MXPA05011365A - Derivados triciclicos de indol y su uso en el tratamiento de la enfermedad de alzheimer. - Google Patents
Derivados triciclicos de indol y su uso en el tratamiento de la enfermedad de alzheimer.Info
- Publication number
- MXPA05011365A MXPA05011365A MXPA05011365A MXPA05011365A MXPA05011365A MX PA05011365 A MXPA05011365 A MX PA05011365A MX PA05011365 A MXPA05011365 A MX PA05011365A MX PA05011365 A MXPA05011365 A MX PA05011365A MX PA05011365 A MXPA05011365 A MX PA05011365A
- Authority
- MX
- Mexico
- Prior art keywords
- methyl
- ethyl
- hydroxy
- dioxide
- carboxamide
- Prior art date
Links
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 19
- 201000010099 disease Diseases 0.000 title claims abstract description 17
- 238000011282 treatment Methods 0.000 title claims abstract description 17
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title claims description 6
- 229940054051 antipsychotic indole derivative Drugs 0.000 title 1
- 102000013455 Amyloid beta-Peptides Human genes 0.000 claims abstract description 31
- 108010090849 Amyloid beta-Peptides Proteins 0.000 claims abstract description 31
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 13
- 208000037259 Amyloid Plaque Diseases 0.000 claims abstract description 9
- -1 cyano, hydroxy, carboxy Chemical group 0.000 claims description 153
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 101
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 96
- 150000001875 compounds Chemical class 0.000 claims description 92
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 75
- 125000000217 alkyl group Chemical group 0.000 claims description 67
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 67
- 239000001257 hydrogen Substances 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 35
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 32
- 239000002253 acid Substances 0.000 claims description 30
- 125000003118 aryl group Chemical group 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 24
- 150000002431 hydrogen Chemical class 0.000 claims description 23
- BXVYJQULAWJPSR-UHFFFAOYSA-N thiadiazepine Chemical compound S1C=CC=CN=N1 BXVYJQULAWJPSR-UHFFFAOYSA-N 0.000 claims description 23
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 22
- 229910052757 nitrogen Inorganic materials 0.000 claims description 21
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- 239000012453 solvate Substances 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 13
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 12
- 125000001188 haloalkyl group Chemical group 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 229910052701 rubidium Inorganic materials 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- NYERMPLPURRVGM-UHFFFAOYSA-N thiazepine Chemical compound S1C=CC=CC=N1 NYERMPLPURRVGM-UHFFFAOYSA-N 0.000 claims description 7
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 150000001721 carbon Chemical group 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000005349 heteroarylcycloalkyl group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 3
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 3
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 3
- ITESSQIOKPXHFN-ZWKOTPCHSA-N (2r,3s)-3-amino-1-[(3-methoxyphenyl)methylamino]-4-phenylbutan-2-ol Chemical compound COC1=CC=CC(CNC[C@@H](O)[C@@H](N)CC=2C=CC=CC=2)=C1 ITESSQIOKPXHFN-ZWKOTPCHSA-N 0.000 claims description 2
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 2
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 2
- 125000006309 butyl amino group Chemical group 0.000 claims description 2
- 125000006312 cyclopentyl amino group Chemical group [H]N(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 125000006308 propyl amino group Chemical group 0.000 claims description 2
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 claims description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims 5
