NO331845B1 - Nye forbindelser, anvendelse derav for a forebygge eller behandle bentilstander, og farmasoytiske sammensetninger med slike forbindelser - Google Patents
Nye forbindelser, anvendelse derav for a forebygge eller behandle bentilstander, og farmasoytiske sammensetninger med slike forbindelser Download PDFInfo
- Publication number
- NO331845B1 NO331845B1 NO20053498A NO20053498A NO331845B1 NO 331845 B1 NO331845 B1 NO 331845B1 NO 20053498 A NO20053498 A NO 20053498A NO 20053498 A NO20053498 A NO 20053498A NO 331845 B1 NO331845 B1 NO 331845B1
- Authority
- NO
- Norway
- Prior art keywords
- phenyl
- isopropyl
- quinazolin
- prop
- ynyloxy
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 74
- 210000000988 bone and bone Anatomy 0.000 title claims abstract description 15
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000011575 calcium Substances 0.000 claims abstract description 16
- 229910052791 calcium Inorganic materials 0.000 claims abstract description 16
- 150000002148 esters Chemical class 0.000 claims abstract description 15
- 239000002253 acid Substances 0.000 claims abstract description 14
- 230000011164 ossification Effects 0.000 claims abstract description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
- 208000001132 Osteoporosis Diseases 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 7
- 230000000638 stimulation Effects 0.000 claims description 7
- 206010006956 Calcium deficiency Diseases 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 5
- WNUBXSUKNMGDHX-UHFFFAOYSA-N 1-[[3-(2-hydroxyethoxy)phenyl]methyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazoline-2-thione Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=S)N1CC1=CC=CC(OCCO)=C1 WNUBXSUKNMGDHX-UHFFFAOYSA-N 0.000 claims description 4
- FZHRWFGQFICKQC-UHFFFAOYSA-N 1-benzyl-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazoline-2-thione Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=S)N1CC1=CC=CC=C1 FZHRWFGQFICKQC-UHFFFAOYSA-N 0.000 claims description 4
- MOQMUMSCPKLYMB-UHFFFAOYSA-N 1-benzyl-6-hydroxy-4-(4-propan-2-ylphenyl)-5-prop-2-enylquinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C(C1=C(CC=C)C(O)=CC=C11)=NC(=O)N1CC1=CC=CC=C1 MOQMUMSCPKLYMB-UHFFFAOYSA-N 0.000 claims description 4
- JTOWEUHRLCFSGP-UHFFFAOYSA-N 1-[(2,3-dimethoxyquinoxalin-6-yl)methyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound C1=C2N=C(OC)C(OC)=NC2=CC=C1CN(C(N=1)=O)C2=CC=C(OCC#C)C=C2C=1C1=CC=C(C(C)C)C=C1 JTOWEUHRLCFSGP-UHFFFAOYSA-N 0.000 claims description 3
- ONIZJZIJALTHQW-UHFFFAOYSA-N 1-[[2-(2-hydroxyethoxy)phenyl]methyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=O)N1CC1=CC=CC=C1OCCO ONIZJZIJALTHQW-UHFFFAOYSA-N 0.000 claims description 3
- KRADDNXZWVNICM-UHFFFAOYSA-N 1-[[2-(2-methoxyethoxy)pyridin-3-yl]methyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound COCCOC1=NC=CC=C1CN1C(=O)N=C(C=2C=CC(=CC=2)C(C)C)C2=CC(OCC#C)=CC=C21 KRADDNXZWVNICM-UHFFFAOYSA-N 0.000 claims description 3
- QUYLWAARGNSPMB-UHFFFAOYSA-N 1-[[6-(2-hydroxyethoxy)pyridin-2-yl]methyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=O)N1CC1=CC=CC(OCCO)=N1 QUYLWAARGNSPMB-UHFFFAOYSA-N 0.000 claims description 3
- 208000002679 Alveolar Bone Loss Diseases 0.000 claims description 3
- 208000020084 Bone disease Diseases 0.000 claims description 3
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- 206010003246 arthritis Diseases 0.000 claims description 3
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- 230000002265 prevention Effects 0.000 claims description 3
- WAWKIXZOXFBJLY-UHFFFAOYSA-N 1-(2,2-dimethylpent-4-enyl)-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C1=NC(=O)N(CC(C)(C)CC=C)C2=CC=C(OCC#C)C=C12 WAWKIXZOXFBJLY-UHFFFAOYSA-N 0.000 claims description 2
- AZFLTODXSFWGBV-UHFFFAOYSA-N 1-(2-methylhex-4-enyl)-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound N=1C(=O)N(CC(C)CC=CC)C2=CC=C(OCC#C)C=C2C=1C1=CC=C(C(C)C)C=C1 AZFLTODXSFWGBV-UHFFFAOYSA-N 0.000 claims description 2
- QSTFOTXJPGATJP-UHFFFAOYSA-N 1-(3,3-dimethylbutyl)-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C1=NC(=O)N(CCC(C)(C)C)C2=CC=C(OCC#C)C=C12 QSTFOTXJPGATJP-UHFFFAOYSA-N 0.000 claims description 2
- ITOJTHZRQMLCBG-UHFFFAOYSA-N 1-(3-bromopropyl)-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C1=NC(=O)N(CCCBr)C2=CC=C(OCC#C)C=C12 ITOJTHZRQMLCBG-UHFFFAOYSA-N 0.000 claims description 2
- DSGLFEFJDLRIIM-UHFFFAOYSA-N 1-(3-methylsulfanylpropyl)-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound N=1C(=O)N(CCCSC)C2=CC=C(OCC#C)C=C2C=1C1=CC=C(C(C)C)C=C1 DSGLFEFJDLRIIM-UHFFFAOYSA-N 0.000 claims description 2
- SOHDUTJWMFWXLW-UHFFFAOYSA-N 1-[(2,4-diaminopyrimidin-5-yl)methyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=O)N1CC1=CN=C(N)N=C1N SOHDUTJWMFWXLW-UHFFFAOYSA-N 0.000 claims description 2
- LZZQFBXWXULZEL-UHFFFAOYSA-N 1-[(2,6-dichlorophenyl)methyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=O)N1CC1=C(Cl)C=CC=C1Cl LZZQFBXWXULZEL-UHFFFAOYSA-N 0.000 claims description 2
- OFHYTVMRWWJJCL-UHFFFAOYSA-N 1-[(2-butyl-4-chloro-1h-imidazol-5-yl)methyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound N1C(CCCC)=NC(CN2C(N=C(C3=CC(OCC#C)=CC=C32)C=2C=CC(=CC=2)C(C)C)=O)=C1Cl OFHYTVMRWWJJCL-UHFFFAOYSA-N 0.000 claims description 2
- CCTYICLJLGAWFF-UHFFFAOYSA-N 1-[(2-chloropyridin-3-yl)methyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=O)N1CC1=CC=CN=C1Cl CCTYICLJLGAWFF-UHFFFAOYSA-N 0.000 claims description 2
- PPAVKZLVZLYFGX-UHFFFAOYSA-N 1-[(2-chloropyridin-4-yl)methyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=O)N1CC1=CC=NC(Cl)=C1 PPAVKZLVZLYFGX-UHFFFAOYSA-N 0.000 claims description 2
- CIZOLISLHNIUSW-UHFFFAOYSA-N 1-[(2-methoxyphenyl)methyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound COC1=CC=CC=C1CN1C(=O)N=C(C=2C=CC(=CC=2)C(C)C)C2=CC(OCC#C)=CC=C21 CIZOLISLHNIUSW-UHFFFAOYSA-N 0.000 claims description 2
- DATYCBHDXBVGCV-UHFFFAOYSA-N 1-[(2-oxo-1h-pyridin-3-yl)methyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=O)N1CC1=CC=CN=C1O DATYCBHDXBVGCV-UHFFFAOYSA-N 0.000 claims description 2
- IGAUNRUWFHIZSB-UHFFFAOYSA-N 1-[(3,5-ditert-butyl-4-hydroxyphenyl)methyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=O)N1CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 IGAUNRUWFHIZSB-UHFFFAOYSA-N 0.000 claims description 2
- IIBRYYCFSIBSFT-UHFFFAOYSA-N 1-[(3-ethoxy-4-methoxyphenyl)methyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound C1=C(OC)C(OCC)=CC(CN2C(N=C(C3=CC(OCC#C)=CC=C32)C=2C=CC(=CC=2)C(C)C)=O)=C1 IIBRYYCFSIBSFT-UHFFFAOYSA-N 0.000 claims description 2
- CXXFLOXCTONKPM-UHFFFAOYSA-N 1-[(3-methylsulfinylphenyl)methyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=O)N1CC1=CC=CC(S(C)=O)=C1 CXXFLOXCTONKPM-UHFFFAOYSA-N 0.000 claims description 2
- QDRDRRIVPQODOZ-UHFFFAOYSA-N 1-[(3-methylsulfonylphenyl)methyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=O)N1CC1=CC=CC(S(C)(=O)=O)=C1 QDRDRRIVPQODOZ-UHFFFAOYSA-N 0.000 claims description 2
- KIZITKARUSPCHY-UHFFFAOYSA-N 1-[(4-bromophenyl)methyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=O)N1CC1=CC=C(Br)C=C1 KIZITKARUSPCHY-UHFFFAOYSA-N 0.000 claims description 2
- WZPYWVQODKUCET-UHFFFAOYSA-N 1-[(5-bromothiophen-2-yl)methyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=O)N1CC1=CC=C(Br)S1 WZPYWVQODKUCET-UHFFFAOYSA-N 0.000 claims description 2
- QCLQPFPFVBOVJY-UHFFFAOYSA-N 1-[(6-methoxypyridin-3-yl)methyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound C1=NC(OC)=CC=C1CN1C(=O)N=C(C=2C=CC(=CC=2)C(C)C)C2=CC(OCC#C)=CC=C21 QCLQPFPFVBOVJY-UHFFFAOYSA-N 0.000 claims description 2
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- SPCKNUOUUWVWLY-UHFFFAOYSA-N 1-[2-(3,5-difluorophenyl)-2-hydroxyethyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=O)N1CC(O)C1=CC(F)=CC(F)=C1 SPCKNUOUUWVWLY-UHFFFAOYSA-N 0.000 claims description 2
- JGWYBODYOPDXRT-UHFFFAOYSA-N 1-[2-(3,5-dimethoxyphenyl)ethyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound COC1=CC(OC)=CC(CCN2C(N=C(C3=CC(OCC#C)=CC=C32)C=2C=CC(=CC=2)C(C)C)=O)=C1 JGWYBODYOPDXRT-UHFFFAOYSA-N 0.000 claims description 2
- LMMPWVOPAUIKGL-UHFFFAOYSA-N 1-[2-hydroxy-2-(2,4,6-trimethylphenyl)ethyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=O)N1CC(O)C1=C(C)C=C(C)C=C1C LMMPWVOPAUIKGL-UHFFFAOYSA-N 0.000 claims description 2
- WAJNWFGEVCJWCF-UHFFFAOYSA-N 1-[[4-[2-[methyl(pyridin-2-yl)amino]ethoxy]phenyl]methyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=O)N1CC(C=C1)=CC=C1OCCN(C)C1=CC=CC=N1 WAJNWFGEVCJWCF-UHFFFAOYSA-N 0.000 claims description 2
- WQMPJQSEVCPQJU-UHFFFAOYSA-N 1-[[6-(hydroxymethyl)pyridin-2-yl]methyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=O)N1CC1=CC=CC(CO)=N1 WQMPJQSEVCPQJU-UHFFFAOYSA-N 0.000 claims description 2
- HOTAYWVTZKVGLN-UHFFFAOYSA-N 4-(4-propan-2-ylphenyl)-6-prop-2-ynoxy-1-(3,3,3-trifluoropropyl)quinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C1=NC(=O)N(CCC(F)(F)F)C2=CC=C(OCC#C)C=C12 HOTAYWVTZKVGLN-UHFFFAOYSA-N 0.000 claims description 2
- JVQRYSPDSHAIMN-UHFFFAOYSA-N 4-(4-propan-2-ylphenyl)-6-prop-2-ynoxy-1-(pyridin-2-ylmethyl)quinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=O)N1CC1=CC=CC=N1 JVQRYSPDSHAIMN-UHFFFAOYSA-N 0.000 claims description 2
- BDECDLHANFXDJY-UHFFFAOYSA-N 4-(4-propan-2-ylphenyl)-6-prop-2-ynoxy-1-(pyridin-3-ylmethyl)quinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=O)N1CC1=CC=CN=C1 BDECDLHANFXDJY-UHFFFAOYSA-N 0.000 claims description 2
- JVIQESIAMKQPQU-UHFFFAOYSA-N 4-(4-propan-2-ylphenyl)-6-prop-2-ynoxy-1-(thiophen-2-ylmethyl)quinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=O)N1CC1=CC=CS1 JVIQESIAMKQPQU-UHFFFAOYSA-N 0.000 claims description 2
- ZJEMENKDYCZBFW-UHFFFAOYSA-N 4-(4-propan-2-ylphenyl)-6-prop-2-ynoxy-1-(thiophen-2-ylmethyl)quinazoline-2-thione Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=S)N1CC1=CC=CS1 ZJEMENKDYCZBFW-UHFFFAOYSA-N 0.000 claims description 2
- QFHVFMRKECVFSV-UHFFFAOYSA-N 4-(4-propan-2-ylphenyl)-6-prop-2-ynoxy-1-[(4-pyrazin-2-ylphenyl)methyl]quinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=O)N1CC1=CC=C(C=2N=CC=NC=2)C=C1 QFHVFMRKECVFSV-UHFFFAOYSA-N 0.000 claims description 2
- DQRPCOXQVRAJSZ-CCEZHUSRSA-N 4-(4-propan-2-ylphenyl)-6-prop-2-ynoxy-1-[(e)-2-(2,4,6-trimethylphenyl)ethenyl]quinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=O)N1\C=C\C1=C(C)C=C(C)C=C1C DQRPCOXQVRAJSZ-CCEZHUSRSA-N 0.000 claims description 2
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- POEBCARWIIPIMG-UHFFFAOYSA-N 7-[[2-oxo-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-1-yl]methyl]-1h-indole-2-carbonitrile Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=O)N1CC1=CC=CC2=C1NC(C#N)=C2 POEBCARWIIPIMG-UHFFFAOYSA-N 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- UBQAUQQIYRRCOB-UHFFFAOYSA-N tert-butyl 2,2-dimethyl-4-[[2-oxo-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-1-yl]methyl]-1,3-oxazolidine-3-carboxylate Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=O)N1CC1N(C(=O)OC(C)(C)C)C(C)(C)OC1 UBQAUQQIYRRCOB-UHFFFAOYSA-N 0.000 claims description 2
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- OGBMKVWORPGQRR-UMXFMPSGSA-N teriparatide Chemical compound C([C@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)[C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CNC=N1 OGBMKVWORPGQRR-UMXFMPSGSA-N 0.000 description 1
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Classifications
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Abstract
Forbindelse med formel I hvori Rl, R2, R3 og Y er som definert heri, eller en farmasøytisk akseptabel og spaltbar ester, eller syreaddisjonssalt derav, anvendelig for å fremme frigivelse av paratyroidhormon, for eksempel for å hindre eller behandle bentilstander som er assosiert med kalsiumutmagring eller resorpsjon eller hvori stimulering av bendannelse og kalsiumfiksering i benet er ønskelig.
Description
Foreliggende oppfinnelse angår 4-aryl-2(lH)-quinazolinonderivater og farmasøytisk anvendelse derav.
4-Aryl-2(lH)-quinazolinonderivater og 2-substituert-4-aryl-quinazolinderivater har blitt beskrevet sammen med deres anvendelse som promotorer av PTH (paratyroidhormon) frigivelse i vår samtidig verserende internasjonale patentsøknad WO 02/102782.
Vi har nå syntetisert nye 4-aryl-2(lH)-quinazolinonderivater som har aktivitet som promotorer av PTH frigivelse.
Forbindelsene ifølge oppfinnelsen er definert i vedheftede krav 1. Ytterligere aspekter ved oppfinnelsen er vist i de øvrige vedheftede krav.
Den foreliggende beskrivelsen omhandler en forbindelse med formel I
hvori Y er O eller S;
RI representerer fra 1 til 3 substituenter uavhengig utvalgt fra OH, eventuelt substituert (lavere alkenyl eller lavere alkynyloksy);
R2 representerer 1 substituent utvalgt fra lavere alkyl;
R3er
A) lavere alkyl eventuelt substituert med 1 til 3 substituenter utvalgt fra lavere alkylen, lavere alkyl, Br, F, eller -Ox-(CH2)y-SOz-lavere alkyl, hvori x er 0 eller 1, y er 0, 1 eller 2 og z er 0,1 eller 2; eller
B) benzyl som er a. mono- eller di- (foretrukket mono-) substituert med -Ox-(CH2)y-SOz-lavere alkyl,
b. substituert med 1 eller 2 substituenter utvalgt fra N-lavere alkyl
substituert arylamino-lavere alkoksy,
c. substituert i 2-posisjonen med lavere alkoksy-, hydroksy-lavere alkoksy-eller lavere alkoksy-lavere alkoksy; eller
C) eventuelt substituert (aryl-C2-Cg-alkyl, aryl- C2-Cg-alkenyl, heteroarylmetyl eller 4-heteroarylbenzyl); eller
når RI er 2 substituenter hvor en av disse er OH, foretrukket i 6-posisjonen, og den andre av disse er lavere alkenyl, foretrukket i 5-posisjonen, er R3 aryl-lavere alkyl; eller når RI er 2-propynyloksy og R2 er isopropyl, er R3 også benzyl som er substituert med 1 til 3 substituenter utvalgt fra lavere alkoksy, halo; eller
når RI er 2-propynyloksy og R2 er isopropyl, er R3 også benzyl som er substituert med OH og en andre og eventuelt tredje substituent utvalgt fra lavere alkyl; eller
når Y er S og RI er som definert ovenfor, er R3 også eventuelt substituert benzyl; eller en forbindelse utvalgt fra l-benzyl-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-lH-quinazolin-2-tion eller 1 -[3-(2-hydroksy-etoksy)-benzyl]-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-tion; eller
en farmasøytisk akseptabel og spaltbar ester, eller syreaddisjonssalt derav; og forutsatt at når Y er O og R3 er lavere alkyl, er R3 ikke isopropyl; eller forutsatt at forbindelsen med formel I ikke er 4-(4-isopropyl-fenyl)-6-metoksy-l-pyridin-3-ylmetyl-1 .H.-quinazolin-2-on, 4-(4-isopropyl-fenyl)-6-metoksy- l-pyridin-2-ylmetyl-1 .H.-quinazolin-2-on, 1 -(6-klor-pyridin-3-ylmetyl)-4-(4-isopropyl-fenyl)-6-metoksy-1 .H.-quinazolin-2-on, 4-(4-isopropyl-fenyl)-6-metoksy-1 -(5-nitro-furan-2-ylmetyl)-l.H.-quinazolin-2-on eller l-[2-(l.H.-indol-2-yl)-etyl]-4-(4-isopropyl-fenyl)-6-metoksy-1 .H.-quinazolin-2-on, 4-(4-isopropyl-fenyl)-6-metoksy-1 -fenetyl-1 H-quinazolin-2-on, 1 -(2-hydroksy-2-fenyl-etyl)-4-(4-isopropyl-feny l)-6-prop-2-yny loksy-1H-quinazolin-2-on, metansulfonsyre 2-[4-(4-isopropyl-fenyl)-2-okso-6-prop-2-ynyloksy-2H-quinazolin-l-ylmetyl]-fenylester, eller eddiksyre 2-[4-(4-isopropyl-fenyl)-2-okso-6-prop-2-ynyloksy-2H-quinazolin-1 -yl]-1 -fenyl-etylester, 5-allyl-6-hydroksy-1 -isopropyl-4-(4-isopropyl-fenyl)-1 .H.-quinazolin-2-on, 1 -cyklopropy lmetyl-4-(o-tolyl)-6-nitro-2(1 H)-quinazolinon, 1 -etyl-4-(o-tolyl)-6-klor-2( 1 H)-quinazolinon, 1 -cyklopropylmetyl-4-(o-tolyl)-6-klor-2( 1 H)-quinazolinon, 1 -cyklopropy lmety l-4-(o-fluorfenyl)-6-klor-2(1 H)-quinazolinon, 1 -cyklopropylmetyl-4-(m-klorfenyl)-6-klor-2( 1 H)-quinazolinon, 1 - cyklopropylmetyl-4-(o-klorfenyl)-6-nitro-2(lH)-quinazolinon.
