NZ539095A - Acetyl 2-hydroxy-1,3 diaminoalkanes - Google Patents
Acetyl 2-hydroxy-1,3 diaminoalkanesInfo
- Publication number
- NZ539095A NZ539095A NZ539095A NZ53909503A NZ539095A NZ 539095 A NZ539095 A NZ 539095A NZ 539095 A NZ539095 A NZ 539095A NZ 53909503 A NZ53909503 A NZ 53909503A NZ 539095 A NZ539095 A NZ 539095A
- Authority
- NZ
- New Zealand
- Prior art keywords
- alkyl
- groups
- optionally substituted
- cycloalkyl
- alkoxy
- Prior art date
Links
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 449
- 125000000217 alkyl group Chemical group 0.000 claims description 416
- 229910052736 halogen Inorganic materials 0.000 claims description 214
- 150000002367 halogens Chemical class 0.000 claims description 203
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 181
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 159
- 125000003545 alkoxy group Chemical group 0.000 claims description 152
- -1 -CHO Chemical group 0.000 claims description 151
- 125000003118 aryl group Chemical group 0.000 claims description 118
- 239000000203 mixture Substances 0.000 claims description 105
- 125000001072 heteroaryl group Chemical group 0.000 claims description 100
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 100
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 84
- 235000019439 ethyl acetate Nutrition 0.000 claims description 73
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 73
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 70
- 238000006243 chemical reaction Methods 0.000 claims description 63
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 62
- 125000003342 alkenyl group Chemical group 0.000 claims description 61
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 58
- 125000000304 alkynyl group Chemical group 0.000 claims description 55
- 125000001424 substituent group Chemical group 0.000 claims description 52
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 51
- 239000000047 product Substances 0.000 claims description 50
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 44
- 239000012044 organic layer Substances 0.000 claims description 44
- 229910052799 carbon Inorganic materials 0.000 claims description 43
- 150000003839 salts Chemical class 0.000 claims description 40
- 125000004432 carbon atom Chemical group C* 0.000 claims description 39
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims description 36
- 239000001257 hydrogen Substances 0.000 claims description 35
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 31
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 31
- 229910052757 nitrogen Inorganic materials 0.000 claims description 30
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 27
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 24
- 125000001188 haloalkyl group Chemical group 0.000 claims description 23
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 21
- 229910052801 chlorine Inorganic materials 0.000 claims description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 19
- 229910052731 fluorine Inorganic materials 0.000 claims description 19
- 125000004076 pyridyl group Chemical group 0.000 claims description 19
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 18
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 18
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
- 150000002431 hydrogen Chemical class 0.000 claims description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 14
- 239000000706 filtrate Substances 0.000 claims description 13
- 125000002971 oxazolyl group Chemical group 0.000 claims description 13
- 125000000335 thiazolyl group Chemical group 0.000 claims description 13
- 125000001544 thienyl group Chemical group 0.000 claims description 13
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 12
- 125000002541 furyl group Chemical group 0.000 claims description 12
- 125000002883 imidazolyl group Chemical group 0.000 claims description 12
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 12
- 125000002619 bicyclic group Chemical group 0.000 claims description 10
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 10
- 125000003386 piperidinyl group Chemical group 0.000 claims description 10
- 125000002950 monocyclic group Chemical group 0.000 claims description 9
