JP6872550B2 - 架橋されたピペリジン誘導体 - Google Patents
架橋されたピペリジン誘導体 Download PDFInfo
- Publication number
- JP6872550B2 JP6872550B2 JP2018529006A JP2018529006A JP6872550B2 JP 6872550 B2 JP6872550 B2 JP 6872550B2 JP 2018529006 A JP2018529006 A JP 2018529006A JP 2018529006 A JP2018529006 A JP 2018529006A JP 6872550 B2 JP6872550 B2 JP 6872550B2
- Authority
- JP
- Japan
- Prior art keywords
- azabicyclo
- octane
- triazolo
- amine
- pyridin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000003053 piperidines Chemical class 0.000 title 1
- -1 3-Methyl-1,2,4-thiadiazol-5-yl Chemical group 0.000 claims description 468
- 150000001875 compounds Chemical class 0.000 claims description 383
- 229910052736 halogen Inorganic materials 0.000 claims description 118
- 150000002367 halogens Chemical class 0.000 claims description 118
- 125000000217 alkyl group Chemical group 0.000 claims description 115
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 65
- 238000000034 method Methods 0.000 claims description 53
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 45
- 239000000203 mixture Substances 0.000 claims description 43
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims description 40
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 claims description 39
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 39
- 150000003839 salts Chemical class 0.000 claims description 37
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 33
- 239000002253 acid Substances 0.000 claims description 32
- 230000008569 process Effects 0.000 claims description 32
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 31
- 239000001257 hydrogen Substances 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- GLAYEAGOETWDPL-UHFFFAOYSA-N 1H-triazolo[1,5-a]pyrazin-2-amine Chemical compound N1N(C=C2N1C=CN=C2)N GLAYEAGOETWDPL-UHFFFAOYSA-N 0.000 claims description 28
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 26
- QGCRJRVFQZXCAZ-UHFFFAOYSA-N 1h-triazolo[1,5-a]pyridin-2-amine Chemical compound C1=CC=CC2=CN(N)NN21 QGCRJRVFQZXCAZ-UHFFFAOYSA-N 0.000 claims description 25
- 125000003342 alkenyl group Chemical group 0.000 claims description 24
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 22
- 230000003287 optical effect Effects 0.000 claims description 22
- 208000024827 Alzheimer disease Diseases 0.000 claims description 19
- 206010012289 Dementia Diseases 0.000 claims description 14
- 150000001412 amines Chemical class 0.000 claims description 13
- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
- XFTQRUTUGRCSGO-UHFFFAOYSA-N pyrazin-2-amine Chemical compound NC1=CN=CC=N1 XFTQRUTUGRCSGO-UHFFFAOYSA-N 0.000 claims description 8
- 208000024667 ABeta amyloidosis, Dutch type Diseases 0.000 claims description 7
- 208000005145 Cerebral amyloid angiopathy Diseases 0.000 claims description 7
- 206010008111 Cerebral haemorrhage Diseases 0.000 claims description 7
- 201000010374 Down Syndrome Diseases 0.000 claims description 7
- 206010008118 cerebral infarction Diseases 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 208000036536 dutch type ABeta amyloidosis Diseases 0.000 claims description 7
- 125000004791 2-fluoroethoxy group Chemical group FCCO* 0.000 claims description 6
- 206010044688 Trisomy 21 Diseases 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- WOTIUKDGJBXFLG-UHFFFAOYSA-N 3-methyl-1,2-thiazole Chemical compound CC=1C=CSN=1 WOTIUKDGJBXFLG-UHFFFAOYSA-N 0.000 claims description 5
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- DBPKMSBWOKAKLA-UHFFFAOYSA-N 4-chloropyrimidine Chemical compound ClC1=CC=NC=N1 DBPKMSBWOKAKLA-UHFFFAOYSA-N 0.000 claims description 2
- KSPDSMOWMQFPBL-UHFFFAOYSA-N 5-fluoropyrimidine Chemical compound FC1=CN=CN=C1 KSPDSMOWMQFPBL-UHFFFAOYSA-N 0.000 claims description 2