Ovenfor og ellers i foreliggende beskrivelse har følgende begreper følgende betyd-ninger: Halo eller halogen betegner I, Br, Cl eller F. Begrepet "lavere" referert til ovenfor og i det følgende i forbindelse med organiske radikaler eller forbindelser definerer respektivt slik som forgrenet eller uforgrenet med opptil og inkluderende 7, foretrukket opptil og inkluderende 4 og fordelaktig en eller to karbonatomer. En lavere alkylgruppe er forgrenet eller uforgrenet og inneholder 1 til 7 karbonatomer, foretrukket 1-4 karbonatomer. Lavere alkyl representerer; for eksempel metyl, etyl, propyl, butyl, isopropyl isobutyl eller tertiære butyl. Halo-substituert lavere alkyl er Ci -C7lavere alkyl substituert med opptil til 6 haloatomer. En lavere alkoksygruppe er forgrenet eller uforgrenet og inneholder 1 til 7 karbonatomer, foretrukket 1-4 karbonatomer. Lavere alkoksy representerer for eksempel metoksy, etoksy, propoksy, butoksy, isopropoksy, isobutoksy eller tertiære butoksy. En lavere alken, alkenyl eller alkenyloksygruppe er forgrenet eller uforgrenet og inneholder 2 til 7 karbonatomer, foretrukket 1-4 karbonatomer og inneholder minst en karbon-karbondobbelbinding. Lavere alken lavere alkenyl eller lavere alkenyloksy representerer for eksempel vinyl, prop-l-enyl, allyl, butenyl, isopropenyl eller isobutenyl og oksyekvivalentene derav. En lavere alkyn, alkynyl eller alkynyloksygruppe er forgrenet eller uforgrenet og inneholder 2 til 7 karbonatomer, foretrukket 1-4 karbonatomer og inneholder minst en karbon-karbon trippelbinding. Lavere alkyn eller alkynyl representerer for eksempel etynyl, prop-1-ynyl, propargyl, butynyl, isopropynyl eller isobutynyl og oksyekvivalentene derav. (I foreliggende beskrivelse omfatter oksygen inneholdende substituenter, for eksempel alkoksy, alkenyloksy, alkynyloksy, karbonyl, etc. deres svovel inneholdende homo-loger, for eksempel tioalkoksy, tioalkenyloksy, tioalkynyloksy, tiokarbonyl, sulfon, sulfoksid etc). Aryl representerer karbocyklisk eller heterocyklisk aryl. Karbocyklisk aryl representerer monocyklisk, bicyklisk eller tricyklisk aryl, for eksempel fenyl eller fenyl mono-, di- eller tri-substituert med en to eller tre radikaler utvalgt fra lavere alkyl, lavere alkoksy, aryl, hydroksy, halogen, cyano, trifluormetyl, lavere alkylendioksy og oksy-C2-C3-alkylen; eller 1- eller 2-naftyl; eller 1- eller 2-fenantrenyl. Lavere alkylendioksy er en divalent substituent bundet til to tilstøtende karbonatomer til fenyl, for eksempel metylendioksy eller etylendioksy. Oksy-C2-C3-alkylen er også en divalent substituent bundet til to tilstøtende karbonatomer til fenyl, for eksempel oksyetylen eller oksypropylen. Et eksempel for oksy-C2-C3-alkylen-fenyl er 2,3-dihydrobenzofuran-5-yl.
Foretrukken som karbocyklisk aryl er fenyl eller fenyl mono-, di- eller trisubstituert med lavere alkoksy, fenyl, halogen, lavere alkyl eller trifluormetyl, særlig fenyl eller fenyl mono- eller disubstituert med lavere alkoksy, halogen eller trifluormetyl, og særlig fenyl.
Heterocyklisk aryl representerer monocyklisk eller bicyklisk heteroaryl, for eksempel pyridyl, indolyl, quinoksalinyl, quinolinyl, isoquinolinyl, benzotienyl, benzofuranyl, benzopyranyl, benzotiopyranyl, benzotiadiazolyl, furanyl, pyrrolyl, tiazolyl, oksazolyl, isoksazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, tienyl, eller nevnte radikal substituert, særlig mono- eller di-substituert, som definert ovenfor.
Foretrukket er heterocyklisk aryl pyridyl, pyrimidyl, indolyl, quinoksalinyl, triazolyl, pyrazolyl, imidazolyl, tienyl, eller et hvilket som helst av nevnte radikal substituert, særlig mono- eller di-substituert, som definert ovenfor.
Cykloalkyl representerer et mettet cyklisk hydrokarbon eventuelt substituert med lavere alkyl som inneholder 3 til 10 ringkarboner og er fordelaktig cyklopropyl, cyklobutyl, cyklopentyl, cykloheksyl, cykloheptyl eller cyklooktyl eventuelt substituert med lavere alkyl.
RI kan representere fra 1 til 3 substituenter; selv om det mer foretrukket representerer 1 eller 2 substituenter. RI substituentene kan være tilstede i en hvilken som helst av posisjonene 5, 6, 7 eller 8; for eksempel i posisjonene 5,6 eller 7, for eksempel når RI representerer 2 substituenter kan disse være tilstede ved 5 og 6 eller 6 og 7 posisjonene. Foretrukket er en av RI substituentene i 6 posisjonen. RI som eventuelt substituert (lavere alkyl, lavere alkoksy, lavere alkenyl, lavere alkenyloksy, lavere alkynyl, lavere alkynyloksy, lavere alkanoyl eller amino) kan være substituert med 1 eller 2 substituenter uavhengig utvalgt fra halo, for eksempel Cl, lavere alkyl, for eksempel etyl eller metyl, lavere alkenyl, lavere alkynyl, cyloalkyl, for eksempel C3-C6cykloalkyl eller cyano.
I en særlig utførelsesform er RI 2 substituenter hvor en er OH, foretrukket i 6-posisjonen, og den andre er lavere alkenyl, for eksempel allyl, foretrukket i 5-posisjonen.
Særlig foretrukne signifikanter for RI er: propargyloksy, hydroksy eller allyl; særlig, for eksempel som i det følgende beskrevet i eksemplene.
R2 representerer 1, 2 eller 3; for eksempel, 1 substituent, i 2-posisjon eller 3-posisjon eller mer foretrukket i 4-posisjon, utvalgt fra lavere alkyl hvori lavere alkyl er foretrukket usubstituert, for eksempel forgrenet lavere alkyl. Foretrukken signifikans for R2 inkluderer: isopropyl. Mest foretrukket er R2 isopropyl i 4-posisjonen.
R3 som alkyl substituert med -Ox-(CH2)y-SOz-lavere alkyl, kan være substituert med - SOz-lavere alkyl, for eksempel -S-lavere alkyl.
R3 som benzyl som er mono- eller di- (foretrukket mono-) substituert med -Ox-(CH2)y-SOz-lavere alkyl, kan være benzyl mono-substituert med -SOz-lavere alkyl, for eksempel -S(0)-CH3 eller-S(02)-CH3.
R3 som eventuelt substituert (aryl-C2-Cg-alkyl, aryl-C2-Cg-alkenyl, heteroarylmetyl eller 4-heteroarylbenzyl) kan være substituert med opptil 8, typisk opptil 5, vanligvis 1, 2 eller 3 substituenter, uavhengig utvalgt fra halo, nitro, cyano, amino, OH, lavere alkyl, lavere alkoksy, lavere tioalkoksy, lavere alkoksykarbonyl, lavere alkylsulfonyl, lavere alkoksysulfonyl, lavere alkylkarbonyloksy, trifluormetyl, eventuelt halo-substituert aryl, eventuelt okso-substituert pyrrolidinyl eller -X-A-Z,
hvori
-X- er -S-,
-A- er Ci-Cioalkyl, og
- Z er H.
R3 som eventuelt substituert (aryl-C2-Cg-alkyl) kan være karbocyklisk aryl-C2-Cg-alkyl, for eksempel fenyl-C2-Cg-alkyl, eller hetrocyklisk aryl-C2-Cg-alkyl, for eksempel pyridyl-C2-Cg-alkyl, hvor alle er eventuelt substituert.
R3 som eventuelt substituert (aryl-C2-Cg-alkyl) kan være aryletyl, for eksempel fenyletyl, hvor alle er eventuelt substituert.
R3 som eventuelt substituert (aryl-C2-Cg-alkenyl) kan være karbocyklisk aryl-C2-Cg-alkenyl, for eksempel fenyl-C2-Cg-alkenyl, hvor alle er eventuelt substituert.
R3 som eventuelt substituert (aryl-C2-Cg-alkenyl) kan være arylvinyl, for eksempel styryl, hvor alle er eventuelt substituert.
R3 som eventuelt substituert (aryl-C2-Cg-alkyl og aryl-C2-Cg-alkenyl) kan være substituert på arylringen foretrukket med 1,2 eller 3 substituenter uavhengig utvalgt fra halogen, nitro, cyano, amino, OH, lavere alkyl, lavere alkoksy, lavere alkyl-SOz-(CH2)y -Ox-, hvori x er 0 eller 1, y er 0, 1 eller 2 og z er 0,1 eller 2, eller -X-A-Z som definert over, HO-(lavere alkoksy)p - eller lavere alkoksy-(lavere alkoksy)p, hvor p er et heltall fra 1 opptil og inkluderende 2.
R3 som eventuelt substituert (aryl-C2-Cg-alkyl) er eventuelt substituert på C2-Cg-alkyl med 1 til 6, foretrukket 1, 2 eller 3 substituenter, for eksempel OH. For eksempel, når C2-Cg-alkyl er etyl, kan den være substituert, for eksempel i 2-posisjon, foretrukket med 1 substituentfor eksempel OH.
R3 som heteroarylmetyl er foretrukket pyridinylmetyl, for eksempel pyridin-2-ylmetyl, pyridin-3-ylmetyl eller pyridin-4-ylmetyl, imidazolylmethyl, for eksempel imidazol-4-ylmetyl, quinoksalinylmetyl, for eksempel quinoksalin-6-ylmetyl, tiofenylmetyl, for eksempel tiofen-2-ylmetyl, pyrazolylmetyl, for eksempel pyrazol-3-ylmetyl, pyrimidi-nylmetyl, for eksempel pyrimidin-5-ylmetyl, indolylmetyl, eller furanylmetyl, for eksempel furan-2-ylmetyl.
R3 som heteroarylmetyl er eventuelt substituert på heteroarylringen foretrukket med 1, 2 eller 3 substituenter uavhengig utvalgt fra halogen, cyano, amino (eventuelt substituert med lavere alkyl), OH, lavere alkyl, lavere alkoksy, hydroksy-lavere alkoksy eller aryl, eller -X-A-Z, HO-(lavere alkoksy)p - eller lavere alkoksy-(lavere alkoksy)p som definert ovenfor.
R3 som 4-heteroarylbenzyl kan innbefatte 4-pyrazinylbenzyl, for eksempel 4-pyrazin-2-ylbenzyl, eller 4-triazolylbenzyl, for eksempel 4-(l,2,3)triazol-2-ylbenzyl.
Ifølge særlige utførelsesformer tilveiebringer beskrivelsen en forbindelse med formel V hvori Y er O eller S;
RI og R2 er som definert ovenfor for formel I;
R3' er
A) lavere alkyl substituert med 1 til 3 substituenter uavhengig utvalgt fra -S-lavere alkyl, lavere alkylen, Br eller F; eller
B) benzyl som er
a. mono- eller di- (foretrukket mono-) substituert med -Ox-(CH2)y-SOz-lavere alkyl, hvori x er 0 eller 1, y er 0,1 eller 2 og z er 0, 1 eller 2,
b. substituert med 1 eller 2 substituenter utvalgt N-lavere alkyl substituert
arylamino-alkoksy,
c. substituert i 2-posisjonen med lavere alkoksy-, hydroksy-lavere alkoksy-eller lavere alkoksy-lavere alkoksy; eller
C) eventuelt substituert (arylvinyl, aryletyl, heteroarylmetyl eller 4-heteroarylbenzyl); eller
når RI er 2 substituenter hvor en av disse er OH, foretrukket i 6-posisjonen, og den andre av disse er lavere alkenyl, foretrukket i 5-posisjonen, er R3' aryl-lavere alkyl; eller
når RI er 2-propynyl og R2 er isopropyl, er R3' også benzyl som er substituert med 1 til 3 substituenter utvalgt fra lavere alkoksy eller halo; eller
når RI er 2-propynyl og R2 er isopropyl, er R3' også benzyl som er substituert med OH og en andre og eventuelt tredje substituent utvalgt fra lavere alkyl; eller når X er S og RI er som definert ovenfor, er R3' også eventuelt substituert benzyl; eller en forbindelse utvalgt fra l-benzyl-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-lH-quinazolin-2-tion eller 1 -[3-(2-hydroksy-etoksy)-benzyl]-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-tion; eller
en farmasøytisk akseptabel og spaltbar ester, eller syreaddisjonssalt derav; og forutsatt at når Y er O og R3' er lavere alkyl, er R3' ikke isopropyl; eller forutsatt at forbindelsen med formel F ikke er 4-(4-isopropyl-fenyl)-6-metoksy-l-pyridin-3-ylmetyl-1 .H.-quinazolin-2-on, 4-(4-isopropyl-fenyl)-6-metoksy- l-pyridin-2-ylmetyl-1 .H.-quinazolin-2-on, 1 -(6-klor-pyridin-3-ylmetyl)-4-(4-isopropyl-fenyl)-6-metoksy-1 .H.-quinazolin-2-on, 4-(4-isopropyl-fenyl)-6-metoksy-1 -(5-nitro-furan-2-ylmetyl)-l.H.-quinazolin-2-on eller l-[2-(l.H.-indol-2-yl)-etyl]-4-(4-isopropyl-fenyl)-6-metoksy-1 .H.-quinazolin-2-on, 4-(4-isopropyl-fenyl)-6-metoksy-1 -fenetyl-1 H-quinazolin-2-on, l-(2-hydroksy-2-fenyl-etyl)-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-lH-quinazolin-2-on, metansulfonsyre 2-[4-(4-isopropyl-fenyl)-2-okso-6-prop-2-ynyloksy-2H-quinazolin-l-ylmetyl]-fenylester, eller eddiksyre 2-[4-(4-isopropyl-fenyl)-2-okso-6-prop-2-ynyloksy-2H-quinazolin-1 -yl]-1 -fenyl-etylester, 5-allyl-6-hydroksy-1 -isopropyl-4-(4-isopropyl-fenyl)-1 .H.-quinazolin-2-on, 1 -cyklopropylmetyl-4-(o-tolyi)-6-nitro-2(1 H)-quinazolinon, 1 -Etyl-4-(o-tolyl)-6-klor-2( 1 H)-quinazolinon, 1 -cyklopropylmetyl-4-(o-tolyl)-6-klor-2( 1 H)-quinazolinon, 1 -cyklopropy lmety l-4-(o-fluorfenyl)-6-klor-2(lH)-quinazolinon, l-cyklopropylmetyl-4-(m-klorfenyl)-6-klor-2(lH)-quinazolinon, 1 - cyklopropylmetyl-4-(o-klorfenyl)-6-nitro-2(lH)-quinazolinon.
Ifølge særlige utførelsesformer tilveiebringer beskrivelsen ytterligere en forbindelse med formel I"
hvori Y er O eller S;
RI" er 2 substituenter hvor en av disse er OH, foretrukket i 6-posisjonen, og den andre av disse er lavere alkenyl, foretrukket i 5-posisjonen; eller RI" er 2-propynyloksy, foretrukket i 6-posisjonen;
R2" er isopropyl;
R3" er benzyl som er substituert med 1 til 3 substituenter utvalgt fra lavere alkoksy eller halo; eller
R3" er benzyl som er substituert med OH og en andre og eventuelt tredje substituent utvalgt fra lavere alkyl; eller
når X er S og RI" er som definert ovenfor, er R3" også eventuelt substituert benzyl; eller
en farmasøytisk akseptabel og spaltbar ester, eller syreaddisjonssalt derav.
Som i det følgende beskrevet kan forbindelser med formel I fremstilles ved syklisering av en forbindelse med formel II
hvori RI, R2 og R3 er som definert ovenfor. Forbindelser med formel II har aktivitet som promotorer av PTH frigivelse og for eksempel nyttige som PTH frigivelsespromoterer.
Som i det følgende beskrevet kan forbindelser med formel F fremstilles ved syklisering av en forbindelse med formel IF
hvori RI, R2 og R3' er som definert ovenfor. Forbindelser med formel II' har aktivitet som promotorer av PTH frigivelse og erfor eksempel nyttige som PTH frigivelsespromoterer. Som i det følgende kan forbindelser med formel I" fremstilles ved syklisering av en forbindelse med formel II" hvori RI", R2" og R3" er som definert ovenfor. Forbindelser med formel II" har aktivitet som promotorer av PTH frigivelse og er for eksempel nyttige som PTH frigivelsespromoterer. Ifølge et ytterligere aspekt tilveiebringer beskrivelsen et mellomprodukt med formel II
hvori RI, R2 og R3 er som definert ovenfor;
forutsatt at forbindelsen med formel II ikke er {2-[2-(3,5-dimetoksy-fenyi)-2-metyl-propylamino]-4,5-dimetoksy-fenyl}-(4-isopropyl-fenyl)-metanon, (4-isopropyl-fenyl)-{5-metoksy-2-[(pyridin-3-ylmetyl)-amino]-fenyl}-metanon, (4-isopropyl-fenyl)-{5-metoksy-2-[(pyridin-2-ylmetyl)-amino]-fenyl} -metanon; eller
en forbindelse utvalgt fra {2-[2-(2-hydroksy-etoksy)-benzylamino]-5-prop-2-ynyloksy-fenyl}-(4-isopropyl-fenyl)-metanon eller {2-[(2,3-dimetoksy-quinoksalin-6-ylmetyi)-amino]-5-prop-2-ynyloksy-fenyl}-(4-isopropyl-fenyl)-metanon;
eller en farmasøytisk akseptabel og spaltbar ester, eller syreaddisjonssalt derav.
