ES2624288T3 - Métodos y compuestos útiles en la síntesis de derivados de aminodihidrotiazina condensados - Google Patents
Métodos y compuestos útiles en la síntesis de derivados de aminodihidrotiazina condensados Download PDFInfo
- Publication number
- ES2624288T3 ES2624288T3 ES12702690.4T ES12702690T ES2624288T3 ES 2624288 T3 ES2624288 T3 ES 2624288T3 ES 12702690 T ES12702690 T ES 12702690T ES 2624288 T3 ES2624288 T3 ES 2624288T3
- Authority
- ES
- Spain
- Prior art keywords
- compound
- mixture
- formula
- jcf
- salt
- 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.)
- Active
Links
- 150000001875 compounds Chemical class 0.000 title claims description 200
- 238000000034 method Methods 0.000 title claims description 47
- 230000015572 biosynthetic process Effects 0.000 title description 12
- 238000003786 synthesis reaction Methods 0.000 title description 11
- 150000003839 salts Chemical group 0.000 claims abstract description 82
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 56
- 239000001257 hydrogen Substances 0.000 claims abstract description 56
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 55
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 45
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 19
- 125000001475 halogen functional group Chemical group 0.000 claims abstract 4
- 239000000203 mixture Substances 0.000 claims description 183
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 123
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 105
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 79
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 75
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 68
- 238000006243 chemical reaction Methods 0.000 claims description 68
- 235000019439 ethyl acetate Nutrition 0.000 claims description 44
- 239000002904 solvent Substances 0.000 claims description 42
- 238000010438 heat treatment Methods 0.000 claims description 16
- 125000001188 haloalkyl group Chemical group 0.000 claims description 15
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 14
- 238000001816 cooling Methods 0.000 claims description 12
- 239000011874 heated mixture Substances 0.000 claims description 12
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 claims description 8
- 238000009835 boiling Methods 0.000 claims description 8
- 125000004122 cyclic group Chemical group 0.000 claims description 7
- 150000008065 acid anhydrides Chemical class 0.000 claims description 5
- 239000012256 powdered iron Substances 0.000 claims description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 4
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 claims description 3
- NTLRGKCNXOJGPY-UHFFFAOYSA-N 2-hydroxy-1,2$l^{5}-oxaphospholane 2-oxide Chemical compound OP1(=O)CCCO1 NTLRGKCNXOJGPY-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims description 3
- NIPZZXUFJPQHNH-UHFFFAOYSA-N pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN=CC=N1 NIPZZXUFJPQHNH-UHFFFAOYSA-N 0.000 claims description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 5
- -1 aminodihydrothiazine compound Chemical class 0.000 abstract description 89
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract description 8
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 123
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 85
- 239000000243 solution Substances 0.000 description 80
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 78
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 74
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 74
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 63
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 60
- 239000011541 reaction mixture Substances 0.000 description 56
- 125000001153 fluoro group Chemical group F* 0.000 description 48
- 230000002829 reductive effect Effects 0.000 description 44
- 239000007787 solid Substances 0.000 description 43
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 41
- 239000000725 suspension Substances 0.000 description 39
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 32
- 239000012074 organic phase Substances 0.000 description 31
- 239000011780 sodium chloride Substances 0.000 description 30
- 239000010410 layer Substances 0.000 description 27
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 26
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 25
- 238000005481 NMR spectroscopy Methods 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 22
- 125000005843 halogen group Chemical group 0.000 description 22
- 238000003756 stirring Methods 0.000 description 22
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 21
- 238000004128 high performance liquid chromatography Methods 0.000 description 21
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 21
- 239000012044 organic layer Substances 0.000 description 20
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 19
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 19
