BRPI0715437A2 - lactamas macrocÍclicas - Google Patents
lactamas macrocÍclicas Download PDFInfo
- Publication number
- BRPI0715437A2 BRPI0715437A2 BRPI0715437-2A BRPI0715437A BRPI0715437A2 BR PI0715437 A2 BRPI0715437 A2 BR PI0715437A2 BR PI0715437 A BRPI0715437 A BR PI0715437A BR PI0715437 A2 BRPI0715437 A2 BR PI0715437A2
- Authority
- BR
- Brazil
- Prior art keywords
- alkyl
- tetrahydro
- dioxo
- benzo
- cycloalkyl
- Prior art date
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- 150000003951 lactams Chemical class 0.000 title abstract description 3
- 239000002253 acid Substances 0.000 claims abstract description 21
- 150000003839 salts Chemical group 0.000 claims abstract description 20
- 239000012458 free base Substances 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- -1 aryl (C1-4) alkyl Chemical group 0.000 claims description 141
- 150000001875 compounds Chemical class 0.000 claims description 66
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 65
- 239000001257 hydrogen Substances 0.000 claims description 43
- 229910052739 hydrogen Inorganic materials 0.000 claims description 43
- 125000000217 alkyl group Chemical group 0.000 claims description 41
- 125000001072 heteroaryl group Chemical group 0.000 claims description 41
- 125000003118 aryl group Chemical group 0.000 claims description 35
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 27
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 24
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 21
- 125000001424 substituent group Chemical group 0.000 claims description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 15
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 10
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 10
- 125000002947 alkylene group Chemical group 0.000 claims description 10
- 230000000926 neurological effect Effects 0.000 claims description 10
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 9
- 125000004414 alkyl thio group Chemical group 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 102000013455 Amyloid beta-Peptides Human genes 0.000 claims description 8
- 108010090849 Amyloid beta-Peptides Proteins 0.000 claims description 8
- 230000002776 aggregation Effects 0.000 claims description 8
- 238000004220 aggregation Methods 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000004043 oxo group Chemical group O=* 0.000 claims description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims description 6
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 6
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 125000005529 alkyleneoxy group Chemical group 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 239000002243 precursor Substances 0.000 claims description 4
- 125000006413 ring segment Chemical group 0.000 claims description 4
- 125000005739 1,1,2,2-tetrafluoroethanediyl group Chemical group FC(F)([*:1])C(F)(F)[*:2] 0.000 claims description 3
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 3
- 125000005237 alkyleneamino group Chemical group 0.000 claims description 3
- 230000006933 amyloid-beta aggregation Effects 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 150000002431 hydrogen Chemical group 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 229910052707 ruthenium Inorganic materials 0.000 claims description 3
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 claims description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 2
- 238000007306 functionalization reaction Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229910052750 molybdenum Inorganic materials 0.000 claims description 2
- 239000011733 molybdenum Substances 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 claims description 2
- 229910052721 tungsten Inorganic materials 0.000 claims description 2
- 239000010937 tungsten Substances 0.000 claims description 2
- 229910052720 vanadium Inorganic materials 0.000 claims description 2
- 208000012902 Nervous system disease Diseases 0.000 claims 4
- 208000025966 Neurological disease Diseases 0.000 claims 4
- 208000019553 vascular disease Diseases 0.000 claims 4
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims 1
- 229940088679 drug related substance Drugs 0.000 claims 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims 1
- 238000005649 metathesis reaction Methods 0.000 claims 1
- 239000008024 pharmaceutical diluent Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 3
- 150000002678 macrocyclic compounds Chemical class 0.000 abstract description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 18
- 239000003795 chemical substances by application Substances 0.000 description 16
- 238000012360 testing method Methods 0.000 description 16
- 239000000203 mixture Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- 125000005605 benzo group Chemical group 0.000 description 10
- 201000010099 disease Diseases 0.000 description 9
- 208000035475 disorder Diseases 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- 125000004076 pyridyl group Chemical group 0.000 description 8