Foretrukne signifikanser for RI, R2 og R3 i formel II er som beskrevet ovenfor for RI, R2 og R3 i formel I.
Særlig signifikanser for R3 i formel II inkluderer:
eventuelt substituert aryl-C2-Cg-alkyl; for eksempel, eventuelt substituert fenyletyl, for eksempel eventuelt mono- eller di-lavere alkoksy substituert fenyletyl, hvori etyl eventuelt er mono- eller di-substituert (for eksempel i 2-posisjon) med halogen, OH, lavere alkyl (for eksempel metyl) eller lavere alkoksy (for eksempel metoksy);
eventuelt substituert heteroarylmetyl; for eksempel, eventuelt substituert pyridinylmetyl eller quinoksalinylmetyl, for eksempel eventuelt mono- eller di-disubstituert med halogen, OH, lavere alkyl (for eksempel metyl), lavere alkoksy (for eksempel metoksy), hydroksy-lavere alkoksy, (for eksempel hydroksy-etoksy) eller lavere alkoksy-lavere alkoksy (for eksempel metoksy-etoksy); og
benzyl som er substituert i 2-posisjon med lavere alkoksy-, hydroksy-lavere alkoksy-eller lavere alkoksy-lavere alkoksy, for eksempel 2-(2-hydroksy-etoksy)-benzyl.
Ifølge særlige utførelsesformer tilveiebringer beskrivelsen et mellomprodukt med formel II' hvori RI og R2 er som definert ovenfor for formel I;
R'3er som definert ovenfor for formel F
forutsatt at forbindelsen med formel IF ikke er {2-[2-(3,5-dimetoksy-fenyl)-2-metyl-propylamino]-4,5-dimetoksy-fenyl}-(4-isopropyl-fenyl)-metanon, (4-isopropyl-fenyl)-{5-metoksy-2-[(pyridin-3-ylmetyl)-amino]-fenyl}-metanon, (4-isopropyl-fenyl)-{5-metoksy-2-[(pyridin-2-ylmetyl)-amino]-fenyl} -metanon; eller
en forbindelse utvalgt fra {2-[2-(2-hydroksy-etoksy)-benzylamino]-5-prop-2-ynyloksy-fenyl}-(4-isopropyl-fenyl)-metanon eller {2-[(2,3-dimetoksy-quinoksalin-6-ylmetyi)-amino]-5-prop-2-ynyloksy-fenyl}-(4-isopropyl-fenyl)-metanon;
eller en farmasøytisk akseptabel og spaltbar ester, eller syreaddisjonssalt derav.
Substituentene og eventuelle substituenter på R3' er som beskrevet ovenfor for eventuelle substituenter på R3, som inkluderer foretrukne signifikanser derav.
Spesielt inkluderer beskrivelsen forbindelser med formel I og formel II som i det følgende beskrevet i eksemplene, eller farmasøytisk akseptable og spaltbare esters, eller syreaddisjonssalter derav.
Forbindelser med formel I og II, og salter og estere derav, særlig som identifisert i eksemplene, er i det følgende referert til som midler ifølge beskrivelsen.
Forbindelsene ifølge oppfinnelsen som er definert i det vedheftede krav 1, er i det følgende referert til som midler ifølge oppfinnelsen.
Midler ifølge oppfinnelsen som innbefatter frie hydroksylgrupper kan også anvendes i
form av farmasøytisk akseptable fysiologisk spaltbare estere, og er som sådan og der de er nye, inkludert innenfor omfanget av foreliggende oppfinnelse. Slike akseptable estere er foretrukket prodrug esterderivater, som omdannes ved solvolyse eller spalting under fysiologiske betingelser til det korresponderende midlet ifølge oppfinnelsen som innbefatter frie hydroksylgrupper. Egnede farmasøytisk akseptable prodrug estere er de avledet fra en karboksylsyre, en karbonsyremonoester eller karbaminsyre, fordelaktig estere avledet fra en eventuelt substituert lavere alkansyre eller en arylkarboksylsyre.
Midler ifølge oppfinnelsen kan også eksistere i form av farmasøytisk akseptable salter, og er som sådan og hvor de er nye, innenfor omfanget av foreliggende oppfinnelse. Farmasøytisk akseptable salter inkluderer syreaddisjonssalter med vanlige syrer, for eksempel, mineralsyre, for eksempel salteryre, svovelsyre eller fosforsyre, eller organiske syrer, for eksempel, alifatiske eller aromatiske karboksyl- eller sulfonsyrer, for eksempel eddiksyre, trifluoreddiksyre, propionsyre, ravsyre, glykolsyre, melkesyre, eplesyre, vinsyre, sitronsyre, askorbinsyre, maleinsyre, fumarsyre, hydroksymaleinsyre, pyrodruesyre, pamoinsyre, metansulfonsyre, toluensulfonsyre, naftalensulfonsyre, sulfanilinsyre eller cykloheksylsulfansyre; også aminosyrer, slik som arginin og lysin. For forbindelser ifølge beskrivelsen som har sure grupper, for eksempel en fri karb-okygruppe, representerer farmasøytisk akseptable salter også metall eller ammoniumsalter, slik som alkalimetall eller jordalkalimetallsalter, for eksempel natrium, kalium, magnesium eller kalsium salter, så vell som ammoniumsalter, som dannes med ammoniakk eller egnede organiske aminer.
Midlene ifølge beskrivelsen med formel I og II kan fremstilles som følger:
Midlene ifølge beskrivelsen med formel I
hvori RI, R2 og R3 er som definert ovenfor kan fremstilles ved syklisering av en forbindelse med formel II med et kondensasjonsmiddel slik som klorsulfonylisocyanat (CISO2NCO), natriumcyanat, benzoylisotiocyanat i THF, fulgt av behandling med K^CC^/metanol eller natriumtiocyanat og eddiksyre, og deretter, hvis påkrevd omdanne RI, R2 eller R3 residuene til alternative RI, R2 eller R3 residuer for å gi alternativ forbindelse med formel II. For eksempel, ved cykliseringsreaksjonen blir benzofenonet til formel II behandlet med en løsning av natriumcyanat, for eksempel i eddiksyre, ved romtemperatur. Benzofenonforbindelser med formel II kan fremstilles ved behandling av det korresponderende aminet med formel X
med det korresponderende halidet, for eksempel bromid, R3Br og en passende base slik som K2CO3. Særlig forbindelser med formel X hvor RI er OH i 6 posisjon og RI er også 2-propenyl, cyklopropyl-metyl eller propyl fremstilles for eksempel som beskrevet i eksemplet for forbindelsen 5-allyl-l-benzyl-6-hydroksy-4-(4-isopropyl-fenyl)-lH-quinazolin-2-on og følgende.
Alternativt kan forbindelser med formel II fremstilles ved reduktiv aminering av det korresponderende aldehydt med aminet X, ved anvendelse av Ti (Oi-pr)4eller molekylsikt som dehydreringsmiddel og NaBH(OAc)3eller NaCNBH3som reduksjonsmiddel. Aminet X oppnås fra det korresponderende nitro derivatet (se nedenfor forbindelse med formel XI) ved reduksjon, for eksempel med jern i eddiksyre.
hvori R2 er som tidligere definert og RI er en aktiverende gruppe.
Forbindelsen med formel XI kan i sin tur oppnås ved oksidering, for eksempel med Jones reagens, til den korresponderende alkohol som i sin tur oppnås ved kopling av en organometallisk forbindelse avledet fra det korresponderende bromidet med formel XIII og aldehydt med formel XII respektivt; for eksempel som beskrevet i eksemplene
I et ytterligere alternativ kan forbindelser med formel II, særlig hvor R3 er substituert pyridyl-metyl, fremstilles ved å omsette den korresponderende alkoholen, R3-OH, for eksempel pyridyl-metyl-hydroksid, med det korresponderende aminet med formel X, for eksempel under nærvær av Hunig's base og mesylklorid; for eksempel som i det følgende beskrevet i eksemplene.
I et enda ytterligere alternativ kan midler ifølge denne beskrivelsen med formel II, hvori R3 er eventuelt substituert aryl-lavere alkyl fremstilles ved alkylering av et middel med formel XX
i 1-posisjon med det korresponderende eventuelt substituerte aryl-lavere alkylhalidet; for eksempel under nærvær av for eksempel LiHMDS og Nal, i løsning, for eksempel THF7DMF, med mild oppvarming.
Alternativt kan forbindelser med formel XXII
hvori Rx er halo, lavere alkyl eller lavere alkoksy; fremstilles ved omsetning av en forbindelse med formel XX med det korresponderende oksiranet med formel XXI
hvor Rx er den eventuelle substitusjonen på fenylringen; for eksempel under nærvær av benzyltrietylammoniumklorid og kaliumkarbonat, for eksempel som i det følgende beskrevet i eksemplene. Korresponderende forbindelser med formel II hvori R3 er eventuelt substituert styryl kan fremstilles ved behandling av en forbindelse med formel XXII med et reagens slik som trifluormetansulfonsyreanhydrid.
Forbindelsen med formel XX kan fremstilles fra den korresponderende forbindelsen med formel II hvori R3 er H ved behandling med et kondensasjonsmiddel som natriumcyanat.
Midler ifølge denne beskrivelsen med formel II kan fremstilles som intermediater ved fremstilling av milder ifølge oppfinnelsen med formel I, for eksempel som beskrevet ovenfor, eller som i det følgende beskrevet i eksemplene.
Følgelig inkluderer denne beskrivelsen fremgangsmåter for fremstilling av midler med formel I
hvori symbolene er som definert ovenfor som innbefatter a) syklisering av en forbindelse med formel II
med et kondensasjonsmiddel slik som klorsulfonylisocyanat (CISO2NCO) eller natrium
cyanat eller natriumtiocyanat; eller
b) for et middel ifølge denne beskrivelsen med formel I, hvori R3 er eventuelt substituert aryl-lavere alkyl, alkylering av en forbindelse med formel XX
i 1-posisjon med det korresponderende eventuelt substituert aryl-lavere alkylhalidet; og deretter, hvis påkrevet, omdanne RI, R2 eller R3 residuene til alternative RI, R2 eller R3 residuer for å gi en alternative forbindelse med formel I.
Følgelig, i et ytterligere aspekt, tilveiebringer denne beskrivelsen en fremgangsmåte for fremstilling av midler ifølge oppfinnelsen med formel II hvori RI, R2 og R3 er som definert ovenfor, som innbefatter alkylering av den korresponderende aminobenzofenonforbindelsen med formel X
hvori RI og R2 er som definert ovenfor, og deretter, hvis påkrevet, omdanne RI, R2 eller R3 residuene til alternative RI, R2 eller R3 residuer for å gi en alternativ forbindelse med formel II.
Denne beskrivelsen er beskrevet kun som illustrasjon i følgende ikke-begrensende eksempler som angår fremstilling av forbindelser med formel I og II.
EKSEMPLER
Eksempel 1: l-(2,3-dimetoksy-quinoksalin-6-ylmetyl)-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-on A. Syntese av {2-[(2,3-dimetoksy-quinoksalin-6-ylmetyl)-amino]-5-prop-2-ynyloksy-fenyl}-(4-isopropyl-fenyl)-metanon
Til en løsning av 82 mg (0,280 mmol) (2-amino-5-propargyloksy-fenyl)-(4-isopropyl-fenyl)-metanon i 3 ml dioksan tilsettes 193 mg (1,40 mmol) kaliumkarbonat og 119 mg
(0,419 mmol) 6-bromometyl-2,3-dimetoksy-quinoksalin. Blandingen røres ved 80°C i to dager, fortynnes med vann og ekstraheres med CH2CI2. Rensing av det urene produktet ved kromatografi (etylacetat/heksaner 1:1) gir en gul olje.
<]>H NMR (300 MHz, CDCI3): 7.04-7.60 (m, 10H), 4.94 (s, 2H), 4.52 (d, 2H), 4.26 (s, 3H), 4.08 (s, 3H), 2.96 (hept, 1H), 2.48 (t, 1H), 1.28 (d, 6H).
MS: 496 (M+l)<+>
B. Syntese av l-(2,3-dimetoksy-quinoksalin-6-ylmetyl)-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-on
Til en løsning av 52 mg (0,105 mmol) {2-[(2,3-dimetoksy-quinoksalin-6-ylmetyl)-amino]-5-prop-2-ynyloksy-fenyl}-(4-isopropyl-fenyl)-metanon i 1 ml eddiksyre tilsettes 14 mg (0,210 mmol) natriumcyanat. Etter røring i 2 timer blir løsemidlet fjernet i vakuum og residuet fordelt mellom CH2CI2og vann. Det organiske sjiktet ekstraheres med 2 M natriumhydroksid og fordampes. Rensing av det urene produktet med flash-kromatografi (etylacetat/heksaner 9:1) gir en gul olje.
<]>H NMR (300 MHz, CDCI3): 7.78 (d, 2H), 7.70 (d, 1H), 7.48 (d, 1H), 7.14-7.51 (m, 6H), 6.10 (s, 2H),4.62 (d, 2H), 4.24 (s, 3H), 4.18 (s, 3H), 3.01 (hept, 1H), 2.52 (m, 1H), 1.32 (d, 6H).
MS: 521 (M+l)<+>
(2-amino-5-propargyloksy-fenyl)-(4-isopropyl-fenyl)-metanon byggeblokker fremstilles som følger:
A. Syntese av 2-nitro-5-propargyloksy-benzaldehyd
En blanding av 25 g (150 mmol) 5-hydroksy-2-nitro-benzaldehyd, 44,9 g (299 mmol) natriumjodid, 44,5 g propargylbromid (80% i toluen), 42 ml N-etyl-diisopropylamin og 400 ml aceton røres ved romtemperatur i 6 dager. Reaksjonsblandingen filtreres, konsentreres, tas opp i IM vandig saltsyre og ekstraheres med etylacetat for å gi 2-nitro-5-propargyloksy-benzaldehyd.
<]>H NMR (300 MHz, CDCI3): 10.49 (s, 1H), 8.19 (d, 1H), 7.43 (s, 1H), 7.25 (d, 2H), 4.85 (s, 2H), 2.60 (s, 1H).
B. Syntese av (4-isopropyl-fenyl)-(2-nitro-5-propargyloksy-fenyl)-metanol
Til en løsning av 30,7 g (150 mmol) 2-nitro-5-propargyloksy-benzaldehyd i 200 ml THF blir det tilsatt ved -75°C tilsatt ved 40 min 200 ml (175 mmol) av en 0,88 M løsning av 4-isopropylmagnesiumbromid i THF. Etter røring i 1 time ved -75°C blir en mettet vandig ammoniumkloridløsning tilsatt og reaksjonsblandingen ekstraheres med porsjoner av etylacetat. Fordampning av de organiske fasene gir (4-isopropyl-fenyl)-(2-nitro-5-propargyloksy-fenyl)-metanol.
<]>H NMR (300 MHz, CDCI3): 8.09 (d, 1H), 7.45 (d, 1H), 7.26 (d, 2H), 7.19 (d, 2H), 6.98 (dd, 1H), 6.52 (bred, 1H), 4.80 (d, 2H), 2.88 (hept, 1H), 2.71 (bred, 1H), 2.56 (t, 1H), 1.23 (d, 6H).
MS: 308 (100) (M-OH)<+>, 294 (50)
C. Syntese av (4-isopropyl-fenyl)-(2-nitro-5-propargyloksy-fenyl)-metanon
Til en iskald løsning av (4-isopropyl-fenyl)-(2-nitro-5-propargyloksy-fenyl)-metanol i 200 ml aceton blir det tilsatt dråpevis 60 ml Jones reagens. Etter røring i 2 timer ved romtemperatur blir reaksjonen stoppet ved tilsetning av isopropanol og natriumbisulfitt-løsning (40%). Ekstraksjon med diklormetan gir (4-isopropyl-fenyl)-(2-nitro-5-propargyloksy-fenyl)-metanon.
<]>H NMR (300 MHz, CDC13): 8.27 (d, 1H), 7.70 (d, 2H), 7.30 (d, 2H), 7.18 (dd, 1H), 6.97 (d, 1H), 4.81 (d, 2H), 2.96 (hept, 1H), 2.59 (t, 1H), 1.27 (d, 6H).
D. Syntese av (2-amino-5-propargyloksy-fenyl)-(4-isopropyl-fenyl)-metanon
Til en løsning av 10,59 g (30,7 mmol) (4-isopropyl-fenyl)-(2-nitro-5-propargyloksy-fenyl)-metanon i 250 ml eddiksyre blir det tilsatt 13,6 g (246 mmol) jernpulver. Etter røring i 20 timer ved romtemperatur blir reaksjonsblandingen gjort basisk ved tilsetning av 2M natriumhydroksidløsning, filtrert og ekstrahert med diklormetan. Etter rensing ved kromatografi ved anvendelse av heksaner / etylacetat (7:3) som eluent blir (2-amino-5-propargyloksy-fenyl)-(4-isopropyl-fenyl)-metanon oppnådd.
<]>H NMR (300 MHz, CDCI3): 7.64 (d, 2H), 7.30 (d, 2H), 7.12 (s, 1H), 7.05 (d, 1H), 6.72 (d, 1H), 5.71 (bred, 2H), 4.64 (s, 2H), 2.98 (hept, 1H), 2.48 (s, 1H), 1.30 (d, 6H).
MS: 294 (M+l)<+>
(2-amino-4,5-dimetoksy-fenyl)-(4-isopropyl-fenyl)-metanonbyggeblokken syntetiseres ved å følge fremgangsmåten angitt umiddelbart nedenfor. Eksempel 2: 4-(4-isopropyl-fenyl)-l-(3-metan-sulfonyl-benzyl)-5-propargyloksy -fenyl-metanon (Referanseeksempel)
En blanding av 100 mg (0,34 mmol) (2-amino-5-propargyloksy-fenyi)-(4-isopropyl-fenyl)-metanon, 80 mg (0,58 mmol) K2CO3og 77 mg (0,375 mmol) l-klormetyl-3-metansulfonyl-benzen i lml dimetylformamid røres ved 80°C i 6 timer og ved 100°C i 3 timer. Deretter blir reaksjonsblandingen helt over i vann og ekstrahert med etylacetat. De kombinerte organiske sjiktene vaskes med vann og saltvann, tørkes over MgSCu, filtreres og konsentreres i vakuum. Residuet renses med flash-kromatografi på silikagel (heksan:EtOAc = 2:1) for å gi tittelforbindelsen som et gult skum.
