TWI385175B - 作為β-分泌酶調節劑之螺旋-三環化合物及其使用方法 - Google Patents

Info

Publication number

TWI385175B

TWI385175B TW098130795A TW98130795A TWI385175B TW I385175 B TWI385175 B TW I385175B TW 098130795 A TW098130795 A TW 098130795A TW 98130795 A TW98130795 A TW 98130795A TW I385175 B TWI385175 B TW I385175B

Authority

TW

Taiwan

Prior art keywords

alkyl

amine

snail

dibenzopyran

pyridyl

Prior art date

2008-09-11

Links

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• 150000001875 compounds Chemical class 0.000 title claims description 204
• 238000000034 method Methods 0.000 title claims description 103
• 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 title description 13
• 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 title description 13
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 329
• -1 C 1-6 -alkyl Chemical group 0.000 claims description 293
• 241000237858 Gastropoda Species 0.000 claims description 176
• 229910020008 S(O) Inorganic materials 0.000 claims description 123
• 125000001188 haloalkyl group Chemical group 0.000 claims description 89
• 125000005843 halogen group Chemical group 0.000 claims description 86
• 230000015572 biosynthetic process Effects 0.000 claims description 81
• 238000006243 chemical reaction Methods 0.000 claims description 74
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 73
• 125000003003 spiro group Chemical group 0.000 claims description 72
• 125000001424 substituent group Chemical group 0.000 claims description 71
• 229920006395 saturated elastomer Polymers 0.000 claims description 69
• 125000004122 cyclic group Chemical group 0.000 claims description 67
• 125000005842 heteroatom Chemical group 0.000 claims description 65
• 229910052760 oxygen Inorganic materials 0.000 claims description 65
• 229910052717 sulfur Inorganic materials 0.000 claims description 62
• 125000002950 monocyclic group Chemical group 0.000 claims description 59
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 56
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 55
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 53
• 229910052731 fluorine Inorganic materials 0.000 claims description 51
• 125000002619 bicyclic group Chemical group 0.000 claims description 48
• 229910052739 hydrogen Inorganic materials 0.000 claims description 48
• 150000003839 salts Chemical class 0.000 claims description 44
• 125000004432 carbon atom Chemical group C* 0.000 claims description 43
• 229910052757 nitrogen Inorganic materials 0.000 claims description 42
• 229910052801 chlorine Inorganic materials 0.000 claims description 40
• 208000024827 Alzheimer disease Diseases 0.000 claims description 35
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
• 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 32
• 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 30
• 125000003118 aryl group Chemical group 0.000 claims description 30
• 229910052794 bromium Inorganic materials 0.000 claims description 30
• FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 30
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 25
• 125000000217 alkyl group Chemical group 0.000 claims description 24
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 23
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
• 229930194542 Keto Natural products 0.000 claims description 22
• 229910052799 carbon Inorganic materials 0.000 claims description 22
• 125000000468 ketone group Chemical group 0.000 claims description 21
• 229910052740 iodine Inorganic materials 0.000 claims description 20
• 101100240516 Caenorhabditis elegans nhr-10 gene Proteins 0.000 claims description 18
• 125000001072 heteroaryl group Chemical group 0.000 claims description 17
• 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 17
• 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 17
• 238000011282 treatment Methods 0.000 claims description 17
• 125000004429 atom Chemical group 0.000 claims description 16
• 125000003943 azolyl group Chemical group 0.000 claims description 16
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 16
• 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 16
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 16
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 16
• 210000004556 brain Anatomy 0.000 claims description 15
• 125000004076 pyridyl group Chemical group 0.000 claims description 15
• 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 description 14
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 13
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
• 125000003545 alkoxy group Chemical group 0.000 claims description 9
• 239000003814 drug Substances 0.000 claims description 9
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
• 238000004519 manufacturing process Methods 0.000 claims description 9
• 125000001544 thienyl group Chemical group 0.000 claims description 9
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
• 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 8
• 125000002757 morpholinyl group Chemical group 0.000 claims description 8
• 125000003554 tetrahydropyrrolyl group Chemical group 0.000 claims description 8
• 206010012289 Dementia Diseases 0.000 claims description 7
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 7
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 7
• 125000002720 diazolyl group Chemical group 0.000 claims description 7
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 7
• 125000002883 imidazolyl group Chemical group 0.000 claims description 7
• 125000001786 isothiazolyl group Chemical group 0.000 claims description 7
• 239000008194 pharmaceutical composition Substances 0.000 claims description 7
• 125000005936 piperidyl group Chemical group 0.000 claims description 7
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 7
• 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 7
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 7
• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 7
• 125000000335 thiazolyl group Chemical group 0.000 claims description 7
• 125000005052 dihydropyrazolyl group Chemical group N1(NCC=C1)* 0.000 claims description 6
• 125000002541 furyl group Chemical group 0.000 claims description 6
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 6
• 125000002769 thiazolinyl group Chemical group 0.000 claims description 6
• 125000001425 triazolyl group Chemical group 0.000 claims description 6
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
• ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims description 4
• MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 4
• 230000006999 cognitive decline Effects 0.000 claims description 4
• 208000010877 cognitive disease Diseases 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
• 210000001175 cerebrospinal fluid Anatomy 0.000 claims description 3
• 125000003396 thiol group Chemical group [H]S* 0.000 claims description 3
• 208000005145 Cerebral amyloid angiopathy Diseases 0.000 claims description 2
• 206010008111 Cerebral haemorrhage Diseases 0.000 claims description 2
• 201000010374 Down Syndrome Diseases 0.000 claims description 2
• 239000004593 Epoxy Substances 0.000 claims description 2
• 206010044688 Trisomy 21 Diseases 0.000 claims description 2
• 206010002022 amyloidosis Diseases 0.000 claims description 2
• 239000001294 propane Substances 0.000 claims description 2
• 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims 2
• 208000012902 Nervous system disease Diseases 0.000 claims 1
• 206010033799 Paralysis Diseases 0.000 claims 1
• 208000018737 Parkinson disease Diseases 0.000 claims 1
• 230000037429 base substitution Effects 0.000 claims 1
• 230000001054 cortical effect Effects 0.000 claims 1
• RUYNTLUDGSFPFZ-UHFFFAOYSA-N cyclobutanol Chemical compound OC1[CH]CC1 RUYNTLUDGSFPFZ-UHFFFAOYSA-N 0.000 claims 1
• 230000007850 degeneration Effects 0.000 claims 1
• 230000003412 degenerative effect Effects 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 365
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 308
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 274
• 235000019439 ethyl acetate Nutrition 0.000 description 166
• 239000000203 mixture Substances 0.000 description 161
• 206010012812 Diffuse cutaneous mastocytosis Diseases 0.000 description 122
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• 239000007787 solid Substances 0.000 description 100
• 239000000243 solution Substances 0.000 description 98
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• 238000004949 mass spectrometry Methods 0.000 description 75
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• 239000010410 layer Substances 0.000 description 61
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• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 53
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• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 49
• 239000000460 chlorine Substances 0.000 description 45
• RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
• 239000012044 organic layer Substances 0.000 description 43
• 229910052938 sodium sulfate Inorganic materials 0.000 description 43
• 235000011152 sodium sulphate Nutrition 0.000 description 43
• 239000012267 brine Substances 0.000 description 41
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• OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 38
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