- 239000003921 oil Substances 0.000 description 19
- 235000019198 oils Nutrition 0.000 description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- 239000002253 acid Substances 0.000 description 18
- 235000019270 ammonium chloride Nutrition 0.000 description 17
- 150000002430 hydrocarbons Chemical class 0.000 description 17
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 229910052799 carbon Inorganic materials 0.000 description 15
- 239000002585 base Substances 0.000 description 14
- 235000019253 formic acid Nutrition 0.000 description 14
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 14
- 239000002245 particle Substances 0.000 description 14
- 239000012071 phase Substances 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 13
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 11
- 150000002576 ketones Chemical class 0.000 description 11
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 10
- 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 10
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 10
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 10
- 125000003342 alkenyl group Chemical group 0.000 description 10
- 150000001414 amino alcohols Chemical class 0.000 description 10
- 230000014759 maintenance of location Effects 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 10
- 208000024827 Alzheimer disease Diseases 0.000 description 9
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 9
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 9
- 235000011114 ammonium hydroxide Nutrition 0.000 description 9
- 239000012455 biphasic mixture Substances 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- 239000008096 xylene Substances 0.000 description 9
- 150000003738 xylenes Chemical class 0.000 description 9
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 8
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 8
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 8
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 150000001408 amides Chemical class 0.000 description 8
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 8
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 8
- 239000011521 glass Substances 0.000 description 8
- 229930195733 hydrocarbon Natural products 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 239000011701 zinc Substances 0.000 description 8
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 description 7
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 7
- 239000004215 Carbon black (E152) Substances 0.000 description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 7
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- 239000006260 foam Substances 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 150000002923 oximes Chemical class 0.000 description 7
- 229910052725 zinc Inorganic materials 0.000 description 7
- QUZPSMZNTIBYAS-UHFFFAOYSA-N 4-benzoylperoxy-4-oxobutanoic acid Chemical compound OC(=O)CCC(=O)OOC(=O)C1=CC=CC=C1 QUZPSMZNTIBYAS-UHFFFAOYSA-N 0.000 description 6
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 description 6
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- MUVYPGHGENGYEB-UHFFFAOYSA-N 2-but-3-en-2-yloxy-1-(2-fluorophenyl)ethanone Chemical compound C=CC(C)OCC(=O)C1=CC=CC=C1F MUVYPGHGENGYEB-UHFFFAOYSA-N 0.000 description 5
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- 125000002070 alkenylidene group Chemical group 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 239000000908 ammonium hydroxide Substances 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 239000001632 sodium acetate Substances 0.000 description 5
- 235000017281 sodium acetate Nutrition 0.000 description 5
- YONLFQNRGZXBBF-KBPBESRZSA-N (2s,3s)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@H](C(=O)O)[C@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-KBPBESRZSA-N 0.000 description 4
- QSFBRTJPNFJTEL-UHFFFAOYSA-N 1-(2-fluorophenyl)-2-(1,1,1-trifluorobut-3-en-2-yloxy)ethanone Chemical compound FC1=CC=CC=C1C(=O)COC(C=C)C(F)(F)F QSFBRTJPNFJTEL-UHFFFAOYSA-N 0.000 description 4
- UUFQTNFCRMXOAE-UHFFFAOYSA-N 1-methylmethylene Chemical compound C[CH] UUFQTNFCRMXOAE-UHFFFAOYSA-N 0.000 description 4
- NFIJLKSZVJGZAR-UHFFFAOYSA-N 1-morpholin-4-yl-2-(1-trityloxybut-3-en-2-yloxy)ethanone Chemical compound C1COCCN1C(=O)COC(C=C)COC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 NFIJLKSZVJGZAR-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- NBYZAYREWQTQBQ-UHFFFAOYSA-N 6a-(2,3-difluorophenyl)-4-(trityloxymethyl)-3,3a,4,6-tetrahydro-1h-furo[3,4-c][1,2]oxazole Chemical compound FC1=CC=CC(C23C(C(COC(C=4C=CC=CC=4)(C=4C=CC=CC=4)C=4C=CC=CC=4)OC2)CON3)=C1F NBYZAYREWQTQBQ-UHFFFAOYSA-N 0.000 description 4
- QNUMYBQXKOPVDO-UHFFFAOYSA-N 6a-(2-fluorophenyl)-4-(trifluoromethyl)-3,3a,4,6-tetrahydro-1h-furo[3,4-c][1,2]oxazole Chemical compound FC1=CC=CC=C1C1(NOC2)C2C(C(F)(F)F)OC1 QNUMYBQXKOPVDO-UHFFFAOYSA-N 0.000 description 4