<]>H-NMR (300 MHz, DMSO): 8.34 (t, 1H), 7.90 (s, 1H), 7.80 (d, 1H), 7.67 (d, 1H), 7.60-7.56 (m, 3H), 7.39 (m, 2H), 7.09 (dd, 1H), 7.01 (d, 1H), 6.70 (d, 1H), 4.61-4.53 (m, 4H), 3.54 (m, 1H), 3.19 (s, 3H), 2.96 (m, 1H), 1.25 (d, 6H).
MS: 462 (M+l)<+>
Utgangsmaterialene kan fremstilles som følger:
A. Syntese av l-klormetyl-3-metansulfonyl-benzen
0,267 ml (3,45 mmol) metansulfonyl-klorid tilsettes til en løsning av 584 mg (3,14 mmol) (3-metansulfonyl-fenyl)-metanol og 0,66 ml (4,71 mmol) trietylamin i 6 ml diklormetan. Denne reaksjonsblandingen røres ved romtemperatur i 1 time og ved 50°C i ytterligere 3 timer. Reaksjonsblandingen blir deretter helt over i vann og ekstrahert to ganger med diklormetan. De kombinerte organiske sjiktene vaskes med vann og saltvann, tørkes, filtreres og konsentreres i vakuum for å gi tittelforbindelsen, som som anvendes i neste trinn uten ytterligere rensing.
<!>H-NMR (300 MHz, DMSO): 7.98 (bred s, 1H), 7.86 (d, 1H), 7.77 (d, 2H), 7.64 (t, 1H), 4.86 (s,2H),3.21 (s, 3H).
B. Syntese av (3-metansulfonyl-fenyl)-metanol
NaBH4tilsettes til en løsning av 750 mg (4,08 mmol) 3-metansulfonyl-benzaldehyd i 20 ml etanol (se P.L. Ornstein, T.J. Bleisch, M.B. Arnold, R.A. Wright, B.G. Johnson, J.P. Tizzano, D.R.Helton, M.J. Kallman, D.D. Schoepp, M. Herin, J. Med. Chem. 1998, 41( 3), 358-378 eller B. Eistert, W. Schade, H. Selzer, Ber. 1964, 97( 5), 1470-81). Reaksjonsblandingen røres ved romtemperatur i 1 time. Reaksjonsblandingen helles over i vann og ekstraheres tre ganger med etylacetat. De kombinerte organiske sjiktene vaskes med vann og saltvann, tørkes, filtreres og konsentreres i vakuum for å gi tittelforbindelsen, som anvendes i neste trinn uten ytterligere rensing.
<]>H-NMR (300 MHz, DMSO): 7.85 (bred s, 1H), 7.78 (d, 1H), 7.62 (d, 2H), 7.59 (t, 1H), 5.45 (t, 3H), 4.58 (d, 2H), 3.19 (s, 3H).
Eksempel 3: 4-(4-isopropyl-feny 1)-1 -(3-metan-sulfonyl-benzyl)-6-propargyloksy-1H-quinazolin-2-on.
En blanding av 97 mg (0,21 mmol) 4-(4-isopropyl-fenyl)-l-(3-metan-sulfonyl-benzyi)-5-propargyloksy-fenyl-metanon og 17 mg (0,25 mmol) natriumcyanat i 3 ml eddiksyre røres ved romtemperatur i 72 timer. Deretter blir reaksjonsblandingen helt over i vann og ekstrahert med etylacetat. De kombinerte organiske sjiktene vaskes med vann og saltvann, tørkes over MgSCu, filtreres og konsentreres i vakuum. Residuet renses med flash-kromatografi på silikagel (heksan:EtOAc 1:3) for å gi tittelforbindelsen som et gult skum.
<]>H-NMR (300 MHz, DMSO): 7.95 (s, 1H), 7.81 (d, 1H), 7.70 (d, 2H), 7.61-7.50 (m, 2H), 7.47 (m, 2H), 7.45 (d, 2H), 7.38 (m, 1H), 5.59 (bred s, 2H), 4.78 (d, 2H), 3.64 (m, 1H), 3.20 (s, 3H), 3.00 (m, 1H), 1.25 (d, 6H).
MS: 487 (M+l)<+>
Eksempel 6: 4-(4-isopropyl-fenyl)-l-[2-(2-metoksy-etyl)-2H-tetrazol-5-ylmetyl]-6-prop-2-ynyloksy-1 H-quinazolin-2-tion (Referanseeksempel)
A. Syntese av [2-(4-isopropyl-benzoyl)-4-prop-2-ynyloksy-fenylamino]-acetonitril
En blanding av 2,0 g (6,83 mmol) 2-amino-5-propargyloksy-fenyl)-(4-isopropyl-fenyi)-metanon, 0,516 g (7,5 mmol) kloracetonitril og 1,6 g K2CO3i 20 ml DMF varmes til 100°C og røres ved denne temperatur i 20 timer. Reaksjonsblandingen avkjøles til romtemperatur og helles over i vann og ekstraheres med etylacetat. De kombinerte organiske sjiktene vaskes med vann og saltvann, tørkes over MgSCU, filtreres og konsentreres i vakuum. Residuet renses med flash-kromatografi på silikagel (heksan/EtOAc = 3:1) for å gi l.,6 g av tittelforbindelsen som et gult krystallinsk faststoff.
<]>H-NMR (300 MHz, DMSO-de): 7.60 (m, 1H), 7.60 (d, 2H), 7.40 (d, 2H), 7.28 (dd, 1H), 7.04 (bs, 1H), 6.96 (d, 1H), 4.67 (s, 2H), 4.42 (d, 2H), 3.59 (s, 1H), 2.98 (m, 1H), 1.25 (d, 6H).
MS: 333 (M+l)<+>
B. Syntese av (4-isopropyl-fenyl)-{5-prop-2-ynyloksy-2-[(lH-tetrazol-5-ylmetyl)-amino] -fenyl} -metanon
En løsning av 0,82 g (2,47 mmol) [2-(4-isopropyl-benzoyl)-4-prop-2-ynyloksy-fenyl-amino]-acetonitril og 0,8 ml (3,31 mmol) Bu3SnN3i 20 ml m-xylen røres ved refluks-temperatur i 5 timer. Deretter blir reaksjonsblandingen avkjølt til romtemperatur og 15 ml 2N KOH og 2 ml MeOH tilsettes. Denne blandingen røres kraftig i 15 min. Deretter blir fasene separert og vannsjiktet tilsatt 4 N HC1 til en pH~1 nåes. Vannfasen ekstraheres med diklormetan / isopropanol = 3:1. De kombinerte organiske sjiktene vaskes med vann og saltvann, tørkes over MgSCu, filtreres og konsentreres i vakuum. Det resulterende faste stoffet suspenderes i dietyleter, røres i 0,5 timer, filtreres og tørkes for å gi 0,89 g av tittelforbindelsen som gule krystaller.
<]>H-NMR (300 MHz, DMSO-de): 8.22 (t, 1H), 7.59 (d, 2H), 7.40 (d, 2H), 7.14 (dd, 1H), 7.04 (bs, 1H), 6.72 (d, 1H), 4.81 (d, 2H), 4.61 (s, 2H), 3.59 (s, 1H), 2.98 (m, 1H), 1.25 (d, 6H).
MS: 376 (M+l)<+>
C. Syntese av (4-isopropyl-fenyl)-(2-{[2-(2-metoksy-etyl)-2H-tetrazol-5-ylmetyl]-amino}-5-prop-2-ynyloksy-fenyl)-metanon.
En blanding av 1,04 g (2,77 mmol) (4-isopropyl-fenyl)-{5-prop-2-ynyloksy-2-[(lH-tetrazol-5-ylmetyl)-amino]-fenyl}-metanon, 0,85 g K2C03, 0,25 g Kl og 0,41 g (2,95 mmol) kloracetonitril og 40 ml etylmetylketon røres ved 60°C i 20 timer. Reaksjonsblandingen avkjøles til romtemperatur og helles over i vann og ekstraheres med etylacetat. De kombinerte organiske sjiktene vaskes med vann og saltvann, tørkes over MgSCv, filtreres og konsentreres i vakuum. Residuet renses med flash-kromatografi på silikagel (heksan/EtOAc = 2:1) for å gi 0,65 g av (4-isopropyl-fenyl)-(2-{[2-(2-metoksy-etyl)-2H-tetrazol-5-ylmetyl]-amino}-5-prop-2-ynyloksy-fenyl)-metanon (gul olje, tittelforbindelse) og 0,3 g av (4-isopropyl-fenyl)-(2-{[l-(2-metoksy-etyl)-lH-tetrazol-5-ylmetyl]-amino}-5-prop-2-ynyloksy-fenyl)-metanon (gul olje).
<]>H-NMR (300 MHz, DMSO-de): 8.32 (t, 1H), 7.56 (d, 2H), 7.38 (d, 2H), 7.18 (dd, 1H), 7.02 (bs, 1H), 6.92 (d, 1H), 4.78 (t, 2H), 4.72 (d, 2H), 4.60 (s, 2H), 3.80 (t, 2H), 3.55 (s, 1H), 3.18 (s, 3H), 2.96 (m, 1H), 1.24 (d, 6H).
MS: 434 (M+l)<+>
D. Syntese av 4-(4-isopropyl-fenyl)-l-[2-(2-metoksy-etyl)-2H-tetrazol-5-ylmetyl]-6-prop-2-ynyloksy-1 H-quinazolin-2-tion.
Tittelforbindelsen (rødt skum) fremstilles fra (4-isopropyl-fenyl)-(2-{[2-(2-metoksy-etyl)-2H-tetrazol-5-ylmetyl]-amino} -5-prop-2-ynyloksy-fenyl)-metanon og benzoylisotiocyanat som beskrevet for fremstilling av eksempel 111.
<]>H-NMR (300 MHz, DMSO-de): 7.74 (d, 2H), 7.73 (d, 1H), 7.60 (dd, 1H), 7.48 (d, 2H), 7.41 (m, 1H), 6.40 (bs, 2H), 4.88 (bs, 2H), 4.77 (t, 2H), 3.76 (t, 2H), 3.74 (m, 1H), 3.16 (s, 3H), 3.00 (m 1H), 1.28 (d, 6H).
MS: 475 (M+l)<+>
Forbindelsene i følgende eksempler fremstilles analogt:
Eksempel 8: 4-(4-isopropyl-feny 1)-1 -(3-metan-sulfinyl-benzyl)-6-propargyloksy-1H-quinazolin-2-on
<]>H-NMR (300 MHz, DMSO): 7.70 (d, 2H), 7.66 (s, 1H), 7.58-7.44 (m, 6H), 7.39 (bred s, 1H), 7.35 (bred s, 1H), 5.59 (bred s, 2H), 4.78 (d, 2H), 3.67 (m, 1 H), 3.02 (m, 1 H), 2.72 (s,3H), 1.28 (d, 6H).
MS: 471 (M+l)+
Eksempel 9: 4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-l-pyridin-2-ylmetyl-lH-quinazolin-2-on
<!>H NMR (300 MHz, CDC13): 8.58 (d, 1H), 7.76 (d, 2H), 7.20-7.70 (m, 8H), 5.68 (s, 2H), 4.64 (d, 2H), 3.02 (hept, 1H), 2.54 (t, 1H), 1.32 (d, 6H).
MS: 410 (M+l)<+>
Eksempel 10: 4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1 -(4-[ 1,2,3]triazol-2-yl-benzyl)-1 H-quinazolin-2-on
<]>H NMR (300 MHz, CDC13): 8.04 (d, 2H), 7.72-7.80 (m, 3H), 7.20-7.52 (m, 8H), 5.60 (s, 2H), 4.64 (d, 2H), 3.02 (hept, 1H), 2.55 (m, 1H), 1.33 (d, 6H).
MS: 476 (M+l)<+>
Eksempel 11: l-(3-brom-propyl)-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-lH-quinazolin-2-on
<!>H NMR (300 MHz, CDC13): 7.69 (d, 2H), 7.46 - 7.53 (m, 3H), 7.37 (d, 2H), 4.63 (d, 2H), 4.42 (m, 2H), 3.58 (t, 2H), 2.99 (hept, 1H), 2.58 (m, 1H), 2.38 (m, 2H), 1.30 (d, 6H).
MS: 441 (M+l)<+>
Eksempel 12: 4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1 -pyridin-3 -ylmetyl- 1H-quinazolin-2-on
<]>H NMR (300 MHz, CDC13): 8.78 (s, 1H), 8.58 (d, 1H), 7.90 (d, 1H), 7.74 (d, 2H), 7.54 (d, 1H), 7.26-7.44 (m, 5H), 5.60 (s, 2H), 4.64 (d, 2H), 3.01 (hept, 1H), 2.56 (t, 1H), 1.32 (d, 6H).
MS: 410 (M+l)<+>
Eksempel 13: l-[2-(2-hydroksy-etoksy)-benzyl]-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy- lH-quinazolin-2-on
A. Syntese av {2-[2-(2-hydroksy-etoksy)-benzylamino]-5-prop-2-ynyloksy-fenyl}-(4-isopropyl-fenyl)-metanon
Til en løsning av 100 mg (0,341 mmol) (2-amino-5-propargyloksy-fenyl)-(4-isopropyl-fenyl)-metanon i 1,5 ml C^Cbblir det tilsatt 61 mg (0,36 mmol) 2-(2-hydroksyet-oksy)benzaldehyd og 84 mg (0,38 mmol) natriumtriacetoksyborohydrid. Blandingen røres ved romtemperatur i to dager, fortynnes med vann og ekstraheres med CH2CI2. Rensing av det urene produktet ved kromatografi (etylacetat/heksaner 1:1) gir et gul faststoff.
<]>H NMR (300 MHz, CD3OD): 7.56 (d, 2H), 7.34 (d, 2H), 7.16-7.30 (m, 2H), 7.06-7.12 (m, 2H), 6.84-7.00 (m, 3H), 4.50-4.54 (m, 4H), 4.12 (t, 2H), 3.96 (t, 2H), 3.00 (hept, 1H), 2.92 (t, 1H), 1.32 (d, 6H).
MS: 444 (M+l)<+>
B. Syntese av l-[2-(2-hydroksy-etoksy)-benzyl]-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-on
Til en løsning av 85 mg (0,192 mmol) {2-[2-(2-hydroksy-etoksy)-benzylamino]-5-prop-2-ynyloksy-fenyl}-(4-isopropyl-fenyl)-metanon i 2 ml eddiksyre tilsettes 25 mg (0,383 mmol) natriumcyanat. Etter røring i 2 timer blir løsemidlet fjernet i vakuum og residuet fordelt mellom CH2CI2og vann. Det organiske sjiktet ekstraheres med 2 M natrium- hydroksidløsning. Etter fordampning av den organiske fasen blir produktet oppnådd som en gul olje.
<!>H NMR (300 MHz, CDC13): 7.76 (d, 2H), 7.20-7.56 (m, 6H), 6.94 (t, 1H), 6.86 (d, 1H), 5.62 (s, 2H), 4.04 (t, 2H), 3.94 (t, 2H), 3.02 (hept, 1H), 2.56 (m, 1H), 1.32 (d, 6H).
MS: 469 (M+l)<+>
Eksempel 15:1 -(3-klor-4-hydroksy-5-metoksy-benzyl)-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy- lH-quinazolin-2-on (Referanseeksempel) A. Syntese av [2-(3-klor-4-hydroksy-5-metoksy-benzylamino)-5-prop-2-ynyloksy-fenyl]-(4-isopropyl-fenyl)-metanon
Til en rørt blanding av 146,7 mg (0,5 mmol) of (2-amino-5-prop-2-ynyloksy-fenyl)-4-isopropyl-fenyl)-metanon og 28,6 jxl (0,5 mmol) eddiksyre i 1,5 ml metanol tilsettes 93,3 mg (0,5 mmol) 5-klorvanillin fulgt av 31,4 mg (0,5 mmol) natriumcyanoborhydrid. Etter røring i 40 timer ved romtemperatur blir reaksjonen stoppet med IN HC1 og deretter gjort alkalisk med IN vandig NaOH løsning. Metanol fjernes i vakuum, residuet fortynnes med vann og ekstrahert to ganger med etylacetat. De kombinerte organiske sjiktene tørkes (Na2SC>4) og fordampes. Flashkromatografi av residuet (Si02, heksan/- etylacetat) gir tittelforbindelsen som et gult faststoff.
<]>H-NMR (400 MHz, DMSO-d6): 9.28 (s, 1H), 8.20 (t, 1H), 7.57 (d, 2H), 7.40 (d, 2H), 7.13 (dd, 1H), 7.02 (d, 1H), 6.95 (d, 1H), 6.90 (d, 1H), 6.76 (d, 1H), 4.59 (d, 2H), 4.34 (d, 2H), 3.77 (s, 3H), 3.54 (t, 1H), 2.97 (m, 1H), 1.24 (d, 6H).
MS: 464 (M+l)<+>
B. Syntese av l-(3-klor-4-hydroksy-5-metoksy-benzyl)-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-on
Til en blanding av 43,1 mg (0,093 mmol) av [2-(3-klor-4-hydroksy-5-metoksy-benzyl-amino)-5-prop-2-ynyloksy-fenyl]-(4-isopropyl-fenyl)-metanon i 1 ml eddiksyre tilsettes 12,1 mg (0,186 mmol) natriumcyanat. Etter røring i 12 timer ved romtemperatur blir løsemidlet fjernet i vakuum og residuet fordelt mellom mettet NaHC03løsning og etylacetat. Det organiske sjiktet separes og den vandig fasen ekstraheres to ganger med etylacetat. De kombinerte organiske ekstraktene tørkes (Na2S04) og fordampes i vakuum. Flashkromatografi (Si02, heksan / etylacetat) gir tittelforbindelsen som et amorft gult faststoff.
<!>H NMR (400 MHz, DMSO-d6): 9.41 (s, 1H), 7.73 (d, 2H), 7.48 - 7.58 (m, 4H), 7.36 (d, 1H), 7.07 (d, 1H), 6.84 (d, 1H), 5.39 (bred s, 2H), 4.81 (d, 2H), 3.81 (s, 3H), 3.68 (t, 1H), 3.03 (m, 1H), 1.29 (d, 6H).
MS: 489 (M+l)<+>
Forbindelsene i følgende eksempler fremstilles på analog måte.
Eksempel 19:1 -(3-etoksy-4-metoksy-benzyl)-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-on
<]>H NMR (400 MHz, DMSO-d6): 7.71 (d, 2H), 7.47-7.55 (m, 4H), 7.35 (d, 1H), 7.05 (s, 1H), 6.86 (d, 1H), 6.73-6.76 (m, 1H), 5.41 (bred s, 2H), 4.79 (d, 2H), 3.97 (q, 2H), 3.69 (s, 3H), 3.66 (m, 1H), 3.02 (m, 1H), 1.26-1.32 (m, 9H).
