JP2006241163A - γ−セクレターゼ阻害剤としてのスルファミド - Google Patents
γ−セクレターゼ阻害剤としてのスルファミド Download PDFInfo
- Publication number
- JP2006241163A JP2006241163A JP2006078136A JP2006078136A JP2006241163A JP 2006241163 A JP2006241163 A JP 2006241163A JP 2006078136 A JP2006078136 A JP 2006078136A JP 2006078136 A JP2006078136 A JP 2006078136A JP 2006241163 A JP2006241163 A JP 2006241163A
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- Prior art keywords
- alkyl
- amino
- cor
- mhz
- added
- Prior art date
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- Granted
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- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 title claims description 85
- 229940125373 Gamma-Secretase Inhibitor Drugs 0.000 title 1
- 239000003540 gamma secretase inhibitor Substances 0.000 title 1
- -1 sulfamide compound Chemical class 0.000 claims abstract description 285
- 150000001875 compounds Chemical class 0.000 claims abstract description 100
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 148
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 100
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 100
- 229910052757 nitrogen Inorganic materials 0.000 claims description 79
- 229910052799 carbon Inorganic materials 0.000 claims description 61
- 125000001072 heteroaryl group Chemical group 0.000 claims description 56
- 229910052739 hydrogen Inorganic materials 0.000 claims description 53
- 229910052736 halogen Inorganic materials 0.000 claims description 51
- 150000002367 halogens Chemical class 0.000 claims description 48
- 238000000034 method Methods 0.000 claims description 43
- 125000003118 aryl group Chemical group 0.000 claims description 41
- 125000004122 cyclic group Chemical group 0.000 claims description 35
- 125000001424 substituent group Chemical group 0.000 claims description 35
- 125000000623 heterocyclic group Chemical group 0.000 claims description 33
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 30
- 150000003839 salts Chemical class 0.000 claims description 26
- 125000006413 ring segment Chemical group 0.000 claims description 25
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- 125000003342 alkenyl group Chemical group 0.000 claims description 22
- 229910052717 sulfur Inorganic materials 0.000 claims description 22
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 claims description 20
- 101150065749 Churc1 gene Proteins 0.000 claims description 20
- 102100038239 Protein Churchill Human genes 0.000 claims description 20
- 125000004429 atom Chemical group 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- 125000000304 alkynyl group Chemical group 0.000 claims description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 19
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 18
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 18
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 17
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 15
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 11
- 125000006719 (C6-C10) aryl (C1-C6) alkyl group Chemical group 0.000 claims description 11
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 11
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 10
- 125000002252 acyl group Chemical group 0.000 claims description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 10
- 239000001301 oxygen Substances 0.000 claims description 10
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 9
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 9
- 125000006574 non-aromatic ring group Chemical group 0.000 claims description 9
- 239000011593 sulfur Substances 0.000 claims description 9
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 7
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000003277 amino group Chemical group 0.000 claims description 6
- 125000003367 polycyclic group Chemical group 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 5
- 239000000470 constituent Substances 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000002950 monocyclic group Chemical group 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 150000003235 pyrrolidines Chemical class 0.000 claims description 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 2
- 125000005322 morpholin-1-yl group Chemical group 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 abstract description 15
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 abstract description 15
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 abstract description 15
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 abstract description 11
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 abstract description 11
- 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 abstract description 5
- 230000002265 prevention Effects 0.000 abstract description 4
- 238000012545 processing Methods 0.000 abstract description 3
- 206010012289 Dementia Diseases 0.000 abstract description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 313
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 261
- 239000000243 solution Substances 0.000 description 137
- 235000019439 ethyl acetate Nutrition 0.000 description 123
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 108
- 239000000203 mixture Substances 0.000 description 105
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 104
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 83
- 239000007787 solid Substances 0.000 description 74
- 239000000047 product Substances 0.000 description 71
- 239000011541 reaction mixture Substances 0.000 description 70
- 238000005481 NMR spectroscopy Methods 0.000 description 69
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 64
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 64
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 63
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 46
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 43
- 239000000284 extract Substances 0.000 description 43
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- 239000011734 sodium Substances 0.000 description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 36
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 34
- 239000000377 silicon dioxide Substances 0.000 description 34
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 31
- 239000000741 silica gel Substances 0.000 description 31
- 229910002027 silica gel Inorganic materials 0.000 description 31
- 239000012267 brine Substances 0.000 description 30
- 238000010992 reflux Methods 0.000 description 30
- 229920006395 saturated elastomer Polymers 0.000 description 30
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 29
- 238000006243 chemical reaction Methods 0.000 description 29
- 238000004587 chromatography analysis Methods 0.000 description 29
- 239000002904 solvent Substances 0.000 description 28
- 239000003921 oil Substances 0.000 description 27
- 235000019198 oils Nutrition 0.000 description 27
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 26
- 150000001412 amines Chemical class 0.000 description 26
- 239000000843 powder Substances 0.000 description 25