- OZGOZGVIMPODOF-UHFFFAOYSA-N 6a-(2-fluorophenyl)-4-(trityloxymethyl)-3,3a,4,6-tetrahydro-1h-furo[3,4-c][1,2]oxazole Chemical compound FC1=CC=CC=C1C1(NOC2)C2C(COC(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)OC1 OZGOZGVIMPODOF-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- 208000037259 Amyloid Plaque Diseases 0.000 description 4
- 150000004703 alkoxides Chemical class 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 4
- 229910052742 iron Inorganic materials 0.000 description 4
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- MKUWVMRNQOOSAT-UHFFFAOYSA-N methylvinylmethanol Natural products CC(O)C=C MKUWVMRNQOOSAT-UHFFFAOYSA-N 0.000 description 4
- 210000002569 neuron Anatomy 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000013557 residual solvent Substances 0.000 description 4
- 239000011975 tartaric acid Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 4
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- FTESIOUFBCJIDO-ZDSQKVDBSA-N (4as,5r,7as)-7a-(2-fluorophenyl)-5-methyl-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-2-amine Chemical compound C1([C@]23CO[C@@H]([C@H]2CSC(N)=N3)C)=CC=CC=C1F FTESIOUFBCJIDO-ZDSQKVDBSA-N 0.000 description 3
- FICBLPSPSCLFQS-ZDSQKVDBSA-N (4as,5s,7as)-7a-(2,3-difluorophenyl)-5-(fluoromethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-2-amine Chemical compound C1([C@@]23N=C(SC[C@@H]2[C@@H](CF)OC3)N)=CC=CC(F)=C1F FICBLPSPSCLFQS-ZDSQKVDBSA-N 0.000 description 3
- PLJQOSOPRCJZKY-UBHAPETDSA-N (4as,5s,7as)-7a-(2-fluorophenyl)-5-(trifluoromethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-2-amine Chemical compound C1([C@@]23N=C(SC[C@@H]2[C@H](OC3)C(F)(F)F)N)=CC=CC=C1F PLJQOSOPRCJZKY-UBHAPETDSA-N 0.000 description 3
- WEBYXODSWKNFTJ-ZDSQKVDBSA-N (4as,5s,7as)-7a-(5-amino-2,3-difluorophenyl)-5-(fluoromethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-2-amine Chemical compound C1([C@@]23N=C(SC[C@@H]2[C@@H](CF)OC3)N)=CC(N)=CC(F)=C1F WEBYXODSWKNFTJ-ZDSQKVDBSA-N 0.000 description 3
- WIEKKYVLFNLXFU-UBHAPETDSA-N (4as,5s,7as)-7a-(5-amino-2-fluorophenyl)-5-(trifluoromethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-2-amine Chemical compound C1([C@@]23N=C(SC[C@@H]2[C@H](OC3)C(F)(F)F)N)=CC(N)=CC=C1F WIEKKYVLFNLXFU-UBHAPETDSA-N 0.000 description 3
- CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical compound C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 description 3
- KMPSWENWHDZRKD-UHFFFAOYSA-N 1-(2,3-difluorophenyl)-2-(1-trityloxybut-3-en-2-yloxy)ethanone Chemical compound FC1=CC=CC(C(=O)COC(COC(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)C=C)=C1F KMPSWENWHDZRKD-UHFFFAOYSA-N 0.000 description 3
- IPWBFGUBXWMIPR-UHFFFAOYSA-N 1-bromo-2-fluorobenzene Chemical compound FC1=CC=CC=C1Br IPWBFGUBXWMIPR-UHFFFAOYSA-N 0.000 description 3
- YMQRPXBBBOXHNZ-UHFFFAOYSA-N 2-chloro-1-morpholin-4-ylethanone Chemical compound ClCC(=O)N1CCOCC1 YMQRPXBBBOXHNZ-UHFFFAOYSA-N 0.000 description 3
- UYWJPTNAOQSWOS-UHFFFAOYSA-N 5-(difluoromethyl)pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN=C(C(F)F)C=N1 UYWJPTNAOQSWOS-UHFFFAOYSA-N 0.000 description 3
- LUIAHRVSHVHLGV-UHFFFAOYSA-N 6a-(2-fluorophenyl)-4-methyl-3,3a,4,6-tetrahydro-1h-furo[3,4-c][1,2]oxazole Chemical compound N1OCC2C(C)OCC21C1=CC=CC=C1F LUIAHRVSHVHLGV-UHFFFAOYSA-N 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 3
- 125000001118 alkylidene group Chemical group 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 238000010533 azeotropic distillation Methods 0.000 description 3
- 125000005569 butenylene group Chemical group 0.000 description 3
- 238000004296 chiral HPLC Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000007850 degeneration Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- QWRWCEVCXOUGCT-AKCHCHLHSA-N n-[(4as,5s,7as)-7a-(2,3-difluorophenyl)-5-(fluoromethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-2-yl]benzamide Chemical compound N([C@]1(CO[C@@H]([C@H]1CS1)CF)C=2C(=C(F)C=CC=2)F)=C1NC(=O)C1=CC=CC=C1 QWRWCEVCXOUGCT-AKCHCHLHSA-N 0.000 description 3
- ZUFBQBUXRULCIX-GNNMJGRWSA-N n-[[(3s,4r,5s)-3-(2,3-difluorophenyl)-4-(hydroxymethyl)-5-(trityloxymethyl)oxolan-3-yl]carbamothioyl]benzamide Chemical compound C([C@@H]1[C@H]([C@](CO1)(NC(=S)NC(=O)C=1C=CC=CC=1)C=1C(=C(F)C=CC=1)F)CO)OC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 ZUFBQBUXRULCIX-GNNMJGRWSA-N 0.000 description 3
- HEKLDVKMLIDKEJ-UHFFFAOYSA-N n-methoxy-n-methyl-2-(1,1,1-trifluorobut-3-en-2-yloxy)acetamide Chemical compound CON(C)C(=O)COC(C=C)C(F)(F)F HEKLDVKMLIDKEJ-UHFFFAOYSA-N 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 230000000391 smoking effect Effects 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- WMGVPDQNPUQRND-UHFFFAOYSA-N (2-methylphenyl)acetonitrile Chemical compound CC1=CC=CC=C1CC#N WMGVPDQNPUQRND-UHFFFAOYSA-N 0.000 description 2
- ACHVKFKRNFWNQV-XBURVNOZSA-N (4as,5r,7as)-7a-(2-fluoro-5-nitrophenyl)-5-methyl-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-2-amine Chemical compound C1([C@]23CO[C@@H]([C@H]2CSC(N)=N3)C)=CC([N+]([O-])=O)=CC=C1F ACHVKFKRNFWNQV-XBURVNOZSA-N 0.000 description 2