MS: 483 (M+l)<+>
Eksempel 35:1 -(2,6-diklor-benzyl)-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy- 1H-quinazolin-2-on
<!>H NMR (300 MHz, CDC13): 7.78 (d, 2H), 7.44 (d, 1H), 7.38 (d, 2H), 7.15-7.40 (m, 5H), 5.90 (s, 2H), 4.62 (d, 2H), 3.01 (hept, 1H), 2.55 (m, 1H), 1.31 (d, 6H).
MS: 477 (M+l)<+>
Eksempel 56: 4-(4-isopropyl-fenyl)-1 -(2-metoksy-benzyl)-6-prop-2-ynyloksy-1H-quinazolin-2-on
<!>H NMR (300 MHz, CDC13): 7.76 (d, 2H), 7.48 (d, 1H), 7.38 (d, 2H), 7.18-7.32 (m, 3H), 6.76-7.02 (m, 3H), 5.56 (s, 2H), 4.62 (d, 2H), 3.96 (s, 3H), 3.02 (hept, 1H), 2.56 (t, 1H), 1.32 (d, 6H).
MS: 439 (M+l)<+>
Eksempel 62: 4-(4-isopropy 1-fenyl)-1 -(2-metoksymetoksy-benzyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-on
<]>H NMR (300 MHz, CDCI3): 7.76 (d, 2H), 7.48 (d, 1H), 7.38 (d, 2H), 7.10-7.32 (m, 4H), 7.02 (d, 1H), 6.86 (t, 1H), 5.58 (s, 2H), 5.34 (s, 2H), 4.62 (d, 2H), 3.58 (s, 3H), 3.02 (hept, 1H), 2.56 (t, 1H), 1.32 (d, 6H).
MS: 469 (M+l)<+>
Eksempel 75:1 -(4-brom-benzyl)-4-(4-isopropyl-feny l)-6-propargyloksy-1 H-quinazolin-2-on
Smeltepunkt 122-123°C.
<]>H NMR (300 MHz, CDCI3): 7.74 (d, 2H), 7.50 (d, 1H), 7.45 (d, 2H), 7.38 (d, 2H), 7.32 (dd, 1H), 7.16-7.22 (m, 3H), 5.49 (bred s, 2H), 4.64 (d, 2H), 3.02 (hept, 1H), 2.55 (bred t, 1H), 1.32 (d, 6H).
MS: 487,489 (M+l)<+>
Eksempel 91: 4-(4-isopropyl-fenyl)-6-propargyloksy-1 -(3,3,3-trifluor-propyl)-1H-quinazolin-2-on
<]>H-NMR (300 MHz, CDCI3): 7.69 (d, 2H), 7.51 (s, 1H), 7.49 (dd, 1H), 7.37 (d, 2H), 7.33 (d, 1H), 4.68 (d, 2H), 4.47-4.56 (m, 2H), 3.01 (hept, 1H), 2.60-2.78 (m, 2H), 2.57 (t, 1H), 1.31 (d, 6H).
MS: 415 (M+l)<+>
Eksempel 92: l-(3,3-dimetyl-butyl)-4-(4-Isopropyl-fenyl)-6-propargyloksy-lH-quinazolin-2-on
<>>H-NMR (300 MHz, CDCl3): 7.68 (d, 2H), 7.42-7.48 (m, 2H), 7.35 (d, 2H), 7.32 (d, 1H), 4.66 (d, 2H), 4.25-4.35 (m, 2H), 3.00 (hept, 1H), 2.56 (t, 1H), 1.66-1.74 (m, 2H), 1.31 (d, 6H), 1.10 (s, 9H). m. p. 69 °C
MS: 403 (M+l)<+>
Eksempel 93: 1 -(2,2-Dimetyl-pent-4-enyl)-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1H- quinazolin-2-on
<J>H NMR (300 MHz, CDC13): 7.78 (d, 2H), 7.36-7.52 (m, 5H), 5.90 (m, 1H), 5.12 (m, 2H), 4.68 (d, 2H), 4.32 (bred s, 2H), 3.02 (hept, 1H), 2.58 (m, 1H), 2.18 (d, 2H), 1.32 (d, 6H), 1.02 (s, 6H).
MS: 415 (M+l)<+>
Eksempel 94: l-(3,5-dimetyl-l-fenyl-lH-pyrazol-4-ylmetyl)-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-on
<]>H NMR (300 MHz, CDCI3): 7.78 (d, 2H), 7.52 (d, 1H), 7.26-7.50 (m, 9H), 5.48 (s, 2H), 4.66 (d, 2H), 3.02 (hept, 1H), 2.56 (m, 1H), 2.32 (s, 3H), 2.22 (s, 3H), 1.32 (d, 6H).
MS: 503 (M+l)<+>
Eksempel 95: 1 -(5-brom-tiofen-2-ylmetyl)-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-on
<]>H NMR (300 MHz, CDCI3): 7.68 (d, 2H), 7.31-7.50 (m, 5H), 7.34 (d, 2H), 6.94 (d, 1H), 6.88 (d, 1H), 5.52 (s, 2H), 4.64 (d, 2H), 3.00 (hept, 1H), 2.56 (m, 1H), 1.30 (d, 6H).
MS: 495 (M+l)<+>
Eksempel 96: 1 -(5-hydxoksymetyl-furan-2-ylmetyl)-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy- lH-quinazolin-2-on
<]>H NMR (300 MHz, CDCI3): 7.70 (d, 2H), 7.62 (d, 1H), 7.42-7.52 (m, 2H), 7.38 (d, 2H), 6.38 (d, 1H), 6.22 (d, 1H), 6.96 (dd, 1H), 5.48 (s, 2H), 4.52-4.70 (m, 4H), 3.02 (hept, 1H), 2.58 (t, 1H), 1.32 (d, 6H).
MS: 429 (M+l)<+>
Eksempel 97: l-(2-butyl-5-klor-lH-imidazol-4-ylmetyl)-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-on
<!>H NMR (300 MHz, CDCI3): 7.72 (d, 1H), 7.46-7.60 (m, 3H), 7.38 (d, 2H), 5.36 (s, 2H), 4.66 (d, 2H), 3.00 (hept, 1H), 2.70 (m, 2H), 2.56 (t, 1H), 1.66 (m, 2H), 1.30 (d, 6H), 0.86 (t, 3H).
MS: 489 (M+l)<+>
Eksempel 98: 4-(4-isopropyl-fenyl)-l-(6-metoksy-pyridin-3-ylmetyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-on
<]>H NMR (300 MHz, CDCI3): 8.22 (m, 1H), 7.64-7.78 (m, 3H), 7.50 (d, 1H), 7.30-7.42 (m, 4H), 6.72 (d, 1H), 5.48 (s, 2H), 4.66 (d, 2H), 3.94 (s, 3H), 3.02 (hept, 1H), 2.56 (t 1H), 1.32 (d, 6H).
MS: 440 (M+l)<+>
Eksempel 99: 7-[4-(4-isopropyl-fenyl)-2-okso-6-prop-2-ynyloksy-2H-quinazolin-1-ylmetyl]-1 H-indol-2-karbonitril
<]>H NMR (300 MHz, CDCI3): 11.52 (s, 1H), 7.92 (d, 1H), 7.74 (d, 2H), 7.64 (t, 2H), 7.46-7.54 (m, 2H), 7.38 (d, 2H), 7.12-7.26 (m, 2H), 6.76 (bred s, 2H), 4.64 (d, 2H), 3.02 (hept, 1H), 2.56 (t 1H), 1.32 (d, 6H).
MS: 473 (M+l)<+>
Eksempel 100: 1 -(2,4-diamino-pyrimidin-5-ylmetyl)-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-on
<]>H NMR (300 MHz, CD3OD): 7.40-7.80 (m, 8H), 5.36 (s, 2H), 4.74 (d, 2H), 2.98-3.12 (m, 2H), 1.32 (d, 6H). MS: 441 (M+l)<+>Eksempel 101:1 -(6-hydroksymetyl-pyridin-2-y lmetyl)-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-on
<]>H NMR (300 MHz, CDC13): 7.76 (d, 2H), 7.64 (t, 1H), 7.20-7.52 (m, 6H), 7.16 (d, 1H), 5.64 (s, 2H), 4.76 (s, 2H), 4.64 (d, 2H), 3.02 (hept, 1H), 2.56 (t, 1H), 1.32 (d, 6H).
MS: 440 (M+l)
Eksempel 102: 1 -(3,5-di-tert-butyl-4-hydroksy-benzyl)-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-on
<]>H NMR (300 MHz, CDCI3): 7.76 (d, 2H), 7.30-7.52 (m, 5H), 7.16 (s, 2H), 5.44 (s, 2H), 4.66 (s, 2H), 3.02 (hept, 1H), 2.56 (t, 1H), 1.30 (d, 6H).
MS: 537 (M+l)<+>
Eksempel 103: 4-[4-(4-isopropyl-fenyl)-2-okso-6-prop-2-ynyloksy-2H-quinazolin-l-ylmetyl]-2,2-dimetyl-oksazolidin-3-karboksylsyre tert-butylester
<!>H NMR (300 MHz, CDCI3): 8.20 (d, 1H), 7.70 (d, 2H), 7.30-7.58 (m, 4H), 4.94 (dd, 1H), 4.66 (d, 2H), 4.31 (d, 2H), 4.20 (m, 1H), 3.84 (dd, 1H), 3.00 (hept, 1H), 2.56 (t, 1H), 1.40-1.64 (m, 15 H), 1.32 (d, 6H).
MS: 532 (M+l)<+>
Eksempel 104: 4-(4-isopropyl-fenyl)-l-(4-metylamino-2-metylsulfanyl-pyrimidin-5-ylmetyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-on
<!>H NMR (300 MHz, CDC13): 8.18 (s, 1H), 7.86 (d, 1H), 7.72 (d, 2H), 7.64 (d, 1H), 7.52 (d, 1H), 7.44 (dd, 1H), 7.38 (d, 2H), 5.34 (bred s, 2H), 4.64 (d, 2H), 3.02 (hept, 1H), 2.96 (d, 3H), 2.58 (t, 1H), 2.50 (s, 3H), 1.32 (d, 6H).
MS: 486 (M+l)<+>
Eksempel 105: 4-(4-isopropyl-fenyl)-l- {4-[2-(metyl-pyridin-2-yl-amino)-etoksy]-benzyl}-6-prop-2-ynyloksy-lH-quinazolin-2-on
<]>H NMR (300 MHz, CDCI3): 8.12 (dd, 1H), 7.74 (d, 2H), 7.20-7.50 (m, 7H), 6.84 (d, 2H), 6.46-6.56 (m, 2H), 5.46 (bred s, 2H), 4.64 (d, 2H), 4.36 (t, 2H), 3.92 (t, 2H), 3.12 (s, 3H), 3.02 (hept, 1H), 2.54 (t, 1H), 1.40-1.64 (m, 15 H), 1.32 (d, 6H).
MS: 559 (M+l)<+>
Eksempel 106: 4-(4-isopropyl-fenyl)-1 -(2-metyl-heks-4-enyl)-6-prop-2-ynyloksy-1H-quinazolin-2-on
<]>H NMR (300 MHz, CDCI3): 7.72 (d, 2H), 7.30-7.52 (m, 5H), 5.42 (m, 2H), 4.64 (d, 2H), 4.24 (m, 2H), 3.00 (hept, 1H), 2.58 (t, 1H), 2.00-2.22 (m, 3 H), 1.62 (d, 3H), 1.30 (d, 6H), 0.98 (d, 3H).
MS: 415 (M+l)<+>
Eksempel 107: 4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-l-(4-pyrazin-2-yl-benzyl)-lH-quinazolin-2-on
<]>H NMR (300 MHz, CDCI3): 8.88 (s, 1H), 8.60 (d, 1H), 8.46 (d, 1H), 7.88 (d, 2H), 7.76 (d, 2H), 7.20-7.58 (m, 6H), 5.62 (bred s, 2H), 4.64 (d, 2H), 3.02 (hept, 1H), 2.56 (t, 1H), 1.32 (d, 6H).
MS: 487 (M+l)<+>
Eksempel 108: 4-(4-isopropyl-fenyl)-1 -(3-metylsulfanyl-propyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-on
<]>H NMR (300 MHz, CDC13): 7.72 (d, 2H), 7.48 - 7.52 (m, 3H), 7.38 (d, 2H), 4.69 (d, 2H), 4.43 (dd, 2H), 3.58 (t, 2H), 3.03 (hept, 1H), 2.71 (m, 2H), 2.58 (m, 1H), 2.08-2.32 (m, 5H), 1.31 (d, 6H).
MS: 407 (M+l)<+>
Eksempel 109: 4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1 -tiofen-2-ylmetyl-1H-quinazolin-2-on
<]>H NMR (300 MHz, CDCI3): 7.72 (d, 2H), 7.39-7.51 (m, 3H), 7.38 (d, 2H), 7.21 (dd, 1H), 7.18 (dd, 1H), 6.96 (dd, 1H), 5.65 (s, 2H), 4.66 (d, 2H), 3.00 (hept, 1H), 2.58 (t, 1H), 1.31 (d, 6H).
MS: 415 (M+l)<+>
Eksempel 110: l-benzyl-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-lH-quinazolin-2-tion
Til en løsning av 140 mg (0,365 mmol) (2-benzylamino-5-propargyloksy-fenyi)-(4-isopropyl-fenyl)-metanon i 5 ml eddiksyre tilsettes 68 mg (0,695 mmol) kaliumtio-cyanat. Reaksjonsblandingen ble rørt i to dager ved 60 °C. Løsemidlet ble fjernet og residuet ble ekstrahert med vann/diklormetan. Etter fordampning av den organiske fasen ble det urene produktet renset med flashkromatografi (MeOH/CHiCb, 1:9) som ga 25 mg (16%) av en gul olje.
<!>H NMR (300 MHz, CDC13): 7.82 (d, 2H), 7.52 (s, 1H), 7.20-7.43 (m, 9H), 6.22 (bred s, 2H), 4.64 (d, 2H), 3.02 (hept, 1H), 2.56 (t, 1H), 1.32 (d, 6H).
MS: 425 (M+l)<+>
Eksempel 111: 4-(4-isopropyl-fenyl)-l-(3-metan-sulfonyl-benzyl)-6-propargyloksy-lH-quinazolin-2-tion (Referanseeksempel)
En løsning av 1,87 g (4,06 mmol) 4-(4-isopropyl-fenyl)-l-(3-metan-sulfonyl-benzyl)-5-propargyloksy-fenyl-metanon (eksempel 2) og 0,72 g (4,.42 mmol) benzoylisotiocyanat i 9 ml THF ble rørt ved 50°C i 2 timer. Deretter blir reaksjonsblandingen avkjølt til romtemperatur og K2CO3(1,2 g suspendert i 17 ml MeOH) ble tilsatt og røringen fortsatt i 20 timer. Deretter ble reaksjonsblandingen helt over i vann og ekstrahert med etylacetat. De kombinerte organiske sjiktene vaskes med vann og saltvann, tørkes over MgS04, filtreres og konsentreres i vakuum. Residuet renses med flashkromatografi på silikagel (heksan/EtOAc = 1:1) for å gi tittelforbindelsen som et mørkt gult skum.<]>H-NMR (300 MHz, DMSO-de): 7.88 (s, 1H), 7.78 (d, 1H), 7.75 (d, 2H), 7.58-7.38 (m, 7H), 4.80 (s, 2H), 3.48 (m, 1H), 3.18 (s, 3H), 2.99 (m, 1H), 1.22 (d, 6H).
MS: 503 (M+l)<+>
Forbindelsene i følgende eksempler ble fremstilt analogt:
Eksempel 112: 4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-l-tiofen-2-ylmetyl-lH quinazolin-2 -tion
<!>H NMR (300 MHz, CDCI3): 7.76 (d, 2H), 7.64 (d, 1H), 7.50 (d, 1H), 7.44 (dd, 1H), 7.38 (d, 2H), 7.12-7.30 (m, 2H), 6.88 (m, 1H), 6.32 (bred s, 2H), 4.68 (d, 2H), 3.02 (hept, 1H), 2.58 (t, 1H), 1.32 (d, 6H).
MS: 431 (M+l)<+>
Eksempel 113: l-[3-(2-hydroksy-etoksy)-benzyl]-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-tion
<]>H-NMR (300 MHz, CDCI3): 7.82 (d, 2H), 7.52 (m, 1H), 7.20-7.42 (m, 5H), 6.76-6.94 (m, 3H), 6.18 (bred s, 2 H), 4.66 (d, 2 H), 4.03 (t, 2H), 3.92 (t, 2H), 3.00 (hept, 1H), 2.56 (t, 1H), 1.30 (d, 6H).
MS: 485 (M+l)<+>
Eksempel 129: 4-(4-isopropyl-fenyl)-l-[2-(2-metoksy-etoksy)-pyridin-3-ylmetyl]-6-prop-2-ynyloksy-1 H-quinazolin-2-on
A. Syntese av (2-klor-pyridin-3-yi)-metanol
Til en løsning av etyl 2-klornikotinat (1 g, 5,39 mmol) i 10 ml EtOH ved romtemperatur tilsettes 2,04 g (53,9 mmol) NaBH.4 over 30 minutter i flere porsjoner. Løsning røres. Overskudd borohydrid omsettes ved tilsetning av metanol. Løsemidlene fordampes og residuet fordeles mellom diklormetan og vann. Den vandige fase ekstraheres 3 x med 10 ml diklormetan. De kombinerte organiske sjiktene vaskes med saltvann, tørkes med MgS04, filtreres og fordampes i vakuum for å gi en lys gul olje.
<]>H-NMR (300 MHz, CDC13): 8.42 (d, 1H), 8.04 (d, 1H), 7.40 (m, 1H), 5.41 (s, 3H) 4.82 (s,2H).
MS: 144 (M+l)<+>
B. Syntese av [2-(2-metoksy-etoksy)-pyridin-3-yl]-metanol
153 mg (19,2 mmol) LiH tilsettes til 10 ml metoksyetanol og blandingen røres i 5 min. til gassutviklingen stopper. 690 mg (4,81 mmol) (2-Klor-pyridin-3-yl)-metanol tilsettes fulgt av 110 mg (1,73 mmol) Cu og 115 mg (0,721 mmol) CUSO4og blandingen røres ved 100°C. Etter 2 dager blir reaksjonsblandingen avkjølt til romtemperatur og filtrert med help av metanol. Etter fordampning blir eter tilsatt til residuet og ekstrahert to ganger med saltvann, tørkt med Na2S04, filtrert og fordampet til konstant vekt oppnås.<]>H-NMR (300 MHz, CDCI3): 8.22 (m, 1H), 7.74 (d, 1H), 7.04 (m, 1H), 5.44 (s, 3H) 4.82 (d, 2H), 4.68 (m, 2H), 3.92 (m, 2H), 3.58 (s, 3H). MS: 184(M+1)<+>C. Syntese av (4-isopropyl-fenyl)-(2-{[2-(2-metoksy-etoksy)-pyridin-3-ylmetyl]-amino}-5-prop-2-ynyloksy-fenyl)-metanon
Til en løsning av 400 mg (2,18 mmol) [2-(2-metoksy-etoksy)-pyridin-3-yl]-metanol i 4 ml dioksan ble det ved romtemperatur tilsatt 1,12 ml (6,55 mmol) Hunig's base fulgt av 170 (il (2,18 mmol) mesylklorid og blandingen røres i 5 minutter. 641 mg (2,18 mmol)
(2-amino-5-propargyloksy-fenyl)-(4-isopropyl-fenyl)-metanon tilsettes til denne blandingen ved tilsetning av 1 ml dioksan. Reaksjonsblandingen blir deretter varmet til 100°C og rørt over natten. Blandingen fordeles mellom eter/vann og det organiske sjiktet vaskes med saltvann, tørkes med NaiSCv, filtreres og fordampes. Flashkromatografi (etylacetat/eter 1:1) gir en gul olje
<]>H NMR (300 MHz, CDC13): 8.04 (m, 1H), 7.56-7.64 (m, 3H), 7.30 (d, 2H), 7.20 (d, 1H), 7.08 (dd, 1H), 6.84 (dd, 1H), 6.70 (d, 1H), 4.58 (m, 2H), 4.46 (s, 2H), 3.80 (m, 2H), 3.44 (s, 3H), 2.98 (hept, 1H),1.32 (d, 6H).
