HUE026338T2 - 6,7-dihydro-pyrazolo[1,5-a]pyrazin-4-ylamine derivatives useful as inhibitors of beta-secretase (bace) - Google Patents

Info

Publication number

HUE026338T2

HUE026338T2 HUE12707276A HUE12707276A HUE026338T2 HU E026338 T2 HUE026338 T2 HU E026338T2 HU E12707276 A HUE12707276 A HU E12707276A HU E12707276 A HUE12707276 A HU E12707276A HU E026338 T2 HUE026338 T2 HU E026338T2

Authority

HU

Hungary

Prior art keywords

mixture

mmol

vacuo

compound

dcm

Prior art date

2011-03-01

Links

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• 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 title description 17
• 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 title description 17
• 239000003112 inhibitor Substances 0.000 title description 6
• IWEFEVCBSHDDLF-UHFFFAOYSA-N 6,7-dihydropyrazolo[1,5-a]pyrazin-4-amine Chemical class NC1=NCCN2N=CC=C12 IWEFEVCBSHDDLF-UHFFFAOYSA-N 0.000 title description 2
• 238000000034 method Methods 0.000 claims description 165
• 150000001875 compounds Chemical class 0.000 claims description 132
• -1 compound compound Chemical class 0.000 claims description 45
• 208000024827 Alzheimer disease Diseases 0.000 claims description 38
• 239000001257 hydrogen Substances 0.000 claims description 38
• 229910052739 hydrogen Inorganic materials 0.000 claims description 38
• 206010012289 Dementia Diseases 0.000 claims description 34
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 28
• 150000003839 salts Chemical class 0.000 claims description 27
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 23
• 238000011282 treatment Methods 0.000 claims description 23
• 125000001072 heteroaryl group Chemical group 0.000 claims description 22
• 239000012453 solvate Substances 0.000 claims description 15
• 239000003795 chemical substances by application Substances 0.000 claims description 14
• 239000008194 pharmaceutical composition Substances 0.000 claims description 14
• 229910052736 halogen Inorganic materials 0.000 claims description 12
• 150000002367 halogens Chemical class 0.000 claims description 12
• 108010090849 Amyloid beta-Peptides Proteins 0.000 claims description 11
• 102000013455 Amyloid beta-Peptides Human genes 0.000 claims description 11
• 208000018737 Parkinson disease Diseases 0.000 claims description 9
• 201000010374 Down Syndrome Diseases 0.000 claims description 8
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 6
• 125000000217 alkyl group Chemical group 0.000 claims description 6
• 230000005764 inhibitory process Effects 0.000 claims description 5
• 230000002265 prevention Effects 0.000 claims description 5
• 239000000126 substance Substances 0.000 claims description 5
• 239000003085 diluting agent Substances 0.000 claims description 4
• 238000002156 mixing Methods 0.000 claims description 4
• 125000002971 oxazolyl group Chemical group 0.000 claims description 4
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
• 239000000460 chlorine Substances 0.000 claims description 3
• 229910052801 chlorine Inorganic materials 0.000 claims description 3
• 229910052742 iron Inorganic materials 0.000 claims description 3
• 230000001149 cognitive effect Effects 0.000 claims description 2
• 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 2
• 125000003545 alkoxy group Chemical group 0.000 claims 3
• DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims 2
• KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 2
• BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims 1
• 101710149863 C-C chemokine receptor type 4 Proteins 0.000 claims 1
• 102100032976 CCR4-NOT transcription complex subunit 6 Human genes 0.000 claims 1
• 239000004471 Glycine Substances 0.000 claims 1
• 241000711286 Heterosais Species 0.000 claims 1
• WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims 1
• 239000002246 antineoplastic agent Substances 0.000 claims 1
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
• 235000009508 confectionery Nutrition 0.000 claims 1
• 238000011109 contamination Methods 0.000 claims 1
• 229940127089 cytotoxic agent Drugs 0.000 claims 1
• 239000002274 desiccant Substances 0.000 claims 1
• 230000008030 elimination Effects 0.000 claims 1
• 238000003379 elimination reaction Methods 0.000 claims 1
• 238000000605 extraction Methods 0.000 claims 1
• 150000002431 hydrogen Chemical class 0.000 claims 1
• 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims 1
• ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims 1
• 230000033764 rhythmic process Effects 0.000 claims 1
• 238000010186 staining Methods 0.000 claims 1
• 150000003573 thiols Chemical class 0.000 claims 1
• 150000003852 triazoles Chemical class 0.000 claims 1
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 354
• 239000000543 intermediate Substances 0.000 description 310
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 241
• 239000000203 mixture Substances 0.000 description 165
• 239000002904 solvent Substances 0.000 description 102