- 125000004193 piperazinyl group Chemical group 0.000 claims description 9
- 125000006582 (C5-C6) heterocycloalkyl group Chemical group 0.000 claims description 8
- 125000001475 halogen functional group Chemical group 0.000 claims description 8
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 8
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 8
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 8
- 125000006288 3,5-difluorobenzyl group Chemical group [H]C1=C(F)C([H])=C(C([H])=C1F)C([H])([H])* 0.000 claims description 7
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 7
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 6
- 239000002002 slurry Substances 0.000 claims description 6
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 5
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 5
- 125000005046 dihydronaphthyl group Chemical group 0.000 claims description 4
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 4
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 4
- 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 3
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 3
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 3
- 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 claims description 3
- 125000002632 imidazolidinyl group Chemical group 0.000 claims description 3
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 3
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 3
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 3
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 3
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 2
- 101100188552 Arabidopsis thaliana OCT3 gene Proteins 0.000 claims 4
- 125000001589 carboacyl group Chemical group 0.000 claims 3
- 229940045348 brown mixture Drugs 0.000 claims 2
- 239000000523 sample Substances 0.000 claims 2
- IBODDUNKEPPBKW-UHFFFAOYSA-N 1,5-dibromopentane Chemical compound BrCCCCCBr IBODDUNKEPPBKW-UHFFFAOYSA-N 0.000 claims 1
- 238000013019 agitation Methods 0.000 claims 1
- 230000002051 biphasic effect Effects 0.000 claims 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims 1
- 208000024827 Alzheimer disease Diseases 0.000 abstract description 61
- 206010012289 Dementia Diseases 0.000 abstract description 33
- 238000002360 preparation method Methods 0.000 abstract description 33
- 208000010877 cognitive disease Diseases 0.000 abstract description 20
- 208000027061 mild cognitive impairment Diseases 0.000 abstract description 20
- 208000005145 Cerebral amyloid angiopathy Diseases 0.000 abstract description 17
- 230000003412 degenerative effect Effects 0.000 abstract description 14
- 201000010374 Down Syndrome Diseases 0.000 abstract description 12
- 206010044688 Trisomy 21 Diseases 0.000 abstract description 12
- 208000007487 Familial Cerebral Amyloid Angiopathy Diseases 0.000 abstract description 9
- 208000032849 Hereditary cerebral hemorrhage with amyloidosis Diseases 0.000 abstract description 9
- 210000004558 lewy body Anatomy 0.000 abstract description 9
- 208000018282 ACys amyloidosis Diseases 0.000 abstract description 8
- 230000001054 cortical effect Effects 0.000 abstract description 7
- 230000007850 degeneration Effects 0.000 abstract description 7
- 208000018737 Parkinson disease Diseases 0.000 abstract description 6
- 201000002212 progressive supranuclear palsy Diseases 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 5
- 201000011240 Frontotemporal dementia Diseases 0.000 abstract description 3
- 208000027089 Parkinsonian disease Diseases 0.000 abstract description 3
- 206010034010 Parkinsonism Diseases 0.000 abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 213
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 166
- 238000000034 method Methods 0.000 description 139
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 97
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 85
- 229910001868 water Inorganic materials 0.000 description 82
- 239000011541 reaction mixture Substances 0.000 description 77
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 74
- 239000000243 solution Substances 0.000 description 69
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 68
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 66