- QTOIROKIMVLYME-XBURVNOZSA-N (4as,5r,7as)-7a-(5-amino-2-fluorophenyl)-5-methyl-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-2-amine Chemical compound C1([C@]23CO[C@@H]([C@H]2CSC(N)=N3)C)=CC(N)=CC=C1F QTOIROKIMVLYME-XBURVNOZSA-N 0.000 description 2
- QRESHFMSFWZCAX-ZDSQKVDBSA-N (4as,5s,7as)-7a-(2,3-difluoro-5-nitrophenyl)-5-(fluoromethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-2-amine Chemical compound C1([C@@]23N=C(SC[C@@H]2[C@@H](CF)OC3)N)=CC([N+]([O-])=O)=CC(F)=C1F QRESHFMSFWZCAX-ZDSQKVDBSA-N 0.000 description 2
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 2
- BXJGLPROAVAGKO-UHFFFAOYSA-N 1-trityloxybut-3-en-2-ol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(OCC(O)C=C)C1=CC=CC=C1 BXJGLPROAVAGKO-UHFFFAOYSA-N 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 2
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 2
- HYAQXXQJUFUJOK-UHFFFAOYSA-N 2-but-3-en-2-yloxy-n-methoxy-n-methylacetamide Chemical compound CON(C)C(=O)COC(C)C=C HYAQXXQJUFUJOK-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- QKFOHTNLZOIEHZ-UHFFFAOYSA-N 2h-1,3-thiazin-2-amine Chemical compound NC1SC=CC=N1 QKFOHTNLZOIEHZ-UHFFFAOYSA-N 0.000 description 2
- YVGVOPNUEFTVQO-UHFFFAOYSA-N 5-methoxypyrazine-2-carboxylic acid Chemical compound COC1=CN=C(C(O)=O)C=N1 YVGVOPNUEFTVQO-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 2
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 2
- 102000009091 Amyloidogenic Proteins Human genes 0.000 description 2
- 108010048112 Amyloidogenic Proteins Proteins 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 description 2
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 2
- 101100167062 Caenorhabditis elegans chch-3 gene Proteins 0.000 description 2
- 101150065749 Churc1 gene Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- 102100038239 Protein Churchill Human genes 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 2
- 238000010936 aqueous wash Methods 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- MDKCFLQDBWCQCV-UHFFFAOYSA-N benzyl isothiocyanate Chemical compound S=C=NCC1=CC=CC=C1 MDKCFLQDBWCQCV-UHFFFAOYSA-N 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000025688 early-onset autosomal dominant Alzheimer disease Diseases 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 208000015756 familial Alzheimer disease Diseases 0.000 description 2
- 229910052736 halogen Chemical group 0.000 description 2
- 150000002367 halogens Chemical group 0.000 description 2
- USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;n-methoxymethanamine;chloride Chemical compound Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 description 2
- 150000004679 hydroxides Chemical class 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 150000002540 isothiocyanates Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- ULWOJODHECIZAU-UHFFFAOYSA-N n,n-diethylpropan-2-amine Chemical compound CCN(CC)C(C)C ULWOJODHECIZAU-UHFFFAOYSA-N 0.000 description 2
- MRRXXRHHUDDQLJ-OWDMVUQNSA-N n-[(4as,5r,7as)-7a-(2-fluorophenyl)-5-methyl-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-2-yl]benzamide Chemical compound N([C@]1(CO[C@@H]([C@H]1CS1)C)C=2C(=CC=CC=2)F)=C1NC(=O)C1=CC=CC=C1 MRRXXRHHUDDQLJ-OWDMVUQNSA-N 0.000 description 2
- XNJUWFWSNYWKQS-GNNMJGRWSA-N n-[(4as,5s,7as)-7a-(2,3-difluorophenyl)-5-(trityloxymethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-2-yl]benzamide Chemical compound FC1=CC=CC([C@@]23[C@@H]([C@@H](COC(C=4C=CC=CC=4)(C=4C=CC=CC=4)C=4C=CC=CC=4)OC2)CSC(NC(=O)C=2C=CC=CC=2)=N3)=C1F XNJUWFWSNYWKQS-GNNMJGRWSA-N 0.000 description 2
- QUNWXOOKFVIZBL-UHFFFAOYSA-N n-[1-(2,3-difluorophenyl)-2-(1-trityloxybut-3-en-2-yloxy)ethylidene]hydroxylamine Chemical compound C=1C=CC(F)=C(F)C=1C(=NO)COC(C=C)COC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 QUNWXOOKFVIZBL-UHFFFAOYSA-N 0.000 description 2
- WUEZEPDJNONFGJ-UHFFFAOYSA-N n-[1-(2-fluorophenyl)-2-(1,1,1-trifluorobut-3-en-2-yloxy)ethylidene]hydroxylamine Chemical compound C=CC(C(F)(F)F)OCC(=NO)C1=CC=CC=C1F WUEZEPDJNONFGJ-UHFFFAOYSA-N 0.000 description 2
- XNGMLIHHABXLLQ-UHFFFAOYSA-N n-[2-but-3-en-2-yloxy-1-(2-fluorophenyl)ethylidene]hydroxylamine Chemical compound C=CC(C)OCC(=NO)C1=CC=CC=C1F XNGMLIHHABXLLQ-UHFFFAOYSA-N 0.000 description 2
- TWNDUYZETRHEJX-FRGNPEFRSA-N n-[3-[(4as,5s,7as)-2-amino-5-(fluoromethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-7a-yl]-4,5-difluorophenyl]-5-methoxypyrazine-2-carboxamide Chemical compound C1=NC(OC)=CN=C1C(=O)NC1=CC(F)=C(F)C([C@@]23[C@@H]([C@@H](CF)OC2)CSC(N)=N3)=C1 TWNDUYZETRHEJX-FRGNPEFRSA-N 0.000 description 2
- FCDKJKUIUSHQDM-OWDMVUQNSA-N n-[[(3s,4r,5r)-3-(2-fluorophenyl)-4-(hydroxymethyl)-5-methyloxolan-3-yl]carbamothioyl]benzamide Chemical compound OC[C@@H]1[C@@H](C)OC[C@]1(C=1C(=CC=CC=1)F)NC(=S)NC(=O)C1=CC=CC=C1 FCDKJKUIUSHQDM-OWDMVUQNSA-N 0.000 description 2