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 21
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 21
- 238000004440 column chromatography Methods 0.000 description 21
- 239000012074 organic phase Substances 0.000 description 21
- 239000002253 acid Substances 0.000 description 20
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 19
- 239000010410 layer Substances 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
- 238000003756 stirring Methods 0.000 description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- MZPWKJZDOCIALD-UHFFFAOYSA-N pyrocatechol sulfate Chemical compound OC1=CC=CC=C1OS(O)(=O)=O MZPWKJZDOCIALD-UHFFFAOYSA-N 0.000 description 16
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- 238000003818 flash chromatography Methods 0.000 description 15
- 150000002576 ketones Chemical class 0.000 description 15
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 15
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 15
- 150000004985 diamines Chemical class 0.000 description 14
- 150000002148 esters Chemical class 0.000 description 14
- 239000006260 foam Substances 0.000 description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 14
- 238000001816 cooling Methods 0.000 description 12
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 11
- FDLDWKIEWAWOSL-UHFFFAOYSA-N ethyl acetate;2-methylpentane Chemical compound CCCC(C)C.CCOC(C)=O FDLDWKIEWAWOSL-UHFFFAOYSA-N 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical group C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 11
- 238000001665 trituration Methods 0.000 description 11
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 10
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 10
- 235000019270 ammonium chloride Nutrition 0.000 description 10
- 239000012230 colorless oil Substances 0.000 description 10
- 150000002825 nitriles Chemical class 0.000 description 10
- 229910000104 sodium hydride Inorganic materials 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 9
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 9
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- 230000009467 reduction Effects 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 8
- 0 N*1C2*C1B2 Chemical compound N*1C2*C1B2 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 238000001704 evaporation Methods 0.000 description 8
- 230000014509 gene expression Effects 0.000 description 8
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- 239000000725 suspension Substances 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- 150000001408 amides Chemical class 0.000 description 7
- 235000019445 benzyl alcohol Nutrition 0.000 description 7
- 230000008020 evaporation Effects 0.000 description 7
- 150000003840 hydrochlorides Chemical class 0.000 description 7
- 239000000463 material Substances 0.000 description 7
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- 238000000746 purification Methods 0.000 description 7
- 239000012312 sodium hydride Substances 0.000 description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- KDUIUFJBNGTBMD-DLMDZQPMSA-N [8]annulene Chemical compound C/1=C/C=C\C=C/C=C\1 KDUIUFJBNGTBMD-DLMDZQPMSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- KMGBZBJJOKUPIA-UHFFFAOYSA-N butyl iodide Chemical compound CCCCI KMGBZBJJOKUPIA-UHFFFAOYSA-N 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 238000012746 preparative thin layer chromatography Methods 0.000 description 6
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 6
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 5
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 5
- KCBWAFJCKVKYHO-UHFFFAOYSA-N 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-[[4-[1-propan-2-yl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyrazolo[3,4-d]pyrimidine Chemical compound C1(CC1)C1=NC=NC(=C1C1=NC=C2C(=N1)N(N=C2)CC1=CC=C(C=C1)C=1N(C=C(N=1)C(F)(F)F)C(C)C)OC KCBWAFJCKVKYHO-UHFFFAOYSA-N 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- 239000004809 Teflon Substances 0.000 description 5
- 229920006362 Teflon® Polymers 0.000 description 5
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 235000015165 citric acid Nutrition 0.000 description 5
- KZZKOVLJUKWSKX-UHFFFAOYSA-N cyclobutanamine Chemical compound NC1CCC1 KZZKOVLJUKWSKX-UHFFFAOYSA-N 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 238000002953 preparative HPLC Methods 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 125000004076 pyridyl group Chemical group 0.000 description 5
- 235000017281 sodium acetate Nutrition 0.000 description 5
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 5
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- 150000003512 tertiary amines Chemical class 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
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 1
- 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- NJYSKMGFVYYAPH-UHFFFAOYSA-N trideca-6,8,10-trien-1-amine Chemical compound CCC=CC=CC=CCCCCCN NJYSKMGFVYYAPH-UHFFFAOYSA-N 0.000 description 1
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
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- A—HUMAN NECESSITIES
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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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
- A61P25/28—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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- C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C307/04—Diamides of sulfuric acids
- C07C307/08—Diamides of sulfuric acids having nitrogen atoms of the sulfamide groups bound to carbon atoms of rings other than six-membered aromatic rings
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
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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
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
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- 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
- C07D213/70—Sulfur atoms
- C07D213/71—Sulfur atoms to which a second hetero atom is attached
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- 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
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- 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
- C07D215/12—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 substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D223/32—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems containing carbocyclic rings other than six-membered
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- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
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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
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- C07D271/107—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with two aryl or substituted aryl radicals attached in positions 2 and 5
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Abstract
【解決手段】γ−セクレターゼによるアミロイド前駆体蛋白質(APP)のプロセッシングに対して阻害作用を発揮し、従って、アルツハイマー病の治療または予防に有用である新規スルファミド化合物を応用する。
【選択図】なし
Description