- 241001589142 Hetaira Species 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims description 2
- WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 11
- 239000004480 active ingredient Substances 0.000 claims 3
- VZWOXDYRBDIHMA-UHFFFAOYSA-N 2-methyl-1,3-thiazole Chemical compound CC1=NC=CS1 VZWOXDYRBDIHMA-UHFFFAOYSA-N 0.000 claims 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims 1
- PENVYHXKYYCYML-UHFFFAOYSA-N 4-methoxypyrimidine Chemical compound COC1=CC=NC=N1 PENVYHXKYYCYML-UHFFFAOYSA-N 0.000 claims 1
- PSSQTQSLTKVMJL-UHFFFAOYSA-N 5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine Chemical compound C1=CC=C(C(F)(F)F)N2N=C(N)N=C21 PSSQTQSLTKVMJL-UHFFFAOYSA-N 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 claims 1
- 239000000543 intermediate Substances 0.000 description 225
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 214
- 239000007787 solid Substances 0.000 description 198
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 135
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 123
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 118
- 239000011541 reaction mixture Substances 0.000 description 113
- 238000010168 coupling process Methods 0.000 description 106
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 100
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 84
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
- 230000002829 reductive effect Effects 0.000 description 80
- 238000005859 coupling reaction Methods 0.000 description 76
- 230000008878 coupling Effects 0.000 description 73
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 72
- 239000000243 solution Substances 0.000 description 69
- 235000019439 ethyl acetate Nutrition 0.000 description 64
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 51
- 238000006243 chemical reaction Methods 0.000 description 51
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 50
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 46
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
- IOQPZZOEVPZRBK-UHFFFAOYSA-N octan-1-amine Chemical compound CCCCCCCCN IOQPZZOEVPZRBK-UHFFFAOYSA-N 0.000 description 45
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 43
- 239000012044 organic layer Substances 0.000 description 43
- 238000003818 flash chromatography Methods 0.000 description 42
- 239000013058 crude material Substances 0.000 description 39
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 38
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 38
- 239000000741 silica gel Substances 0.000 description 37
- 229910002027 silica gel Inorganic materials 0.000 description 37
- 229910052786 argon Inorganic materials 0.000 description 36
- 239000003921 oil Substances 0.000 description 34
- 235000019198 oils Nutrition 0.000 description 34
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 33
- 239000002904 solvent Substances 0.000 description 33
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 29
- 229920006395 saturated elastomer Polymers 0.000 description 26
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 24
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 23
- 238000002360 preparation method Methods 0.000 description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 21
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 description 20
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 description 20
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 20
- 239000012414 tert-butyl nitrite Substances 0.000 description 20
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 19
- 230000015572 biosynthetic process Effects 0.000 description 19