- 125000000714 pyrimidinyl group Chemical group 0.000 description 8
- 210000004881 tumor cell Anatomy 0.000 description 7
- 230000002792 vascular Effects 0.000 description 7
- 206010027476 Metastases Diseases 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 230000009401 metastasis Effects 0.000 description 6
- 230000002265 prevention Effects 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 125000003107 substituted aryl group Chemical group 0.000 description 5
- 102000003908 Cathepsin D Human genes 0.000 description 4
- 108090000258 Cathepsin D Proteins 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 230000001629 suppression Effects 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 3
- ALEZWDWARSRIRW-UHFFFAOYSA-N 1-(3-propan-2-ylphenyl)cyclopropan-1-amine Chemical compound CC(C)C1=CC=CC(C2(N)CC2)=C1 ALEZWDWARSRIRW-UHFFFAOYSA-N 0.000 description 3
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- 101000894895 Homo sapiens Beta-secretase 1 Proteins 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 125000006317 cyclopropyl amino group Chemical group 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 230000005284 excitation Effects 0.000 description 3
- RWNJOXUVHRXHSD-UHFFFAOYSA-N hept-6-enoic acid Chemical compound OC(=O)CCCCC=C RWNJOXUVHRXHSD-UHFFFAOYSA-N 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 238000010561 standard procedure Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 241000701447 unidentified baculovirus Species 0.000 description 3
- HWUWVNZQHHMGEX-YFQNEARWSA-N (3s,14r,16s)-16-[(1r)-1-hydroxy-2-[[1-(3-propan-2-ylphenyl)cyclopropyl]amino]ethyl]-3,4,14-trimethyl-1,4-diazacyclohexadecane-2,5-dione Chemical compound CC(C)C1=CC=CC(C2(CC2)NC[C@@H](O)[C@H]2NC(=O)[C@H](C)N(C)C(=O)CCCCCCCC[C@@H](C)C2)=C1 HWUWVNZQHHMGEX-YFQNEARWSA-N 0.000 description 2
- JELJLRDRTPRWRI-UHFFFAOYSA-N 1,3,4,5-tetrahydro-2-benzoxepine Chemical compound C1CCOCC2=CC=CC=C21 JELJLRDRTPRWRI-UHFFFAOYSA-N 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N 1-ethenoxybutane Chemical compound CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- UMCMPZBLKLEWAF-BCTGSCMUSA-N 3-[(3-cholamidopropyl)dimethylammonio]propane-1-sulfonate Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCC[N+](C)(C)CCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 UMCMPZBLKLEWAF-BCTGSCMUSA-N 0.000 description 2
- LWYFMTMRWRGREZ-UHFFFAOYSA-N 3-propan-2-ylbenzonitrile Chemical compound CC(C)C1=CC=CC(C#N)=C1 LWYFMTMRWRGREZ-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 description 2
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- 241001465754 Metazoa Species 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
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 2
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- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 206010029216 Nervousness Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000004280 Sodium formate Substances 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
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- 125000005115 alkyl carbamoyl group Chemical group 0.000 description 1
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- 238000005804 alkylation reaction Methods 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- XKMRRTOUMJRJIA-UHFFFAOYSA-N ammonia nh3 Chemical compound N.N XKMRRTOUMJRJIA-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 208000025698 brain inflammatory disease Diseases 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- PVEOYINWKBTPIZ-UHFFFAOYSA-N but-3-enoic acid Chemical compound OC(=O)CC=C PVEOYINWKBTPIZ-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- YCDLGAFLEUBSPU-UHFFFAOYSA-N dec-9-en-3-ol Chemical compound CCC(O)CCCCCC=C YCDLGAFLEUBSPU-UHFFFAOYSA-N 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- OLAMWIPURJGSKE-UHFFFAOYSA-N et2o diethylether Chemical compound CCOCC.CCOCC OLAMWIPURJGSKE-UHFFFAOYSA-N 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 102000044297 human BACE1 Human genes 0.000 description 1
- 102000053356 human CTSD Human genes 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- IXHBTMCLRNMKHZ-LBPRGKRZSA-N levobunolol Chemical compound O=C1CCCC2=C1C=CC=C2OC[C@@H](O)CNC(C)(C)C IXHBTMCLRNMKHZ-LBPRGKRZSA-N 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- JTRJZLMPZMYZAU-NEPJUHHUSA-N methyl (2s,4r)-4-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]oct-7-enoate Chemical compound CC(C)(C)OC(=O)N[C@H](C(=O)OC)C[C@H](C)CCC=C JTRJZLMPZMYZAU-NEPJUHHUSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- KARXIZHXFYAUBJ-YDZRNGNQSA-N n-[(2s)-1-[[(2s,3s,5r)-1-chloro-2-hydroxy-5-methylnon-8-en-3-yl]amino]-1-oxopropan-2-yl]-n-methylhept-6-enamide Chemical compound C=CCC[C@@H](C)C[C@@H]([C@H](O)CCl)NC(=O)[C@H](C)N(C)C(=O)CCCCC=C KARXIZHXFYAUBJ-YDZRNGNQSA-N 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000000626 neurodegenerative effect Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 238000005949 ozonolysis reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001639 phenylmethylene group Chemical group [H]C(=*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007974 sodium acetate buffer Substances 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- LNDCCSBWZAQAAW-UHFFFAOYSA-M sodium hydrogen sulfate sulfuric acid Chemical compound [Na+].OS(O)(=O)=O.OS([O-])(=O)=O LNDCCSBWZAQAAW-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- 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