Xは、ハロゲン、R9、−OR9、−SR9、−S(O)tR10(この式中、tは、1または2である)、−OSO2R9、−N(R9)2、−COR9、−CO2R9、−OCOR10、−OCO2R10、−CON(R9)2、−SO2N(R9)2、−OSO2N(R9)2、NR9COR10、−NR9CO2R10もしくは−NR9SO2R10を表し;
Yは、HもしくはC1〜6アルキルを表すか;または
XとYは、一緒に、=O、=S、=N−OR11もしくは=CHR11を表すが;但し、
AおよびBは、いずれも、−CH2−以外の−CXY−部分を一つより多く含まないことを条件とし;
Zは、原子数5〜10(このうち、0〜3個は、窒素、酸素および硫黄から選択され、残りは炭素である)の芳香族環構造を完成しているか、またはZは、原子数5〜10(このうち、0〜3個は、酸素、窒素および硫黄から独自に選択され、残りは炭素である)の非芳香族環構造を完成しており;
Z1は、原子数5〜10(このうち、0〜3個は、酸素、窒素および硫黄から独自に選択され、残りは炭素である)の非芳香族環構造を完成しており;
Z2は、5または6員ヘテロアリール環を完成しており;
pは、1〜6の整数であり;
qおよびrは、独自に、0、1または2であり;
xおよびyは、独自に、0、1または2であるが;但し、
AおよびBの少なくとも一方は、AおよびBによって完成された環が少なくとも原子5個を含むように、原子2個以上の鎖を含むことを条件とし;
R1は、H、C1〜4アルキル、もしくはC2〜4アルケニルを表すか、またはR1とR15が、一緒に、5、6または7員の環状スルファミドを完成していてもよく;
R2は、カルボン酸基またはアミノ基で場合によっては置換されている、H、C1〜6アルキル、C6〜10アリール、C6〜10アリールC1〜6アルキル、C3〜6シクロアルキルまたはC2〜6アシルを表し;
R4、R5およびR6は、R9、ハロゲン、CN、NO2、−OR9、−SR9、−S(O)tR10(この式中、tは、1または2である)、−N(R9)2、−COR9、−CO2R9、−OCOR10、−CH=N−OR11、−CON(R9)2、−SO2N(R9)2、−NR9COR10、−NR9CO2R10、−NR9SO2R10、−CH=CHCH2N(R16)2、−CH2OR10、−CH2N(R16)2、−NHCOCH2OR10または−NHCOCH2N(R16)2を独自に表し;
R7は、HもしくはR8を表すか;または2個のR7基が、それらが互いに結合している窒素原子と一緒に、ピロリジン、ピペリジン、ピペラジンもしくはモルホリン環を完成していてもよく;
R8は、C1〜10アルキル、過フルオロC1〜6アルキル、C3〜10シクロアルキル、C3〜6シクロアルキルC1〜6アルキル、C2〜10アルケニル、C2〜10アルキニル、Arまたは−C1〜6アルキルArを表し;
R9は、HもしくはR10を表すか;または2個のR9基が、それらが互いに結合している窒素原子と一緒に、R12、−COR12または−SO2R12により場合によっては置換されている、ピロリジン、ピペリジン、ピペラジンもしくはモルホリン環を完成していてもよく;
R10は、C1〜10アルキル、過フルオロC1〜6アルキル、C3〜10シクロアルキル、C3〜6シクロアルキルC1〜6アルキル、C2〜10アルケニル、C2〜10アルキニル、C6〜10アリール、ヘテロアリール、ヘテロシクリル、C6〜10アリールC1〜6アルキル、ヘテロアリールC1〜6アルキル、ヘテロシクリルC1〜6アルキル、C6〜10アリールC2〜6アルケニル、またはヘテロアリールC2〜6アルケニルを表し、この場合、アルキル、シクロアルキル、アルケニルおよびアルキニル基は、ハロゲン、CF3、NO2、CN、−OR11、−SR11、−SO2R12、−COR11、−CO2R11、−CON(R11)2、−OCOR12、−N(R11)2および−NR11COR12から選択された置換基1個を場合によっては有し、ならびにアリール、ヘテロアリールおよび複素環基は、ハロゲン、NO2、CN、R12、−OR11、−SR11、−SO2R12、−COR11、−CO2R11、−CON(R11)2、−OCOR12、−N(R11)2および−NR11COR12から独自に選択された置換基3個以下を場合によっては有し;
R11は、HもしくはR12を表すか;または2個のR11基が、それらが互いに結合している窒素原子と一緒に、原子数3〜10(前記窒素原子に加えて、このうち0〜2個は、O、NおよびSから選択される)の複素環構造を完成していてもよく、前記環構造は、ハロゲン、CN、NO2、オキソ、R12、OH、OR12、NH2、NHR12、CHO、CO2H、COR12およびCO2R12から選択された置換基0〜2個を有し;
R12は、C1〜6アルキル(ハロゲン、CN、OH、C1〜4アルコキシまたはC1〜4アルコキシカルボニルで場合によっては置換されている)、過フルオロC1〜6アルキル、C3〜7シクロアルキル、C2〜6アルケニル、C2〜6アルキニル、Ar、−C1〜6アルキルAr、ArOC1〜6アルキルまたはC−ヘテロシクリル(ハロゲン、CN、C1〜6アルキル、OH、過フルオロC1〜6アルキル、C2〜6アシル、C1〜4アルコキシまたはC1〜4アルコキシカルボニルで場合によっては置換されている)を表し;
R13は、R9、−COR10、−CO2R10、−SO2R10、−CON(R9)2または−SO2N(R9)2を表し;
R14は、H、C1〜10アルキル、過フルオロC1〜6アルキル、C3〜10シクロアルキル、C3〜6シクロアルキルC1〜6アルキル、C2〜10アルケニル、C2〜10アルキニル、C6〜10アリール、ヘテロアリール、C6〜10アリールC1〜6アルキル、またはヘテロアリールC1〜6アルキルを表し、この場合、アルキル、シクロアルキル、アルケニルおよびアルキニル基は、ハロゲン、CN、NO2、−OR7、−SR7、−S(O)tR8(この式中、tは、1または2である)、−N(R7)2、−COR7、−CO2R7、−OCOR8、−CON(R7)2、−NR7COR8、−C1〜6アルキルNR7COR8、−NR7CO2R8および−NR7SO2R8から選択された置換基1個を場合によっては有し、ならびにアリールおよびヘテロアリール基は、R8、ハロゲン、CN、NO2、−OR7、−SR7、−S(O)tR8(この式中、tは、1または2である)、−N(R7)2、−COR7、−CO2R7、−OCOR8、−CON(R7)2、−NR7COR8、−C1〜6アルキルNR7COR8、−NR7CO2R8および−NR7SO2R8から選択された置換基3個以下を場合によっては有し;
R15は、HもしくはC1〜6アルキルを表すか;またはR15とR1が、一緒に、5、6もしくは7員の環状スルファミドを完成しており;
各R16は、HもしくはR10を独自に表すか、または2個のR16基は、それらが互いに結合している窒素と一緒に、C、N、OおよびSから選択された環原子5〜10個の単環式もしくは二環式の複素環式環構造を完成しており、該環構造は独自にそれに縮合した付加的なアリールもしくはヘテロアリール環を有し、前記複素環構造および場合によっては縮合環は、ハロゲン、オキソ、NO2、CN、R12、−OR11、−SR11、−SO2R12、−COR11、−CO2R11、−CON(R11)2、−OCOR12、−N(R11)2および−NR11COR12から独自に選択された置換基0〜3個を有し;
Arは、フェニルまたはヘテロアリールを表し、これらは、いずれも、ハロゲン、CF3、NO2、CN、OCF3、C1〜6アルキルおよびC1〜6アルコキシから独自に選択された置換基3個以下を場合によっては有し、
「ヘテロシクリル」は、その出現のたびに、C、N、OおよびSから選択された環原子10個以下の環状または多環式構造を意味し、この場合、いずれの構成環も芳香族性ではなく、且つ、少なくとも一つの環原子は、C以外であり;ならびに
「ヘテロアリール」は、その出現のたびに、C、N、OおよびSから選択された環原子10個以下の環状または多環式構造を意味し、この場合、少なくとも1個の構成環は、芳香族性であり、且つ、少なくとも1個の環原子は、C以外である)
の化合物またはその医薬適合性の塩を提供する。
R1は、H、C1〜4アルキルもしくはC2〜4アルケニルを表すか、またはR1とR15が、一緒に、5員の環状スルファミドを完成していてもよく;
R4、R5およびR6は、R9、ハロゲン、CN、NO2、−OR9、−SR9、−S(O)tR10(この式中、tは、1または2である)、−N(R9)2、−COR9、−CO2R9、−OCOR10、−CON(R9)2、−SO2N(R9)2、−NR9COR10、−NR9CO2R10、−NR9SO2R10、−CH=CHCH2N(R16)2、−CH2OR10、−CH2N(R16)2、−NHCOCH2OR10または−NHCOCH2N(R16)2を独自に表し;
R10は、C1〜10アルキル、過フルオロC1〜6アルキル、C3〜10シクロアルキル、C3〜6シクロアルキルC1〜6アルキル、C2〜10アルケニル、C2〜10アルキニル、C6〜10アリール、ヘテロアリール、ヘテロシクリル、C6〜10アリールC1〜6アルキル、ヘテロアリールC1〜6アルキル、C6〜10アリールC2〜6アルケニル、またはヘテロアリールC2〜6アルケニルを表し、この場合、アルキル、シクロアルキル、アルケニルおよびアルキニル基は、ハロゲン、CF3、NO2、CN、−OR11、−SR11、−SO2R12、−COR11、−CO2R11、−CON(R11)2、−OCOR12、−N(R11)2および−NR11COR12から選択された置換基1個を場合によっては有し、ならびにアリール、ヘテロアリールおよび複素環基は、ハロゲン、NO2、CN、R12、−OR11、−SR11、−SO2R12、−COR11、−CO2R11、−CON(R11)2、−OCOR12、−N(R11)2および−NR11COR12から独自に選択された置換基3個以下を場合によっては有し;
R11は、HまたはR12を表し;
R12は、C1〜6アルキル、過フルオロC1〜6アルキル、C3〜7シクロアルキル、C2〜6アルケニル、C2〜6アルキニル、Ar、−C1〜6アルキルArまたはArOC1〜6アルキルを表し;
R15は、HもしくはC1〜6アルキルを表すか;またはR15とR1が、一緒に、5員の環状スルファミドを完成しており;ならびに
各R16は、HもしくはR10を独自に表すか、または2個のR16基が、それらが互いに結合している窒素と一緒に、C、N、OおよびSから選択された環原子5〜10個の単環式もしくは二環式の複素環式環構造を完成しており、前記複素環構造は、それらと縮合した追加のアリールまたはヘテロアリール環を場合によっては有し、前記複素環構造および/または追加の縮合環は、ハロゲン、NO2、CN、R12、−OR11、−SR11、−SO2R12、−COR11、−CO2R11、−CON(R11)2、−OCOR12、−N(R11)2および−NR11COR12から独自に選択された置換基0〜3個を有する。
pは、1〜6、好ましくは2〜5、および最も好ましくは3または4の整数であり;
qおよびrは、独自に、0、1または2であるが、好ましくは、両方とも1であるかまたは両方とも0であり;および
xおよびyは、独自に、0、1または2であるが、好ましくは、両方とも0ではなく;但し、
AおよびBの少なくとも一方は、AおよびBによって完成された環が少なくとも5個の原子を含むように、原子2個以上の鎖を含まなければならないことを条件とする。従って、例えば、AおよびBが、それぞれ、−(CXY)p−および−(CXY)x−NR13−(CXY)y−を表す場合には、pは、1より大きくなくてはならないか、またはxおよびyのうちの少なくとも一方が、0より大きくなければならない。
−CXY−、−CH2CXY−、−CH2CXYCH2−、−CH2CH2CXYCH2−、−CH=CH−、−CH2CH=CHCXY−、−CH2NR13CXY−、−CH2CH2NR13CXY−、−CH2CXYNR13CH2−、−CXYCH2NR13CH2−、−NR13CXY−、および下記:
R1aは、H、C1〜4アルキルまたはC2〜4アルケニルを表し;
R15aは、HまたはC1〜6アルキルを表し;および
A、B、R1、R2およびR14は、前のものと同じ意味を有する)
によって定義される。
VIIからVIへの還元は、PtO2などの触媒の存在下、酢酸などの溶媒中で水素化する、またはアルコール溶液中、シアノ水素化ホウ素ナトリウムで処理し、得られたヒドロキシルアミンを、続いて、Zn/酢酸で還元する、などの通常の手段によって行うことができる。ケトンVIIIからオキシムVIIへの転化は、酢酸ナトリウムなどの穏やかな塩基の存在下、還流エタノール溶液中で前記ケトンと塩酸ヒドロキシルアミンとを縮合させることによって、容易に達成される。
とRLiとを反応させることによって、調製することができる。この反応は、炭化水素溶媒中、低温度で有利に行われ、酸水溶液によって停止する。
とスルファミド(H2NSO2NH2)とを反応させ、場合によってはその後、(XIV中のR14がHである時には)R14b−L(この式中、R14bは、H以外のR14であり、Lは、脱離基(特に、臭化物またはヨウ化物)である)でN−アルキル化することによって、調製することができる。
の還元によって得ることができる。この還元は、典型的にはTHFなどの非プロトン性溶媒中、無水条件のもと、窒素下、0℃で水素化アルミニウムリチウムを用いて行われる。
とR14NH2(この式中、R14は、前のものと同じ意味を有する)との反応、およびその後のt−ブチルスルホニル基の開裂を含む。アジリジンの開環は、典型的には封管内でDMF溶液中、R14NH2とともに100℃で加熱することによって行われ、一方、t−ブチルスルホニル基の開裂は、0℃で、トリフルオロメタンスルホン酸で処理することによって行うことができる。
とヨウ化トリメチルスルホキソニウムとを水素化ナトリウムの存在下で反応させることによって得ることができる。その反応は、THF−DMSO混合物中、周囲温度で行うことができる。
(1)ヒトapp695を発現しているマウス神経芽腫神経2a細胞を、滅菌酪酸ナトリウム10mMの存在下、集密度50〜70%で培養する。
実施例1.[N’−(11−エンド)]−N’−(5,6,7,8,9,10−ヘキサヒドロ−6,9−メタノベンゾ[a][8]アヌレン−11−イル)−N,N−ジメチルスルファミド。
中間体1:[11−エンド]5,6,7,8,9,10−ヘキサヒドロ−6,9−メタノベンゾ[a][8]アヌレン−11−イルスルファミン酸2−ヒドロキシフェニル。
乾燥ジオキサン(7mL/mmol)中の中間体1(1当量)および適切なアミン(3当量)の溶液を封管内で、1時間、80℃で加熱した。室温に冷却した後、その反応混合物をDCMで希釈し、その後、2Nの水酸化ナトリウム水溶液で洗浄した。水性層をDCMで抽出した(x2)。一緒にした有機抽出物を乾燥させ(Na2SO4)、濾過し、蒸発させた。残留物を、適切な酢酸エチル/DCM混合物で溶離するシリカゲルでのクロマトグラフィーによって精製して、対応するスルファミドを得た。
塩酸ヒドロキシルアミン(1.53g、22.0mmol)および酢酸ナトリウム(2.99g、36.4mmol)をビシクロ[4.2.1]ノン−3−エン−9−オン(1.0g、7.3mmol)の溶液に添加し、得られた溶液を温めて、一晩還流させた。その後、その反応混合物を室温に冷却し、溶媒を減圧下で除去した。残留物をEtOAc(50mL)とNaOH溶液(1Nの水溶液、50mL)の間で分配し、有機層を分離し、MgSO4で乾燥させて、濾過し、減圧下で溶媒を除去して、表題化合物(1.02g、93%)を得た。m/z 152(M+H)+。