- STGJACGAXIFRQZ-SIXWZSSISA-N n-[[(3s,4r,5s)-3-(2-fluorophenyl)-4-(hydroxymethyl)-5-(trifluoromethyl)oxolan-3-yl]carbamothioyl]benzamide Chemical compound OC[C@@H]1[C@@H](C(F)(F)F)OC[C@]1(C=1C(=CC=CC=1)F)NC(=S)NC(=O)C1=CC=CC=C1 STGJACGAXIFRQZ-SIXWZSSISA-N 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- GNWXVOQHLPBSSR-UHFFFAOYSA-N oxolane;toluene Chemical compound C1CCOC1.CC1=CC=CC=C1 GNWXVOQHLPBSSR-UHFFFAOYSA-N 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- XYKIUTSFQGXHOW-UHFFFAOYSA-N propan-2-one;toluene Chemical compound CC(C)=O.CC1=CC=CC=C1 XYKIUTSFQGXHOW-UHFFFAOYSA-N 0.000 description 2
- 125000006410 propenylene group Chemical group 0.000 description 2
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 239000010453 quartz Substances 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-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
- 150000003512 tertiary amines Chemical class 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- VSGAXYHKARCITI-RBJCUBAZSA-N (4as,5s,7as)-7a-(2-fluoro-5-nitrophenyl)-5-(trifluoromethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-2-amine;hydrochloride Chemical compound Cl.C1([C@@]23N=C(SC[C@@H]2[C@H](OC3)C(F)(F)F)N)=CC([N+]([O-])=O)=CC=C1F VSGAXYHKARCITI-RBJCUBAZSA-N 0.000 description 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 description 1
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 1
- IDFPQEHZYBXIFO-GFCCVEGCSA-N (R)-(4-fluoro-2-propylphenyl)-(1H-imidazol-2-yl)methanol Chemical compound CCCc1cc(F)ccc1[C@@H](O)c1ncc[nH]1 IDFPQEHZYBXIFO-GFCCVEGCSA-N 0.000 description 1
- WNEOCWSLTHNURP-UHFFFAOYSA-N 1,3,3a,4,6,6a-hexahydrofuro[3,4-c][1,2]oxazole Chemical compound N1OCC2COCC21 WNEOCWSLTHNURP-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
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- RKWWASUTWAFKHA-UHFFFAOYSA-N 1-bromo-2,3-difluorobenzene Chemical compound FC1=CC=CC(Br)=C1F RKWWASUTWAFKHA-UHFFFAOYSA-N 0.000 description 1
- LEUCSPLRSIJMKF-UHFFFAOYSA-N 2,3,3a,5,6,6a-hexahydrofuro[2,3-d][1,2]oxazole Chemical class O1NCC2OCCC21 LEUCSPLRSIJMKF-UHFFFAOYSA-N 0.000 description 1
- FQMZXMVHHKXGTM-UHFFFAOYSA-N 2-(1-adamantyl)-n-[2-[2-(2-hydroxyethylamino)ethylamino]quinolin-5-yl]acetamide Chemical compound C1C(C2)CC(C3)CC2CC13CC(=O)NC1=CC=CC2=NC(NCCNCCO)=CC=C21 FQMZXMVHHKXGTM-UHFFFAOYSA-N 0.000 description 1
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- USYBRPZRFIAESY-UHFFFAOYSA-N 2-but-3-en-2-yloxy-1-morpholin-4-ylethanone Chemical compound C=CC(C)OCC(=O)N1CCOCC1 USYBRPZRFIAESY-UHFFFAOYSA-N 0.000 description 1
- ZKQJYEOZKPDAEU-UHFFFAOYSA-N 2-carbamothioylbenzamide Chemical compound NC(=O)C1=CC=CC=C1C(N)=S ZKQJYEOZKPDAEU-UHFFFAOYSA-N 0.000 description 1
- XQDBTULWMUIZKS-UHFFFAOYSA-N 2H-thiazine-3,4-diamine Chemical compound NC1=C(N)C=CSN1 XQDBTULWMUIZKS-UHFFFAOYSA-N 0.000 description 1
- JOPJLJTXWMIJKO-UHFFFAOYSA-N 2h-thiazin-3-amine Chemical compound NC1=CC=CSN1 JOPJLJTXWMIJKO-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- LZYQFKPLSBGGTK-UHFFFAOYSA-N 3-methoxypyrazine-2-carboxamide Chemical compound COC1=NC=CN=C1C(N)=O LZYQFKPLSBGGTK-UHFFFAOYSA-N 0.000 description 1
- QMBVXJHMDYOKSG-UHFFFAOYSA-N 4-nitro-3-phenyl-2H-thiazine Chemical compound N1SC=CC([N+](=O)[O-])=C1C1=CC=CC=C1 QMBVXJHMDYOKSG-UHFFFAOYSA-N 0.000 description 1
- BKUJEHHWQQBLTE-UHFFFAOYSA-N 5-(fluoromethyl)pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN=C(CF)C=N1 BKUJEHHWQQBLTE-UHFFFAOYSA-N 0.000 description 1
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 229940125759 BACE1 protease inhibitor Drugs 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 1
- 101710132601 Capsid protein Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 201000010374 Down Syndrome Diseases 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 102100034004 Gamma-adducin Human genes 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 101000799011 Homo sapiens Gamma-adducin Proteins 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- QAADZYUXQLUXFX-UHFFFAOYSA-N N-phenylmethylthioformamide Natural products S=CNCC1=CC=CC=C1 QAADZYUXQLUXFX-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241001483078 Phyto Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 102000012412 Presenilin-1 Human genes 0.000 description 1
- 108010036933 Presenilin-1 Proteins 0.000 description 1
- 102000012419 Presenilin-2 Human genes 0.000 description 1
- 108010036908 Presenilin-2 Proteins 0.000 description 1
- 102000015499 Presenilins Human genes 0.000 description 1
- 108010050254 Presenilins Proteins 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- FAMVOZPGRWJEJE-HLUHBDAQSA-N [(2r,3r,4s)-4-amino-4-(2-fluorophenyl)-2-methyloxolan-3-yl]methanol Chemical compound OC[C@@H]1[C@@H](C)OC[C@@]1(N)C1=CC=CC=C1F FAMVOZPGRWJEJE-HLUHBDAQSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003941 amyloidogenesis Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-L aspartate group Chemical class N[C@@H](CC(=O)[O-])C(=O)[O-] CKLJMWTZIZZHCS-REOHCLBHSA-L 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 125000004618 benzofuryl 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