- ROVTUJRZGCDHDL-UHFFFAOYSA-N tert-butyl 2-ethylheptanoate Chemical compound CCCCCC(CC)C(=O)OC(C)(C)C ROVTUJRZGCDHDL-UHFFFAOYSA-N 0.000 description 19
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 18
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- LNAMMBFJMYMQTO-FNEBRGMMSA-N chloroform;(1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].ClC(Cl)Cl.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 LNAMMBFJMYMQTO-FNEBRGMMSA-N 0.000 description 18
- 239000008346 aqueous phase Substances 0.000 description 17
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 17
- 238000003786 synthesis reaction Methods 0.000 description 17
- PMZURENOXWZQFD-UHFFFAOYSA-L sodium sulphate Substances [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 16
- MGAXYKDBRBNWKT-UHFFFAOYSA-N (5-oxooxolan-2-yl)methyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCC1OC(=O)CC1 MGAXYKDBRBNWKT-UHFFFAOYSA-N 0.000 description 15
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 13
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000460 chlorine Substances 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- BDTDECDAHYOJRO-UHFFFAOYSA-N ethyl n-(sulfanylidenemethylidene)carbamate Chemical compound CCOC(=O)N=C=S BDTDECDAHYOJRO-UHFFFAOYSA-N 0.000 description 11
- GCSKOIZKVFVVCY-UHFFFAOYSA-N 2-bromo-8-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine Chemical compound FC(F)(F)COC1=CC=C(N2N=C(Br)N=C12)C(F)(F)F GCSKOIZKVFVVCY-UHFFFAOYSA-N 0.000 description 10
- SVYZUHSGVZDUDT-UHFFFAOYSA-N FC(F)(F)COC1=CC=CN2N=C(Br)N=C12 Chemical compound FC(F)(F)COC1=CC=CN2N=C(Br)N=C12 SVYZUHSGVZDUDT-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- SMHORIXQSMDYEY-UHFFFAOYSA-N 2-ethylheptanenitrile Chemical compound CCCCCC(CC)C#N SMHORIXQSMDYEY-UHFFFAOYSA-N 0.000 description 8
- HRCKNYWKHBWFJH-UHFFFAOYSA-N 8-bromo-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine Chemical compound NC1=NN2C(=N1)C(Br)=CC=C2C(F)(F)F HRCKNYWKHBWFJH-UHFFFAOYSA-N 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 238000000926 separation method Methods 0.000 description 8
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 8
- 0 CC=CN1N=C(NC(C(CC2)C3)C2CN3c2nnc(C)[o]2)N[C@]1C(O*)=*C=C* Chemical compound CC=CN1N=C(NC(C(CC2)C3)C2CN3c2nnc(C)[o]2)N[C@]1C(O*)=*C=C* 0.000 description 7
- 108010064539 amyloid beta-protein (1-42) Proteins 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 7
- 235000019798 tripotassium phosphate Nutrition 0.000 description 7
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 6
- WFNSSRVVNZGTTR-UHFFFAOYSA-N tert-butyl n-octylcarbamate Chemical compound CCCCCCCCNC(=O)OC(C)(C)C WFNSSRVVNZGTTR-UHFFFAOYSA-N 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 239000007903 gelatin capsule Substances 0.000 description 5
- SGQFQIOHTBBYFS-UHFFFAOYSA-N octylcarbamic acid Chemical compound CCCCCCCCNC(O)=O SGQFQIOHTBBYFS-UHFFFAOYSA-N 0.000 description 5
- 102000004196 processed proteins & peptides Human genes 0.000 description 5
- 238000007363 ring formation reaction Methods 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 235000005074 zinc chloride Nutrition 0.000 description 5
- 239000011592 zinc chloride Substances 0.000 description 5
- YHPDMEBZIOVFAE-UHFFFAOYSA-N 2-bromo-5-(trifluoromethyl)-8-(1,1,1-trifluoropropan-2-yloxy)-[1,2,4]triazolo[1,5-a]pyridine Chemical compound BrC1=NN2C(C(=CC=C2C(F)(F)F)OC(C(F)(F)F)C)=N1 YHPDMEBZIOVFAE-UHFFFAOYSA-N 0.000 description 4
- WFHYFKBQGLFGRQ-UHFFFAOYSA-N 2-bromo-8-(1,1,1-trifluoropropan-2-yloxy)-[1,2,4]triazolo[1,5-a]pyridine Chemical compound CC(Oc1cccn2nc(Br)nc12)C(F)(F)F WFHYFKBQGLFGRQ-UHFFFAOYSA-N 0.000 description 4
- QBPDSKPWYWIHGA-UHFFFAOYSA-N 3-hydroxy-2-nitropyridine Chemical class OC1=CC=CN=C1[N+]([O-])=O QBPDSKPWYWIHGA-UHFFFAOYSA-N 0.000 description 4