NaCNBH3(451mg、7.3mmol)を、メチルオレンジ指示薬(0.1%溶液20μL)を含有する−30℃のMeOH(10mL)中のビシクロ[4.2.1]ノン−3−エン−9−オンオキシム(550mg、3.6mmol)の溶液に添加し、その後、充分なHCl(5N、水溶液)を添加して、溶液をピンク色に変えた。反応の進行に伴い、充分なHCLを添加して、ピンク色を維持した。2時間後、その反応混合物を放置して室温に温め、氷/NaOH(4N、水溶液)に注ぎ込み、それをEtOAc(30mL)中に抽出し、MgSO4で乾燥させて、濾過し、溶媒を減圧下で除去した。回収したヒドロキシルアミンをAcOH(2mL)に吸収させ、AcOH(50mL)中の活性Zn粉末(4.72g、72.6mmol)の攪拌懸濁液に添加した。30分後、TLC(2N NH3/MeOH:DCM 5:95)は、ヒドロキシルアミンが完全に還元して、さらに極性が大きい生成物になっていることを示した。その溶液をセライトを通して濾過して、亜鉛を除去し、溶媒を減圧下で除去した。残留物をNaHCO3で塩基性化し、EtOAc(50mL)中に抽出し、MgSO4で乾燥させ、濾過し、溶媒を減圧下で除去して、表題生成物(220mg、46%)を生じた。1H NMR(CDCl3)δ1.33−1.43(2H,m)、1.48(2H bs,NH2)、1.78−1.81(2H,m)、1.82(2H,bd,J=16Hz)、2.09−2.32(4H,m)、3.39(1H,t,J=8.0Hz)、5.48(2H,d,J=4Hz)。m/z 138(M+H)+。
この化合物は、段階3からのスルファメートとn−プロピルアミンを用い、実施例2から16の方法によって調製した。これによって、表題のスルファミド(70mg、90%)を無色の固体として得た。δ(1H、400MHz、CDCl3)0.96(3H,t,J=7.4)、1.40−1.46(2H,m)、1.55−1.64(2H,m)、1.78−1.84(2H,m)、2.15−2.33(4H,m)、2.45−2.52(2H,m)、3.00−3.05(2H,m)、3.81−3.88(1H,m)、4.11(1H,br t,J=6)、4.23(1H,br d,J=11)、5.46−5.49(2H,m)。
リチウムビス(トリメチルシリル)アミド(テトラヒドロフラン中1.0M、330μL、0.33mmol)を、窒素下、0℃で、乾燥テトラヒドロフラン(3mL)中の段階1からの生成物(92mg、0.33mmol)の攪拌溶液に添加した。冷却浴を取り外し、反応混合物を室温で1時間攪拌した。その後、ヨードメタン(20μL、0.32mmol)を添加し、反応混合物を室温で一晩攪拌した。その混合物を酢酸エチルと水の間で分配した。水性層を酢酸エチルでさらに抽出した(x2)。一緒にした有機抽出物を乾燥させ(Na2SO4)、濾過し、蒸発させた。残留物を2%〜5%酢酸エチル/DCMで溶離するシリカゲルでのクロマトグラフィーによって精製した。最初のサンプルを分取HPLCによってさらに精製して、表題の環状スルファミド(16mg、17%)を無色の固体として得た。δ(1H、360MHz、CDCl3)1.24−1.31(2H,m)、1.65−1.71(2H,m)、2.38−2.44(2H,m)、2.68(2H,dd,J=16.1,7.6)、2.76(3H,s)、3.14−3.21(4H,m)、4.71(1H,br s)、7.06−7.14(4H,m);δ(13C、90MHz、CDCl3)26.5、34.4、38.2、45.1、66.1、70.9、128.1、133.3、140.4;MS(ES+)293([MH]+)。
水素化ナトリウム(油中60%分散液、15mg、0.38mmol)を、窒素下、室温で、乾燥DMF(2mL)中の段階1からの環状スルファミド(87mg、0.38mmol)の攪拌溶液に、一度に添加した。1時間後、1−ブロモプロパン(36μL、0.40mmol)を添加した。その反応混合物を室温で1.5時間攪拌した後、水で反応を停止させた。その後、その混合物を酢酸エチルと水の間で分配した。水性層を酢酸エチルでさらに抽出した(x2)。一緒にした有機抽出物を水(x1)および塩化ナトリウム飽和水溶液(x1)で洗浄し、その後、乾燥させ(Na2SO4)、濾過し、蒸発させた。残留物を20%酢酸エチル/ヘキサンで溶離するシリカゲルでのクロマトグラフィーによって精製して、N−アルキル化環状スルファミド(64mg、85%)を無色の固体として得た。δ(1H、360MHz、CDCl3)0.98(3H,t,J=7.4)、1.49−1.55(2H,m)、1.60−1.70(2H,m)、1.84−1.92(2H,m)、2.13−2.22(2H,m)、2.32−2.43(4H,m)、2.95−3.00(2H,m)、3.21(2H,s)、4.31(1H,br s)、5.46−5.53(2H,m);δ(13C、90MHz、CDCl3)13.2、23.0、28.4、34.5、45.4、50.1、63.2、71.0、128.6;MS(ES+)271([MH]+)。
塩酸ヒドロキシルアミン(9.72g)を、無水エタノール(50mL)と水(50mL)の混合物中の5−ニトロ−トリシクロ[8.2.1.03,8]トリデカ−3(8),4,6−トリエン−13−オン*(10.82g)および酢酸ナトリウム(19.08g)の攪拌溶液に添加した。その反応混合物を温めて18時間還流させ、室温に冷却して、水(200mL)で希釈した。生成物を濾過して取り出し、高真空下で乾燥させて、表題化合物を白色の粉末として得た(10.73g)、m/z 247(M+H+)。
段階2 N−(5−ニトロ−トリシクロ[8.2.1.03,8]トリデカ−3(8),4,6−トリエン−13−イル)−ヒドロキシルアミン
DCM(20mL)中のジ−t−ブチルジカーボネート(864mg)の溶液を、−20℃で、DCM(50mL)中の段階3からのジアミン(800mg)の攪拌溶液に、4時間かけて添加した。さらに2時間後、その溶液を室温に温め、溶媒を減圧下で除去した。残留油をシリカゲル(30%EtOAc/イソヘキサン)でのクロマトグラフィーによって精製して、生成物を白色の固体として得た(500mg)。1H NMR(CDCl3 400MHz)δ1.20−1.25(2H,m)、1.46(9H,s)、1.65−1.69(2H,m)、2.40−2.46(4H,m)、2.86−2.90(2H,m)、4.05(1H,brs)、5.29(1H,brs)、6.41−6.44(2H,m)、6.84(1H,d,J=5.0Hz)。
実施例28.[11−エンド]2’,3’,4’,5,5’,6,7,8,9,10−デカヒドロ−2’−アセチル−5’−プロピルスピロ[6,9−メタノベンゾシクロオクテン−11,3’−[1,2,5]チアジアゾール]−1’,1’−ジオキシド。
実施例31.N−シクロブチル−N’−[(6S/R,9R/S,11R/S)−1−フルオロ−5,6,7,8,9,10−ヘキサヒドロ−6,9−メタノベンゾ[a][8]アヌレン−11−イル]スルファミド
四塩化炭素(60mL)中で3−フルオロ−o−キシレン(5.05mL、40.3mmol)、NBS(15.8g、88.71mmol)およびAIBN(20mg)を攪拌し、還流下で18時間加熱した。冷却し次第、その混合物を濾過し、濾液を濃縮乾固した。その粗生成物をメタノールに溶解し、−50℃で溶液から固体を沈殿させ、濾過によって分離した。この手順をもう一度繰り返して、純粋な二臭化物4.84g(43%)を得た。1H NMR(CDCl3、360MHz)δ7.26−7.32(1H,m)、7.17(1H,d,J=7.6Hz)、7.05(1H,t,J=8.6Hz)、4.70(2H,s)、4.63(2H,s)。
MeCN(10mL)中の1,2−ビス−ブロモメチル−3−フルオロ−ベンゼン(4.4g、15.6mmol)の溶液を、MeCN(20mL)中の1−シクロペント−1−エニル−ピロリジン(2.3mL、15.6mmol)およびDIPEA(5.4mL、31.2mmol)の攪拌溶液に添加した。その混合物を室温で18時間攪拌し、その後、濾過した。冷MeCNでの洗浄によって、オフホワイトの固体1.02g(19%)を生じた。m/z 258(M+)。
2:1のエタノール−水(12mL)中の段階2からの生成物(1.02g、3.02mmol)、塩酸ヒドロキシルアミン(624mg、9.05mmol)および酢酸ナトリウム・三水和物(1.23g、9.05mmol)を加熱して還流させ、放置して室温に冷却し、その後、この温度で18時間攪拌した。水(10mL)を添加し、その混合物を濾過した。その白色の固体を水で洗浄し、真空下で乾燥させた。590mg(89%)。m/z 220(M+H+)。
AcOH(20mL)中の段階3からのオキシム(590mg、2.69mmol)および二酸化白金(40mg)をパー反応器内で2時間、30psiで水素化した。セライトを通してその混合物を濾過し、濾液を凍結乾燥によって濃縮して、オフホワイトの固体を得た。この固体を1NのNaOHに分散させ、DCMで抽出した。有機抽出物を乾燥させ、濃縮乾固して、黄色の油525mg(95%)を得た。m/z 206(M+H+)。
硫酸カテコール(332mg、1.93mmol)を、THF(5mL)中の段階4からのアミン(360mg、1.76mmol)の氷冷溶液に添加した。その混合物を放置して室温に温め、18時間攪拌し、酢酸エチルで希釈し、塩化アンモニウム(水溶液)、続いてブラインで洗浄した。有機相を乾燥させ、蒸発させて、粗油を得、それを、4:1のイソヘキサン−酢酸エチルで溶離するシリカゲルでのカラムクロマトグラフィーによって精製して、橙色の油335mg(51%)を得た。1H NMR(CDCl3、360MHz)δ7.27(1H,m)、7.21(1H,m)、7.05(2H,m)、6.85−7.95(3H,m)、6.32(1H,br s)、5.40(1H,br d,J=7.5Hz)、4.02(1H,q,J=6.4Hz)、3.19−3.25(1H,dd,J=16.7,7.6Hz)、3.04(1H,d,J=16.3Hz)、2.70(1H,m)、2.50−2.61(3H,m)、1.74(2H,m)、1.21(2H,m)。m/z 376(M−H)−。
1,4−ジオキサン中の段階5からの生成物(335mg、0.889mmol)およびシクロブチルアミンを攪拌し、封管内で75分間、80℃で加熱した。その混合物を放置して室温に冷却し、DCMで希釈して、1MのNaOH溶液で洗浄して、有機相を硫酸ナトリウムで乾燥させ、濾過し、濃縮した。その粗生成物を、4:1のイソヘキサン−酢酸エチルで溶離するシリカゲルでのカラムクロマトグラフィーによって精製して、白色の固体を得た(これを、その後、ジエチルエーテルで研和した)163mg(54%)。1H NMR(CDCl3、400MHz)δ7.03(1H,m)、6.86(2H,m)、4.68(1H,br d,J=7.5Hz)、4.49(1H,br d,J=8.9Hz)、3.89(1H,m)、3.74(1H,m)、3.18−3.24(1H,dd,J=16.6,7.7Hz)、3.09(1H,d,J=16.0Hz)、2.69(1H,m)、2.49−2.61(3H,m)、2.39(2H,m)、1.92−2.01(2H,m)、1.65−1.79(4H,m)、1.13−1.25(2H,m)。m/z 339(M+H+)。
DCM(50mL)中の段階1からのアミン(3.0g、12.24mmol)およびジ−t−ブチルジカーボネート(2.94g、13.47mmol)を90分間、氷冷しながら攪拌した。その反応をN,N−ジメチルエチレンジアミンで停止させ、DCMで希釈して、10%のクエン酸(水溶液)、水で洗浄し、乾燥させ、濃縮した。その粗生成物を5:1のイソヘキサン−酢酸エチルで溶離するシリカゲルでのカラムクロマトグラフィーによって精製して、無色の油を得た。1H NMR(CDCl3、360MHz)δ7.73−7.78(2H,m)、7.16(1H,d,J=7.8Hz)、4.98(1H,m)、4.03(1H,m)、3.89(3H,s)、3.05(2H,m)、2.70(2H,m)、2.53(2H,m)、1.73(2H,m)、1.48(9H,s)、1.14(2H,m)。
[5−(3−ヒドロキシ−プロペニル)−トリシクロ[8.2.1.03,8]トリデカ−3(8),4,6−トリエン−13−イル]−カルバミン酸t−ブチルエステル
[5−(3−モルホリン−4−イル−プロペニル)−トリシクロ[8.2.1.03,8]トリデカ−3(8),4,6−トリエン−13−イル]−カルバミン酸t−ブチルエステル
段階4からの粗Boc−アミン(532mg)を20分間、ジオキサン中4MのHCl(20mL)で処理した。溶媒を減圧下で除去し、残留固形物を冷却EtOAcで研和して、濾過した。残留物を1Mの水酸化ナトリウム(20mL)とDCM(30mL)の間で分配した。水性相をDCM(3×30mL)で抽出し、一緒にした有機相を乾燥させ(Na2SO4)、濃縮して、淡黄色の油(230mg)を得た。m/z 313(M+H)+。
ブロモ酢酸エチル(8.01g)を乾燥DMF(150mL)中の[6S/R,9R/S]2−ヒドロキシ−5,6,7,8,9,10−ヘキサヒドロ−6,9−メタノベンゾ[a][8]アヌレン−11−オン(9.7g;J.Org.Chem 1982,47,4329)および炭酸カリウム(6.6g)の攪拌溶液に添加した。その反応混合物を18時間、90℃に温め、室温に冷却して、水(200mL)で希釈し、エーテル(4×100mL)中に抽出した。有機抽出物を水(100mL)、ブライン(100mL)で洗浄し、MgSO4で乾燥させ、濾過し、減圧下で溶媒を除去した。シリカでのフラッシュクロマトグラフィー(200〜400メッシュ、0〜30%EtOAc/イソヘキサン)によって、(13−オキソ−トリシクロ[8.2.1.03,8]トリデカ−3,5,7−トリエン−5−イルオキシ)−酢酸エチルエステル(11.07g)を得た。1H NMR(CDCl3 400MHz)δ1.28(3H,m)、1.84(2H,m)、2.58(2H,m)、2.86(4H,m)、4.15(2H,m)、4.22(2H,m)、4.59(2H,s)、6.71(1H,dd,J=8.0,4.0Hz)、6.80(1H,d,J=4.0Hz)、7.10(1H,d,J=8.0Hz)。
実施例17、段階1および2の方法を用いて、段階1から回収した生成物(11.07g)を(13−アミノ−トリシクロ[8.2.1.03,8]トリデカ−3,5,7−トリエン−5−イルオキシ)−酢酸エチルエステルに転化させた。回収したアミン(7.4g)を乾燥DCM(100mL)に取り込み、ジ−t−ブチルジカーボネート(5.6g)で処理した。24時間後、その反応混合物を水で希釈して、有機層を分離し、MgSO4で乾燥させ、濾過し、溶媒を減圧下で除去して、透明な油を得た。シリカでのフラッシュクロマトグラフィー(200〜400メッシュ、30%EtOAc/イソヘキサン)による精製によって、(13−t−ブトキシカルボニルアミノ−トリシクロ[8.2.1.03,8]トリデカ−3,5,7−トリエン−5−イルオキシ)−酢酸エチルエステルを白色の固体として得た(5.7g)。1H NMR(CDCl3 400MHz)δ1.19(2H,m)、1.27(3H,t、J=8.0Hz)、1.52(9H,m)、1.68(2H,m)、2.5(4H,m)、2.94(2H,m)、4.16(1H,brm)、4.25(2H,q,J=8.0Hz)、4.57(2H,s)、4.99(1H,brm)、6.17(1H,dd,J=8.0,1.0Hz)、6.67(1H,d,J=1.0Hz)、6.98(1H,d,J=8.0Hz)。
水素化ホウ素リチウム(56mg)を、乾燥THF(20mL)中の段階2からの生成物(1.0g)の攪拌溶液に、一度に添加した。得られた溶液を室温で18時間攪拌し、NH4Cl(飽和水溶液 50mL)で反応を停止させて、DCM中に抽出した。有機抽出物をMgSO4で乾燥させ、濾過し、溶媒を減圧下で除去し、生成物をシリカでのフラッシュクロマトグラフィー(200〜400メッシュ、10〜60%EtOAc/イソヘキサン)によって精製して、[5−(2−ヒドロキシ−エトキシ)−トリシクロ[8.2.1.03,8]トリデカ−3,5,7−トリエン−13−イル]−カルバミン酸t−ブチルエステルを白色の固体として得た(340mg)。1H NMR(CDCl3 400MHz)δ1.20(2H,m)、1.47(9H,s)、1.69(2H,m)、2.04(1H,m)、2.50(4H,m)、2.96(2H,m)、3.94(2H,m)、4.05(3H,s)、4.99(1H,brm)、6.62(1H,dd,J=8.0,1.0Hz)、6.67(1H,d,J=1.0Hz)、6.98(1H,d,J=8.0Hz)。