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims 4
- XVTYOWLPIKJSML-UHFFFAOYSA-N 1,2,5-thiadiazepine Chemical compound S1C=CN=CC=N1 XVTYOWLPIKJSML-UHFFFAOYSA-N 0.000 claims 3
- 125000006317 cyclopropyl amino group Chemical group 0.000 claims 3
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 2
- 125000004350 aryl cycloalkyl group Chemical group 0.000 claims 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims 1
- OHDJISGEMQIVIJ-UHFFFAOYSA-N 2h-1,2,5-thiadiazine Chemical compound N1SC=NC=C1 OHDJISGEMQIVIJ-UHFFFAOYSA-N 0.000 claims 1
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims 1
- HORNXRXVQWOLPJ-UHFFFAOYSA-N 3-chlorophenol Chemical compound OC1=CC=CC(Cl)=C1 HORNXRXVQWOLPJ-UHFFFAOYSA-N 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- 125000001589 carboacyl group Chemical group 0.000 claims 1
- 125000006311 cyclobutyl amino group Chemical group [H]N(*)C1([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims 1
- DZLNHFMRPBPULJ-UHFFFAOYSA-N thioproline Chemical compound OC(=O)C1CSCN1 DZLNHFMRPBPULJ-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 52
- 238000000034 method Methods 0.000 abstract description 49
- 102100021257 Beta-secretase 1 Human genes 0.000 abstract description 22
- 101710150192 Beta-secretase 1 Proteins 0.000 abstract description 19
- 230000008569 process Effects 0.000 abstract description 17
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 abstract description 7
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 abstract description 7
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical class NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 abstract description 3
- 101000894895 Homo sapiens Beta-secretase 1 Proteins 0.000 abstract description 3
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 98
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 64
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 59
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 58
- 238000000746 purification Methods 0.000 description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 48
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 45
- 150000001412 amines Chemical class 0.000 description 42
- 239000007787 solid Substances 0.000 description 42
- 239000012074 organic phase Substances 0.000 description 40
- 239000007864 aqueous solution Substances 0.000 description 38
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 29
- 235000019341 magnesium sulphate Nutrition 0.000 description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- 229910001868 water Inorganic materials 0.000 description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 23
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- 229920006395 saturated elastomer Polymers 0.000 description 21
- 239000002904 solvent Substances 0.000 description 21
- 150000002148 esters Chemical class 0.000 description 20
- 238000003818 flash chromatography Methods 0.000 description 20
- 239000002243 precursor Substances 0.000 description 19
- 239000000741 silica gel Substances 0.000 description 19
- 229910002027 silica gel Inorganic materials 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 17
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 229910000104 sodium hydride Inorganic materials 0.000 description 14
- 102000004190 Enzymes Human genes 0.000 description 13
- 108090000790 Enzymes Proteins 0.000 description 13
- 229940088598 enzyme Drugs 0.000 description 13
- 239000010410 layer Substances 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- 230000005764 inhibitory process Effects 0.000 description 12
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- 239000012267 brine Substances 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 239000002480 mineral oil Substances 0.000 description 10