- 150000001412 amines Chemical class 0.000 description 66
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 65
- 230000002829 reductive effect Effects 0.000 description 64
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 63
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 50
- 239000007787 solid Substances 0.000 description 47
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 46
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
- 239000003921 oil Substances 0.000 description 39
- 235000019198 oils Nutrition 0.000 description 39
- 239000002904 solvent Substances 0.000 description 36
- 238000003818 flash chromatography Methods 0.000 description 35
- 238000005481 NMR spectroscopy Methods 0.000 description 34
- 150000001540 azides Chemical class 0.000 description 34
- 125000004093 cyano group Chemical group *C#N 0.000 description 34
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 33
- 238000005160 1H NMR spectroscopy Methods 0.000 description 32
- 235000019441 ethanol Nutrition 0.000 description 32
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 31
- 201000010099 disease Diseases 0.000 description 31
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 28
- 238000011282 treatment Methods 0.000 description 28
- 238000000746 purification Methods 0.000 description 26
- 239000000741 silica gel Substances 0.000 description 26
- 229910002027 silica gel Inorganic materials 0.000 description 26
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 25
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 25
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 25
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 24
- 238000003786 synthesis reaction Methods 0.000 description 24
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 description 23
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 description 23
- 239000000463 material Substances 0.000 description 23
- 239000010410 layer Substances 0.000 description 22
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 21
- 150000002576 ketones Chemical class 0.000 description 21
- 150000003457 sulfones Chemical class 0.000 description 21
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 20
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 20
- 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 20
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 19
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 19
- 239000000460 chlorine Substances 0.000 description 19
- 125000001624 naphthyl group Chemical group 0.000 description 19
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 18
- 229910052938 sodium sulfate Inorganic materials 0.000 description 18
- 235000011152 sodium sulphate Nutrition 0.000 description 18
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 17
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- 230000002401 inhibitory effect Effects 0.000 description 17
- 150000002924 oxiranes Chemical class 0.000 description 17
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 239000002585 base Substances 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 16
- 230000000694 effects Effects 0.000 description 16
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 16
- 238000010992 reflux Methods 0.000 description 16
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 15
- 239000012267 brine Substances 0.000 description 15
- 238000005859 coupling reaction Methods 0.000 description 15
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 15
- 230000009467 reduction Effects 0.000 description 15
- 238000006722 reduction reaction Methods 0.000 description 15
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 15
- 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 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 230000009466 transformation Effects 0.000 description 14
- 210000004556 brain Anatomy 0.000 description 13
- 238000010168 coupling process Methods 0.000 description 13
- 239000012442 inert solvent Substances 0.000 description 13
- 229910052705 radium Inorganic materials 0.000 description 13
- 229910052701 rubidium Inorganic materials 0.000 description 13
- 102000004190 Enzymes Human genes 0.000 description 12