- MMERROPKZFZEAL-UHFFFAOYSA-N 5-(trifluoromethyl)-8-(1,1,1-trifluoropropan-2-yloxy)-[1,2,4]triazolo[1,5-a]pyridin-2-amine Chemical compound FC(F)(F)C1=CC=C(C=2N1N=C(N=2)N)OC(C(F)(F)F)C MMERROPKZFZEAL-UHFFFAOYSA-N 0.000 description 4
- KJLKRLDWQPENMK-UHFFFAOYSA-N 5-iodo-3-methyl-1,2-oxazole Chemical compound CC=1C=C(I)ON=1 KJLKRLDWQPENMK-UHFFFAOYSA-N 0.000 description 4
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 4
- AJSRUPTXYSCBFT-UHFFFAOYSA-N 6-bromo-2-nitro-3-(2,2,2-trifluoroethoxy)pyridine Chemical compound BrC1=CC=C(C(=N1)[N+](=O)[O-])OCC(F)(F)F AJSRUPTXYSCBFT-UHFFFAOYSA-N 0.000 description 4
- AENHEFDZKPSDCK-UHFFFAOYSA-N 6-methyl-2-nitro-3-(2,2,2-trifluoroethoxy)pyridine Chemical compound CC1=CC=C(C(=N1)[N+](=O)[O-])OCC(F)(F)F AENHEFDZKPSDCK-UHFFFAOYSA-N 0.000 description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 4
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 4
- 108010050254 Presenilins Proteins 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
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Classifications
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- 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
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- 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
-
- 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
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| EP15199260.9 | 2015-12-10 | ||
| EP15199260 | 2015-12-10 | ||
| PCT/EP2016/079816 WO2017097728A1 (en) | 2015-12-10 | 2016-12-06 | Bridged piperidine derivatives |
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| JP2018536671A JP2018536671A (ja) | 2018-12-13 |
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| PE20180773A1 (es) | 2015-10-02 | 2018-05-07 | Hoffmann La Roche | Anticuerpos biespecificos para pd1 y tim3 |
| CN108697709A (zh) | 2015-12-10 | 2018-10-23 | Ptc医疗公司 | 用于治疗亨廷顿病的方法 |
| EP3475279B1 (en) * | 2016-06-27 | 2021-07-14 | F. Hoffmann-La Roche AG | Triazolopyridines as gamma-secretase modulators |
| AR109829A1 (es) * | 2016-09-29 | 2019-01-30 | Hoffmann La Roche | Derivados de piperidina puenteados |
| AR110001A1 (es) * | 2016-11-01 | 2019-02-13 | Hoffmann La Roche | Derivados heteroarilo bicíclicos |
| PT3606946T (pt) | 2017-04-03 | 2022-10-17 | Hoffmann La Roche | Imunoconjugados de um anticorpo anti-pd-1 com uma il-2 mutante ou com il-15 |
| CN116375876A (zh) | 2017-04-05 | 2023-07-04 | 豪夫迈·罗氏有限公司 | 特异性结合pd1和lag3的双特异性抗体 |
| AU2018282154B2 (en) | 2017-06-05 | 2022-04-07 | 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 |
| WO2019005993A1 (en) | 2017-06-28 | 2019-01-03 | Ptc Therapeutics, Inc. | METHODS OF TREATING HUNTINGTON'S DISEASE |
| BR112020019373A2 (pt) | 2018-03-27 | 2020-12-29 | Ptc Therapeutics, Inc. | Compostos para o tratamento da doença de hutington |
| WO2020005877A1 (en) | 2018-06-27 | 2020-01-02 | Ptc Therapeutics, Inc. | Heteroaryl compounds for treating huntington's disease |
| IL279688B2 (en) | 2018-06-27 | 2025-01-01 | Ptc Therapeutics Inc | Heterocyclic and heteroaryl compounds for the treatment of Huntington's disease |
| HUE064554T2 (hu) | 2018-09-03 | 2024-03-28 | Hoffmann La Roche | Bicikluszos heteroaril származékok |
| PL3894411T3 (pl) | 2018-12-13 | 2024-10-07 | F. Hoffmann-La Roche Ag | Pochodne 7-fenoksy-N-(3-azabicyklo[3.2.1]oktan-8-ylo)-6,7-dihydro-5H-pirolo[1,2-b][1,2,4]triazolo-2-aminy i związki pokrewne jako modulatory gamma-sekretazy do leczenia choroby Alzheimera |
| AU2019412747B8 (en) | 2018-12-27 | 2025-04-24 | F. Hoffmann-La Roche Ag | Process for the preparation exo-tert-butyl N-(3-azabicyclo[3.2.1]octan-8-yl)carbamate |