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- 239000002439 beta secretase inhibitor Substances 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- KIZFHUJKFSNWKO-UHFFFAOYSA-M calcium monohydroxide Chemical compound [Ca]O KIZFHUJKFSNWKO-UHFFFAOYSA-M 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 230000006999 cognitive decline Effects 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- 230000009699 differential effect Effects 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- UZUODNWWWUQRIR-UHFFFAOYSA-L disodium;3-aminonaphthalene-1,5-disulfonate Chemical compound [Na+].[Na+].C1=CC=C(S([O-])(=O)=O)C2=CC(N)=CC(S([O-])(=O)=O)=C21 UZUODNWWWUQRIR-UHFFFAOYSA-L 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical class CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000003540 gamma secretase inhibitor Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000002306 glutamic acid derivatives Chemical class 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 229960002050 hydrofluoric acid Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- IKGLACJFEHSFNN-UHFFFAOYSA-N hydron;triethylazanium;trifluoride Chemical compound F.F.F.CCN(CC)CC IKGLACJFEHSFNN-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 230000006984 memory degeneration Effects 0.000 description 1
- 208000023060 memory loss Diseases 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
- CCVUGHCTYWFGPJ-UHFFFAOYSA-N methyl 2-acetamido-2-(1,3-benzothiazol-2-ylamino)-3,3,3-trifluoropropanoate Chemical compound C1=CC=C2SC(NC(NC(C)=O)(C(=O)OC)C(F)(F)F)=NC2=C1 CCVUGHCTYWFGPJ-UHFFFAOYSA-N 0.000 description 1
- QAFJIJWLEBLXHH-UHFFFAOYSA-N methyl 2-fluorobenzoate Chemical compound COC(=O)C1=CC=CC=C1F QAFJIJWLEBLXHH-UHFFFAOYSA-N 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- GFVGHIGODGQYRY-AKCHCHLHSA-N n-[(4as,5s,7as)-7a-(2,3-difluorophenyl)-5-(hydroxymethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-2-yl]benzamide Chemical compound N([C@]1(CO[C@@H]([C@H]1CS1)CO)C=2C(=C(F)C=CC=2)F)=C1NC(=O)C1=CC=CC=C1 GFVGHIGODGQYRY-AKCHCHLHSA-N 0.000 description 1
- MTAAMFBCQCSRBX-DJCROIMJSA-N n-[3-[(4as,5s,7as)-2-amino-5-(trifluoromethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide Chemical compound C1=NC(OC)=CN=C1C(=O)NC1=CC=C(F)C([C@@]23[C@@H]([C@H](OC2)C(F)(F)F)CSC(N)=N3)=C1 MTAAMFBCQCSRBX-DJCROIMJSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- LUYQYZLEHLTPBH-UHFFFAOYSA-N perfluorobutanesulfonyl fluoride Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)S(F)(=O)=O LUYQYZLEHLTPBH-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- IKNCGYCHMGNBCP-UHFFFAOYSA-N propan-1-olate Chemical compound CCC[O-] IKNCGYCHMGNBCP-UHFFFAOYSA-N 0.000 description 1
- ATLPLEZDTSBZQG-UHFFFAOYSA-N propan-2-ylphosphonic acid Chemical compound CC(C)P(O)(O)=O ATLPLEZDTSBZQG-UHFFFAOYSA-N 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- WGRULTCAYDOGQK-UHFFFAOYSA-M sodium;sodium;hydroxide Chemical compound [OH-].[Na].[Na+] WGRULTCAYDOGQK-UHFFFAOYSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- KGLLLFAJIAUYMA-UHFFFAOYSA-N tert-butyl 2-but-3-en-2-yloxy-3-(2-fluorophenyl)-3-oxopropanoate Chemical compound C=CC(C)OC(C(=O)OC(C)(C)C)C(=O)C1=CC=CC=C1F KGLLLFAJIAUYMA-UHFFFAOYSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl 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
- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical group C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 125000002827 triflate group Chemical class FC(S(=O)(=O)O*)(F)F 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
Classifications
-
- 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
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/22—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Medicinal Chemistry (AREA)
- Neurology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Furan Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201161434849P | 2011-01-21 | 2011-01-21 | |
| US201161434849P | 2011-01-21 | ||
| PCT/US2012/022053 WO2012100179A1 (en) | 2011-01-21 | 2012-01-20 | Methods and compounds useful in the synthesis of fused aminodihydrothiazine derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2624288T3 true ES2624288T3 (es) | 2017-07-13 |
Family
ID=45563570
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES12702690.4T Active ES2624288T3 (es) | 2011-01-21 | 2012-01-20 | Métodos y compuestos útiles en la síntesis de derivados de aminodihidrotiazina condensados |
Country Status (12)
| Country | Link |
|---|---|
| US (3) | US8426584B2 (OSRAM) |
| EP (1) | EP2665716B1 (OSRAM) |
| JP (2) | JP5993875B2 (OSRAM) |
| CN (2) | CN106632401B (OSRAM) |
| BR (1) | BR112013016241A2 (OSRAM) |
| CA (1) | CA2814014A1 (OSRAM) |
| ES (1) | ES2624288T3 (OSRAM) |