- 108090000790 Enzymes Proteins 0.000 description 12
- 230000008878 coupling Effects 0.000 description 12
- 229940088598 enzyme Drugs 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 238000004519 manufacturing process Methods 0.000 description 12
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- 150000003462 sulfoxides Chemical class 0.000 description 12
- ANWPEHPJCBJNNI-UHFFFAOYSA-N 6-iodo-3,4-dihydro-2h-chromen-4-ol Chemical compound C1=C(I)C=C2C(O)CCOC2=C1 ANWPEHPJCBJNNI-UHFFFAOYSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 125000003282 alkyl amino group Chemical group 0.000 description 11
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 11
- 229910052740 iodine Inorganic materials 0.000 description 11
- 238000002953 preparative HPLC Methods 0.000 description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 11
- VKQBMFKBNMKUBE-UHFFFAOYSA-N 2-iodo-2H-chromene Chemical compound C1=CC=C2C=CC(I)OC2=C1 VKQBMFKBNMKUBE-UHFFFAOYSA-N 0.000 description 10
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 10
- 125000002252 acyl group Chemical group 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 238000004587 chromatography analysis Methods 0.000 description 10
- 125000000623 heterocyclic group Chemical group 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- 125000006239 protecting group Chemical group 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- 125000005233 alkylalcohol group Chemical group 0.000 description 9
- 229910052794 bromium Inorganic materials 0.000 description 9
- 150000001721 carbon Chemical group 0.000 description 9
- 239000003638 chemical reducing agent Substances 0.000 description 9
- 238000003776 cleavage reaction Methods 0.000 description 9
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 9
- 239000012280 lithium aluminium hydride Substances 0.000 description 9
- 230000007017 scission Effects 0.000 description 9
- 239000000377 silicon dioxide Substances 0.000 description 9
- 229910000104 sodium hydride Inorganic materials 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- 238000000844 transformation Methods 0.000 description 9
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 8
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- 230000001953 sensory effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- NIAITESZNQFOMI-UHFFFAOYSA-N tert-butyl n-(6-bromo-3,4-dihydro-1h-isochromen-4-yl)carbamate Chemical compound C1=C(Br)C=C2C(NC(=O)OC(C)(C)C)COCC2=C1 NIAITESZNQFOMI-UHFFFAOYSA-N 0.000 description 1
- PGQCNUZIKLRBKJ-PCCBWWKXSA-N tert-butyl n-[(2s,3r)-1-(3,5-difluorophenyl)-3-hydroxy-4-[[(4s)-6-hydroxy-3,4-dihydro-2h-chromen-4-yl]amino]butan-2-yl]carbamate Chemical compound C([C@H](NC(=O)OC(C)(C)C)[C@H](O)CN[C@@H]1C2=CC(O)=CC=C2OCC1)C1=CC(F)=CC(F)=C1 PGQCNUZIKLRBKJ-PCCBWWKXSA-N 0.000 description 1
- VUVALAJRANHWTN-PCCBWWKXSA-N tert-butyl n-[(2s,3r)-1-(3,5-difluorophenyl)-3-hydroxy-4-[[(4s)-6-iodo-3,4-dihydro-2h-chromen-4-yl]amino]butan-2-yl]carbamate Chemical compound C([C@H](NC(=O)OC(C)(C)C)[C@H](O)CN[C@@H]1C2=CC(I)=CC=C2OCC1)C1=CC(F)=CC(F)=C1 VUVALAJRANHWTN-PCCBWWKXSA-N 0.000 description 1
- RTEJVQDVLLEQHH-KMDXXIMOSA-N tert-butyl n-[(2s,3r)-1-(3,5-difluorophenyl)-3-hydroxy-4-[[(4s)-6-propan-2-yl-3,4-dihydro-2h-chromen-4-yl]amino]butan-2-yl]carbamate Chemical compound C([C@@H]([C@H](O)CN[C@H]1CCOC2=CC=C(C=C21)C(C)C)NC(=O)OC(C)(C)C)C1=CC(F)=CC(F)=C1 RTEJVQDVLLEQHH-KMDXXIMOSA-N 0.000 description 1
- BGEABFACPQXBIX-KMDXXIMOSA-N tert-butyl n-[(2s,3r)-1-(3,5-difluorophenyl)-3-hydroxy-4-[[(4s)-6-propan-2-yloxy-3,4-dihydro-2h-chromen-4-yl]amino]butan-2-yl]carbamate Chemical compound C([C@@H]([C@H](O)CN[C@H]1CCOC2=CC=C(C=C21)OC(C)C)NC(=O)OC(C)(C)C)C1=CC(F)=CC(F)=C1 BGEABFACPQXBIX-KMDXXIMOSA-N 0.000 description 1
- SCYVDDAGYMDGMO-JAFNVKOHSA-N tert-butyl n-[(2s,3r)-1-(3,5-difluorophenyl)-4-(3,4-dihydro-1h-isochromen-4-ylamino)-3-hydroxybutan-2-yl]carbamate Chemical compound C([C@H](NC(=O)OC(C)(C)C)[C@H](O)CNC1C2=CC=CC=C2COC1)C1=CC(F)=CC(F)=C1 SCYVDDAGYMDGMO-JAFNVKOHSA-N 0.000 description 1
- LPMHWDNMHNOVKX-GJGLBJJNSA-N tert-butyl n-[(2s,3r)-1-(3,5-difluorophenyl)-4-(3,4-dihydro-2h-chromen-4-ylamino)-3-hydroxybutan-2-yl]carbamate Chemical compound C([C@H](NC(=O)OC(C)(C)C)[C@H](O)CNC1C2=CC=CC=C2OCC1)C1=CC(F)=CC(F)=C1 LPMHWDNMHNOVKX-GJGLBJJNSA-N 0.000 description 1
