AU2009291602B2 - Spiro-tetracyclic ring compounds as betasecretase modulators and methods of use - Google Patents

Info

Publication number

AU2009291602B2

AU2009291602B2 AU2009291602A AU2009291602A AU2009291602B2 AU 2009291602 B2 AU2009291602 B2 AU 2009291602B2 AU 2009291602 A AU2009291602 A AU 2009291602A AU 2009291602 A AU2009291602 A AU 2009291602A AU 2009291602 B2 AU2009291602 B2 AU 2009291602B2

Authority

AU

Australia

Prior art keywords

amine

spiro

oxazole

alkyl

xanthen

Prior art date

2008-09-11

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.)

Ceased

Links

• Espacenet
• Global Dossier
• Discuss

• 150000001875 compounds Chemical class 0.000 title claims abstract description 266
• 238000000034 method Methods 0.000 title claims description 105
• 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 title abstract description 16
• 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 title abstract description 16
• 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 41
• 238000011282 treatment Methods 0.000 claims abstract description 9
• 125000003003 spiro group Chemical group 0.000 claims description 307
• -1 20 C 1 _ 6 -alkyl Chemical group 0.000 claims description 252
• ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 104
• 125000005843 halogen group Chemical group 0.000 claims description 97
• 125000001188 haloalkyl group Chemical group 0.000 claims description 93
• 125000001424 substituent group Chemical group 0.000 claims description 79
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 78
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 77
• 125000005842 heteroatom Chemical group 0.000 claims description 75
• SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 70
• 150000003839 salts Chemical class 0.000 claims description 69
• 125000002950 monocyclic group Chemical group 0.000 claims description 68
• 229920006395 saturated elastomer Polymers 0.000 claims description 65
• 125000002619 bicyclic group Chemical group 0.000 claims description 60
• 229910052757 nitrogen Inorganic materials 0.000 claims description 57
• 125000004076 pyridyl group Chemical group 0.000 claims description 57
• 125000004432 carbon atom Chemical group C* 0.000 claims description 55
• 229910052731 fluorine Inorganic materials 0.000 claims description 51
• 150000001412 amines Chemical class 0.000 claims description 50
• 229910052739 hydrogen Inorganic materials 0.000 claims description 47
• 125000004122 cyclic group Chemical group 0.000 claims description 42
• 229910052801 chlorine Inorganic materials 0.000 claims description 41
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 41
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 38
• 229910052794 bromium Inorganic materials 0.000 claims description 33
• 125000003118 aryl group Chemical group 0.000 claims description 30
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 28
• 125000000217 alkyl group Chemical group 0.000 claims description 27
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 26
• 229910052740 iodine Inorganic materials 0.000 claims description 23
• 125000003282 alkyl amino group Chemical group 0.000 claims description 22
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 22