| IL (1) | IL226405A0 (OSRAM) |
| MX (1) | MX2013005115A (OSRAM) |
| RU (1) | RU2013138226A (OSRAM) |
| SG (2) | SG191710A1 (OSRAM) |
| WO (1) | WO2012100179A1 (OSRAM) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100317850A1 (en) | 2008-01-18 | 2010-12-16 | Yuichi Suzuki | Condensed aminodihydrothiazine derivative |
| GB0912777D0 (en) | 2009-07-22 | 2009-08-26 | Eisai London Res Lab Ltd | Fused aminodihydropyrimidone derivatives |
| GB0912778D0 (en) | 2009-07-22 | 2009-08-26 | Eisai London Res Lab Ltd | Fused aminodihydro-oxazine derivatives |
| GB201100181D0 (en) | 2011-01-06 | 2011-02-23 | Eisai Ltd | Fused aminodihydrothiazine derivatives |
| GB201101140D0 (en) | 2011-01-21 | 2011-03-09 | Eisai Ltd | Fused aminodihydrothiazine derivatives |
| GB201101139D0 (en) | 2011-01-21 | 2011-03-09 | Eisai Ltd | Fused aminodihydrothiazine derivatives |
| UY34278A (es) | 2011-08-25 | 2013-04-05 | Novartis Ag | Derivados novedosos de oxazina y su uso en el tratamiento de enfermedades |
| GB201212816D0 (en) * | 2012-07-19 | 2012-09-05 | Eisai Ltd | Novel compounds |
| JO3318B1 (ar) | 2013-06-18 | 2019-03-13 | Lilly Co Eli | مثبطات bace |
| CN107106568B (zh) * | 2014-10-10 | 2023-09-26 | 卫材R&D管理有限公司 | 稠合氨基二氢噻嗪衍生物的药物组合物 |
| AU2017347838B2 (en) | 2016-10-27 | 2023-04-27 | Eisai R&D Management Co., Ltd. | Composition comprising an anti-Αβ protofibril antibody and a beta-secretase BACE1 inhibitor for the treatment of Alzheimer's disease |
| IL280315B2 (en) | 2018-07-24 | 2024-06-01 | Eisai R&D Man Co Ltd | Methods for treating and preventing Alzheimer's disease |
Family Cites Families (35)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3227713A (en) | 1966-01-04 | Azine derivatives | ||
| US3235551A (en) | 1966-02-15 | Novel derivatives of | ||
| JPH0967355A (ja) | 1995-08-31 | 1997-03-11 | Tokyo Tanabe Co Ltd | チアジン誘導体、チアゾール誘導体及びそれらの製造方法 |
| AU2001258771A1 (en) | 2000-05-19 | 2001-11-26 | Takeda Chemical Industries Ltd. | -secretase inhibitors |
| US6562783B2 (en) | 2001-05-30 | 2003-05-13 | Neurologic, Inc. | Phosphinylmethyl and phosphorylmethyl succinic and glutauric acid analogs as β-secretase inhibitors |
| WO2004014843A1 (ja) | 2002-08-09 | 2004-02-19 | Takeda Chemical Industries, Ltd. | 置換アミノ化合物およびその用途 |
| WO2004037212A2 (en) | 2002-10-24 | 2004-05-06 | Sepracor, Inc. | Compositions comprising zopiclone derivatives and methods of making and using the same |
| JP2004149429A (ja) | 2002-10-29 | 2004-05-27 | Takeda Chem Ind Ltd | インドール化合物およびその用途 |
| ATE443043T1 (de) | 2002-11-12 | 2009-10-15 | Merck & Co Inc | Phenylcarboxamide als beta-sekretase-hemmer zur behandlung von alzheimer |
| EP2153832B1 (en) | 2003-12-15 | 2016-03-09 | Merck Sharp & Dohme Corp. | Heterocyclic aspartyl protease inhibitors |
| WO2005097767A1 (en) | 2004-03-30 | 2005-10-20 | Merck & Co., Inc. | 2-aminothiazole compounds useful as aspartyl protease inhibitors |
| PE20060664A1 (es) | 2004-09-15 | 2006-08-04 | Novartis Ag | Amidas biciclicas como inhibidores de cinasa |
| WO2006041405A1 (en) | 2004-10-15 | 2006-04-20 | Astrazeneca Ab | Substituted amino-pyrimidones and uses thereof |
| CN101084199A (zh) | 2004-10-15 | 2007-12-05 | 阿斯利康(瑞典)有限公司 | 取代的氨基化合物及其用途 |
| WO2006078577A1 (en) | 2005-01-19 | 2006-07-27 | Merck & Co., Inc. | Tertiary carbinamines having substituted heterocycles, which are active as inhibitors of beta-secretase, for the treatment of alzheimer's disease |
| PE20070135A1 (es) | 2005-06-14 | 2007-03-09 | Schering Corp | Compuestos heterociclicos como inhibidores de aspartil proteasas |
| ATE550338T1 (de) | 2005-07-18 | 2012-04-15 | Merck Sharp & Dohme | Spiropiperidininhibitoren von beta-secretase zur behandlung von alzheimer-krankheit |
| KR101052122B1 (ko) | 2005-10-25 | 2011-07-26 | 시오노기세야쿠 가부시키가이샤 | 아미노디히드로티아진 유도체 |
| US20090099217A1 (en) | 2006-04-05 | 2009-04-16 | Astex Therapeutics Ltd. | 2-Aminopyrimidin-4-Ones And Their Use For Treating Or Preventing Alpha Beta-Related Pathologies |
| MX2008015196A (es) | 2006-05-31 | 2008-12-15 | Asubio Pharma Co Ltd | Compuesto de anillo de 7 miembros, proceso para producir el mismo, y su uso medico. |
| AU2007332754A1 (en) | 2006-12-12 | 2008-06-19 | Schering Corporation | Aspartyl protease inhibitors |
| EP2147914B1 (en) | 2007-04-24 | 2014-06-04 | Shionogi&Co., Ltd. | Aminodihydrothiazine derivatives substituted with cyclic groups |
| EP2151435A4 (en) | 2007-04-24 | 2011-09-14 | Shionogi & Co | PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF ALZHEIMER'S DISEASE |
| WO2008146871A1 (ja) | 2007-05-29 | 2008-12-04 | Santen Pharmaceutical Co., Ltd. | グルココルチコイド受容体結合活性を有する、スルホン酸エステル又はスルホン酸アミド構造を導入したフェニル基を置換基として有する新規１，２，３，４－テトラヒドロキノキサリン誘導体 |
| PE20091236A1 (es) | 2007-11-22 | 2009-09-16 | Astrazeneca Ab | Derivados de pirimidina como immunomoduladores de tlr7 |
| US20100317850A1 (en) * | 2008-01-18 | 2010-12-16 | Yuichi Suzuki | Condensed aminodihydrothiazine derivative |
| TWI431004B (zh) | 2008-05-02 | 2014-03-21 | Lilly Co Eli | Ｂａｃｅ抑制劑 |