MS: 459 (M+l)<+>
D. Syntese av 4-(4-isopropyl-fenyl)-l-[2-(2-metoksy-etoksy)-pyridin-3-ylmetyl]-6-prop-2-ynyloksy-1 H-quinazolin-2-on
Til en løsning av 200 mg (0,436 mmol) (4-Isopropyl-fenyi)-(2-{[2-(2-metoksy-etoksy)-pyridin-3-ylmetyl]-amino}-5-prop-2-ynyloksy-fenyl)-metanon i 1,5 ml eddiksyre tilsettes 28 mg (0,436 mmol) natriumcyanat. Etter røring i 2 timer blir løsemidlet fjernet i vakuum og residuet fordelt mellom CH2CI2og vann. Det organiske sjiktet tørkes og fordampes. Rensing av det urene produktet med flash-kromatografi (CH^CVeter 3:7) gir en gul olje.
<]>H NMR (300 MHz, CDCI3): 8.06 (d, 1H), 7.74 (d, 2H), 7.30-7.52 (m, 6H), 6.78 (dd, 1H), 5.64 (s, 2H), 4.62-4.66 (m, 4H), 3.84n(dd, 2H), 3.50 (s, 3H), 3.02 (hept, 1H), 2.56 (t, 1H), 1.32 (d, 6H).
MS: 484 (M+l)<+>
Eksempel 130: Syntese av l-[6-(2-hydroksy-etoksy)-pyridin-2-ylmetyl]-4-(4-isopropyl-fenyl)-6-propargyloksy-1 H-quinazolin-2-on
A. Syntese av 6-klor-pyridin-2-karboksylsyre
B.
En suspensjon av 4,0 g (28,8 mmol) av 6-hydroksypikolinsyre, 6,0 ml fosforoksyklorid og 20 g fosforpentaklorid blir sakte varmet til 90°C i løpet av 1,5 timer. Røring fort-setter i ytterligere 12 timer. Etter avkjøling til romtemperatur blir reaksjonen stoppet ved forsiktig tilsetning av 1,4 ml maursyre. Konsentrering under høyvakuum gir 5,36 g av et mørkt faststoff som hydrolyseres i vann (50 ml) under nærvær av 5,56 g (40 mmol) kaliumkarbonat. Ekstraktiv opparbeiding med petroleumeter/ vann og konsen-trert i.v. resulterer i et gult faststoff.
Smeltepunkt 188-190°C.
<]>H-NMR (300 MHz, CDC13): 8.17 (dd, 1H), 7.93 (t, 1H), 7.62 (dd, 1H).
MS: 158 (M+l)<+>
B. Syntese av 6-tert-butoksy-pyridin-2-karboksylsyre
En løsning av 2,70 g (17,1 mmol) av 6-klor-pyridin-2-karboksylsyre i 200 ml THF varmes opp i 19 timer til refluks. Blandingen helles over i vann og justeres til nøytral pH ved tilsetning av sitronsyre. Ekstraktiv opparbeidning med etylacetat gir et svakt gult faststoff.
<!>H-NMR (300 MHz, CDCI3): 7.72 (m, 2H), 6.94 (dd, 1H), 1.64 (s, 9H).
MS: 140 [(M+l)<+->buten]
C. Syntese av 6-tert-butoksy-pyridin-2-karboksylsyre metylester
En gul suspensjonen av 2,60 g (13,3 mmol) 2-tert-butoksy-pyridin-2-karboksylsyre og 2,8 g (20 mmol) kaliumkarbonat i 40 ml aceton behandles ved romtemperatur med 2,64 g (18,6 mmol) jodometan. Etter røring i 4 timer ved 40°C blir blandingen fordelt mellom vann og etylacetat. Konsenterring av det organiske sjiktet gir en gul olje.<!>H-NMR (300 MHz, CDC13): 7.58-7.64 (m, 2H), 6.81 (dd, 1H), 3.94 (s, 3H), 1.64 (s, 9H).
MS: 154 [(M+l)<+->buten]
D. Syntese av (6-tert-butoksy-pyirdin-2-yl)-metanol
En løsning av 2,32 g (11,1 mmol) av ester fra trinn C i 25 ml etanol reduseres ved porsjonsvis tilsetning av 2,09 g (55,4 mmol) natriumborohydrid. HPLC analyse etter røring ved romtemperatur i 12 timer viser fullstendig reaksjon. Blandingen fortynnes med metanol og ekstraheres med etylacetat / vann for å gi en gul olje.
'H-NMPv (300 MHz, CDC13): 7.61 (dd, 1H), 6.74 (dd, 1H), 6.56 (dd, 1H), 4.65 (d, 2H), 3.42 (t, 1H), 1.60 (s,9H).
E. Syntese av 6-tert-butoksy-pyridin-2-karbaldehyd
1.65 g (9,10 mmol) av alkohol oppnådd i trinn D i 50 ml diklormetan oksideres med 3,86 g (9,10 mmol) Dess-Martin periodinan. Reaksjonen er fullstendig etter 12 timer. Reaksjonsblandingen ekstraheres med etylacetat / vandig natriumtiosulfatløsning og det organiske sjiktet konsentreres i vakuum. Flash-kromatografi av det urene produktet (petroleumeter / etylacetat) gir en gul olje.
<]>H-NMR (300 MHz, CDCI3): 9.91 (s, 1H), 7.67 (t, 1H), 7.50 (dd, 1H), 6.86 (dd, 1H), 1.66 (s,9H).
MS: 124 [(M+l)<+->buten]
F. Syntese av {2-[(6-tert-butoksy-pyridin-2-ylmetyl)-amino]-5-propargyloksy-fenyl}-(4-isopropyl-fenyl)-metanon
En løsning av 600 mg (2,05 mmol) (2-amino-5-propargyloksy-fenyl)-4-isopropyl-fenyl)-metanon og 403 mg (2,25 mmol) av aldehydet oppnådd i trinnet ovenfor i 18 ml diklormetan behandles med 872 mg (3,07 mmol) titanium(IV)isopropoksyd. Det opp-nådde aminet etter røring over natten blir redusert med 650 mg (3,07 mmol) natriumtriacetoksyborohydrid under nærvær av 2,4 ml av EtOH. Det urene produktet etter ekstraktiv opparbeiding med etylacetat / petroleumeter renset med flashkromatografi (etylacetat / petroleum eter) for å gi en gul olje.
<!>H-NMR (300 MHz, CDC13): 7.61 (d, 2H), 7.46 (dd, 1H), 7.30 (d, 2H), 7.21 (d, 1H), 7.04-7.11 (m, 1H), 6.86 (d, 1H), 6.72 (d, 1H), 6.63 (d, 1H), 4.53 (d, 2H), 4.48 (d, 2H), 2.99 (hept, 1H), 2.48 (t, 1H), 1.60 (s, 9H), 1.34 (d, 6H).
MS: 457 (M+l)<+>
G. Syntese av l-[(6-tert-butoksy-pyridin-2-ylmetyl)-4-(4-isopropyl-fenyl)-6-propargyloksy-1 H-quinazolin-2-on
En løsning av 120 mg (0,26 mmol) av utgangsmaterialet (trinn F) i 3 ml eddiksyre cykliseres med 21 mg (0,315 mmol) natriumcyanat over natten for å gi quinazolinonet etter flashkromatografi (heksan / etylacetat).
Smeltepunkt 62-65°C.
<]>H-NMR (300 MHz, CDC13): 7.72 (d, 2H), 7.46-7.50 (m, 2H), 7.43 (d, 1H), 7.39 (d, 2H), 7.31 (dd, 1H), 6.90 (d, 1H), 6.52 (d, 1H), 5.56 (bred s, 2H), 3.03 (hept, 1H), 2.55 (t, 1H), 1.41 (s, 9H), 1.33 (d, 6H).
MS: 482 (M+l)<+>
H. Syntese av l-[(6-tert-pyridin-2-ylmetyl)-4-(4-isopropyl-fenyl)-6-propargyloksy-lH-quinazolin-2-on
En blanding av 60 mg (0,13 mmol) av t-butyleteren (trinn G) i 6 ml diklormetan behandles med 15 ul trifluoreddiksyre og røres over natten ved romtemperatur. Ekstraktiv opparbeiding med vandig natriumbikarbonatløsning / diklormetan gir et gult faststoff.
Smeltepunkt 219-222°C.
<]>H-NMR (300 MHz, CDCI3): 7.76 (d, 2H), 7.55 (d, 1H), 7.32-7.48 (m, 5H), 6.50 (d, 1H), 6.23 (d, 1H), 5.38 (bred s, 2H), 4.69 (d, 2H), 3.04 (hept, 1H), 2.58 (t, 1H), 1.34 (d, 6H).
MS: 426 (M+l)<+>
I. Syntese av l-[6-(2-hydroksy-etoksy)-pyridin-2-ylmetyl]-4-(4-isopropyl-fenyl)-6-propargyloksy-1 H-quinazolin-2-on
En suspensjon av 40 mg (0,094 mmol) av pyridyl-alkoholen oppnådd i trinn H, 16 mg (0,132 mmol) 2-bromoetanol og 19 mg (0,141 mmol) kaliumkarbonat i 4 ml aceton røres over natten ved 70°C. Det urene produktet oppnådd etter ekstraksjon med etylacetat /vann renses med flashkromatografi (heksan / etylacetat) for å gi en gul olje.
<!>H-NMR (300 MHz, CDC13): 7.74 (d, 2H), 7.32-7.56 (m, 6H), 6.92 (d, 1H), 6.68 (d, 1H), 5.53 (bred s, 2H), 4.66 (d, 2H), 4.38-4.52 (m, 2H), 3.91 (bred, 2H), 3.02 (hept, 1H), 2.75 (bred, OH), 2.56 (t, 1H), 1.33 (d, 6H).
MS: 470 (M+l)<+>
Eksempel 131: l-[6-klor-pyridin-3-ylmetyl]-4-(4-isopropyl-fenyl)-6-propargyloksy-lH-quinazolin-2-on A. Syntese av 2-brommetyl-2-klor-pyridin
En løsning av 1,28 g (10,0 mmol) 2-klor-5-metyl-pyridin i 25 ml karbontetraklorid behandles med 1,79 g (10,0 mmol) nylig rekrystallisert N-bromosuccinimid og 30 mg benzoylperoksid. Blandingen varmes opp til refluks i 17 timer og filtreres. Filtratet vaskes med vann og konsentreres. Flashkromatografi (heksan/etylacetat) resulterer i et hvitt lavtsmeltende faststoff.
Smeltepunkt 40-43°C.
MS: 210 (2), 208 (100), 206 (75) (klor-bromisotopmønster) (M+l)<+>
B. Syntese av {2-[(6-klor-pyridin-3-ylmetyl)-amino]-5-propargyloksy-fenyl}-(4-isopropyl-fenyl)-metanon
Til en løsning av 323 mg (1,10 mmol) (2-amino-5-propargyloksy-fenyl)-4-isopropyl-fenyl)-metanon og 250 mg (1,21 mmol) 2-bromometyl-2-klor-pyridin (trinn A) i 2 ml l,3-dimetyl-2-imidazolidinon (DMEU) 213 mg (1,54 mmol) kaliumkarbonat tilsettes. Reaksjonen er fullstendig etter røring i 2 timer ved 60 °C. Den avkjølte gule suspensjonen fordeles mellom etylacetat og bikarbonatløsning. Flashkromatografi (heksan/ etylacetat) gir et gult faststoff.
Smeltepunkt 96°C.
<!>H-NMR (300 MHz, CDC13): 8.49 (t, 1H), 8.40 (d, 1H), 7.67 (dd, 1H), 7.61 (d, 2H), 7.31 (d, 2H), 7.30 (d, 1H), 7.23 (d, 1H), 7.08 (dd, 1H), 6.59 (d, 1H), 4.53 (d, 2H), 4.48 (d, 2H), 2.99 (hept, 1H), 2.48 (t, 1H), 1.31 (d, 6H).
MS: 419 (M+l)<+>
C. Syntese av l-[(6-klor-pyridin-3-ylmetyl)-4-(4-isopropyl-fenyl)-6-propargyloksy-lH-quinazolin-2-on
En løsning av 320 mg (0,764 mmol) av utgangsmaterialet (trinn B) i 4 ml eddiksyre cykliseres med 74 mg (1,15 mmol) natriumcyanat. En tykk suspensjonen blir resultatet etter 3 timer. Fordeling mellom etylacetat og vandig bikarbonatløsning, konsentrering av det organiske sjiktet og flashkromatografi (heksan/etylacetat) av det urene produktet gir tittelquinazolinonet i form av et gult faststoff.
Smeltepunkt 210°C.
<]>H-NMR (300 MHz, CDC13): 8.44 (d, 1H), 7.72 (d, 2H), 7.67 (dd, 1H), 7.61 (d, 1H), 7.38 (d, 2H), 7.36 (dd, 1H), 7.27 (d, 1H), 7.21 (d, 1H), 5.51 (bred, 2H), 4.65 (d, 2H), 3.01 (hept, 1H), 2.55 (t, 1H), 1.31 (d, 6H).
MS: 444 (M+l)<+>
Eksempel 133: 1- (2-hydroksy-pyridin-3-ylmetyl)-4-(4-isopropy-fenyl)-6-propargyloksy-1 H-quinazolin-2-on
En løsning av 290 mg (0,635 mmol) {2-[(2-tert-butoksy-pyridin-3-ylmetyl)-amino]-5-propargyloksy-feny}-(4-isopropyl-fenyl)-metanon og i 7 ml eddiksyre omsettes med 50 mg (0,762 mmol) natriumcyanat. Etter røring over natten blir blandingen fordelt mellom etylacetat og vandig bikarbonatløsning. Det organiske sjiktet konsentreres for å gi tittelforbindelsen i form av et gult faststoff.
Smeltepunkt 121-123°C.
<]>H-NMR (300 MHz, CDC13): 7.74 (d, 2H), 7.48-7.55 (m, 3H), 7.32-7.43 (m, 4H), 6.26 (t, 1H), 5.48 (s, 2H), 4.66 (d, 2H, 3.02 (hept, 1H), 2.66 (t, 1H), 1.33 (d, 6H).
MS: 426 (M+l)<+>
Forbindelsene i følgende eksempler blir fremstilt analogt med eksemplet beskrevet ovenfor: Eksempel 134: 4-(4-isopropyl-fenyl)-1 -(5-metoksy-pyridin-2-ylmetyl)-6-propargyloksy-1 H-quinazolin-2-on
Smeltepunkt 136-137°C
<]>H-NMR (300 MHz, CDCI3): 8.25 (dd, 1H), 7.68-7.74 (m, 3H), 7.42-7.48 (m, 2H), 7.34-7.41 (m, 3H), 7.14 (dd, 1H), 5.60 (bred, 2H), 4..65 (d, 2H), 3.84 (s, 3H), 3.02 (hept, 1H), 2.65 (t, 1H), 1.33 (d, 6H).
MS: 440 (M+l)<+>
Eksempel 135: 4-(4-isopropyl-fenyl)-l-(6-metyl-pyridin-2-ylmetyl)-6-propargyloksy-1 H-quinazolin-2-on
Smeltepunkt 165-166°C
'H-NMR (300 MHz, CDCI3): 7.75 (d, 2H), 7.45-7.55 (m, 3H), 7.38 (d, 2H), 7.34 (dd, 1H), 7.10 (d, 1H), 7.05 (d, 1H), 5.62 (bred, 2H), 4..65 (d, 2H), 3.02 (hept, 1H), 2.60 (s, 3H), 2.55 (t, 1H), 1.33 (d,6H).
MS: 424 (M+l)<+>
Eksempel 136: l-(2-klor-pyridin-4-ylmetyl)-4-(4-isopropyl-fenyl)-6-propargyloksy-lH-quinazolin-2-on
<]>H-NMR (300 MHz, CDC13): 8.35 (d, 1H), 7.77 (d, 2H), 7.57 (d, 1H), 7.41 (d, 2H), 7.37 (dd, 1H), 7.24 (s, 1H), 7.16 (d, 1H), 7.06 (d, 1H), 5.62 (bred s, 2H), 4.67 (d, 2H), 3.04 (hept, 1H), 2.57 (t, 1H), 1.34 (d, 6H).
MS: 444 (M+l)<+>
Eksempel 137: l-(2-klor-pyridin-3-ylmetyl)-4-(4-isopropyl-fenyl)-6-propargyloksy-lH-quinazolin-2-on
<]>H-NMR (300 MHz, CDC13): 8.84 (d, 1H), 7.77 (d, 2H), 7.65 (d, 1H), 7.41 (d, 2H), 7.31-7.39 (m, 2H), 7.16 (dd, 1H), 7.07 (d, 1H), 5.61 (s, 2H), 4.67 (d, 2H), 3.91 (bred, 2H), 3.04 (hept, 1H), 2.56 (t, 1H), 1.33 (d, 6H).
MS: 444 (M+l)<+>
Eksempel 138: 4-(4-isopropyl-fenyl)-l-{6-[2-(2-metoksy-etoksy)-etoksy]-pyridin-2-ylmetyl)-6-propargyloksy-1 H-quinazolin-2-on
<]>H-NMR (300 MHz, CDCI3): 7.74 (d, 2H), 7.47-7.65 (m, 3H), 7.38 (d, 2H), 7.35 (dd, 1H), 6.93 (d, 1H), 6.66 (d, 1H), 5.52 (bred, 2H), 4.66 (d, 2H), 4.41 (dd, 2H), 3.78 (dd, 2H), 3.79 (dd, 2H), 3.65-3.71 (m, 2H), 3.54-3.60 (m, 2H), 3.39 (s, 3H), 3.02 (hept, 1H), 2.57 (t, 1H), 1.33 (d, 6H).