| CN117396490A (zh) * | 2021-05-14 | 2024-01-12 | Bm医药咨询有限公司 | 用于预防和治疗病毒感染的双环杂环化合物 |
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| GB1383409A (en) | 1972-09-09 | 1974-02-12 | Pfizer Ltd | Derivatives of 2-amino- and 4-amino-quinazoline and pharmaceutical compositions containing them |
| US6774134B2 (en) | 2000-12-20 | 2004-08-10 | Bristol-Myers Squibb Company | Heterocyclic substituted 2-methyl-benzimidazole antiviral agents |
| ES2360222T3 (es) | 2003-12-24 | 2011-06-02 | Biota Scientific Management Pty. Ltd. | Agentes policíclicos para el tratamiento de infecciones respiratorias por virus sincicial. |
| CA2624558C (en) * | 2005-10-06 | 2011-02-22 | Nippon Soda Co., Ltd. | Cross-linked cyclic amine compounds and agents for pest control |
| FR2914188B1 (fr) | 2007-03-28 | 2012-06-22 | Trophos | Nouvelle composition a base d'oxime de cholest-4-en-3-one |
| WO2009151546A2 (en) | 2008-05-27 | 2009-12-17 | Ptc Therapeutics, Inc. | Methods for treating spinal muscular atrophy |
| EP2337609B1 (en) | 2008-08-14 | 2016-08-17 | Cardiac Pacemakers, Inc. | Performance assessment and adaptation of an acoustic communication link |
| US8486967B2 (en) * | 2010-02-17 | 2013-07-16 | Hoffmann-La Roche Inc. | Heteroaryl substituted piperidines |
| US8703763B2 (en) * | 2011-03-02 | 2014-04-22 | Hoffmann-La Roche Inc. | Bridged piperidine derivatives |
| US8871756B2 (en) | 2011-08-11 | 2014-10-28 | Hoffmann-La Roche Inc. | Compounds for the treatment and prophylaxis of Respiratory Syncytial Virus disease |
| GB201119538D0 (en) | 2011-11-10 | 2011-12-21 | Viral Ltd | Pharmaceutical compounds |
| WO2013101974A1 (en) | 2011-12-30 | 2013-07-04 | Ptc Therapeutics, Inc. | Compounds for treating spinal muscular atrophy |
| BR112014018027B1 (pt) | 2012-01-26 | 2020-10-27 | Ptc Therapeutics, Inc | composto, composição farmacêutica e usos dos mesmos e métodos para aumentar a inclusão de éxon 7 de ame2 em rnam que é transcrito a partir do gene ame2 e para aumentar a quantidade de proteína smn |
| EP2812004B1 (en) | 2012-02-10 | 2018-06-27 | PTC Therapeutics, Inc. | Compounds for treating spinal muscular atrophy |
| WO2014012050A2 (en) | 2012-07-13 | 2014-01-16 | Indiana University Research & Technology Corporation | Compounds for treatment of spinal muscular atrophy |
| MX2015015691A (es) | 2013-05-14 | 2016-03-04 | Hoffmann La Roche | Aza-oxo-indoles novedosos para el tratamiento y profilaxis de la infeccion del virus sincital respiratorio. |
| MX363456B (es) | 2013-06-25 | 2019-03-25 | Hoffmann La Roche | Compuestos para tratar atrofia muscular espinal. |
| AR099134A1 (es) | 2014-01-24 | 2016-06-29 | Hoffmann La Roche | Procedimiento para la preparación de n-[(3-aminooxetán-3-il)metil]-2-(1,1-dioxo-3,5-dihidro-1,4-benzotiazepín-4-il)-6-metil-quinazolín-4-amina |
| HRP20230637T1 (hr) | 2014-05-15 | 2023-09-29 | F. Hoffmann - La Roche Ag | Postupak za proizvodnju spojeva korisnih za liječenje spinalne mišićne atrofije |
| KR102162062B1 (ko) | 2015-11-12 | 2020-10-07 | 에프. 호프만-라 로슈 아게 | 척수성 근위축증의 치료용 조성물 |
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2016
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- 2016-12-06 WO PCT/EP2016/079816 patent/WO2017097728A1/en not_active Ceased
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| WO2017097728A1 (en) | 2017-06-15 |
| CN108137579A (zh) | 2018-06-08 |
| EP3386978B1 (en) | 2021-01-27 |
| TW201725209A (zh) | 2017-07-16 |
| EP3386978A1 (en) | 2018-10-17 |
| TWI629278B (zh) | 2018-07-11 |
| US20200291034A1 (en) | 2020-09-17 |
| CN108137579B (zh) | 2022-01-07 |
| US20190010156A1 (en) | 2019-01-10 |
| JP2018536671A (ja) | 2018-12-13 |
| AR107010A1 (es) | 2018-03-14 |
| US10562903B2 (en) | 2020-02-18 |
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