- 235000010446 mineral oil Nutrition 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 235000019198 oils Nutrition 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 9
- SKKTUOZKZKCGTB-UHFFFAOYSA-N butyl carbamate Chemical compound CCCCOC(N)=O SKKTUOZKZKCGTB-UHFFFAOYSA-N 0.000 description 9
- 125000004494 ethyl ester group Chemical group 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- 239000000872 buffer Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical group COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 238000010511 deprotection reaction Methods 0.000 description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 6
- 150000002118 epoxides Chemical class 0.000 description 6
- LZNXSMZJMKWFQR-UHFFFAOYSA-N ethyl 2-(3-methoxyphenyl)-2-methylpropanoate Chemical compound CCOC(=O)C(C)(C)C1=CC=CC(OC)=C1 LZNXSMZJMKWFQR-UHFFFAOYSA-N 0.000 description 6
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 6
- PRTLMEWWYBJZPN-UHFFFAOYSA-N methyl 4-amino-3-bromo-5-nitrobenzoate Chemical compound COC(=O)C1=CC(Br)=C(N)C([N+]([O-])=O)=C1 PRTLMEWWYBJZPN-UHFFFAOYSA-N 0.000 description 6
- HNTLUEZVPLRQEV-UHFFFAOYSA-N methyl 4-amino-3-nitrobenzoate Chemical compound COC(=O)C1=CC=C(N)C([N+]([O-])=O)=C1 HNTLUEZVPLRQEV-UHFFFAOYSA-N 0.000 description 6
- 238000001665 trituration Methods 0.000 description 6
- IJHKKRQRUUQIJU-UHFFFAOYSA-N 2-(hydroxymethylidene)propanedial Chemical compound OC=C(C=O)C=O IJHKKRQRUUQIJU-UHFFFAOYSA-N 0.000 description 5
- ZKLBPUYMTHPNOQ-UHFFFAOYSA-N 5-bromothiophene-3-carbaldehyde Chemical compound BrC1=CC(C=O)=CS1 ZKLBPUYMTHPNOQ-UHFFFAOYSA-N 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- QSVHOENZNLGNQE-UHFFFAOYSA-N ethyl 7-(3-chloropropanoylamino)-3-ethyl-1h-indole-5-carboxylate Chemical compound CCOC(=O)C1=CC(NC(=O)CCCl)=C2NC=C(CC)C2=C1 QSVHOENZNLGNQE-UHFFFAOYSA-N 0.000 description 5
- ZRVDQBPIHQYYCU-UHFFFAOYSA-N ethyl 7-amino-3-ethyl-1h-indole-5-carboxylate Chemical compound CCOC(=O)C1=CC(N)=C2NC=C(CC)C2=C1 ZRVDQBPIHQYYCU-UHFFFAOYSA-N 0.000 description 5
- PQEPFVIAMNKHAV-UHFFFAOYSA-N methyl 3-ethyl-7-nitro-1h-indole-5-carboxylate Chemical compound C1=C(C(=O)OC)C=C2C(CC)=CNC2=C1[N+]([O-])=O PQEPFVIAMNKHAV-UHFFFAOYSA-N 0.000 description 5
- OXERBZQPYKPVFA-UHFFFAOYSA-N methyl 7-amino-3-ethyl-1h-indole-5-carboxylate Chemical compound C1=C(C(=O)OC)C=C2C(CC)=CNC2=C1N OXERBZQPYKPVFA-UHFFFAOYSA-N 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 5
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 5
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 5
- SGFFFEYHPPBPHU-UHFFFAOYSA-N 2,6-dimethylheptan-2-amine Chemical compound CC(C)CCCC(C)(C)N SGFFFEYHPPBPHU-UHFFFAOYSA-N 0.000 description 4
- AJBGTOYTKPVUPX-UHFFFAOYSA-N 2-(3-methoxyphenyl)-2-methylpropanoic acid Chemical compound COC1=CC=CC(C(C)(C)C(O)=O)=C1 AJBGTOYTKPVUPX-UHFFFAOYSA-N 0.000 description 4
- XJRLZIBKKHJOHI-UHFFFAOYSA-N 2-(3-methoxyphenyl)propan-2-amine Chemical compound COC1=CC=CC(C(C)(C)N)=C1 XJRLZIBKKHJOHI-UHFFFAOYSA-N 0.000 description 4
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
- 102100021277 Beta-secretase 2 Human genes 0.000 description 4
- 101710150190 Beta-secretase 2 Proteins 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- 102000003908 Cathepsin D Human genes 0.000 description 4
- 108090000258 Cathepsin D Proteins 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 125000004639 dihydroindenyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 4
- 238000007865 diluting Methods 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- VDHOIZQKJIGJKD-UHFFFAOYSA-N ethyl 3-ethyl-7-(phenylmethoxycarbonylamino)-1h-indole-5-carboxylate Chemical compound C=12NC=C(CC)C2=CC(C(=O)OCC)=CC=1NC(=O)OCC1=CC=CC=C1 VDHOIZQKJIGJKD-UHFFFAOYSA-N 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
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- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
