CN1253554A - 杂环化合物及其抑制β－淀粉样肽的用途 - Google Patents

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Publication number

CN1253554A

CN1253554A CN98802875A CN98802875A CN1253554A CN 1253554 A CN1253554 A CN 1253554A CN 98802875 A CN98802875 A CN 98802875A CN 98802875 A CN98802875 A CN 98802875A CN 1253554 A CN1253554 A CN 1253554A

Authority

CN

China

Prior art keywords

phenyl

base

alkyl

group

substituted

Prior art date

1997-02-28

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Pending

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• 108090000765 processed proteins & peptides Proteins 0.000 title description 6
• 150000002391 heterocyclic compounds Chemical class 0.000 title 1
• 230000002401 inhibitory effect Effects 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 204
• 238000000034 method Methods 0.000 claims abstract description 192
• 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 claims abstract description 30
• 230000015572 biosynthetic process Effects 0.000 claims abstract description 20
• -1 heterocyclic radical Chemical class 0.000 claims description 915
• 125000003118 aryl group Chemical group 0.000 claims description 278
• 125000001072 heteroaryl group Chemical group 0.000 claims description 247
• 125000000217 alkyl group Chemical group 0.000 claims description 246
• 229910052739 hydrogen Inorganic materials 0.000 claims description 207
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 206
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 202
• 239000001257 hydrogen Substances 0.000 claims description 192
• 125000000304 alkynyl group Chemical group 0.000 claims description 175
• 150000002431 hydrogen Chemical class 0.000 claims description 164
• 125000003342 alkenyl group Chemical group 0.000 claims description 121
• 239000000203 mixture Substances 0.000 claims description 118
• 125000005017 substituted alkenyl group Chemical group 0.000 claims description 117
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 108
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 97
• 229910052760 oxygen Inorganic materials 0.000 claims description 92
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 91
• 239000001301 oxygen Substances 0.000 claims description 90
• 239000011737 fluorine Substances 0.000 claims description 81
• 229910052731 fluorine Inorganic materials 0.000 claims description 81
• 125000005309 thioalkoxy group Chemical group 0.000 claims description 80
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 74
• 229910052799 carbon Inorganic materials 0.000 claims description 73
• 125000003545 alkoxy group Chemical group 0.000 claims description 70
• YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 61
• 229910052757 nitrogen Inorganic materials 0.000 claims description 60
• 125000002252 acyl group Chemical group 0.000 claims description 57
• 125000005415 substituted alkoxy group Chemical group 0.000 claims description 57
• WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 57
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 56
• 239000005864 Sulphur Substances 0.000 claims description 56
• 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 54
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 52
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 50
• 125000003282 alkyl amino group Chemical group 0.000 claims description 47
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 47
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 43
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 43
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 36
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 36
• 125000001207 fluorophenyl group Chemical group 0.000 claims description 36
• 125000005605 benzo group Chemical group 0.000 claims description 35
• 125000005843 halogen group Chemical group 0.000 claims description 35
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 32
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 32
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 31
• 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 30
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 30
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 30
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 30
• 150000001733 carboxylic acid esters Chemical class 0.000 claims description 30
• 125000004423 acyloxy group Chemical group 0.000 claims description 29
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 28
• 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 27
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 27
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 27
• 125000004181 carboxyalkyl group Chemical group 0.000 claims description 25
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 25
• 125000000623 heterocyclic group Chemical group 0.000 claims description 23
• 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 claims description 21
• 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 20
• MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 20
• 125000006289 hydroxybenzyl group Chemical group 0.000 claims description 20
• VEUMBMHMMCOFAG-UHFFFAOYSA-N 2,3-dihydrooxadiazole Chemical compound N1NC=CO1 VEUMBMHMMCOFAG-UHFFFAOYSA-N 0.000 claims description 19
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 18
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 18
• 150000003573 thiols Chemical class 0.000 claims description 17
• 125000004122 cyclic group Chemical group 0.000 claims description 14