無水トリフルオロメタンスルホン酸(162μL)を、−78℃で、乾燥DCM中、段階3からの生成物(340mg)および2,6−ジ−t−ブチル−4−メチルピリジン(198mg)の溶液に添加した。30分後、過剰のモルホリンを添加し、その反応混合物を放置して、4時間かけて室温に温めた。NH4Cl(飽和水溶液 50mL)で反応を停止させ、DCM中に抽出した。有機抽出物をMgSO4で乾燥させ、濾過し、溶媒を減圧下で除去した。回収した材料を3時間、20%TFA/DCMで処理し、NaHCO3(飽和水溶液)で塩基性化し、有機相を分離して、MgSO4で乾燥させ、濾過し、溶媒を減圧下で除去した。シリカでのフラッシュクロマトグラフィー(200〜400メッシュ、3% 2N NH3/MeOH/DCM)によって生成物を精製して、5−(2−モルホリン−4−イル−エトキシ)−トリシクロ[8.2.1.03,8]トリデカ−3,5,7−トリエン−13−イルアミン(190mg)を得た。1H NMR(CDCl3 400MHz)δ1.17(2H,m)、1.67(4H,m)、2.24(2H,m)、2.45(2H,m)、2.56(4H,m)、2.76(2H,m)、3.17(2H,m)、3.36(1H,m)、3.73(4H,m)、4.05(2H,m)、6.61(1H,dd,J=8.0,1.0Hz)、6.65(1H,d,J=1.0Hz)、6.96(1H,d,J=8.0Hz)。
シクロブチル−スルファミン酸2−ヒドロキシ−フェニルエステル(実施例117、段階5にあるように調製したもの)(167mg)を乾燥CH3CN(10mL)中の段階4からの生成物(182mg)およびDMAP(触媒量)の攪拌溶液に添加し、得られた溶液を温めて、18時間還流させた。この後、溶媒を減圧下で除去し、シリカでの残留物のフラッシュクロマトグラフィー(200〜400メッシュ、3% 2N NH3/MeOH/DCM)によって、ゴムとして生成物を得た。HClエーテル溶液で処理し、エーテルで研和することによって、塩酸N−シクロブチル−N’−[(6S/R,9S/R,11S/R)−2−(2−モルホリン−4−イルエトキシ)−5,6,7,8,9,10−ヘキサヒドロ−6,9−メタノベンゾ[a][8]アヌレン−11−イル]スルファミドを白色の粉末として生じた(40mg)。m/z ES+(M+H)+450。
段階3からの生成物(60mg)をDCM(5mL)に溶解し、−20℃に冷却した後、DCM中1MのPBr3(150μL)を一滴ずつ添加した。添加が完了したら、温度を1時間かけて室温に上昇させた。その反応混合物を再び−20℃に冷却した後、モルホリン(280μL)を一滴ずつ添加し、その後、そのフラスコ内の温度を2時間かけて室温に上昇させた。蒸発乾固させ、その後、溶離剤としてイソヘキサン中65%のEtOAcを用いるカラムクロマトグラフィーによって精製することによって、表題化合物を遅速結晶化性の油として得た(15.6mg)。
アセトニトリル(4mL)中の段階1からの酸(0.125g)、ジイソプロピルエチルアミン(0.07mL)、HBTU(0.15g)および4−フルオロベンズヒドラジド(0.06g)の溶液を40℃で18時間攪拌した。その混合物を水(20mL)で希釈して、白色の固体を回収し、それを酢酸エチルに再び溶解して、Na2SO4で乾燥させ、濾過して、濃縮した。得られた白色の固体(0.088g)およびバージェス試薬(0.17g)をテトラヒドロフラン(2mL)に溶解し、マイクロ波を照射した(120℃、240秒、Smith Personal Synthesiser マイクロ波反応器)。40%酢酸エチル−イソヘキサンで溶離するシリカでのフラッシュカラムクロマトグラフィー、次いで20%酢酸エチル−イソヘキサンで溶離する分取薄層クロマトグラフィーによって、表題のスルファミド(0.006g、7%)を白色の固体として得た。δ(1H、360MHz、CDCl3)1.17−1.28(2H,m)、1.73−1.77(2H,m)、2.58−2.64(2H,m)、2.70−2.81(2H,m)、3.15(2H,d,J=16)、3.72−3.92(3H,m)、4.97−5.06(2H,m)、7.20−7.25(3H,m)、7.82(2H,d,J=8)、7.86(1H,s)、8.13−8.16(2H,m);MS(ES+)511([M+H]+)。
THF(20mL)中の実施例65からの生成物(5.46g)の溶液を窒素下、0℃で、THF(20mL)中のNaH(0.61g)に一滴ずつ添加した。その反応混合物を30分間攪拌し、その後、塩化MOM(1.0mL)を添加した。反応混合物を放置して、攪拌しながら1時間、室温に温めた。水(40mL)を添加し、EtOAc(3×50mL)で抽出した。一緒にした有機相をブライン(50mL)で洗浄した。乾燥させ、濃縮し、10%EtOAc/ヘキサンで溶離するシリカでのカラムクロマトグラフィーによって、MOM−保護スルファミド(5.82g、97%)を得た。1H NMR(360MHz、CDCl3)δH1.33(2H,m)、1.63(2H,m)、2.56−2.73(4H,m)、3.34−3.44(4H,m)、3.41(3H,s)、3.69(2H,dq,J=1.4,8.8)、4.95(2H,s)、5.03(2H,s)、6.72(2H,m)、6.98(1H,d,J=7.7)、7.37(5H,m)。
アセトニトリル(2mL)中の段階3からの生成物(50mg)と炭酸カリウム(16mg)とヨウ化カリウム(16mg)とモルホリン(10mg)の混合物を室温で3日間攪拌した。水を添加し、その反応混合物を酢酸エチルで抽出した(x3)。一緒にした有機抽出物をブラインで洗浄し、乾燥させ(MgSO4)、濾過し、蒸発させた。残留物を、DCM−2%MeOH/DCMで溶離するシリカゲルでのクロマトグラフィーによって精製し、その後、DCMに再溶解して、2滴のTFAとともに1時間、室温で攪拌した。その反応混合物を濃縮して、所望の生成物(25mg、44%)を得た。1H NMR(360MHz、MeOH)δH1.20(2H,m)、1.73(2H,m)、2.42(2H,m)、2.59(2H,m)、3.19−3.68(8H,m)、3.62(2H,t,J=4.9)、3.80(2H,m)、3.84(2H,q,J=9.2)、4.06(2H,m)、4.35(2H,t,J=4.9)、6.76(2H,m)、7.04(1H,d,J=8.1)。MS(ES+)490,MH+。
0℃に冷却したDCM(100mL)中の実施例44からのフェノール(6.1g)の懸濁液に、無水トリフルオロメタンスルホン酸(4.5mL)およびピリジン(2.2mL)を一滴ずつ添加し、その反応混合物を放置して、攪拌しながら2時間、室温に温めた。水を添加し、DCMで抽出し(x3)、乾燥させ(MgSO4)、濾過して、濃縮した。エーテル/ヘキサンで研和して、トリフレート(8g)を白色の粉末として得た。
このトリフレート(6g)をジメチルスルホキシド/メタノール(240:150mL)およびトリエチルアミン(23mL)に溶解し、その後、15分間脱気した。1,3−ビス(ジフェニルホスフィノ)プロパン(527mg)および酢酸パラジウム(287mg)を添加し、その溶液を一酸化炭素で飽和させ、その後、4時間、85℃に加熱して、その反応混合物中に一酸化炭素を連続的にバブリングした。放置して冷却し、水を添加して、EtOAcで抽出し(x3)、水およびブラインで洗浄して、乾燥させ、濾過した。真空下で濃縮し、その後、2〜4%EtOAc/DCMで溶離するシリカでのクロマトグラフィーによって、所望の化合物を白色の粉末として得た(4.06g)。1H NMR(360MHz、CDCl3)δH0.97(3H,t,J=7.3)、1.24(2H,m)、1.68(5H,m)、2.45(2H,brs)、2.76(2H,m)、3.02(2H,t,J=7.2)、3.22(4H,m)、3.90(3H,s)、4.89(1H,s)、7.16(1H,m)、7.77(2H,m)。
実施例18、段階1に記載の手順を用い、次いで実施例20を用いて、段階1からの生成物をN−プロピル環状スルファミドに転化させた。分取HPLCによる最終的な精製によって、N−プロピル環状スルファミド(17mg)を固体として得た。δ(1H、360MHz、CDCl3)0.98(3H,t,J=7.3)、1.21−1.30(2H,m)、1.61−1.78(5H,m)、2.49(2H,br m)、2.62(1H,dd,J=16.1,7.3)、2.99−3.30(6H,m)、4.77(1H,br s)、7.05−7.09(1H,m)、7.40(1H,br d,J=7.6)、8.36(1H,br d,J=3.4);MS(ES+)322([MH]+)。
THF(10mL)中の実施例26、段階2からのニトリル(0.41g、1.29mmol)の溶液にクロロトリメチルシラン(0.163mL、1.29mmol)を添加した。その溶液を冷却(−40℃)し、ジエチルエーテル中の臭化アリルマグネシウム(1M、4mL、3.1mmol)を添加した。溶液を15分間、−40℃で攪拌し、その後、30分間、室温に温めた。溶液を酢酸エチルと炭酸カリウム水溶液の間で分配し、有機相を乾燥させて(MgSO4)、蒸発乾固させた。残留物を100%酢酸エチルで溶離するシリカゲルでのクロマトグラフィーによって精製して、[11−エンド]−11−アリル−11−アミノ−2−(ベンジルオキシ)−5,6,7,8,9,10−ヘキサヒドロ−6,9−メタノベンゾ[a][8]アヌレン(104mg)を第一溶離化合物として得、その後、酢酸エチル中10%メタノールおよび0.4%のアンモニア水での溶離によって、[11−エンド]−11−[4−アミノヘプタ−1,6−ジエン−4−イル]−11−アミノ−2−(ベンジルオキシ)−5,6,7,8,9,10−ヘキサヒドロ−6,9−メタノベンゾ[a][8]アヌレン(117mg)を得た。MS m/z 403(M+H)。
ピリジン(0.5mL)中の段階1の第二生成物(117mg)およびスルファミド(120mg)の溶液を0.5時間、120℃で加熱した。溶液を蒸発乾固させ、残留物を酢酸エチルと0.2Mの塩酸水溶液の間で分配した。有機相を飽和ブラインで洗浄し、乾燥させて(MgSO4)、蒸発させた。残留物をDCMに溶解し、シリカゲルでのクロマトグラフィー(イソヘキサン中10%の酢酸エチルで溶離する)によって精製して、[11−エンド][6S/R,9R/S,11R/S]2’,3’,4’,5,5’,6,7,8,9,10−デカヒドロ−4’,4’−ジアリル−2−ベンジルオキシ−スピロ[6,9−メタノベンゾシクロオクテン−11,3’−[1,2,5]チアジアゾール]−1’,1’−ジオキシドを得た。
DCM(10mL)中の段階2の生成物(24mg)の溶液に、二塩化ビス(トリシクロヘキシルホスフィン)ベンジリデンルテニウム(IV)(グラブ(Grubb)触媒、4mg)を添加した。その溶液を1時間、室温で攪拌した後、溶媒を真空下で除去し、残留物をシリカゲルでのクロマトグラフィー(イソヘキサン中10%、次いで25%の酢酸エチルで溶離する)によって精製して、表題化合物を得た。
モルホリンの代わりに適切なアミン(4当量)およびフーニッヒ(Hunig)塩基(5当量)を用い、実施例54の方法によって、対応するアリルアルコールから表1中の化合物を調製した。アリルアルコールは、実施例27における適切なハロゲン化アルキルを用い、実施例27、44、51、80、81、82および54(第一段階)の逐次的手順によって得た。
**−アリルアルコール前駆物質−実施例89。実施例75についてのNMRデータ−1H−NMR(360MHz、d6−DMSO)δH1.03(2H,m)、1.69(2H,m)、1.86(2H,brm)、2.04(2H,brm)、2.37(2H,brs)、2.60(3H,m)、2.97(2H,brm)、3.18(2H,m)、3.46(2H,s)、3.54(2H,d,J=12)、3.84(2H,m)、4.02(2H,q,J=8.7)、6.32(1H,dt,J=5.6,15.9)、6.77(1H,d,J=15.6)、7.12(1H,d,J=7.6)、7.22(2H,m)、8.02(1H,s)、10.67(1H,s)。
***−アミンの代わりに3−メルカプト−4−メチル−1,2,4−トリアゾールを用いる。
THF(10mL)中の実施例26、段階2からのニトリル(0.384g、1.21mmol)の溶液に、臭化アリルマグネシウム(ジエチルエーテル中1M、2.4mL)を添加した。その溶液の反応を飽和塩化アンモニウムの添加によって停止させ、生成物を酢酸エチル中に抽出した。乾燥させ(MgSO4)、溶媒を真空下で除去した後、残留物をシリカゲルでのクロマトグラフィー(イソヘキサン中30%の酢酸エチルで溶離する)によって精製して、[11−エンド]−11−アリル−11−アミノ−2−(ベンジルオキシ)−5,6,7,8,9,10−ヘキサヒドロ−6,9−メタノベンゾ[a][8]アヌレンを得た。
−80℃で、メタノール:DCM(1:1)の混合物中の段階1からの塩酸塩(228mg、0.62mmol)の溶液を、永続的な青色が生じるまで、オゾン分解した。酸素および窒素でその溶液をパージした後、硫化ジメチル(0.5mL)を添加し、溶液を2時間、室温に温めた。残留物にプロピルアミン(0.2mL)およびDCM(10mL)を添加し、15分後、トリアセトキシ水素化ホウ素ナトリウム(0.51g)を添加した。その溶液を室温で2時間攪拌した後、溶媒を蒸発によって除去し、残留物を酢酸エチルとK2CO3水溶液の間で分配した。有機相を乾燥させ、蒸発させ、残留物をシリカゲルでのクロマトグラフィー(DCM中10%、20%、30%の漸増濃度のメタノール:アンモニア水:DCM(10:0.4:90)の混合物で溶離する)によって、[11−エンド]−11−(2−(プロピルアミノ)エチル)−11−アミノ−2−(ベンジルオキシ)−5,6,7,8,9,10−ヘキサヒドロ−6,9−メタノベンゾ[a][8]アヌレンを得た。
段階2からの生成物(36mg)およびスルファミド(42mg)を120℃で8時間、ピリジン(0.5mL)中で加熱した。その溶液を真空下で蒸発させて、溶媒を除去し、DCMに溶解した残留物をシリカゲルでのクロマトグラフィー(イソヘキサン中0、10%、20%の漸増濃度の酢酸エチルで溶離する)に付した。生成物を蒸発させ、残留物をジエチルエーテルから結晶化して、表題生成物を得た。
DCM(40mL)中の実施例43、段階3からのMOM保護2−ブロモエトキシ誘導体(1.324g)の溶液にTFA(1mL)を添加した。その反応混合物を室温で3時間攪拌し、濃縮し、残留物をDCMと炭酸水素ナトリウム飽和溶液の間で分配した。水性層をDCMで抽出して(x2)、一緒にした有機抽出物をブラインで洗浄し、乾燥させて(MgSO4)、濾過し、蒸発させた。残留物を10〜20%EtOAc/ヘキサンで溶離するシリカゲルでのクロマトグラフィーによって精製して、脱保護スルファミド(0.957g、79%)を得た。1H NMR(360MHz、CDCl3)δH1.33(2H,m)、1.70(2H,m)、2.43(2H,m)、2.63(1H,dt,J=15.8,7.9)、3.16(2H,dd,J=15.9,32.9)、3.43(2H,m)、3.63(2H,t,J=6.3)、3.67(2H,dq,J=2.4,8.7)、4.26(2H,t,J=6.3)、4.67(1H,s)、6.66(2H,m)、6.99(1H,d,J=7.8)。
アセトニトリル(1mL)中の段階1からの臭化物(50mg)、フーニッヒ塩基(40mg)およびトリフルオロメチルピペリジン(32mg)の溶液をマイクロ波反応器内で、10分間、180℃で加熱した。その混合物を濃縮し、生成物を30〜40%EtOAc/ヘキサンで溶離するシリカゲルでのクロマトグラフィーによって精製し、その後、塩酸塩に転化させた(32mg、52%)。1H NMR(360MHz、MeOH)δH1.20(2H,m)、1.73(2H,m)、1.92(2H,m)、2.20(2H,m)、2.42(2H,m)、2.61(3H,m)、3.14−3.51(6H,m)、3.59(2H,m)、3.78(2H,m)、3.85(2H,q,J=9.2)、4.34(2H,t,J=4.8)、6.76(2H,m)、7.04(1H,d,J=8.1)。MS(ES+)556,MH+。
4−トリフルオロメチルピペリジンの代わりに適当なアミンを用い、実施例105の手順によって表2中の化合物を調製し、質量志向型分取HPLCによって精製した。