- A61P25/28—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
- A61P35/00—Antineoplastic agents
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D245/00—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms
- C07D245/02—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
- C07D273/02—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00 having two nitrogen atoms and only one oxygen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP06117583.2 | 2006-07-20 | ||
| EP06117583 | 2006-07-20 | ||
| PCT/EP2007/057492 WO2008009734A1 (en) | 2006-07-20 | 2007-07-19 | Macrocyclic lactams |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| BRPI0715437A2 true BRPI0715437A2 (pt) | 2013-04-16 |
Family
ID=37451237
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BRPI0715437-2A BRPI0715437A2 (pt) | 2006-07-20 | 2007-07-19 | lactamas macrocÍclicas |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US20090170878A1 (https=) |
| EP (1) | EP2046760A1 (https=) |
| JP (1) | JP2009544597A (https=) |
| KR (1) | KR20090041387A (https=) |
| CN (1) | CN101484431A (https=) |
| AU (1) | AU2007275132A1 (https=) |
| BR (1) | BRPI0715437A2 (https=) |
| CA (1) | CA2656869A1 (https=) |
| MX (1) | MX2009000768A (https=) |
| RU (1) | RU2009105764A (https=) |
| WO (1) | WO2008009734A1 (https=) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0325830D0 (en) * | 2003-11-05 | 2003-12-10 | Novartis Ag | Organic compounds |
| US7763609B2 (en) | 2003-12-15 | 2010-07-27 | Schering Corporation | Heterocyclic aspartyl protease inhibitors |
| US20080132477A1 (en) * | 2005-01-13 | 2008-06-05 | Claudia Betschart | Macrocyclic Compounds Useful as Bace Inhibitors |
| GB0500683D0 (en) * | 2005-01-13 | 2005-02-23 | Novartis Ag | Organic compounds |
| GB0526614D0 (en) | 2005-12-30 | 2006-02-08 | Novartis Ag | Organic compounds |
| JP2009544599A (ja) * | 2006-07-20 | 2009-12-17 | ノバルティス アクチエンゲゼルシャフト | Ｂａｃｅ阻害剤として有用な大環状化合物 |
| US20140371283A1 (en) | 2013-02-12 | 2014-12-18 | Buck Institute For Research On Aging | Hydantoins that modulate bace-mediated app processing |
| US11834515B2 (en) | 2017-10-11 | 2023-12-05 | Cornell University | Macrocyclic compounds as proteasome inhibitors |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002100856A1 (en) * | 2001-06-12 | 2002-12-19 | Elan Pharmaceuticals, Inc. | Macrocycles useful in the treatment of alzheimer's disease |
| BR0210391A (pt) * | 2001-06-12 | 2004-06-15 | Elan Pharm Inc | Composto, métodos de tratar um paciente que tenha ou de prevenir um paciente de contrair uma doença ou condição e de preparar um composto, e, uso de um composto |
| GB0325830D0 (en) * | 2003-11-05 | 2003-12-10 | Novartis Ag | Organic compounds |
| DE602005007245D1 (https=) * | 2004-07-28 | 2008-07-10 | Schering Corp | |
| US20080132477A1 (en) * | 2005-01-13 | 2008-06-05 | Claudia Betschart | Macrocyclic Compounds Useful as Bace Inhibitors |
| GB0500683D0 (en) * | 2005-01-13 | 2005-02-23 | Novartis Ag | Organic compounds |
| GB0526614D0 (en) * | 2005-12-30 | 2006-02-08 | Novartis Ag | Organic compounds |
| JP2009544599A (ja) * | 2006-07-20 | 2009-12-17 | ノバルティス アクチエンゲゼルシャフト | Ｂａｃｅ阻害剤として有用な大環状化合物 |
-
2007
- 2007-07-19 CA CA002656869A patent/CA2656869A1/en not_active Abandoned
- 2007-07-19 MX MX2009000768A patent/MX2009000768A/es unknown
- 2007-07-19 JP JP2009519989A patent/JP2009544597A/ja not_active Withdrawn
- 2007-07-19 US US12/374,469 patent/US20090170878A1/en not_active Abandoned
- 2007-07-19 EP EP07819907A patent/EP2046760A1/en not_active Withdrawn
- 2007-07-19 WO PCT/EP2007/057492 patent/WO2008009734A1/en not_active Ceased
- 2007-07-19 BR BRPI0715437-2A patent/BRPI0715437A2/pt not_active Application Discontinuation
- 2007-07-19 AU AU2007275132A patent/AU2007275132A1/en not_active Abandoned
- 2007-07-19 CN CNA2007800255206A patent/CN101484431A/zh active Pending
- 2007-07-19 RU RU2009105764/04A patent/RU2009105764A/ru not_active Application Discontinuation
- 2007-07-19 KR KR1020097001068A patent/KR20090041387A/ko not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| CN101484431A (zh) | 2009-07-15 |
| EP2046760A1 (en) | 2009-04-15 |
| KR20090041387A (ko) | 2009-04-28 |
| WO2008009734A1 (en) | 2008-01-24 |
| MX2009000768A (es) | 2009-01-28 |
| AU2007275132A1 (en) | 2008-01-24 |
| CA2656869A1 (en) | 2008-01-24 |
| JP2009544597A (ja) | 2009-12-17 |
| RU2009105764A (ru) | 2010-08-27 |
| US20090170878A1 (en) | 2009-07-02 |
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