MS: 528 (M+l)<+>
Eksempel 139: 4-(4-isopropyl-fenyl)-l-[6-(2-metoksy-etoksy)-etoksy)-pyridin-2-ylmetyl)-6-propargyloksy-1 H-quinazolin-2-on
<]>H-NMR (300 MHz, CDC13): 7.74 (d, 2H), 7'.47'-7.63 (m, 3H), 7.39 (d, 2H), 7.34 (dd, 1H), 6.92 (d, 1H), 6.69 (d, 1H), 5.53 (bred, 2H), 4.66 (d, 2H), 4.38-4.43 (m, 2H), 3.66-3.71 (m, 2H), 3.42 (s, 3H), 3.02 (hept, 1H), 2.56 (t, 1H), 1.33 (d, 6H).
MS: 484 (M+l)<+>
Eksempel 140: 5-allyl-l-benzyl-6-hydroksy-4-(4-isopropyl-fenyl)-lH-quinazolin-2-on A. Syntese av 5-allyloksy-2-nitro-benzaldehyd
Til en løsning av 25 g (150 mmol) 5-hydroksy-2-nitro-benzaldehyd og 44,8 g (299 mmol) natriumjodid i 400 ml aceton blir det tilsatt 51,2 ml (299 mmol) N-etyldiisopro- pylamin og 25,3 ml (299 mmol) allylbromid. Etter røring i 18 timer ved romtemperatur blir reaksjonsblandingen filtrert og løsemidlet fordampt. Ekstraksjon av residuet med 1 M vandig saltsyre/diklormetan fulgt av kromatografi (heksan/etylacetat) gir 5-allyloksy-2-nitro-benzaldehyd.
<]>H NMR (300 MHz, CDCI3): 10.45 (s, 1H), 8.15 (d, 1H), 7.32 (d, 1H), 7.16 (dd, 1H), 6.03 (ddt, 1H), 5.45 (dq, 1H), 5.37 (dq, 1H), 4.69 (dt, 2H).
B. Syntese av (5-allyloksy-2-nitro-fenyl)-(4-isopropyl-fenyl)-metanol
En løsning av 4-isopropylfenylmagnesiumbromid fremstilt fra 2,35 g (96,5 mmol) magnesium og 18,15 g (96,5 mmol) l-bromo-4-isopropylbenzen i 80 ml THF blir sakte tilsatt ved -78°C til en løsning av 20 g (96.5 mmol) 5-allyloksy-2-nitro-benzaldehyd i 200 ml THF. Etter at reaksjonsblandingen har blitt varmet til romtemperatur blir mettet vandig ammoniumkloridløsning tilsatt. Ekstraksjon med etylacetat fulgt av kromato-grafisk rensing på silika (heksan / etylacetat) gir (5-allyloksy-2-nitro-fenyl)-(4-isopropyl-fenyl)-metanol.
<]>H NMR (300 MHz, CDCI3): 8.05 (d, 1H), 7.34 (d, 1H), 7.25 (d, 2H), 7.16 (d, 2H), 6.88 (dd, 1H), 6.50 (s, 1H), 6.01 (ddt, 1H), 5.40 (d, 1H), 5.33 (d, 1H), 4.62 (d, 2H), 2.88 (hept, 1H), 1.22 (d, 6H).
MS:310(M-OH)<+>
C. Syntese av (5-allyloksy-2-nitro-fenyl)-(4-isopropyl-fenyl)-metanon
En løsning av 16,38 g (50 mmol) (5-allyloksy-2-nitro-fenyl)-(4-isopropyl-fenyl)-metanol i 60 ml aceton behandles ved 0°C med 20 ml (53,4 mmol) Jones reagens. Etter røring i 2 timer ved romtemperatur blir isopropanol, en vandig løsning av natriumbisul-fitt og mettet vandig ammoniumkloridløsning tilsatt. Ekstraksjon med diklormetan gir (5-allyloksy-2-nitro-fenyl)-(4-isopropyl-fenyl)-metanon.
<]>H NMR (300 MHz, CDCI3): 8.24 (d, 1H), 7.69 (d, 2H), 7.30 (d, 2H), 7.09 (dd, 1H), 6.89 (d, 1H), 6.03 (ddt, 1H), 5.43 (dq, 1H), 5.36 (dq, 1H), 4.65 (dt, 2H), 2.97 (hept, 1H), 1.27 (d, 6H).
D. Syntese av (5-allyloksy-2-amino-fenyl)-(4-isopropyl-fenyl)-metanon
Til en iskjølt løsning av 16 g (5-allyloksy-2-nitro-fenyl)-(4-isopropyl-fenyl)-metanon i 65 ml eddiksyre blir det tilsatt 21,8 g jernpulver. Et presipitat som blir dannet blir brakt i løsning ved tilsetning av ytterligere eddiksyre. Etter røring i 16 timer ved romtemperatur blir reaksjonsblandingen filtrert og gjort basisk ved tilsetning av vandig kalium-hydroksidløsning. Ekstraksjon med diklormetan gir (5-allyloksy-2-amino-fenyl)-(4-isopropyl-fenyl)-metanon.
<]>H NMR (300 MHz, CDCI3): 7.62 (d, 2H), 7.31 (d, 2H), 7.03 - 6.98 (m, 2H), 6.71 (d, 1H), 5.98 (ddt, 1H), 5.32 (dd, 1H), 5.25 (dd, 1H), 4.39 (d, 2H), 2.99 (hept, 1H), 1.31 (d, 6H).
MS: 296 (M+l)<+>
E. Syntese av (2-allyl-6-amino-3-hydroksy-fenyl)-(4-isopropyl-fenyl)-metanon
I et forseglet rør blir en blanding av 50 mg (0,17 mmol) (5-allyloksy-2-nitro-fenyi)-(4-isopropyl-fenyl)-metanon, 1 ml DMEU og 1 ml vann varmet ved mikrobølgestråling til 180°C i 30 min. Vannet fordampes og den resulterende løsning renses med omvendt fase preparativ HPLC for å gi det omleirede produktet.
<]>H NMR (300 MHz, CDCI3): 7.79 (d, 2H), 7.30 (d, 2H), 6.81 (d, 1H), 6.60 (d, 1H), 5.80 (ddt, 1H), 5.03 (dq, 1H), 5.01 (dq, 1H), 3.16 (dt, 2H), 2.97 (hept, 1H), 1.28 (d, 6H).
MS: 296 (M+l)<+>
F. Syntese av (2-allyl-6-benzylamino-3-hydroksy-fenyl)-(4-isopropyl-fenyl)-metanon
Til en løsning av 39 mg (0,13 mmol) (2-allyl-6-amino-3-hydroksy-fenyl)-(4-isopropyl-fenyl)-metanon og 13,34 ul (13 mmol) benzaldehyd i 1,3 ml 1,2-dikloretan og 0,3 g molekylsikt (4 Å porestørrelse) blir det etter 1 time tilsatt 13 mg (0,18 mmol) natrium-cyanoborohydrid og 7,55 ul eddiksyre (0,13 mmol). Etter røring i 16 timer ved romtemperatur 1 M saltsyre tilsatt for å ødelegge overskudd hydridekvivalenter. Ved å til-sette 1 M NaOH blir blandingen gjort basisk. Det urene produktet oppnådd ved ekstraksjon med diklormetan renses med omvendt fase preparativ kromatografi.
<!>H NMR (300 MHz, CDCI3): 7.78 (d, 2H), 7.31 (d, 2H), 7.28 - 7.16 (m, 5H), 6.82 (d, 1H), 6.56 (d, 1H), 5.79 (ddt, 1H), 5.02 (dd, 1H), 5.01 (dd, 1H), 4.22 (s, 2H), 3.17 (d, 2H), 2.99 (hept, 1H), 1.30 (d, 6H).
MS: 386 (M+l)<+>
G. Syntese av 5-allyl-l-benzyl-6-hydroksy-4-(4-isopropyl-fenyl)-lH-quinazolin-2-on
En løsning av 15 mg (39 urnol) (2-allyl-6-benzylamino-3-hydroksy-fenyl)-(4-isopropyl-fenyl)-metanon og 2,5 mg natriumcyanat i 0,2 ml eddiksyre røres ved romtemperatur i 16 timer. Vandig natriumhydroksidløsning tilsettes og produktet ekstraheres med diklormetan.
<]>H NMR (300 MHz, CDC13): 7.48 (d, 2H), 7.33 - 7.24 (m, 8H), 7.14 (d, 1H), 5.65 (ddt, 1H), 5.52 (s, 2H), 5.10 (dd, 1H), 4.95 (dd, 1H), 3.20 (d, 2H), 2.97 (hept, 1H), 1.28 (d, 6H).
MS: 411 (M+l)<+>
Eksempel 160: {2-[2-(3,4-dimetoksy-fenyl)-2-metyl-propylamino]-4,5-dimetoksy-fenyl} -(4-isopropyl-fenyl)-metanon (Referanseeksempel)
A. Syntese av 2-(3,4-dimetoksy-fenyl)-2-metyl-propionsyre acid etylester En løsning av 2,00 g (8,92 mmol) etyl-3,4-dimetoksyfenylacetat, 2,85 ml (17,84 mmol) HMPA og 3,34 ml (53,52 mmol) metyljodid i 50 ml THF behandles ved -75°C med 51,9 ml (35,7 mmol) av en LDA løsning fremstilt i THF. Etter 18 timer med røring ved -75°C blir den kalde reaksjonsblandingen helt over i en vandig mettet ammonium-kloridløsning og ekstrahert med etylacetat. Etter fordamping av den urene dimetylerte forbindelsen oppnådd som fremdeles inneholder noe HMPA og blir direkte ytterligere omdannet som beskrevet nedenfor.
<]>H NMR (300 MHz, CDC13): 6.88 (dd, 1H), 6.86 (d, 1H), 6.82 (d, 1H), 4.12 (q, 2H), 3.87 (s, 3H), 3.87 (s, 3H), 1.57 (s, 6H), 1.20 (t, 3H).
B. Syntese av 2-(3,4-dimetoksy-fenyl)-2-metyl-propan-l-og lignende
En løsning av 909 mg (ca. 2 mmol) av det urene produktet beskrevet direkte ovenfor i 5 ml toluen behandles to ganger med 2,69 ml (3,2 mmol) 1,2 M DIB AH løsning i toluen ved 5°C. Etter røring i 20 timer blir mettet ammoniumkloridløsning tilsatt. Reaksjonsblandingen filtreres og ekstraheres med dietyleter for å gi etter fordampning av løsemid-let 2-(3,4-dimetoksy-fenyl)-2-metyl-propan-1 -ol.
<]>H NMR (300 MHz, CDCI3): 6.94 -6.91 (m, 2H), 6.85 (d, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.60 (s, 2H), 1.34 (s, 6H).
C. Syntese av 2-(3,4-dimetoksy-fenyl)-2-metyl-propionaldehyd
En løsning av 100 mg (0,476 mmol) 2-(3,4-dimetoksy-fenyl)-2-metyl-propan-l-ol i 1 ml diklormetan behandles med 202 mg (0,476 mmol) Dess-Martin reagens ved romtemperatur. Etter 1 time vandig natriumbikarbonat og natriumtiosulfatløsninger tilsatt og produktet ekstraheres med diklormetan. De organiske sjiktene fordampes og aldehydet som oppnås i tilstrekkelig renhet til å bli anvendt i reduktive amineringer.<]>H NMR (300 MHz, CDCI3): 9.44 (s, 1H), 6.88 (d, 1H), 6.83 (dd, 1H), 6.74 (d, 1H), 3.88 (s,6H), 1.46 (s, 6H).
D. Syntese av {2-[2-(3,4-dimetoksy-fenyl)-2-metyl-propylamino]-4,5-dimetoksy-fenyl}-(4-isopropyl-fenyl)-metanon
Etter en times røring av en blanding av 143 mg (0,476 mmol) (2-amino-4,5-dimetoksy-fenyl)-(4-isopropyl-fenyl)-metanon, 98 mg (0,476 mmol) 2-(3,4-dimetoksy-fenyl)-2-metyl-propionaldehyd, 1,1 g molekylsikt 4 Å porestørrelse, 5 ml 1,2-dikloretan og 31 ul (0,476 mmol) eddiksyre blir 41 mg (0,666 mmol) NaCNBH3tilsatt. I løpet av 4 dager blir tre ytterligere porsjoner av 31 ul eddiksyre (0,476 mmol) og 41 mg NaCNBH3(0,666 mmol) tilsatt. Overskudd hydrid ødelegges ved tilsetning av 1 M saltsyre og reaksjonsblandingen gjøres basisk ved hjelp av 1 M natriumhydroksid. {2-[2-(3,4-Dimetoksy-fenyl)-2-metyl-propylamino]-4,5-dimetoksy-fenyl}-(4-isopropyl-fenyl)-metanon isoleres ved filtrering fulgt av ekstraksjon med diklormetan og omvendt fase preparativ HPLC.
<]>H NMR (300 MHz, CDC13): 7.50 (d, 2H), 7.28 (d, 2H), 7.13 - 7.00 (m, 3H), 6.84 (d, 1H), 6.14 (s, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.86 (s, 3H), 3.66 (s, 3H), 3.35 (s, 2H), 2.97 (hept, 1H), 1.52 (s, 6H), 1.29 (d, 6H).
MS: 492 (M+l)<+>
Forbindelser i følgende eksempler fremstilles analogt med eksemplet beskrevet ovenfor.
Eksempel 167: 1 -[2-(3,5-dimetoksy-fenyl)-etyl]-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-on
En løsning av 15 mg (33 umoi) {2-[2-(3,5-dimetoksy-fenyl)-etylamino]-5-prop-2-ynyloksy-fenyl}-(4-isopropyl-fenyl)-metanon og 2,1 mg (33 umol) NaOCN i 300 ul eddiksyre røres i 1 time ved romtemperatur. Løsemidlet fordampes og produktet rekrystalliseres fra CH2CI2/dietyleter.
<]>H NMR (300 MHz, CDCI3): 7.70 (d, 2H), 7.49 (d, 1H), 7.43 (dd, 1H), 7.37 (d, 2H), 7.34 (d, 1H), 6.50 (d, 2H), 6.36 (t, 1H), 4.68 (d, 2H), 4.48 (dd, 2H), 3.80 (s, 6H), 3.09 - 2.97 (m, 3H), 2.57 (t, 1H), 1.32 (d, 6H).
MS: 483 (M+l)<+>
Eksempel 168: {2-[2-(3,5-dimetoksy-fenyl)-2-metyl-propylamino]-4-hydroksy-5-metoksy-fenyl} -(4-isopropyl-fenyl)-metanon (Referanseeksempel) A. Syntese av (2-amino-4-hydroksy-5-metoksy-fenyl)-(4-isopropyl-fenyl)-metanon
En blanding av 1,34 g (4,48 mmol) (2-amino-4,5-dimetoksy-fenyl)-(4-isopropyl-fenyl)-metanon, 1,88 g natriumetanetiolat og 10 ml DMF varmes opp til 110°C i 5 timer. Mettet vandig bikarbonatløsning (10 ml) og 100 ml vann tilsettes. Produktet ekstraheres med CH2CI2og kromatograferes på silika (heksan / etylacetat).
<]>H NMR (300 MHz, CDCI3): 7.56 (d, 2H), 7.30 (d, 2H), 6.96 (s, 1H), 6.31 (s, 1H), 3.70 (s,3H), 1.30 (d, 6H).
MS: 286 (M+l)<+>
B. Syntese av {2-[2-(3,5-dimetoksy-fenyl)-2-metyl-propylamino]-4-hydroksy-5-metoksy-fenyl}-(4-isopropyl-fenyl)-metanon
En blanding av 41,1 mg (144 umol) (2-amino-4-hydroksy-5-metoksy-fenyl)-(4-isopropyl-fenyl)-metanon, 45 mg (216 umol) 2-(3,5-dimetoksy-fenyi)-2-metyl-propionaldehyd, 180 mg molekylsikt (porestørrelse 4Å) og 0,50 ml CH2CI2røres i 90 minutter før tilsetning av 8,23 ul (144 umol) og 22 mg NaCNBH3. Etter 16 timer blir overskudd reduksjonsmiddel ødelagt ved tilsetning av 1 M saltsyre og blandingen gjøres basisk med 1 M natriumhydroksidløsning. Produktet ekstraheres med CH2CI2og renses med omvendt fase preparativ HPLC.
<]>H NMR (300 MHz, deDMSO): 10.07 (s, 1H), 8.71 (t, bred, 1H), 7.40 (d, 2H), 7.31 (d, 2H), 6.84 (s, 1H), 6.56 (d, 2H), 6.33 (t, 1H), 6.26 (s, 1H), 3.71 (s, 6H), 3.50 (s, 3H), 3.27 (d, 2H), 2.94 (hept, 1H), 1.35 (s, 6H), 1.23 (d, 6H).
MS: 478 (M+l)<+>
Forbindelsen i følgende eksempel fremstilles analogt med eksemplet beskrevet ovenfor: Eksempel 171:1 -[2-hydroksy-2-(2,4,6-trimetyl-fenyl)-etyl]-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-on
En blanding av 0,5 g (1,57 mmol) 4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-lH-quinazolin-2-on, 0,254 g (1,57 mmol) mesityloksiran, 35,7 mg (0,157 mmol) benzyltrietylammoniumklorid og 21,7 mg (0,157 mmol) kaliumkarbonat røres i 1 ml dioksan ved 90°C i 6 dager. Reaksjonsblandingen ekstraheres med vann / diklormetan og, etter fordampning av de organiske fasene, blir residuet renset med preparativ omvendt fase
HPLC.
<]>H NMR (300 MHz, CDCI3): 7.72 (d, 2H), 7.54 (d, 1H), 7.50 (d, 1H), 7.43 (dd, 1H), 7.38 (d, 2H), 6.88 (s, 2H), 5.66 (dd, 1H), 4.93 (d, 1H), 4.68 (d, 2H), 4.37 (dd, 1H), 3.02 (hept, 1H), 2.60 (s, 6H), 2.57 (t, 1H), 2.28 (s, 3H), 1.33 (d, 6H).
MS: 481 (M+l)<+>
Forbindelsen i følgende eksempel fremstilles analogt med eksemplet beskrevet ovenfor: Eksempel 172: l-[2-(3,5-difluor-fenyl)-2-hydroksy-etyl]-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-on
<]>H NMR (300 MHz, CDC13): 7.67 (d, 2H), 7.49 - 7.43 (m, 3H), 7.37 (d, 2H), 7.10 (m, 2H), 6.74 (tt, 1H), 5.81 (dd, 1H), 4.68 (d, 2H), 4.51 (dd, 2H), 4.38 (dd, 2H), 3.01 (hept, 1H), 2.57 (t, 1H), 1.32 (d, 6H).
MS: 475 (M+l)<+>
Eksempel 173: 4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1 -[(E)-2-(2,4,6-trimetyl-fenyl)-vinyl]- lH-quinazolin-2-on
En løsning av 50 mg (0,104 mmol) l-[2-hydroksy-2-(2,4,6-tirmetyl-fenyi)-etyl]-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-lH-quinazolin-2-on og 34,3 ul (0,208 mmol) trifluormetansulfonsyreanhydrid i 0,5 ml 1,2 dikloretan varmes opp til 80°C i 15 min. Ekstraksjon med diklormetan/vandig NaHC03fulgt av preparativ omvendt fase HPLC gir tittelforbindelsen.