エタノール(30mL)中の3−(13−t−ブトキシカルボニルアミノ−トリシクロ[8.2.1.03,8]トリデカ−3(8),4,6−トリエン−5−イル)−アクリル酸メチルエステル(300mg、0.809mmol、実施例32、段階3で調製したもの)および20%水酸化パラジウム/炭素(30mg)を水素1気圧のもと、室温で18時間攪拌した。セライトを通してその混合物を濾過し、濾液を濃縮して、無色の油285mg(94%)を得た。1H−NMR(CDCl3、400MHz)δ7.00(1H,d,J=8.2Hz)、6.90(2H,m)、4.97(1H,m)、4.03(1H,m)、3.67(3H,s)、2.99(2H,m)、2.89(2H,m)、2.55−2.62(4H,m)、2.48(2H,m)、1.71(2H,m)、1.47(9H,s)、1.19(2H,m)。
―70℃未満に反応温度を維持しながら、トルエン(8mL)中の段階1の生成物(290mg、0.777mmol)の攪拌溶液に、DIBAL−H(トルエン中1M、855μL、0.855mmol)を一滴ずつ添加した。−78℃で2時間攪拌した後、さらにDIBAL−H(77μL)を添加し、さらに2時間、−78℃で攪拌し続けた。その混合物の反応を−78℃でメタノールによって停止させ、放置して室温に温めて、酢酸エチルと1NのHClの間に分散させた。有機相を炭酸水素ナトリウム溶液(飽和)、ブラインで洗浄して、乾燥させ、濃縮して、無色の油を得た。NMRによる分析が〜15%の出発エステルの存在を示したので、生成物をさらに、上に記載したように、−78℃で2時間、DIBAL−H(122μL)で処理した。その粗生成物を5:1のイソヘキサン−酢酸エチルで溶離するシリカゲルでのカラムクロマトグラフィーによって精製して、無色の油149mg(56%)を得た。1H−NMR(CDCl3、360MHz)δ9.81(1H,s)、7.00(1H,m)、6.90(2H,m)、4.97(1H,m)、4.04(1H,m)、2.86−3.03(4H,m)、2.75(2H,m)、2.45−2.63(4H,m)、1.71(2H,m)、1.47(9H,s)、1.19(2H,m)。
メタノール(15mL)中の段階2からの生成物(140mg、0.408mmol)、塩酸4−トリフルオロメチルピペリジン(78mg、0.408mmol)およびシアノ水素化ホウ素ナトリウム(77mg、1.22mmol)を室温で18時間攪拌した。その混合物の反応を水、次いで炭酸水素ナトリウム溶液(飽和)で停止させた。生成物をDCMで抽出し、有機相を乾燥させて、濃縮した。その粗生成物を、MeOH中40:1のDCM−2MのNH3で溶離するシリカゲルでのカラムクロマトグラフィーによって精製して、無色の油を得た。その生成物を、7:1のイソヘキサン−酢酸エチルで溶離するシリカゲルでのカラムクロマトグラフィーによって再び精製して、無色の油87mg(44%)を得た。1H−NMR(CDCl3、400MHz)δ6.99(1H,d,J=8.0Hz)、6.89(2H,m)、4.98(1H,m)、4.02(1H,m)、2.95−3.02(4H,m)、2.45−2.62(6H,m)、2.35(2H,m)、1.58−2.04(11H,m)、1.47(9H,m)、1.19(2H,m)。m/z 481(M+H+)。
段階3の生成物(87mg、0.181mmol)を3:1のDCM−TFA(4mL)に溶解し、0℃で1時間攪拌することによって、Boc保護基を除去した。その混合物を濃縮乾固し、CDM中の残留物の溶液を炭酸ナトリウム水溶液(飽和)で洗浄した。有機相を乾燥させ、蒸発させて、無色の油66mg(96%)を得た。1H−NMR(CDCl3、360MHz)δ6.99(1H,d,J=8.4Hz)、6.90(2H,m)、3.66(1H,t,J=6.1Hz)、3.21(2H,m)、2.99(2H,m)、2.45−2.59(4H,m)、2.35(2H,m)、2.23(2H,m)、1.57−2.04(11H,m)、1.17(2H,m)。
(a)DCM(2mL)中の硫酸カテコール(1.32g、7.7mmol)の溶液を、0℃で、DMF中のシクロブチルアミン(600μL、7.0mmol)およびTEA(1.07mL、7.7mmol)の攪拌溶液に添加し、この温度で3時間攪拌することによって、シクロブチル−スルファミン酸2−ヒドロキシ−フェニルエステルを調製した。この混合物の反応を1MのHCl(50mL)で停止させ、ジエチルエーテルで抽出した。有機抽出物を水、ブラインで洗浄し、乾燥させて、濃縮乾固した。定量収率。
実施例128;R=4−フルオロフェニル、MS(ES+)512,MH+
実施例129;R=4−(トリフルオロメチル)フェニル、MS(ES+)562,MH+。
1,2−ビス(ブロモメチル)ベンゼンの代わりに3,4−ビス(ブロモメチル)安息香酸メチルを用い、11−オキソ−5,6,7,8,9,10−ヘキサヒドロ−6,9−メタノベンゾシクロオクテンについて記載された手順(Justus Liebigs Ann.Chem.1961,650,115)を用いて調製した。
エタノール(2mL)中の段階8からのジケトン(0.029g)およびヒドラジン水和物(0.5mL)の溶液を窒素下で4時間、還流させた。その溶液を冷却し、水(20mL)で希釈して、1Mのクエン酸水溶液で酸性化し、酢酸エチル(2×10mL)で抽出した。抽出物を、テフロン膜を通して濾過し、濃縮した。50%酢酸エチル−イソヘキサンで溶離する分取薄層クロマトグラフィーによって、表題のピラゾール(0.014g、49%)を白色の粉末として得た。δ(1H、400MHz、CDCl3)0.99(3H,t,J=7)、1.21−1.28(2H,m)、1.62−1.74(4H,m)、2.43−2.46(2H,m)、2.68−2.76(2H,m)、3.04(2H,t,J=7)、3.19−3.25(4H,m)、4.90(1H,s)、6.77(1H,s)、7.11−7.16(3H,m)、7.41−7.43(2H,m)、7.72(2H,dd,J=9,5);MS(ES+)481([MH]+)。
実施例143、段階6に記載した手順を用いて、段階2からのジアミンを環状スルファミドに転化させた。収率60%。δ(1H、360MHz、CDCl3)1.24−1.29(2H,m)、1.60−1.80(8H,m)、1.95−2.05(2H,m)、2.38−2.43(2H,m)、2.67(2H,dd,J=16,8)、3.16(2H,d,J=16)、3.21(2H,s)、3.50(1H,tt,J=7,7)、4.62(1H,s)、7.05−7.12(4H,m);MS(ES+)347([MH]+)。
1−アセチルピペリジン−4−カルボニトリル(300mg、1.96mmol)、塩酸ヒドロキシルアミン(204mg、2.94mmol)およびトリエチルアミン(492μl、3.53mmol)をエタノール(10ml)中で混合し、還流下で一晩加熱した。溶媒を真空下で除去し、残留物をエタノールで研和して、このアミドオキシムを塩酸塩として得た(100mg、23%)。
N,N’−カルボニルジイミダゾール(53mg、0.33mmol)を、DMF(3mL)中の実施例104からのカルボン酸(120mg、0.30mmol)の溶液に添加し、室温で1時間攪拌した。DMF(3mL)中の段階1からの塩酸アミドオキシム(73mg、0.33mmol)とフーニッヒ塩基(114μl、0.66mmol)の超音波処理混合物を添加し、その反応混合物を一晩、70℃で攪拌した。冷却した反応混合物を酢酸エチル(25mL)で希釈し、水(4×25mL)およびブライン(25mL)で洗浄して、乾燥させた(Na2SO4)。溶媒を真空下で除去した。残留物(95mg)をTHF(10mL)に溶解し、カリウムt−ブトキシド(THF中1.0M;0.5mL、0.5mmol)を添加した。室温で65時間攪拌した後、その混合物を水(25mL)に注入し、酢酸エチル(2×25mL)で抽出した。一緒にした有機層をブライン(25mL)で洗浄し、乾燥させ(Na2SO4)、減圧下で蒸発させた。残留物を(フラッシュカラムクロマトグラフィーおよび分取TLCによる不純物の除去が失敗した後)FractionLynxによって精製して、表題の環状スルファミド(6mg、2段階を通して4%)を得た。
o/n − 一晩
DCM − ジクロロメタン
PDC − 二クロム酸ピリジニウム
DMF − N,N−ジメチルホルムアミド
DMSO − ジメチルスルホキシド
THF − テトラヒドロフラン
DIBAL − ジイソブチルアルミニウムヒドリド
LAH − 水素化アルミニウムリチウム
MOM − メトキシメチル
TFA − トリフルオロ酢酸
TEA − トリエチルアミン
DMAP − 4−(ジメチルアミノ)ピリジン
Boc − t−ブトキシカルボニル
DIPEA − ジイソプロピルエチルアミン
HBTU − ヘキサフルオロリン酸O−ベンゾトリアゾール−1−イル−N,N,N’,N’−テトラメチルウロニウム
DME − ジメトキシエタン
Claims (16)
- 下記式I:
AおよびBは、−(CXY)p−;−(CXY)qCY=CY(CXY)r−;−(CXY)xNR13(CXY)y−;および下記:
Xは、ハロゲン、R9、−OR9、−SR9、−S(O)tR10(この式中、tは、1または2である)、−OSO2R9、−N(R9)2、−COR9、−CO2R9、−OCOR10、−OCO2R10、−CON(R9)2、−SO2N(R9)2、−OSO2N(R9)2、NR9COR10、−NR9CO2R10もしくは−NR9SO2R10を表し;
Yは、HもしくはC1〜6アルキルを表すか;または
XとYは、一緒に、=O、=S、=N−OR11もしくは=CHR11を表すが;但し、
AおよびBは、いずれも、−CH2−以外の−CXY−部分を一つより多く含まないことを条件とし;
Zは、0〜3個は、窒素、酸素および硫黄から選択され、残りは炭素である原子5〜10個の芳香族環構造を完成しているか、またはZは、0〜3個は、酸素、窒素および硫黄から独自に選択され、残りは炭素である原子5〜10個の非芳香族環構造を完成しており;
Z1は、0〜3個は、酸素、窒素および硫黄から独自に選択され、残りは炭素である原子5〜10個の非芳香族環構造を完成しており;
Z2は、5または6員ヘテロアリール環を完成しており;
pは、1〜6の整数であり;
qおよびrは、独自に、0、1または2であり;
xおよびyは、独自に、0、1または2であるが;但し、
AおよびBの少なくとも一方は、AおよびBによって完成された環が少なくとも原子5個を含むように、原子2個以上の鎖を含むことを条件とし;
R1は、H、C1〜4アルキル、もしくはC2〜4アルケニルを表すか、またはR1とR15が、一緒に、5、6または7員の環状スルファミドを完成していてもよく;
R2は、カルボン酸基またはアミノ基で場合によっては置換されている、H、C1〜6アルキル、C6〜10アリール、C6〜10アリールC1〜6アルキル、C3〜6シクロアルキルまたはC2〜6アシルを表し;
R4、R5およびR6は、R9、ハロゲン、CN、NO2、−OR9、−SR9、−S(O)tR10(この式中、tは、1または2である)、−N(R9)2、−COR9、−CO2R9、−OCOR10、−CH=N−OR11、−CON(R9)2、−SO2N(R9)2、−NR9COR10、−NR9CO2R10、−NR9SO2R10、−CH=CHCH2N(R16)2、−CH2OR10、−CH2N(R16)2、−NHCOCH2OR10または−NHCOCH2N(R16)2を独自に表し;
R7は、HもしくはR8を表すか;または2個のR7基が、それらが互いに結合している窒素原子と一緒に、ピロリジン、ピペリジン、ピペラジンもしくはモルホリン環を完成していてもよく;
R8は、C1〜10アルキル、過フルオロC1〜6アルキル、C3〜10シクロアルキル、C3〜6シクロアルキルC1〜6アルキル、C2〜10アルケニル、C2〜10アルキニル、Arまたは−C1〜6アルキルArを表し;
R9は、HもしくはR10を表すか;または2個のR9基が、それらが互いに結合している窒素原子と一緒に、R12、−COR12または−SO2R12により場合によっては置換されている、ピロリジン、ピペリジン、ピペラジンもしくはモルホリン環を完成していてもよく;
R10は、C1〜10アルキル、過フルオロC1〜6アルキル、C3〜10シクロアルキル、C3〜6シクロアルキルC1〜6アルキル、C2〜10アルケニル、C2〜10アルキニル、C6〜10アリール、ヘテロアリール、ヘテロシクリル、C6〜10アリールC1〜6アルキル、ヘテロアリールC1〜6アルキル、ヘテロシクリルC1〜6アルキル、C6〜10アリールC2〜6アルケニル、またはヘテロアリールC2〜6アルケニルを表し、この場合、アルキル、シクロアルキル、アルケニルおよびアルキニル基は、ハロゲン、CF3、NO2、CN、−OR11、−SR11、−SO2R12、−COR11、−CO2R11、−CON(R11)2、−OCOR12、−N(R11)2および−NR11COR12から選択された置換基1個を場合によっては有し、ならびにアリール、ヘテロアリールおよび複素環基は、ハロゲン、NO2、CN、R12、−OR11、−SR11、−SO2R12、−COR11、−CO2R11、−CON(R11)2、−OCOR12、−N(R11)2および−NR11COR12から独自に選択された置換基3個以下を場合によっては有し;
R11は、HもしくはR12を表すか;または2個のR11基が、それらが互いに結合している窒素原子と一緒に、(前記窒素原子に加えて)0〜2個は、O、NおよびSから選択される原子3〜10個の複素環構造を完成していてもよく、前記環構造は、ハロゲン、CN、NO2、オキソ、R12、OH、OR12、NH2、NHR12、CHO、CO2H、COR12およびCO2R12から選択された置換基0〜2個を有し;
R12は、C1〜6アルキル(ハロゲン、CN、OH、C1〜4アルコキシまたはC1〜4アルコキシカルボニルで場合によっては置換されている)、過フルオロC1〜6アルキル、C3〜7シクロアルキル、C2〜6アルケニル、C2〜6アルキニル、Ar、−C1〜6アルキルAr、ArOC1〜6アルキルまたはC−ヘテロシクリル(ハロゲン、CN、C1〜6アルキル、OH、過フルオロC1〜6アルキル、C2〜6アシル、C1〜4アルコキシまたはC1〜4アルコキシカルボニルで場合によっては置換されている)を表し;
R13は、R9、−COR10、−CO2R10、−SO2R10、−CON(R9)2または−SO2N(R9)2を表し;
R14は、H、C1〜10アルキル、過フルオロC1〜6アルキル、C3〜10シクロアルキル、C3〜6シクロアルキルC1〜6アルキル、C2〜10アルケニル、C2〜10アルキニル、C6〜10アリール、ヘテロアリール、C6〜10アリールC1〜6アルキル、またはヘテロアリールC1〜6アルキルを表し、この場合、アルキル、シクロアルキル、アルケニルおよびアルキニル基は、ハロゲン、CN、NO2、−OR7、−SR7、−S(O)tR8(この式中、tは、1または2である)、−N(R7)2、−COR7、−CO2R7、−OCOR8、−CON(R7)2、−NR7COR8、−C1〜6アルキルNR7COR8、−NR7CO2R8および−NR7SO2R8から選択された置換基1個を場合によっては有し、ならびにアリールおよびヘテロアリール基は、R8、ハロゲン、CN、NO2、−OR7、−SR7、−S(O)tR8(この式中、tは、1または2である)、−N(R7)2、−COR7、−CO2R7、−OCOR8、−CON(R7)2、−NR7COR8、−C1〜6アルキルNR7COR8、−NR7CO2R8および−NR7SO2R8から選択された置換基3個以下を場合によっては有し;
R15は、HもしくはC1〜6アルキルを表すか;またはR15とR1が、一緒に、5、6もしくは7員の環状スルファミドを完成しており;
各R16は、HもしくはR10を独自に表すか、または2個のR16基が、それらが互いに結合している窒素と一緒に、C、N、OおよびSから選択された環原子5〜10個の単環式もしくは二環式の複素環式環構造を完成しており、該環構造は独自にそれに縮合した付加的なアリールもしくはヘテロアリール環を有し、前記複素環構造および場合によっては縮合環は、ハロゲン、オキソ、NO2、CN、R12、−OR11、−SR11、−SO2R12、−COR11、−CO2R11、−CON(R11)2、−OCOR12、−N(R11)2および−NR11COR12から独自に選択された置換基0〜3個を有し;
Arは、フェニルまたはヘテロアリールを表し、これらは、いずれも、ハロゲン、CF3、NO2、CN、OCF3、C1〜6アルキルおよびC1〜6アルコキシから独自に選択された置換基3個以下を場合によっては有し、