• 238000002360 preparation method Methods 0.000 description 99
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 94
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• 238000006243 chemical reaction Methods 0.000 description 86
• 239000000741 silica gel Substances 0.000 description 85
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• 238000003818 flash chromatography Methods 0.000 description 76
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 74
• 239000007787 solid Substances 0.000 description 68
• 239000012043 crude product Substances 0.000 description 43
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 38
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 38
• 239000012044 organic layer Substances 0.000 description 38
• 229910000069 nitrogen hydride Inorganic materials 0.000 description 34
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 30
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 30
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
• 239000012071 phase Substances 0.000 description 27
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 26
• 238000005160 1H NMR spectroscopy Methods 0.000 description 25
• 108010064539 amyloid beta-protein (1-42) Proteins 0.000 description 25
• 239000003921 oil Substances 0.000 description 25
• 125000004435 hydrogen atom Chemical class [H]* 0.000 description 23
• 239000011541 reaction mixture Substances 0.000 description 22
• 229910000029 sodium carbonate Inorganic materials 0.000 description 22
• 125000005843 halogen group Chemical group 0.000 description 21
• 239000012047 saturated solution Substances 0.000 description 21
• 238000004808 supercritical fluid chromatography Methods 0.000 description 19
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
• BMTZEAOGFDXDAD-UHFFFAOYSA-M 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium;chloride Chemical compound [Cl-].COC1=NC(OC)=NC([N+]2(C)CCOCC2)=N1 BMTZEAOGFDXDAD-UHFFFAOYSA-M 0.000 description 17
• 239000002585 base Substances 0.000 description 17
• 238000010438 heat treatment Methods 0.000 description 17
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
• 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 16
• 229910002092 carbon dioxide Inorganic materials 0.000 description 16
• 239000012442 inert solvent Substances 0.000 description 16
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 15
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 13
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
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• 239000000047 product Substances 0.000 description 12
• 125000001424 substituent group Chemical group 0.000 description 12
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
• 238000003556 assay Methods 0.000 description 11
• ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
• 239000003937 drug carrier Substances 0.000 description 11
• JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 11
• 108090000765 processed proteins & peptides Proteins 0.000 description 11
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
• 102100021257 Beta-secretase 1 Human genes 0.000 description 10
• 239000002253 acid Substances 0.000 description 10
• 239000003054 catalyst Substances 0.000 description 10
• 230000000694 effects Effects 0.000 description 10
• 239000007924 injection Substances 0.000 description 10
• 238000002347 injection Methods 0.000 description 10
• 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 9
• 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 9
• 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 9
• ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 9
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• 125000004076 pyridyl group Chemical group 0.000 description 9
• 125000000714 pyrimidinyl group Chemical group 0.000 description 9
• 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 8
• MNLXDZRHZRSOGL-UHFFFAOYSA-N 6-(5-amino-2-fluorophenyl)-6-(difluoromethyl)-7h-pyrazolo[1,5-a]pyrazin-4-amine Chemical compound C1N2N=CC=C2C(N)=NC1(C(F)F)C1=CC(N)=CC=C1F MNLXDZRHZRSOGL-UHFFFAOYSA-N 0.000 description 8
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
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• CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 8
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• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 6
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• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
• 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 6
• 125000005412 pyrazyl group Chemical group 0.000 description 6
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• MBACRDZWRXWNMY-UHFFFAOYSA-N oxathiazolidine 2,2-dioxide Chemical compound O=S1(=O)NCCO1 MBACRDZWRXWNMY-UHFFFAOYSA-N 0.000 description 4
• CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 4
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