| WO2010013302A1 (ja) | 2008-07-28 | 2010-02-04 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | スピロアミノジヒドロチアジン誘導体 |
| AU2009277485B2 (en) | 2008-07-28 | 2013-05-02 | Eisai R&D Management Co., Ltd. | Spiroaminodihydrothiazine derivatives |
| JP5666304B2 (ja) | 2008-09-30 | 2015-02-12 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 新規な縮合アミノジヒドロチアジン誘導体 |
| AR077277A1 (es) * | 2009-07-09 | 2011-08-17 | Lilly Co Eli | Compuestos de biciclo (1,3)tiazin-2-amina formulacion farmaceutica que lo comprende y su uso para la manufactura de un medicamento util para el tratamiento de la enfermedad de alzheimer |
| GB0912778D0 (en) | 2009-07-22 | 2009-08-26 | Eisai London Res Lab Ltd | Fused aminodihydro-oxazine derivatives |
| GB0912777D0 (en) | 2009-07-22 | 2009-08-26 | Eisai London Res Lab Ltd | Fused aminodihydropyrimidone derivatives |
| WO2012003274A1 (en) | 2010-07-01 | 2012-01-05 | Amgen Inc. | Heterocyclic compounds and their use as inhibitors of pi3k activity |
| GB201101140D0 (en) | 2011-01-21 | 2011-03-09 | Eisai Ltd | Fused aminodihydrothiazine derivatives |
-
2012
- 2012-01-20 SG SG2013027461A patent/SG191710A1/en unknown
- 2012-01-20 EP EP12702690.4A patent/EP2665716B1/en active Active
- 2012-01-20 MX MX2013005115A patent/MX2013005115A/es active IP Right Grant
- 2012-01-20 BR BR112013016241A patent/BR112013016241A2/pt not_active IP Right Cessation
- 2012-01-20 JP JP2013550622A patent/JP5993875B2/ja not_active Expired - Fee Related
- 2012-01-20 CA CA2814014A patent/CA2814014A1/en not_active Abandoned
- 2012-01-20 RU RU2013138226/04A patent/RU2013138226A/ru not_active Application Discontinuation
- 2012-01-20 ES ES12702690.4T patent/ES2624288T3/es active Active
- 2012-01-20 SG SG10201601516QA patent/SG10201601516QA/en unknown
- 2012-01-20 CN CN201610875412.9A patent/CN106632401B/zh active Active
- 2012-01-20 WO PCT/US2012/022053 patent/WO2012100179A1/en not_active Ceased
- 2012-01-20 US US13/355,030 patent/US8426584B2/en not_active Expired - Fee Related
- 2012-01-20 CN CN201280004193.7A patent/CN103502231A/zh active Pending
-
2013
- 2013-03-12 US US13/795,308 patent/US8802871B2/en active Active
- 2013-05-16 IL IL226405A patent/IL226405A0/en unknown
-
2014
- 2014-06-26 US US14/316,321 patent/US8962858B2/en not_active Expired - Fee Related
-
2016
- 2016-03-03 JP JP2016041508A patent/JP6087005B2/ja not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN103502231A (zh) | 2014-01-08 |
| CN106632401B (zh) | 2020-12-29 |
| US8962858B2 (en) | 2015-02-24 |
| RU2013138226A (ru) | 2015-02-27 |
| CN106632401A (zh) | 2017-05-10 |
| JP2014503001A (ja) | 2014-02-06 |
| US8426584B2 (en) | 2013-04-23 |
| IL226405A0 (en) | 2013-07-31 |
| US8802871B2 (en) | 2014-08-12 |
| SG10201601516QA (en) | 2016-03-30 |
| JP2016121177A (ja) | 2016-07-07 |
| JP5993875B2 (ja) | 2016-09-14 |
| US20130197244A1 (en) | 2013-08-01 |
| SG191710A1 (en) | 2013-08-30 |
| EP2665716A1 (en) | 2013-11-27 |
| CA2814014A1 (en) | 2012-07-26 |
| JP6087005B2 (ja) | 2017-03-01 |
| WO2012100179A1 (en) | 2012-07-26 |
| EP2665716B1 (en) | 2017-03-08 |
| US20140309429A1 (en) | 2014-10-16 |
| US20120190848A1 (en) | 2012-07-26 |
| MX2013005115A (es) | 2013-06-03 |
| BR112013016241A2 (pt) | 2016-07-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2624288T3 (es) | Métodos y compuestos útiles en la síntesis de derivados de aminodihidrotiazina condensados | |
| AU2009205072B2 (en) | Condensed aminodihydrothiazine derivative | |
| AU2010270691B8 (en) | BACE inhibitors | |
| ES2689526T3 (es) | Moduladores de P2X7 | |
| JP2021523200A (ja) | Ｍａｇｌ阻害剤 | |
| EP2297120A1 (en) | Aminodihydrothiazine derivatives as bace inhibitors for the treatment of alzheimer's disease | |
| WO2016022724A1 (en) | Cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use | |
| JPWO2020241853A5 (OSRAM) | ||
| US20230416252A1 (en) | Process toward the manufacture of (6r,10s)-10-{4-[5-chloro-2-(4-chloro-1h-1,2,3-triazol-1-yl)phenyl]-6-oxo-1(6h)-pyrimidinyl}- 1-(difluoromethyl)-6-methyl-1,4,7,8,9,10-hexahydro-11,15-(metheno)pyrazolo[4,3-b][1,7]diazacyclotetradecin-5(6h)-one | |
| JP2022511167A (ja) | 選択的ｂａｃｅ１阻害活性を有する二環式複素環誘導体 | |
| KR101950129B1 (ko) | N-[3-[(4aR,7aS)-2-아미노-6-(5-플루오로피리미딘-2-일)-4,4a,5,7-테트라히드로피롤로[3,4-d][1,3]티아진-7a-일]-4-플루오로-페닐]-5-메톡시-피라진-2-카르복스아미드의 토실레이트 염 | |
| KR101915419B1 (ko) | BACE 억제제로서의 테트라히드로피롤로[3,4-d][1,3]티아진-유도체 | |
| AU2004289652B2 (en) | Processes for preparing bicyclo [3.1.0] hexane derivatives, and intermediates thereto | |
| WO2014015125A1 (en) | Fused aminodihydrothiazine derivative salts and uses thereof | |
| GB2504615A (en) | Fused aminodihydrothiazine derivatives | |
| US12351577B2 (en) | Inhibiting cyclic AMP-responsive element-binding protein (CREB) | |
| MXPA06005039A (en) | Processes for preparing bicyclo [3.1.0]hexane derivatives, and intermediates thereto | |
| MXPA06006148A (en) | Process for the preparation of thiazolopyrimidines | |
| MX2008008161A (en) | Anti-viral compounds |