「ヘテロシクリル」は、その出現のたびに、C、N、OおよびSから選択された環原子10個以下の環状または多環式構造を意味し、この場合、いずれの構成環も芳香族性ではなく、且つ、少なくとも一つの環原子は、C以外であり;ならびに
「ヘテロアリール」は、その出現のたびに、C、N、OおよびSから選択された環原子10個以下の環状または多環式構造を意味し、この場合、少なくとも1個の構成環は、芳香族性であり、且つ、少なくとも1個の環原子は、C以外である)
の化合物またはその医薬適合性の塩。 - Xが、H,メチル、ヒドロキシメチルおよびCO2Etから選択され、Yが、HもしくはC1〜6アルキルであるか、またはXとYが一緒に、=O、=S,=N−OMe、=N−OEt、=N−OPh、=N−OCH2Phもしくは=CH2を表す、請求項1または請求項2に記載の化合物。
- R2がHである、前記請求項のいずれかに記載の化合物。
- R2が、Hであり、R14が、n−プロピルであり、およびR4が、3−ピリジル、(ピリジン−3−イル)メトキシ、−CO2Me、2−(ピリジン−2−イル)エトキシ、3−(モルホリン−4−イル)プロピル、−CH2OH、−CHO、−CH=CHCO2Me、3−[(4−メチル−1,2,4−トリアゾール−3−イル)チオ]プロプ−1−エニル、−CN、5−(4−フルオロフェニル)オキサゾール−2−イル、5−(4−フルオロフェニル)−1,3,4−オキサジアゾール−2−イル、3−(ピリジン−2−イル)−1,2,4−オキサジアゾール−5−イル、3−ピラジニル−1,2,4−オキサジアゾール−5−イル、−CH=CHCH2OHおよび5−(4−フルオロフェニル)ピラゾール−3−イルから選択されるか;または
R2が、Hであり、R14が、n−プロピルであり、およびR4が、−CH=CHCH2N(R16)2(この式中、−N(R16)2は、モルホリン−4−イル、4−トリフルオロメチルピペリジン−1−イル、4,4−ジフルオロピペリジン−1−イル、4−カルバモイルピペリジン−1−イル、4−エトキシカルボニルピペリジン−1−イル、4−カルボキシピペリジン−1−イル、4−ヒドロキシピペリジン−1−イル、1,2,3,6−テトラヒドロピリジニル、5−アザ−2−オキサビシクロ[2.2.1]ヘプト−1−イル、N−[(フラン−2−イル)メチル]アミノ、N,N−ビス(2−メトキシエチル)アミノ、N−(インダン−1−イル)アミノおよびN−[(ピリジン−2−イル)メチル]アミノから選択される)であるか;または
R2が、Hであり、R14が、n−プロピルであり、およびR4が、−OCH2CH2N(R11)2(式中、−N(R11)2は、モルホリン−4−イルおよび2−オキソ−イミダゾリン−1−イルから選択される)であるか;または
R2が、Hであり、R14が、2,2,2−トリフルオロエチルであり、およびR4が、−OH、−CO2Me、−CH2OH,−CHO、−CO2H、−CH=CHCO2Me、−CH=CHCO2H、−CH=CHCH2OH、−CH=N−OH、−CH=N−OEt、−CH2CH2CO2Me、−CH2CH2CO2H、(モルホリン−4−イル)メチル、2−(イミダゾール−1−イル)エトキシ、3−(4−トリフルオロメチルピペリジン−1−イル)プロピル、−CH=N−OCH2Ph、−CH=N−OCH2(4−F−C6H4)、−CH=N−OCH2(4−CF3−C6H4)、3−ピラジニル−1,2,4−オキサジアゾール−5−イル、3−(4−フルオロフェニル)−1,2,4−オキサジアゾール−5−イル、3−(ピリジン−2−イル)−1,2,4−オキサジアゾール−5−イル、−CH=N−OCH2(2−F−C6H4)、−CH=N−OCH2CH=CH2、−CH=N−OCH2(3−F−C6H4)および−CH=N−OCH2(2,4−ジ−Cl−C6H3)から選択されるか;または
R2が、Hであり、R14が、2,2,2−トリフルオロエチルであり、およびR4が、−CH=CHCH2N(R16)2(この式中、−N(R16)2は、モルホリン−4−イル、4−トリフルオロメチルピペリジン−1−イル、5−アザ−2−オキサビシクロ[2.2.1]ヘプト−1−イル、4,4−ジフルオロピペリジン−1−イル、4−ヒドロキシ−4−トリフルオロメチルピペリジン−1−イル、4−メチルピペリジン−1−イル、3−オキソ−4−フェニルピペラジン−1−イル、3−オキソ−4−シクロヘキシルピペラジン−1−イル、3−オキソ−ピペラジン−1−イル、N−(テトラヒドロフラン−3−イル)アミノ、N−メチル−N−(テトラヒドロフラン−3−イル)アミノ、N−(テトラヒドロピラン−4−イル)アミノ、N−メチル−N−(テトラヒドロピラン−4−イル)アミノ、N−(ジオキサニルメチル)アミノ、N−[(テトラヒドロピラン−2−イル)メチル]アミノ、3−ヒドロキシピペリジン−1−イル、5−アザ−2−オキサビシクロ[5.4.0]ウンデカ−7,9,11−トリエン−5−イル、2−(フェノキシメチル)モルホリン−4−イル、N−[(4−フェニルモルホリン−2−イル)メチル]アミノ、3,3−ジフルオロピロリジン−1−イル、N−(2,2,2−トリフルオロエチル)アミノおよび3−(ピリジン−3−イル)ピロリジン−1−イルから選択される)であるか;または
R2が、Hであり、R14が、2,2,2−トリフルオロエチルであり、およびR4が、−OCH2CH2N(R11)2(この式中、−N(R11)2は、モルホリン−1−イル、4−アセチルピペラジン−1−イル、N−(2−メトキシエチル)アミノ、N−[(チオフェン−2−イル)メチル]アミノ、N−[(ピリジン−3−イル)メチル]アミノ、N−(メトキシカルボニルメチル)アミノ、3−オキソ−4−フェニルピペラジン−1−イルおよび4−トリフルオロメチルピペリジン−1−イルから選択される)である、請求項12の実施態様(A)に記載の化合物。 - 前記請求項のいずれかに記載の化合物一つ以上および医薬適合性の担体を含む医薬組成物。
- 人体の治療法に使用するための請求項1から13のいずれかに記載の化合物。
- アルツハイマー病を治療または予防するための医薬品の製造における請求項1〜13のいずれかに記載の化合物の使用。
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Families Citing this family (72)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2001240861B2 (en) * | 2000-03-20 | 2006-03-30 | Merck Frosst Canada Ltd | Sulphonamido-substituted bridged bicycloalkyl derivatives |
GB0209997D0 (en) | 2002-05-01 | 2002-06-12 | Merck Sharp & Dohme | Therapeutic agents |
GB0209991D0 (en) * | 2002-05-01 | 2002-06-12 | Merck Sharp & Dohme | Therapeutic agents |
DE60328182D1 (de) * | 2002-05-01 | 2009-08-13 | Merck Sharp & Dohme | Heteroaryl substituierte spirocyclische sulfamide zur hemmung von gamma sekretase |
GB0209995D0 (en) * | 2002-05-01 | 2002-06-12 | Merck Sharp & Dohme | Therapeutic agents |
GB0225475D0 (en) * | 2002-11-01 | 2002-12-11 | Merck Sharp & Dohme | Therapeutic agents |
GB0225474D0 (en) | 2002-11-01 | 2002-12-11 | Merck Sharp & Dohme | Therapeutic agents |
US7521481B2 (en) | 2003-02-27 | 2009-04-21 | Mclaurin Joanne | Methods of preventing, treating and diagnosing disorders of protein aggregation |
DE602004011767T2 (de) | 2003-05-16 | 2009-02-19 | Merck Sharp & Dohme Ltd., Hoddesdon | Cyclohexylsulfone als gamma-sekretase-inhibitoren |
GB0318447D0 (en) * | 2003-08-05 | 2003-09-10 | Merck Sharp & Dohme | Therapeutic agents |
AU2004276050B2 (en) * | 2003-09-24 | 2010-02-25 | Merck Sharp & Dohme Limited | Gamma-secretase inhibitors |
GB0326039D0 (en) | 2003-11-07 | 2003-12-10 | Merck Sharp & Dohme | Therapeutic agents |
JP4764418B2 (ja) * | 2004-04-20 | 2011-09-07 | メルク・シャープ・エンド・ドーム・コーポレイション | アルツハイマー病の治療のためのβ−セクレターゼ阻害剤として有用な2,4,6−置換ピリジル誘導体化合物 |
EP1888050B1 (en) | 2005-05-17 | 2012-03-21 | Merck Sharp & Dohme Ltd. | cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexanepropanoic acid for the treatment of cancer |
US8242103B2 (en) | 2005-05-19 | 2012-08-14 | Merck Sharp & Dohme Limited | Sulphamides for treatment of cancer |
EP2198863A1 (en) | 2006-02-27 | 2010-06-23 | The Johns Hopkins University | Cancer treatment with gamma-secretase inhibitors |
WO2008055945A1 (en) | 2006-11-09 | 2008-05-15 | Probiodrug Ag | 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases |
WO2008076556A2 (en) | 2006-11-15 | 2008-06-26 | Massachusetts Eye & Ear Infirmary | Generation of inner ear cells |
US9126987B2 (en) | 2006-11-30 | 2015-09-08 | Probiodrug Ag | Inhibitors of glutaminyl cyclase |
AU2008215948A1 (en) | 2007-02-12 | 2008-08-21 | Merck & Co., Inc. | Piperazine derivatives for treatment of AD and related conditions |
CN101668525A (zh) | 2007-03-01 | 2010-03-10 | 前体生物药物股份公司 | 谷氨酰胺酰环化酶抑制剂的新用途 |
WO2008108445A1 (ja) | 2007-03-07 | 2008-09-12 | Takeda Pharmaceutical Company Limited | ベンゾオキサゼピン誘導体およびその用途 |
EP2142514B1 (en) | 2007-04-18 | 2014-12-24 | Probiodrug AG | Thiourea derivatives as glutaminyl cyclase inhibitors |
US8377886B2 (en) * | 2007-09-14 | 2013-02-19 | Albert Einstein College Of Medicine Of Yeshiva University | Use of gamma secretase inhibitors and notch pathway inhibitors for treatment and prevention of renal disease |
US8354446B2 (en) | 2007-12-21 | 2013-01-15 | Ligand Pharmaceuticals Incorporated | Selective androgen receptor modulators (SARMs) and uses thereof |
US8461389B2 (en) | 2008-04-18 | 2013-06-11 | University College Dublin, National University Of Ireland, Dublin | Psycho-pharmaceuticals |
CA2743436C (en) | 2008-11-24 | 2017-10-31 | Massachusetts Eye & Ear Infirmary | Pathways to generate hair cells |
WO2010114780A1 (en) | 2009-04-01 | 2010-10-07 | Merck Sharp & Dohme Corp. | Inhibitors of akt activity |
SG178953A1 (en) | 2009-09-11 | 2012-04-27 | Probiodrug Ag | Heterocylcic derivatives as inhibitors of glutaminyl cyclase |
EA023838B1 (ru) | 2009-10-14 | 2016-07-29 | Мерк Шарп Энд Домэ Корп. | ЗАМЕЩЕННЫЕ ПИПЕРИДИНЫ, КОТОРЫЕ ПОВЫШАЮТ АКТИВНОСТЬ p53, И ИХ ПРИМЕНЕНИЕ |
WO2011046774A1 (en) * | 2009-10-16 | 2011-04-21 | Merck Sharp & Dohme Corp. | Diaryl ether derivatives as notch sparing gamma secretase inhibitors |
ES2586231T3 (es) | 2010-03-03 | 2016-10-13 | Probiodrug Ag | Inhibidores de glutaminil ciclasa |
DK2545047T3 (da) | 2010-03-10 | 2014-07-28 | Probiodrug Ag | Heterocycliske inhibitorer af glutaminylcyclase (QC, EC 2.3.2.5) |
WO2011131748A2 (en) | 2010-04-21 | 2011-10-27 | Probiodrug Ag | Novel inhibitors |
EP2584903B1 (en) | 2010-06-24 | 2018-10-24 | Merck Sharp & Dohme Corp. | Novel heterocyclic compounds as erk inhibitors |
WO2012018754A2 (en) | 2010-08-02 | 2012-02-09 | Merck Sharp & Dohme Corp. | RNA INTERFERENCE MEDIATED INHIBITION OF CATENIN (CADHERIN-ASSOCIATED PROTEIN), BETA 1 (CTNNB1) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