• 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 19
• 210000004556 brain Anatomy 0.000 claims description 19
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 19
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 19
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 18
• 206010012289 Dementia Diseases 0.000 claims description 18
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 18
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 18
• 125000001072 heteroaryl group Chemical group 0.000 claims description 18
• 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 18
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 18
• GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 18
• 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 18
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 18
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 18
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 18
• QMYGFTJCQFEDST-UHFFFAOYSA-N 3-methoxybutyl acetate Chemical group COC(C)CCOC(C)=O QMYGFTJCQFEDST-UHFFFAOYSA-N 0.000 claims description 17
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 17
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 17
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 17
• 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 17
• 125000004043 oxo group Chemical group O=* 0.000 claims description 17
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 17
• MXIYRNSRKGMBLQ-UHFFFAOYSA-N 5h-chromeno[2,3-b]pyridine Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=N1 MXIYRNSRKGMBLQ-UHFFFAOYSA-N 0.000 claims description 15
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 14
• 239000008194 pharmaceutical composition Substances 0.000 claims description 14
• XTFIVUDBNACUBN-UHFFFAOYSA-N 1,3,5-trinitro-1,3,5-triazinane Chemical compound [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)C1 XTFIVUDBNACUBN-UHFFFAOYSA-N 0.000 claims description 13
• 239000003814 drug Substances 0.000 claims description 13
• 125000004306 triazinyl group Chemical group 0.000 claims description 13
• 125000002757 morpholinyl group Chemical group 0.000 claims description 12
• 125000001544 thienyl group Chemical group 0.000 claims description 12
• 125000002541 furyl group Chemical group 0.000 claims description 11
• 238000004519 manufacturing process Methods 0.000 claims description 11
• 125000004193 piperazinyl group Chemical group 0.000 claims description 11
• 125000003386 piperidinyl group Chemical group 0.000 claims description 11
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 11
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
• 208000010877 cognitive disease Diseases 0.000 claims description 10
• 125000002883 imidazolyl group Chemical group 0.000 claims description 10
• 125000001786 isothiazolyl group Chemical group 0.000 claims description 10
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 10
• 125000001715 oxadiazolyl group Chemical group 0.000 claims description 10
• 125000002971 oxazolyl group Chemical group 0.000 claims description 10
• 230000007505 plaque formation Effects 0.000 claims description 10
• 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 10
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 10
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 10
• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 10
• 125000000335 thiazolyl group Chemical group 0.000 claims description 10
• 125000001425 triazolyl group Chemical group 0.000 claims description 10
• 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 9
• 125000003971 isoxazolinyl group Chemical group 0.000 claims description 9
• 125000005968 oxazolinyl group Chemical group 0.000 claims description 9
• 125000002755 pyrazolinyl group Chemical group 0.000 claims description 9
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 9
• 125000002769 thiazolinyl group Chemical group 0.000 claims description 9
• CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 claims description 8
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 8
• 208000028698 Cognitive impairment Diseases 0.000 claims description 7
• PFKCYCIUJHGSHR-UHFFFAOYSA-N 2'-chloro-7'-pyrimidin-5-ylspiro[5h-1,3-oxazole-4,9'-xanthene]-2-amine Chemical compound C1OC(N)=NC21C1=CC(C=3C=NC=NC=3)=CC=C1OC1=CC=C(Cl)C=C12 PFKCYCIUJHGSHR-UHFFFAOYSA-N 0.000 claims description 6
• 208000005145 Cerebral amyloid angiopathy Diseases 0.000 claims description 6
• 208000012902 Nervous system disease Diseases 0.000 claims description 6
• 210000001175 cerebrospinal fluid Anatomy 0.000 claims description 6
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
• 201000010374 Down Syndrome Diseases 0.000 claims description 5
• 206010044688 Trisomy 21 Diseases 0.000 claims description 5
• 230000007850 degeneration Effects 0.000 claims description 5
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
• QTYGIEOEIDRQAB-DEOSSOPVSA-N (4s)-2'-(3,6-dihydro-2h-pyran-4-yl)-3'-fluoro-7'-pyrimidin-5-ylspiro[5h-1,3-oxazole-4,9'-xanthene]-2-amine Chemical compound C1OC(N)=N[C@]21C1=CC(C=3CCOCC=3)=C(F)C=C1OC1=CC=C(C=3C=NC=NC=3)C=C12 QTYGIEOEIDRQAB-DEOSSOPVSA-N 0.000 claims description 4
• PZROFGPRPCCYLH-VWLOTQADSA-N (4s)-2'-(3,6-dihydro-2h-pyran-4-yl)-4'-fluoro-7'-pyridin-3-ylspiro[5h-1,3-oxazole-4,9'-xanthene]-2-amine Chemical compound C1OC(N)=N[C@]21C1=CC(C=3CCOCC=3)=CC(F)=C1OC1=CC=C(C=3C=NC=CC=3)C=C12 PZROFGPRPCCYLH-VWLOTQADSA-N 0.000 claims description 4
• RELFHNWJEPECSA-VWLOTQADSA-N (4s)-3'-(3,6-dihydro-2h-pyran-4-yl)-7'-phenylspiro[5h-1,3-oxazole-4,5'-chromeno[2,3-c]pyridine]-2-amine Chemical compound C1OC(N)=N[C@]21C1=CC(C=3CCOCC=3)=NC=C1OC1=CC=C(C=3C=CC=CC=3)C=C12 RELFHNWJEPECSA-VWLOTQADSA-N 0.000 claims description 4
• BNXYWTJNPPCGPW-QHCPKHFHSA-N (4s)-4'-fluoro-2'-(2-fluoro-2-methylpropoxy)-7'-pyrimidin-5-ylspiro[5h-1,3-oxazole-4,9'-xanthene]-2-amine Chemical compound C12=CC(OCC(C)(F)C)=CC(F)=C2OC2=CC=C(C=3C=NC=NC=3)C=C2[C@]21COC(N)=N2 BNXYWTJNPPCGPW-QHCPKHFHSA-N 0.000 claims description 4
• JWSHQJYDXNPIKG-UHFFFAOYSA-N 2'-(2-methylpropoxy)-7'-pyrimidin-5-ylspiro[5h-1,3-oxazole-4,9'-xanthene]-2-amine Chemical compound C12=CC(OCC(C)C)=CC=C2OC2=CC=C(C=3C=NC=NC=3)C=C2C21COC(N)=N2 JWSHQJYDXNPIKG-UHFFFAOYSA-N 0.000 claims description 4
• GXLBLAWTCDBEDC-UHFFFAOYSA-N 2'-propoxy-7'-pyrimidin-5-ylspiro[5h-1,3-oxazole-4,9'-xanthene]-2-amine Chemical compound C12=CC(OCCC)=CC=C2OC2=CC=C(C=3C=NC=NC=3)C=C2C21COC(N)=N2 GXLBLAWTCDBEDC-UHFFFAOYSA-N 0.000 claims description 4
• 206010008111 Cerebral haemorrhage Diseases 0.000 claims description 4