- PGZNVQZFCHDJSV-CCDWMCETSA-N tert-butyl n-[(2s,3r)-1-(3,5-difluorophenyl)-4-[[(4s)-6-(2,2-dimethylpropyl)-3,4-dihydro-2h-chromen-4-yl]amino]-3-hydroxybutan-2-yl]carbamate Chemical compound C([C@@H]([C@H](O)CN[C@H]1CCOC2=CC=C(C=C21)CC(C)(C)C)NC(=O)OC(C)(C)C)C1=CC(F)=CC(F)=C1 PGZNVQZFCHDJSV-CCDWMCETSA-N 0.000 description 1
- TTXVFBIUURWQOL-KCIKGWAESA-N tert-butyl n-[(2s,3r)-1-(3,5-difluorophenyl)-4-[[6-(2,2-dimethylpropyl)-3,4-dihydro-1h-isochromen-4-yl]amino]-3-hydroxybutan-2-yl]carbamate Chemical compound C([C@@H]([C@H](O)CNC1COCC2=CC=C(C=C21)CC(C)(C)C)NC(=O)OC(C)(C)C)C1=CC(F)=CC(F)=C1 TTXVFBIUURWQOL-KCIKGWAESA-N 0.000 description 1
- PGZNVQZFCHDJSV-NCPLZGKYSA-N tert-butyl n-[(2s,3r)-1-(3,5-difluorophenyl)-4-[[6-(2,2-dimethylpropyl)-3,4-dihydro-2h-chromen-4-yl]amino]-3-hydroxybutan-2-yl]carbamate Chemical compound C([C@@H]([C@H](O)CNC1CCOC2=CC=C(C=C21)CC(C)(C)C)NC(=O)OC(C)(C)C)C1=CC(F)=CC(F)=C1 PGZNVQZFCHDJSV-NCPLZGKYSA-N 0.000 description 1
- YGXUJJSRMOUIBX-CCDWMCETSA-N tert-butyl n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)-3,4-dihydro-2h-chromen-4-yl]amino]-1-(3-fluorophenyl)-3-hydroxybutan-2-yl]carbamate Chemical compound C([C@@H]([C@H](O)CN[C@H]1CCOC2=CC=C(C=C21)CC(C)(C)C)NC(=O)OC(C)(C)C)C1=CC=CC(F)=C1 YGXUJJSRMOUIBX-CCDWMCETSA-N 0.000 description 1
- MNCZFZJFVNLIBJ-QWHCGFSZSA-N tert-butyl n-[(2s,3r)-4-amino-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]([C@H](O)CN)CC1=CC(F)=CC(F)=C1 MNCZFZJFVNLIBJ-QWHCGFSZSA-N 0.000 description 1
- LJMGYUWQMIXDEA-HNNXBMFYSA-N tert-butyl n-[(4s)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2h-chromen-4-yl]carbamate Chemical compound C([C@@H](C1=C2)NC(=O)OC(C)(C)C)COC1=CC=C2B1OC(C)(C)C(C)(C)O1 LJMGYUWQMIXDEA-HNNXBMFYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 229940102001 zinc bromide Drugs 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- DSDCDMKASWVZHI-UHFFFAOYSA-M zinc;2-methanidylpropane;bromide Chemical compound Br[Zn+].CC(C)[CH2-] DSDCDMKASWVZHI-UHFFFAOYSA-M 0.000 description 1
- 125000004933 β-carbolinyl group Chemical group C1(=NC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
- C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/36—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/10—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
- C07C235/74—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton
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- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C311/05—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups
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- C07C327/00—Thiocarboxylic acids
- C07C327/20—Esters of monothiocarboxylic acids
- C07C327/30—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
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- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
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- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/61—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
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- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
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| PCT/US2003/028503 WO2004024081A2 (en) | 2002-09-10 | 2003-09-10 | Acetyl 2-hydroxy-1,3 diaminoalkanes |
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| US7618978B2 (en) | 2004-04-22 | 2009-11-17 | Eli Lilly And Company | Amides as BACE inhibitors |
| US7585885B2 (en) | 2004-04-22 | 2009-09-08 | Eli Lilly And Company | Pyrrolidine derivatives useful as BACE inhibitors |
| EP1773756A2 (en) | 2004-07-09 | 2007-04-18 | Elan Pharmaceuticals, Inc. | Oxime derivative substituted hydroxyethylamine aspartyl protease inhibitors |
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| US7745484B2 (en) | 2005-11-21 | 2010-06-29 | Amgen Inc. | Beta-secretase modulators and methods of use |
| US7872009B2 (en) | 2005-11-21 | 2011-01-18 | Amgen Inc. | Beta-Secretase modulators and methods of use |
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| BRPI0719336A2 (pt) * | 2006-11-23 | 2014-02-04 | Novartis Ag | Derivados de 2-hidróxi-1,3-diaminopropano |