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- OITAMJBKJGSZDG-UHFFFAOYSA-N tert-butyl n-[(3-ethyl-1,2-oxazol-5-yl)methyl]carbamate Chemical compound CCC=1C=C(CNC(=O)OC(C)(C)C)ON=1 OITAMJBKJGSZDG-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/06—Peri-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—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
- C07D513/06—Peri-condensed systems
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Neurology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Hospice & Palliative Care (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Psychiatry (AREA)
- Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB0309221.0A GB0309221D0 (en) | 2003-04-23 | 2003-04-23 | Novel compounds |
| PCT/EP2004/004244 WO2004094430A1 (en) | 2003-04-23 | 2004-04-21 | Tricyclic indole derivatives and their use in the treatment of alzheimer’s disease |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA05011365A true MXPA05011365A (es) | 2005-11-28 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MXPA05011365A MXPA05011365A (es) | 2003-04-23 | 2004-04-21 | Derivados triciclicos de indol y su uso en el tratamiento de la enfermedad de alzheimer. |
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| EP (1) | EP1620438A1 (cg-RX-API-DMAC7.html) |
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| CN (1) | CN1809573A (cg-RX-API-DMAC7.html) |
| BR (1) | BRPI0409622A (cg-RX-API-DMAC7.html) |
| CA (1) | CA2523291A1 (cg-RX-API-DMAC7.html) |
| CO (1) | CO5700829A2 (cg-RX-API-DMAC7.html) |
| GB (1) | GB0309221D0 (cg-RX-API-DMAC7.html) |
| IS (1) | IS8135A (cg-RX-API-DMAC7.html) |
| MA (1) | MA27674A1 (cg-RX-API-DMAC7.html) |
| MX (1) | MXPA05011365A (cg-RX-API-DMAC7.html) |
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| RU (1) | RU2005136370A (cg-RX-API-DMAC7.html) |
| WO (1) | WO2004094430A1 (cg-RX-API-DMAC7.html) |
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| EP1565428A1 (en) * | 2002-11-27 | 2005-08-24 | Elan Pharmaceuticals, Inc. | Substituted ureas and carbamates |
| GB0328900D0 (en) * | 2003-12-12 | 2004-01-14 | Glaxo Group Ltd | Novel compounds |
| US7763609B2 (en) | 2003-12-15 | 2010-07-27 | Schering Corporation | Heterocyclic aspartyl protease inhibitors |
| GB0411404D0 (en) * | 2004-05-21 | 2004-06-23 | Glaxo Group Ltd | Novel compounds |
| BRPI0515383A (pt) * | 2004-09-21 | 2008-07-22 | Pfizer Prod Inc | n-etil hidroxietilamina útil no tratamento de condições do snc |
| GB0422766D0 (en) * | 2004-10-13 | 2004-11-17 | Glaxo Group Ltd | Novel compounds |
| GB0422765D0 (en) * | 2004-10-13 | 2004-11-17 | Glaxo Group Ltd | Novel compounds |
| GB0422755D0 (en) * | 2004-10-13 | 2004-11-17 | Glaxo Group Ltd | Novel compounds |
| WO2006088705A1 (en) * | 2005-02-14 | 2006-08-24 | Wyeth | Terphenyl guanidines as [beta symbol] -secretase inhibitors |
| GB0506562D0 (en) * | 2005-03-31 | 2005-05-04 | Glaxo Group Ltd | Novel compounds |
| KR20080015079A (ko) | 2005-04-08 | 2008-02-18 | 코멘티스, 인코포레이티드 | 베타 세크레타제 활성을 억제하는 화합물 및 이것의 사용방법 |
| WO2007019078A2 (en) * | 2005-08-03 | 2007-02-15 | Merck & Co., Inc. | Tricyclic beta-secretase inhibitors for the treatment of alzheimer's disease |
| WO2007061670A1 (en) * | 2005-11-21 | 2007-05-31 | 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 |
| US7745484B2 (en) | 2005-11-21 | 2010-06-29 | Amgen Inc. | Beta-secretase modulators and methods of use |
| US7838676B2 (en) * | 2005-11-21 | 2010-11-23 | Amgen Inc. | Beta-secretase modulators and methods of use |
| TW200901991A (en) | 2007-05-25 | 2009-01-16 | Amgen Inc | Substituted hydroxyethyl amine compounds as beta-secretase modulators and methods of use |
| MX2009012608A (es) | 2007-05-25 | 2009-12-07 | Amgen Inc | Compuestos de hidroxietil amina substituidos como moduladores de beta-secretasa y metodos de uso. |