• 208000018737 Parkinson disease Diseases 0.000 claims description 4
• 206010048327 Supranuclear palsy Diseases 0.000 claims description 4
• 206010002022 amyloidosis Diseases 0.000 claims description 4
• 230000001054 cortical effect Effects 0.000 claims description 4
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• 210000004558 lewy body Anatomy 0.000 claims description 4
• RUIBVXOIMNQJGF-RUZDIDTESA-N (4r)-2'-(3-methoxy-3-methylbut-1-ynyl)-7'-pyrimidin-5-ylspiro[5h-1,3-oxazole-4,9'-xanthene]-2-amine Chemical compound C12=CC(C#CC(C)(C)OC)=CC=C2OC2=CC=C(C=3C=NC=NC=3)C=C2[C@]21COC(N)=N2 RUIBVXOIMNQJGF-RUZDIDTESA-N 0.000 claims description 3
• GXLBLAWTCDBEDC-JOCHJYFZSA-N (4r)-2'-propoxy-7'-pyrimidin-5-ylspiro[5h-1,3-oxazole-4,9'-xanthene]-2-amine Chemical compound C12=CC(OCCC)=CC=C2OC2=CC=C(C=3C=NC=NC=3)C=C2[C@@]21COC(N)=N2 GXLBLAWTCDBEDC-JOCHJYFZSA-N 0.000 claims description 3
• CHZHWZAKWGFQNL-DEOSSOPVSA-N (4s)-2'-(2,2-dimethylpropoxy)-7'-pyrimidin-5-ylspiro[5h-1,3-oxazole-4,9'-xanthene]-2-amine Chemical compound C12=CC(OCC(C)(C)C)=CC=C2OC2=CC=C(C=3C=NC=NC=3)C=C2[C@]21COC(N)=N2 CHZHWZAKWGFQNL-DEOSSOPVSA-N 0.000 claims description 3
• GXLBLAWTCDBEDC-QFIPXVFZSA-N (4s)-2'-propoxy-7'-pyrimidin-5-ylspiro[5h-1,3-oxazole-4,9'-xanthene]-2-amine Chemical compound C12=CC(OCCC)=CC=C2OC2=CC=C(C=3C=NC=NC=3)C=C2[C@]21COC(N)=N2 GXLBLAWTCDBEDC-QFIPXVFZSA-N 0.000 claims description 3
• XONWQXLKECCSLM-VWLOTQADSA-N (4s)-3'-(3,6-dihydro-2h-pyran-4-yl)-7'-(2-fluoro-5-methylpyridin-3-yl)spiro[5h-1,3-oxazole-4,5'-chromeno[2,3-c]pyridine]-2-amine Chemical compound CC1=CN=C(F)C(C=2C=C3[C@]4(N=C(N)OC4)C4=CC(=NC=C4OC3=CC=2)C=2CCOCC=2)=C1 XONWQXLKECCSLM-VWLOTQADSA-N 0.000 claims description 3
• JPLLCRNRSHLGBN-DEOSSOPVSA-N (4s)-7'-(2-fluoropyridin-3-yl)-3'-pyridin-4-ylspiro[5h-1,3-oxazole-4,5'-chromeno[2,3-c]pyridine]-2-amine Chemical compound C1OC(N)=N[C@]21C1=CC(C=3C=CN=CC=3)=NC=C1OC1=CC=C(C=3C(=NC=CC=3)F)C=C12 JPLLCRNRSHLGBN-DEOSSOPVSA-N 0.000 claims description 3
• CHZHWZAKWGFQNL-UHFFFAOYSA-N 2'-(2,2-dimethylpropoxy)-7'-pyrimidin-5-ylspiro[5h-1,3-oxazole-4,9'-xanthene]-2-amine Chemical compound C12=CC(OCC(C)(C)C)=CC=C2OC2=CC=C(C=3C=NC=NC=3)C=C2C21COC(N)=N2 CHZHWZAKWGFQNL-UHFFFAOYSA-N 0.000 claims description 3
• 208000027061 mild cognitive impairment Diseases 0.000 claims description 3
• KHZHMWVTRYYGRT-SANMLTNESA-N (4s)-2'-(2,2-dimethylmorpholin-4-yl)-7'-(2-fluoropyridin-3-yl)spiro[5h-1,3-oxazole-4,9'-xanthene]-2-amine Chemical compound C1COC(C)(C)CN1C1=CC=C(OC=2C(=CC(=CC=2)C=2C(=NC=CC=2)F)[C@]23N=C(N)OC3)C2=C1 KHZHMWVTRYYGRT-SANMLTNESA-N 0.000 claims description 2
• UBJVRJGPVXTXQB-VWLOTQADSA-N (4s)-2'-(3,6-dihydro-2h-pyran-4-yl)-4'-fluoro-7'-(2-fluoropyridin-3-yl)spiro[5h-1,3-oxazole-4,9'-xanthene]-2-amine Chemical compound C1OC(N)=N[C@]21C1=CC(C=3CCOCC=3)=CC(F)=C1OC1=CC=C(C=3C(=NC=CC=3)F)C=C12 UBJVRJGPVXTXQB-VWLOTQADSA-N 0.000 claims description 2
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• CSZKMRAGEMUOOW-ZDXGUKGBSA-N (4s)-2'-[(2s,6r)-2,6-dimethylmorpholin-4-yl]-7'-pyridin-3-ylspiro[5h-1,3-oxazole-4,9'-xanthene]-2-amine Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC=C(OC=2C(=CC(=CC=2)C=2C=NC=CC=2)[C@]23N=C(N)OC3)C2=C1 CSZKMRAGEMUOOW-ZDXGUKGBSA-N 0.000 claims description 2
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