nav1.8 inhibitors |
| JP7576552B2 (ja) * | 2019-01-18 | 2024-10-31 | バイオジェン・エムエイ・インコーポレイテッド | イミダゾ［１，２－ａ］ピリジニル誘導体及び疾患の処置におけるその使用 |
| WO2020163248A1 (en) | 2019-02-04 | 2020-08-13 | Skyhawk Therapeutics, Inc. | Methods and compositions for modulating splicing |
| KR102913697B1 (ko) | 2019-02-05 | 2026-01-15 | 스카이호크 테라퓨틱스, 인코포레이티드 | 스플라이싱을 조절하는 방법 및 조성물 |
| WO2020163541A1 (en) | 2019-02-05 | 2020-08-13 | Skyhawk Therapeutics, Inc. | Methods and compositions for modulating splicing |
| KR102925385B1 (ko) | 2019-02-06 | 2026-02-11 | 스카이호크 테라퓨틱스, 인코포레이티드 | 스플라이싱을 조절하는 방법 및 조성물 |
| JP7603594B2 (ja) | 2019-02-06 | 2024-12-20 | スカイホーク・セラピューティクス・インコーポレーテッド | スプライシングを調節するための方法および組成物 |
| SG11202109213RA (en) * | 2019-02-25 | 2021-09-29 | Beijing Innocare Pharma Tech Co Ltd | Process for preparing 6- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) nicotinamide |
| KR20210134003A (ko) | 2019-02-27 | 2021-11-08 | 스톡 테라퓨틱스, 인크. | 병태 및 질환의 치료를 위한 안티센스 올리고머 |
| CA3139821A1 (en) | 2019-05-13 | 2020-11-19 | Ptc Therapeutics, Inc. | Compounds for treating huntington's disease |
| WO2021007378A1 (en) | 2019-07-11 | 2021-01-14 | Ptc Therapeutics, Inc. | Compounds for use in treating huntington's disease |
| AU2021228284A1 (en) * | 2020-02-28 | 2022-09-29 | Remix Therapeutics Inc. | Compounds and methods for modulating splicing |
| US12338437B2 (en) | 2020-05-11 | 2025-06-24 | Stoke Therapeutics, Inc. | OPA1 antisense oligomers for treatment of conditions and diseases |
| WO2021231571A1 (en) | 2020-05-13 | 2021-11-18 | Chdi Foundation, Inc. | Htt modulators for treating huntington's disease |
| WO2022169230A1 (ko) * | 2021-02-03 | 2022-08-11 | 단국대학교 천안캠퍼스 산학협력단 | 6-메톡시니코틴아미드를 유효성분으로 포함하는 근감소증의 예방 또는 치료용 조성물 |
| AU2022394333A1 (en) | 2021-11-17 | 2024-06-27 | Chdi Foundation, Inc. | HTT modulators for treating Huntington’s disease |
| CN118748995A (zh) * | 2021-12-03 | 2024-10-08 | 亚根达医疗公司 | 5-嘧啶甲酰胺衍生物和其使用方法 |
| WO2023196972A1 (en) * | 2022-04-08 | 2023-10-12 | John Phillip Adams | Improving brain function |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE9801526D0 (sv) * | 1998-04-29 | 1998-04-29 | Astra Ab | New compounds |
| ES2359836T3 (es) * | 2004-04-23 | 2011-05-27 | Bristol-Myers Squibb Company | Heterociclos monociclicos como inhibidores de quinasa. |
| US7666880B2 (en) * | 2005-03-21 | 2010-02-23 | S*Bio Pte Ltd. | Imidazo[1,2-A]pyridine derivatives: preparation and pharmaceutical applications |
| AR056187A1 (es) * | 2005-03-21 | 2007-09-26 | S Bio Pte Ltd | Derivados de imidazo[1,2-a)piridina: preparacion, composiciones farmaceuticas y uso para preparar medicamentos |
| JP2009514859A (ja) * | 2005-11-03 | 2009-04-09 | メルク エンド カムパニー インコーポレーテッド | 置換ニコチンアミド化合物 |
| CA2700841A1 (en) * | 2007-09-27 | 2009-04-02 | The United States Of America, As Represented By The Secretary, Departmen T Of Health And Human Services | Isoindoline compounds for the treatment of spinal muscular atrophy and other uses |
| US8633019B2 (en) * | 2008-05-27 | 2014-01-21 | Ptc Therapeutics, Inc. | Methods for treating spinal muscular atrophy |
| WO2009147190A1 (en) * | 2008-06-05 | 2009-12-10 | Glaxo Group Limited | Novel compounds |
| WO2010019236A1 (en) * | 2008-08-13 | 2010-02-18 | Ptc Therapeutics, Inc | Methods for treating spinal muscular atrophy |