• 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 13
• 238000010189 synthetic method Methods 0.000 claims description 13
• 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 12
• 125000004076 pyridyl group Chemical group 0.000 claims description 12
• GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 claims description 11
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 11
• 101150065749 Churc1 gene Proteins 0.000 claims description 11
• 102100038239 Protein Churchill Human genes 0.000 claims description 11
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 11
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 11
• 238000002156 mixing Methods 0.000 claims description 11
• 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 10
• FNRMMDCDHWCQTH-UHFFFAOYSA-N 2-chloropyridine;3-chloropyridine;4-chloropyridine Chemical compound ClC1=CC=NC=C1.ClC1=CC=CN=C1.ClC1=CC=CC=N1 FNRMMDCDHWCQTH-UHFFFAOYSA-N 0.000 claims description 10
• 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 10
• 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 10
• 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 10
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 10
• 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims description 10
• 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 10
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 10
• 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
• 125000004861 4-isopropyl phenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 10
• WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 10
• 125000006502 nitrobenzyl group Chemical group 0.000 claims description 10
• 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 10
• 125000003107 substituted aryl group Chemical group 0.000 claims description 10
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
• 229910052794 bromium Inorganic materials 0.000 claims description 9
• AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 claims description 8
• 125000005842 heteroatom Chemical group 0.000 claims description 7
• 229910052740 iodine Inorganic materials 0.000 claims description 7
• 239000011630 iodine Substances 0.000 claims description 7
• AELZBYQHJCEGBO-UHFFFAOYSA-N CC(C)(C)C[O] Chemical compound CC(C)(C)C[O] AELZBYQHJCEGBO-UHFFFAOYSA-N 0.000 claims description 6
• 230000005764 inhibitory process Effects 0.000 claims description 6
• HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical group [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 6
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 6
• IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 claims description 5
• 125000006323 alkenyl amino group Chemical group 0.000 claims description 5
• 239000012954 diazonium Substances 0.000 claims description 5
• GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 5
• UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 4
• JUIQOABNSLTJSW-UHFFFAOYSA-N 2-Methyl-4,5-dihydro-1,3-thiazole Chemical compound CC1=NCCS1 JUIQOABNSLTJSW-UHFFFAOYSA-N 0.000 claims description 3
• 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 3
• SIAAJNCKMVLBCL-UHFFFAOYSA-N CC1C(C(=O)O)(C=CC=C1C(=O)O)C Chemical compound CC1C(C(=O)O)(C=CC=C1C(=O)O)C SIAAJNCKMVLBCL-UHFFFAOYSA-N 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• QTPQNONFUNQORN-UHFFFAOYSA-N ethyl 2-methyl-4,5-dihydro-1,3-thiazole-4-carboxylate Chemical compound CCOC(=O)C1CSC(C)=N1 QTPQNONFUNQORN-UHFFFAOYSA-N 0.000 claims description 3
• GRNYICVXEZMNSA-UHFFFAOYSA-N methyl 2-methyl-4,5-dihydro-1,3-thiazole-4-carboxylate Chemical compound COC(=O)C1CSC(C)=N1 GRNYICVXEZMNSA-UHFFFAOYSA-N 0.000 claims description 3
• 125000004432 carbon atom Chemical group C* 0.000 claims 36
• UPUWMQZUXFAUCJ-UHFFFAOYSA-N 2,5-dihydro-1,2-thiazole Chemical compound C1SNC=C1 UPUWMQZUXFAUCJ-UHFFFAOYSA-N 0.000 claims 4
• 238000003786 synthesis reaction Methods 0.000 abstract description 14
• 239000008194 pharmaceutical composition Substances 0.000 abstract description 5
• 208000024827 Alzheimer disease Diseases 0.000 abstract 2
• 239000002585 base Substances 0.000 description 182
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 91
• 238000006243 chemical reaction Methods 0.000 description 88
• 238000002360 preparation method Methods 0.000 description 69
• 125000002947 alkylene group Chemical group 0.000 description 60
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• 239000000243 solution Substances 0.000 description 44
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 43
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• 238000005481 NMR spectroscopy Methods 0.000 description 24
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• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
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• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 17
• 125000000266 alpha-aminoacyl group Chemical group 0.000 description 17
• 239000003513 alkali Substances 0.000 description 16
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• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 15
• 230000002829 reductive effect Effects 0.000 description 15
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• 230000000875 corresponding effect Effects 0.000 description 13
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• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 7
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• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
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