| FR2919288B1 (fr) * | 2007-07-27 | 2009-09-04 | Sanofi Aventis Sa | Derives de 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6- carboxamides, leur preparation et leur application en therapeutique. |
| FR2919285B1 (fr) | 2007-07-27 | 2012-08-31 | Sanofi Aventis | Derives de 1-oxo-isoindoline-4-carboxamides et de 1-oxo- 1,2,3,4-tetrahydroisoquinoleine-5-carboxamides, leur preparation et leur application en therapeutique. |
| ATE512968T1 (de) * | 2007-07-27 | 2011-07-15 | Sanofi Aventis | 1,2,3,4-tetrahydropyrrolo(1,2-a)pyrazin-6- carboxamid und 2,3,4,5-tetrahydropyrrolo(1,2-a)- diazepin-7-carboxamid- derivate, ihre herstellung und therapeutische verwendung |
| FR2919286A1 (fr) | 2007-07-27 | 2009-01-30 | Sanofi Aventis Sa | Derives de derives de 1-oxo-1,2-dihydroisoquinoleine-5- carboxamides et de 4-oxo-3,4-dihydroquinazoline-8- carboxamides,leur preparation et leur application en therapeutique. |
| FR2919289B1 (fr) * | 2007-07-27 | 2009-09-04 | Sanofi Aventis Sa | Derives de 2,3,4,5-tetrahydropyrrolo[1,2-a][1,4]- diazepine-7-carboxamides, leur preparation et leur application en therapeutique. |
| US9096541B2 (en) | 2012-03-29 | 2015-08-04 | Oklahoma Medical Research Foundation | Inhibition of memapsin 1 cleavage in the treatment of diabetes |
| EP3684767B1 (en) * | 2017-09-22 | 2024-04-24 | Jubilant Epipad LLC | Heterocyclic compounds as pad inhibitors |
| US12043631B2 (en) | 2017-10-13 | 2024-07-23 | Purdue Research Foundation | BACE1 inhibitors for the treatment of Alzheimer's disease |
| US11214579B2 (en) | 2017-10-13 | 2022-01-04 | Purdue Research Foundation | BACE1 inhibitors for the treatment of Alzheimer's disease |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998033795A1 (en) * | 1997-02-04 | 1998-08-06 | The Regents Of The University Of California | Nanomolar, non-peptide inhibitors of cathepsin d |
| US6207664B1 (en) * | 1998-11-25 | 2001-03-27 | Pfizer Inc. | Squalene synthetase inhibitor agents |
| CA2410680A1 (en) * | 2000-06-30 | 2002-01-10 | Elan Pharmaceuticals, Inc. | Compounds to treat alzheimer's disease |
-
2003
- 2003-04-23 GB GBGB0309221.0A patent/GB0309221D0/en not_active Ceased
-
2004
- 2004-04-21 CN CNA2004800175617A patent/CN1809573A/zh active Pending
- 2004-04-21 EP EP04728567A patent/EP1620438A1/en not_active Withdrawn
- 2004-04-21 CA CA002523291A patent/CA2523291A1/en not_active Abandoned
- 2004-04-21 US US10/553,878 patent/US20060229302A1/en not_active Abandoned
- 2004-04-21 BR BRPI0409622-3A patent/BRPI0409622A/pt not_active IP Right Cessation
- 2004-04-21 WO PCT/EP2004/004244 patent/WO2004094430A1/en not_active Ceased
- 2004-04-21 JP JP2006505223A patent/JP2006524206A/ja not_active Withdrawn
- 2004-04-21 KR KR1020057019979A patent/KR20050111797A/ko not_active Withdrawn
- 2004-04-21 RU RU2005136370/04A patent/RU2005136370A/ru not_active Application Discontinuation
- 2004-04-21 MX MXPA05011365A patent/MXPA05011365A/es not_active Application Discontinuation
-
2005
- 2005-10-05 ZA ZA200508041A patent/ZA200508041B/en unknown
- 2005-10-19 MA MA28563A patent/MA27674A1/fr unknown
- 2005-10-21 CO CO05107375A patent/CO5700829A2/es not_active Application Discontinuation
- 2005-11-17 NO NO20055442A patent/NO20055442L/no not_active Application Discontinuation
- 2005-11-21 IS IS8135A patent/IS8135A/is unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO2004094430A1 (en) | 2004-11-04 |
| GB0309221D0 (en) | 2003-06-04 |
| CA2523291A1 (en) | 2004-11-04 |
| BRPI0409622A (pt) | 2006-04-18 |
| MA27674A1 (fr) | 2005-12-01 |
| EP1620438A1 (en) | 2006-02-01 |
| JP2006524206A (ja) | 2006-10-26 |
| US20060229302A1 (en) | 2006-10-12 |
| ZA200508041B (en) | 2007-02-28 |
| NO20055442L (no) | 2005-11-17 |
| AU2004232475A1 (en) | 2004-11-04 |
| IS8135A (is) | 2005-11-21 |
| CO5700829A2 (es) | 2006-11-30 |
| KR20050111797A (ko) | 2005-11-28 |
| RU2005136370A (ru) | 2006-05-27 |
| CN1809573A (zh) | 2006-07-26 |
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| FA | Abandonment or withdrawal |