| UY32138A (es) * | 2008-09-25 | 2010-04-30 | Boehringer Ingelheim Int | Amidas sustituidas del ácido 2-(2,6-dicloro-fenilamino)-6-fluoro-1-metil-1h-bencimidazol-5-carboxílico y sus sales farmacéuticamente aceptables |
| WO2012142459A1 (en) * | 2011-04-14 | 2012-10-18 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Isoindoline compounds for the treatment of spinal muscular atrophy and other uses |
-
2014
- 2014-06-23 CA CA2913785A patent/CA2913785C/en active Active
- 2014-06-23 BR BR112015030288-2A patent/BR112015030288B1/pt active IP Right Grant
- 2014-06-23 CN CN201480035676.2A patent/CN105358151B/zh active Active
- 2014-06-23 AR ARP140102349A patent/AR096684A1/es unknown
- 2014-06-23 JP JP2016523822A patent/JP6492071B2/ja active Active
- 2014-06-23 MX MX2015017345A patent/MX363456B/es unknown
- 2014-06-23 US US14/899,397 patent/US20160145270A1/en not_active Abandoned
- 2014-06-23 RU RU2015154676A patent/RU2673542C2/ru active
- 2014-06-23 KR KR1020157036344A patent/KR102314290B1/ko active Active
- 2014-06-23 WO PCT/US2014/043577 patent/WO2014209841A2/en not_active Ceased
- 2014-06-23 EP EP14816651.5A patent/EP3013345B1/en active Active
- 2014-06-24 TW TW103121679A patent/TW201542543A/zh unknown
-
2018
- 2018-04-09 US US15/948,444 patent/US10501482B2/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| EP3013345A4 (en) | 2016-11-30 |
| US20180222925A1 (en) | 2018-08-09 |
| KR102314290B1 (ko) | 2021-10-21 |
| HK1215399A1 (zh) | 2016-08-26 |
| BR112015030288B1 (pt) | 2022-10-18 |
| MX363456B (es) | 2019-03-25 |
| CN105358151A (zh) | 2016-02-24 |
| EP3013345B1 (en) | 2017-11-22 |
| WO2014209841A2 (en) | 2014-12-31 |
| RU2015154676A (ru) | 2017-07-28 |
| AR096684A1 (es) | 2016-01-27 |
| JP2016530231A (ja) | 2016-09-29 |
| US10501482B2 (en) | 2019-12-10 |
| RU2673542C2 (ru) | 2018-11-28 |
| WO2014209841A3 (en) | 2015-10-29 |
| BR112015030288A2 (enExample) | 2017-08-22 |
| KR20160022312A (ko) | 2016-02-29 |
| RU2015154676A3 (enExample) | 2018-03-15 |
| CN105358151B (zh) | 2019-04-12 |
| CA2913785C (en) | 2021-08-31 |
| MX2015017345A (es) | 2016-08-03 |
| EP3013345A2 (en) | 2016-05-04 |
| JP6492071B2 (ja) | 2019-03-27 |
| US20160145270A1 (en) | 2016-05-26 |
| CA2913785A1 (en) | 2014-12-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2673542C2 (ru) | Соединения для лечения спинальной мышечной атрофии | |
| JP6675334B2 (ja) | 脊髄性筋萎縮症を処置するためのイミダゾ［１，２−ａ］ピラジン−１−イルベンズアミド化合物 | |
| US12110292B2 (en) | Ligands to cereblon (CRBN) | |
| JP6236173B2 (ja) | 脊髄性筋萎縮症を処置するための化合物 | |
| JP5094398B2 (ja) | 複素環式誘導体およびステアロイル−ＣｏＡデサチュラーゼのメディエータとしてのそれらの使用 | |
| US20120135997A1 (en) | Pharmaceutical composition comprising a lactam or benzenesulfonamide compound | |
| CN101511819A (zh) | N-(氨基-杂芳基)-1h-吲哚-2-酰胺的衍生物、它们的制备和它们在治疗中的应用 | |
| EA016829B1 (ru) | Производные n-(аминогетероарил)-1h-индол-2-карбоксамидов, их получение и их применение в терапии | |
| TW201920135A (zh) | 吡唑衍生化合物及其用途 | |
| EA013748B1 (ru) | Производные n-(гетероарил)-1-гетероарилалкил-1h-индол-2-карбоксамидов, их получение и их применение в терапии | |
| HK1215399B (en) | Compounds for treating spinal muscular atrophy | |
| CN109071457A (zh) | 吲哚胺2,3-双加氧酶的抑制剂 | |
| TWI313602B (en) | Gyrase inhibitors and uses thereof | |
| CN117777124A (zh) | Parp选择性抑制剂 | |
| HK1230198B (en) | Imidazo[1,2-a]pyrazin-1yl-benzamide compounds for treating spinal muscular atrophy | |
| HK1230198A1 (en) | Imidazo[1,2-a]pyrazin-1yl-benzamide compounds for treating spinal muscular atrophy |