| TW200901991A (en) | 2007-05-25 | 2009-01-16 | Amgen Inc | Substituted hydroxyethyl amine compounds as beta-secretase modulators and methods of use |
| CA2687608C (en) | 2007-05-25 | 2013-07-02 | Amgen Inc. | Substituted hydroxyethyl amine compounds as beta-secretase modulators and methods of use |
| US7803809B2 (en) | 2008-11-12 | 2010-09-28 | Amgen Inc. | Substituted pyrano [2,3-b] pyridinamine compounds as beta-secretase modulators and methods of use |
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| EP2504330A1 (en) | 2009-11-23 | 2012-10-03 | Amgen Inc. | Amino heteroaryl compounds as beta-secretase modulators and methods of use |
| US9296698B2 (en) | 2009-11-23 | 2016-03-29 | Amgen Inc. | Amino heteroaryl compounds as beta-secretase modulators and methods of use |
| CA2788363A1 (en) | 2010-01-19 | 2011-07-28 | Amgen Inc. | Amino heteroaryl compounds as beta-secretase modulators and methods of use |
| ES2450568T3 (es) | 2010-03-15 | 2014-03-25 | Amgen Inc. | Compuestos espiero de amino-dihidrooxazina y amino-dihidrotiazina como moduladores de beta-secretasa y su uso médico |
| MX2012010658A (es) | 2010-03-15 | 2012-12-05 | Amgen Inc | Compuestos de anillo espiro tetraciclico como moduladores de beta-secretasa. |
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2003
- 2003-09-09 UY UY27967A patent/UY27967A1/es not_active Application Discontinuation
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- 2003-09-10 JP JP2004571986A patent/JP2006504793A/ja active Pending
- 2003-09-10 EA EA200500472A patent/EA009196B1/ru not_active IP Right Cessation
- 2003-09-10 AU AU2003267132A patent/AU2003267132A1/en not_active Abandoned
- 2003-09-10 PE PE2003000914A patent/PE20041079A1/es not_active Application Discontinuation
- 2003-09-10 GE GEAP20038737A patent/GEP20074166B/en unknown
- 2003-09-10 WO PCT/US2003/028503 patent/WO2004024081A2/en not_active Ceased
- 2003-09-10 KR KR1020057004161A patent/KR20060057520A/ko not_active Ceased
- 2003-09-10 TW TW092125081A patent/TWI336320B/zh not_active IP Right Cessation
- 2003-09-10 NZ NZ539095A patent/NZ539095A/en not_active IP Right Cessation
- 2003-09-10 UA UAA200502191A patent/UA84407C2/ru unknown
- 2003-09-10 PL PL376511A patent/PL376511A1/pl not_active Application Discontinuation
- 2003-09-10 US US10/658,959 patent/US7244725B2/en not_active Expired - Fee Related
- 2003-09-10 BR BR0314188-8A patent/BR0314188A/pt not_active IP Right Cessation
- 2003-09-10 AR ARP030103276A patent/AR043679A1/es unknown
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- 2003-09-10 OA OA1200500066A patent/OA12919A/en unknown
- 2003-09-10 CA CA002498248A patent/CA2498248A1/en not_active Abandoned
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- 2005-03-10 NO NO20051239A patent/NO20051239L/no not_active Application Discontinuation
- 2005-03-21 EC EC2005005696A patent/ECSP055696A/es unknown
- 2005-04-06 MA MA28202A patent/MA27472A1/fr unknown
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2006
- 2006-06-06 US US11/447,789 patent/US7645780B2/en not_active Expired - Fee Related
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Also Published As
| Publication number | Publication date |
|---|---|
| PE20041079A1 (es) | 2005-02-05 |
| US20040180939A1 (en) | 2004-09-16 |
| JP2011084568A (ja) | 2011-04-28 |
| US7244725B2 (en) | 2007-07-17 |
| EP1565443A2 (en) | 2005-08-24 |
| WO2004024081A3 (en) | 2005-06-23 |
| PL376511A1 (pl) | 2006-01-09 |
| EP1565443A4 (en) | 2007-07-18 |
| UY27967A1 (es) | 2004-05-31 |
| EA200500472A1 (ru) | 2005-10-27 |
| WO2004024081A2 (en) | 2004-03-25 |
| UA84407C2 (en) | 2008-10-27 |
| US20100145056A1 (en) | 2010-06-10 |
| TWI336320B (en) | 2011-01-21 |
| EA009196B1 (ru) | 2007-12-28 |
| TW200417534A (en) | 2004-09-16 |
| ECSP055696A (es) | 2005-07-06 |
| BR0314188A (pt) | 2005-08-09 |
| US7645780B2 (en) | 2010-01-12 |
| AU2003267132A1 (en) | 2004-04-30 |
| MA27472A1 (fr) | 2005-08-01 |
| IS7732A (is) | 2005-03-09 |
| JP2006504793A (ja) | 2006-02-09 |
| AR043679A1 (es) | 2005-08-10 |
| OA12919A (en) | 2006-10-13 |
| KR20060057520A (ko) | 2006-05-26 |
| NO20051239L (no) | 2005-06-06 |
| GEP20074166B (en) | 2007-07-25 |
| MXPA05002695A (es) | 2005-09-08 |
| CA2498248A1 (en) | 2004-03-25 |
| US20070293483A1 (en) | 2007-12-20 |
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