CA2807307C (en) | 2010-08-17 | 2021-02-09 | Merck Sharp & Dohme Corp. | Rna interference mediated inhibition of hepatitis b virus (hbv) gene expression using short interfering nucleic acid (sina) |
US8946216B2 (en) | 2010-09-01 | 2015-02-03 | Merck Sharp & Dohme Corp. | Indazole derivatives useful as ERK inhibitors |
EP2615916B1 (en) | 2010-09-16 | 2017-01-04 | Merck Sharp & Dohme Corp. | Fused pyrazole derivatives as novel erk inhibitors |
US9260471B2 (en) | 2010-10-29 | 2016-02-16 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using short interfering nucleic acids (siNA) |
EP2654748B1 (en) | 2010-12-21 | 2016-07-27 | Merck Sharp & Dohme Corp. | Indazole derivatives useful as erk inhibitors |
ES2570167T3 (es) | 2011-03-16 | 2016-05-17 | Probiodrug Ag | Derivados de benzimidazol como inhibidores de glutaminil ciclasa |
ES2389416B1 (es) * | 2011-03-30 | 2013-09-16 | Fundación Instituto Mediterraneo Para El Avance De La Biotecnología Y La Investigación Sanitaria (Imabis) | Uso de derivados de sulfamidas como neuroprotectores. |
WO2013016411A1 (en) * | 2011-07-28 | 2013-01-31 | Garry Robert Smith | Novel fluorinated cyclic sulfamides exhibiting neuroprotective action and their method of use |
US9023865B2 (en) | 2011-10-27 | 2015-05-05 | Merck Sharp & Dohme Corp. | Compounds that are ERK inhibitors |
EP3453762B1 (en) | 2012-05-02 | 2021-04-21 | Sirna Therapeutics, Inc. | Short interfering nucleic acid (sina) compositions |
EP3970725A1 (en) | 2012-09-07 | 2022-03-23 | Massachusetts Eye & Ear Infirmary | A gamma secretase inhibitor for treating hearing loss |
JP6280554B2 (ja) | 2012-09-28 | 2018-02-14 | メルク・シャープ・アンド・ドーム・コーポレーションMerck Sharp & Dohme Corp. | Erk阻害剤である新規化合物 |
ME02925B (me) | 2012-11-28 | 2018-04-20 | Merck Sharp & Dohme | Kompozicije i postupci za liječenje kancera |
TW201429969A (zh) | 2012-12-20 | 2014-08-01 | Merck Sharp & Dohme | 作爲hdm2抑制劑之經取代咪唑吡啶 |
EP2951180B1 (en) | 2013-01-30 | 2018-05-02 | Merck Sharp & Dohme Corp. | 2,6,7,8 substituted purines as hdm2 inhibitors |
US8859286B2 (en) | 2013-03-14 | 2014-10-14 | Viacyte, Inc. | In vitro differentiation of pluripotent stem cells to pancreatic endoderm cells (PEC) and endocrine cells |
US20160194368A1 (en) | 2013-09-03 | 2016-07-07 | Moderna Therapeutics, Inc. | Circular polynucleotides |
EP3613418A1 (en) | 2014-01-17 | 2020-02-26 | Ligand Pharmaceuticals, Inc. | Methods and compositions for modulating hormone levels |
CN106488775A (zh) | 2014-07-11 | 2017-03-08 | 基因泰克公司 | Notch途径抑制 |
WO2016022776A2 (en) | 2014-08-06 | 2016-02-11 | Massachusetts Eye And Ear Infirmary | Increasing atoh1 life to drive sensorineural hair cell differentiantion |
ES2747386T3 (es) | 2015-01-14 | 2020-03-10 | Bristol Myers Squibb Co | Dímeros de benzodiacepina unidos por heteroarileno, conjugados de los mismos y métodos de preparación y uso |
KR20180033232A (ko) | 2015-07-24 | 2018-04-02 | 온코트랙커 인코포레이티드 | 면역계 기능장애의 치료를 위한 감마 세크레타제 조절제 |
WO2017096233A1 (en) | 2015-12-04 | 2017-06-08 | Massachusetts Eye And Ear Infirmary | Treatment of hearing loss by inhibition of casein kinase 1 |
AU2017212655B2 (en) | 2016-01-29 | 2024-01-18 | Decibel Therapeutics, Inc. | Expansion and differentiation of inner ear supporting cells and methods of use thereof |
CA3024424A1 (en) | 2016-05-16 | 2017-11-23 | The General Hospital Corporation | Human airway stem cells in lung epithelial engineering |
RU2757276C2 (ru) | 2016-12-16 | 2021-10-12 | Пайплайн Терапьютикс, Инк. | Способы лечения кохлеарной синаптопатии |
IL268349B1 (en) | 2017-02-17 | 2024-04-01 | Hutchinson Fred Cancer Res | Combination therapies for the treatment of BCMA-associated cancer and autoimmune disorders |
PL3461819T3 (pl) | 2017-09-29 | 2020-11-30 | Probiodrug Ag | Inhibitory cyklazy glutaminylowej |
WO2019094311A1 (en) | 2017-11-08 | 2019-05-16 | Merck Sharp & Dohme Corp. | Prmt5 inhibitors |
US11993602B2 (en) | 2018-08-07 | 2024-05-28 | Merck Sharp & Dohme Llc | PRMT5 inhibitors |
EP3833667B1 (en) | 2018-08-07 | 2024-03-13 | Merck Sharp & Dohme LLC | Prmt5 inhibitors |
WO2021126731A1 (en) | 2019-12-17 | 2021-06-24 | Merck Sharp & Dohme Corp. | Prmt5 inhibitors |
BR112022018987A2 (pt) | 2020-03-26 | 2022-11-01 | Seagen Inc | Métodos de tratamento de mieloma múltiplo |
US20240116945A1 (en) | 2022-09-02 | 2024-04-11 | Merck Sharp & Dohme Llc | Exatecan-derived topoisomerase-1 inhibitors pharmaceutical compositions, and uses thereof |
WO2024091437A1 (en) | 2022-10-25 | 2024-05-02 | Merck Sharp & Dohme Llc | Exatecan-derived adc linker-payloads, pharmaceutical compositions, and uses thereof |
WO2024129628A1 (en) | 2022-12-14 | 2024-06-20 | Merck Sharp & Dohme Llc | Auristatin linker-payloads, pharmaceutical compositions, and uses thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002037731A (ja) * | 2000-05-19 | 2002-02-06 | Takeda Chem Ind Ltd | βセクレターゼ阻害剤 |
JP2003520266A (ja) * | 2000-01-24 | 2003-07-02 | メルク シャープ エンド ドーム リミテッド | γ−セクレターゼ阻害薬 |
JP2003528076A (ja) * | 2000-03-20 | 2003-09-24 | メルク シャープ エンド ドーム リミテッド | スルホンアミド置換架橋ビシクロアルキル誘導体 |
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US3406184A (en) * | 1966-05-04 | 1968-10-15 | Du Pont | Addition compounds of norbornadienes and quadricyclenes with bis(trifluoromethyl) thioketene and their s-oxides and s-dioxides |
US3715362A (en) * | 1970-08-17 | 1973-02-06 | Lilly Co Eli | Tetracyclic aziridine and method for its preparation |
US5703129A (en) * | 1996-09-30 | 1997-12-30 | Bristol-Myers Squibb Company | 5-amino-6-cyclohexyl-4-hydroxy-hexanamide derivatives as inhibitors of β-amyloid protein production |
US6310107B1 (en) | 1997-02-27 | 2001-10-30 | Takeda Chemical Industries, Ltd. | Amine compounds, their production and use as amyloid-β production inhibitors |
DE60328182D1 (de) * | 2002-05-01 | 2009-08-13 | Merck Sharp & Dohme | Heteroaryl substituierte spirocyclische sulfamide zur hemmung von gamma sekretase |
GB0209997D0 (en) * | 2002-05-01 | 2002-06-12 | Merck Sharp & Dohme | Therapeutic agents |
GB0209995D0 (en) * | 2002-05-01 | 2002-06-12 | Merck Sharp & Dohme | Therapeutic agents |
GB0209991D0 (en) * | 2002-05-01 | 2002-06-12 | Merck Sharp & Dohme | Therapeutic agents |
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JP2003520266A (ja) * | 2000-01-24 | 2003-07-02 | メルク シャープ エンド ドーム リミテッド | γ−セクレターゼ阻害薬 |
JP2003528076A (ja) * | 2000-03-20 | 2003-09-24 | メルク シャープ エンド ドーム リミテッド | スルホンアミド置換架橋ビシクロアルキル誘導体 |
JP2002037731A (ja) * | 2000-05-19 | 2002-02-06 | Takeda Chem Ind Ltd | βセクレターゼ阻害剤 |
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AU1074702A (en) | 2002-05-15 |
US20040049038A1 (en) | 2004-03-11 |
JP3880051B2 (ja) | 2007-02-14 |
AU2002210747B2 (en) | 2006-06-01 |
JP4495686B2 (ja) | 2010-07-07 |
EP1334085A1 (en) | 2003-08-13 |
JP2004513108A (ja) | 2004-04-30 |
CA2427206A1 (en) | 2002-05-10 |
DE60112957T2 (de) | 2006-05-18 |
DE60112957D1 (de) | 2005-09-29 |
CA2427206C (en) | 2011-06-28 |
EP1334085B1 (en) | 2005-08-24 |
ATE302753T1 (de) | 2005-09-15 |
US7138400B2 (en) | 2006-11-21 |
ES2248397T3 (es) | 2006-03-16 |
WO2002036555A1 (en) | 2002-05-10 |
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