<]>H NMR (300 MHz, CDC13): 7.76 (d, 2H), 7.68 (d, 1H), 7.51 (d, 1H), 7.41 (dd, 1H), 7.40 (d, 2H), 7.03 (d, 1H), 6.94 (s, 2H), 6.71 (d, 1H), 4.69 (d, 2H), 3.03 (hept, 1H), 2.58 (t, 1H), 2.47 (s, 6H), 2.32 (s, 3H), 1.33 (d, 6H).
MS: 463 (M+l)<+>
Forbindelsene i følgende eksempler ble fremstilt analogt til eksemplet beskrevet ovenfor: Eksempel 174: 4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1 -((E)-styryl)-1 H-quinazolin-2-on
<!>H NMR (300 MHz, CDCI3): 7.78 (d, 2H), 7.64 (d, 1H), 7.56 - 7.53 (m, 2H), 7.51 (d, 1H), 7.43 - 7.35 (m, 6H), 7.25 (d, 1H), 7.03 (d, 1H), 4.70 (d, 2H), 3.03 (hept, 1H), 2.58 (t, 1H), 1.34 (d, 6H).
MS: 421 (M+l)+
Eksempel 175: l-[(E)-2-(3-klor-4-metoksy-fenyl)-vinyl]-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-on
<!>H NMR (300 MHz, CDCI3): 7.77 (d, 2H), 7.60 (d, 1H), 7.59 (s, 1H), 7.51 (d, 1H), 7.41 - 7.37 (m, 4H), 7.13 (d, 1H), 6.96 (d, 1H), 6.92 (d, 1H), 4.70 (d, 2H), 3.95 (s, 3H), 3.03 (hept, 1H), 2.58 (t, 1H), 1.33 (d, 6H).
MS: 487 (30), 485 (100) (M+l)<+>(klorinisotopmønster)
Eksempel 176: l-[(E)-2-(3,5-dimetyl-fenyl)-vinyl]-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-on
<]>H-NMR (300 MHz, CDCI3): 7.78 (d, 2H), 7.64 (d, 1H), 7.50 (d, 1H), 7.40 (d, 2H), 7.37 (dd, 1H), 7.23 (d, 1H), 7.17 (s, 2H), 7.00 (s, 1H), 6.93 (d, 1H), 4.69 (d, 2H), 3.03 (hept, 1H), 2.58 (t, 1H), 2.36 (s, 6H), 1.33 (d, 6H).
MS: 449 (M+l)<+>
Midlene ifølge beskrivelsen, som definert ovenfor, for eksempel med formel I eller II, særlig som eksemplifisert, i fri eller farmasøytisk akseptabel syreaddisjonssaltform, fremviser farmakologisk aktivitet og er anvendelig som farmasøytisk middel, for eksempel for behandling, i forbindelse med sykdommer og tilstander som fremsatt i det følgende.
Inositolfosfatdannelsesundersøkelse:
For å bestemme den antagonistiske aktiviteten ved den humane paratyroide kalsium-sensereaeptoren (PcaR), ble forbindelsene testet i funksjonelle undersøkelser for å måle inhibering av kalsiumindusert inositolfosfatdannelse i CCL39 fibroblaster stabilt transfektert med human PcaR.
Cellene ble sådd i 24 brønns plater og dyrket til konfluens. Kulturer ble deretter merket med [<3>H]inositol (74 Mbq/ml) i serum-fritt medium i 24 timer. Etter merking ble cellene vasket en gang med en modifisert Hepes-bufret saltløsning (mHBS: 130 mM NaCl, 5,4 mM KC1, 0,5 mM CaCl2, 0,9 mM MgS04, 10 mM glukos, 20 mM HEPES, pH 7,4) og inkubert med mHBS ved 37°C under nærvær av 20 mM LiCl for å blokkere inositol-monofosfataseaktivitet. Testforbindelsene ble tilsatt 3 minutter før stimulering av PcaR med 5,5 mM kalsium og inkuberingene fortsatte i ytterligere 20 min. Deretter ble cellene ekstrahert med 10 mM is-kald maursyre og inositolfosfater som ble dannet ble bestemt ved anvendelse av anionebytterkromatografi og væskescintillasjonsteIling.
Undersøkelse for intracellulart fritt kalsium:
En alternativ fremgangsmåte for å bestemme antagonismen til PcaR består i å måle inhiberingen av intracellulær kalsiumtransient stimulert med ekstracellulær kalsium. CCL39 fibroblaster stabilt transfektert med human PcaR ble sådd ved 40.000 celler/- brønn i en 96-brønns Viewplates og inkubert i 24 timer. Mediet ble deretter fjernet og erstattet med nytt medium som inneholdt 2 uM Fluo-3 AM (Molecular Probes, Leiden, The Netherlands). I rutineeksperimenter ble cellene inkubert ved 37°C, 5 % CO2i 1 time. Deretter ble platene vasket to ganger med mHBS og brønnene ble fylt en gang til med 100 (il mHBS inneholdende testforbindelsene. Inkuberingen fortsatte ved romtemperatur i 15 minutter. For å avlese forandringer av intracellulært fritt kalsium ble platene overført til fluoressensavbildningsplateavleser (Molecular Devices, Sunnyvale, CA, USA). En grunnlinje som besto av 5 målinger på 0,4 sekunder hver (lasereksitasjon 488 nm) ble avlest. Cellene ble deretter stimulert med kalsium (2,5 mM endelig), og fluoressensforandringer avlest i løpet av en periode på 3 minutter.
Når målt i undersøkelsene ovenfor, har midlene ifølge beskrivelsen inkludert midlene ifølge oppfinnelsen typisk IC50Sverdier i området av ca. 50^iM ned til ca. 10 nM eller mindre.
Det er nå godt etablert at kontrollert behandling av pasienter med paratyroidhormon (PTH) og analoger og fragmenter derav har en uttalt anabolisk effekt på bendannelse. Således kan forbindelser som fremmer PTH frigivelse, slik som milder ifølge oppfinnelsen, anvendes for å hindre eller behandle tilstander vedrørende ben som er assosiert med økt kalsiumutarming eller resporsjon eller hvori stilmulering av bendannelse og kalsiumfiksering i benet er ønskelig.
Således, i et ytterligere aspekt, inkluderer denne beskrivelsen anvendelsen av de foreliggende forbindelsene til fremstilling av et medikament for å hindre eller behandle bentilstander som er assosiert med økt kalsiumutarming eller resorpsjon eller hvori stimulering av bendannelse og kalsiumfiksering i benet er ønskelig hvori en effektiv mengde av et middel ifølge beskrivelsen administreres til en pasient som trenger slik behandling.
I et ytterligere annet aspekt inkluderer beskrivelsen en farmasøytisk sammensetning for å hindre eller behandle bentilstander som er assosiert med økt kalsiumutarming eller resorpsjon eller hvori slik stimulering av bendannelse og kalsiumfiksering i benet er ønskelig som innbefatter et middel ifølge beskrivelsen sammenblandet med en farma-søytisk akseptabel eksipient, fortynningsmiddel eller bærer.
Midler ifølge beskrivelsen inkludert midler ifølge oppfinnelsen er følgelig indikert for hindring eller behandling av alle bentilstander som er assosiert med økt kalsiumutarming eller resorpsjon eller hvori stimulering av bendannelse og kalsiumfiksering i benet er ønskelig, for eksempel osteoporose av forskjellige opphav (for eksempel juvenil, menopausal, post-menopausal, post-traumatisk, forårsaket av høy alder eller ved korti-kosteroid behandling eller inaktivering), frakturer, osteopati, som inkluder akutte og kroniske tilstander assosiert med skjelettdemineralisering, osteo-malasi, periodontalt bentap eller bentap på grunn av artritt eller osteoartritt eller for behandling av hypoparatyroidisme.
Ytterligere sykdommer og forstyrrelser som kan hindres eller behandles inkluderer for eksempel seizurer, slag, hodetraume, ryggradskade, hypoksi-indusert nervecelleskade slik som hjertearrest eller neonatal stress, epilepsi, neurodegenerative sykdommer slik som Alzheimers sykdom, Huntington's sykdom og Parkinson's sykdom, demens, muskelspenning, depressjon, angst, panikkforstyrrelse, obsessiv-kompulsiv forstyrrelse, post-traumatisk stressforstyrrelse, schizofreni, neuroleptisk malignant syndrom, konge-stiv hjertesvikt; hypertensjon; gikt motilitetsforstyrrelser slik som diare og spastiske kolon og dermatologiske forstyrrelser, for eksempel ved vevshelbredning, for eksempel brannskader, ulcerasjoner og sår.
Midlene ifølge beskrivelsen inkludert midlene ifølge oppfinnelsen er særlig indikert for å hindre eller behandle osteoporose av forskjellig opprinnelse.
For alle anvendelsene ovenfor er en indikert daglig dose i området fra ca. 0,03 til ca. 300 mg foretrukket 0,03 til 30, mer foretrukket 0,1 til 10 mg av en forbindelse ifølge oppfinnelsen. Midlene ifølge oppfinnelsen kan administreres to ganger daglig eller opptil to ganger pr. uke.
Midlene ifølge oppfinnelsen kan administreres i fri form eller i farmasøytisk akseptabel saltform. Slike salter kan fremstilles på vanlig måte og fremvise den samme aktivitets-grad som de frie forbindelsene. Foreliggende oppfinnelse tilveiebringer også en farma-søytisk sammensetning som innbefatter et middel ifølge oppfinnelsen i fri baseform eller i farmasøytisk akseptabel saltform i assosiasjon med et farmasøytisk akseptabelt fortynningsmiddel eller bærer. Slike sammensetninger kan formuleres på vanlig måte. Midlene ifølge oppfinnelsen kan administreres ved en hvilken som helst vanlig rute, for eksempel parenteralt, for eksempel i form av injiserbare løsninger eller suspensjoner, enteralt, for eksempel oralt, for eksempel i form av tabletter eller kapsler eller i en trans-dermal, nasal eller en stikkpilleform.
I henhold til det foregående tilveiebringer foreliggende oppfinnelser ytterligere:
et middel ifølge oppfinnelsen eller et farmasøytisk akseptabelt salt derav for anvendelse som et farmasøytisk middel;
anvendelsen av et middel ifølge oppfinnelsen for fremstilling av et medikament for å hindre eller behandle ovenfor nevnte forstyrrelser og sykdommer hos et subjekt som
trenger slik behandling, hvilken fremgangsmåte innbefatter administrering av nevnte subjekt av en effektiv mengde av et middel ifølge oppfinnelsen eller et farmasøytisk akseptabelt salt derav;
c) et middel ifølge oppfinnelsen eller et farmasøytisk akseptabelt salt derav for anvendelse ved fremstilling av en farmasøytisk sammensetning, for eksempel for anvendelse i
fremgangsmåten i b) ovenfor.
Ifølge en ytterligere utførelsesform av oppfinnelsen kan midlene ifølge oppfinnelsen anvendes som hjelpestoff eller adjuvans sammen med annen behandling, for eksempel behandling ved anvendelse av en benresorpsjonsinhibitor, for eksempel som i osteopor-osebehandling, særlig en behandling som anvender kalsium, en kalsitonin eller analog eller derivat derav, for eksempel laks, ål eller human kalsitonin, et steroid hormon, for eksempel et østrogen, en delvis østrogenagonist eller østrogen-gestagen kombinasjon, en SERM (selektiv østrogenreseptormodulator) for eksempel raloksifen, lasofoksifen, TSE-424, FC1271, tibolon (Livial ®), vitamin D eller en analog derav eller PTH, et PTH fragment eller et PTH derivat for eksempel PTH (1-84), PTH (1-34), PTH (1-36), PTH (1-38), PTH (1-31)NH2eller PTS 893.
Når midlene ifølge oppfinnelsen administreres sammen med, for eksempel som en adjuvans ved benresorpsjonsinhiberingsbehandling, vil doseringen for den ko-administrerte inhibitoren selvfølgelig variere avhengig av type inhibitorlegemiddel som anvendes, for eksempel om det er et steroid eller et kalsitonin, på tilstanden som behandles, om det er en kurativ eller preventiv behandling, og på regimet og så videre.
Claims (4)
1.
Forbindelse,karakterisert vedat den er valgt fra gruppen av forbindelser med de følgende navnene: l-(2,3-Dimetoksy-quinoksalin-6-ylmetyl)-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-lH-quinazolin-2-on;
4-(4-Isopropyl-fenyl)-1 -(3-metan-sulfonyl-benzyl)-6-propargyloksy-1 H-quinazolin-2-on; 4-(4-Isopropyl-fenyl)-l-(3-metan-sulfinyl-benzyl)-6-propargyloksy-lH-quinazolin-2-on;
4-(4-Isopropyl-fenyl)-6-prop-2-ynyloksy-1 -pyridin-2-ylmetyl-1 H-quinazolin-2-on; 4-(4-Isopropyl-fenyl)-6-prop-2-ynyloksy-1 -(4-[ 1,2,3]triazol-2-yl-benzyl)-1H-quinazolin-2-on;
1 -(3-Brom-propyl)-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-on; 4-(4-Isopropyl-fenyl)-6-prop-2-ynyloksy-1 -pyridin-3-ylmetyl-1 H-quinazolin-2-on;
1- [2-(2-Hydroksy-etoksy)-benzyl]-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-lH-quinazolin-2-on;
1 -(2,6-Diklor-benzyl)-4-(4-isopropyl-feny l)-6-prop-2-yny loksy-1 H-quinazolin-2-on; 4-(4-Isopropyl-fenyl)-1 -(2-metoksy-benzyl)-6-prop-2-yny loksy-1 H-quinazolin-2-on; 4-(4-Isopropyl-fenyl)-1 -(2-metoksymetoksy-benzyl)-6-prop-2-ynyloksy-1 H-quinazolin-2- on; 4-(4-Isopropyl-fenyl)-6-propargyloksy-1 -(3,3,3-trifluor-propyl)- lH-quinazolin-2-on;
1 -(3,3-Dimetyl-butyl)-4-(4-Isopropyl-fenyl)-6-propargyloksy-1 H-quinazolin-2-on;
1 -(2,2-Dimetyl-pent-4-enyl)-4-(4-isopropy l-fenyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-on;
1 -(3,5-Dimetyl-1 -fenyl- lH-pyrazol-4-ylmetyl)-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-on;
1 -(5-Brom-tiofen-2-ylmetyl)-4-(4-isopropy l-fenyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-on;
1 -(5-Hydroksymetyl-furan-2-ylmetyl)-4-(4-isopropy 1-feny l)-6-prop-2-ynyloksy-1H-quinazolin-2-on;
1 -(2-Butyl-5 -klor-1 H-imidazol-4-ylmetyl)-4-(4-isopropyl-feny l)-6-prop-2-yny loksy-1 H-quinazolin-2-on;
4-(4-Isopropyl-fenyl)-l-(6-metoksy-pyirdin-3-ylmetyl)-6-prop-2-ynyloksy-lH-quinazolin-2-on; 7-[4-(4-Isopropyl-fenyl)-2-okso-6-prop-2-ynyloksy-2H-quinazolin-l-ylrnetyl]-lH-indol-2 -karbonitril; l-(2,4-Diamino-pyrimidin-5-ylme1yl)-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-lH-quinazolin-2-on;
1 -(6-Hydroksymetyl-pyridin-2-ylmetyl)-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1H-quinazolin-2-on; l-(3,5-Di-tert-butyl-4-hydroksy-benzyl)-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-lH-quinazolin-2-on;
4-[4-(4-Isopropyl-fenyl)-2-okso-6-prop-2-ynyloksy-2H-quinazolin-l-ylmetyl]-2,2-dimetyl-oksazolidin-3-karboksylsyre tert-butylester;
4-(4-Isopropyl-fenyl)-l-(4-me1ylamino-2-me1ylsulfany ynyloksy-1 H-quinazolin-2-on; 4-(4-Isopropyl-fenyl)-l-{4-[2-(metyl-pyridin-2-yl-amino)-etoksy]-benzyl}-6-prop-2-ynyloksy-1 H-quinazolin-2-on;
4-(4-Isopropyl-fenyl)-l-(2-metyl-heks-4-enyl)-6-prop-2-ynyloksy-lH-quinazolin-2-on; 4-(4-Isopropyl-fenyl)-6-prop-2-ynyloksy-1 -(4-pyrazin-2-y 1-benzyl)-1 H-quinazolin-2-on;
4-(4-Isopropyl-fenyl)-1 -(3-metylsulfanyl-propyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-on;
4-(4-Isopropyl-fenyl)-6-prop-2-ynyloksy-1 -tiofen-2-ylmetyl-1 H-quinazolin-2-on; l-Benzyl-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-lH-quinazoline-2-tion; 4-(4-Isopropyl-fenyl)-6-prop-2-ynyloksy-1 -tiofen-2-ylmetyl-1H quinazolin-2-tion; 4-(4-Isopropyl-fenyl)-l-[2-(2-metoksy-etoksy)-pyridin-3-ylmetyl]-6-prop-2-ynyloksy-1 H-quinazolin-2-on; l-[6-(2-hydroksy-etoksy)-pyridin-2-ylmetyl]-4-(4-isopropyl-fenyl)-6-propargyloksy-1 H-quinazolin-2-on;
1 -[6-klor-pyridin-3-ylmetyl]-4-(4-isopropyl-fenyl)-6-propargyloksy-1 H-quinazolin-2-on;
1 - (2-Hydroksy-pyridin-3-ylmetyl)-4-(4-isopropy-fenyl)-6-propargyloksy-1H-quinazolin-2-on;
4-(4-Isopropyl-fenyl)-l-(5-metoksy-pyridin-2-ylmetyl)-6-propargyloksy-lH-quinazolin-2-on; 4-(4-Isopropyl-fenyl)-1 -(6-metyl-pyridin-2-ylmetyl)-6-propargyloksy-1 H-quinazolin-2-on;
1 -(2-klor-pyridin-4-ylmetyl)-4-(4-isopropyl-fenyl)-6-propargy loksy-1 H-quinazolin-2-on; l-(2-klor-pyridin-3-ylmetyl)-4-(4-isopropyl-fenyl)-6-propargyloksy-lH-quinazolin-2-on;
4-(4-Isopropyl-fenyl)-1 - {6-[2-(2-metoksy-etoksy)-etoksy]-pyridin-2-ylmetyl)-6-propargyloksy-1 H-quinazolin-2-on;
4- (4-Isopropyl-fenyl)-l-[6-(2-metoksy-etoksy)-etoksy)-pyirdin-2-ylmetyl)-6-propargyloksy-1 H-quinazolin-2-on;
5- Allyl-l-benzyl-6-hydroksy-4-(4-isopropyl-fenyl)-lH-quinazolin-2-on;
1 -[2-(3,5-Dimetoksy-fenyl)-etyl]-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1H-quinazolin-2-on; l-[2-Hydroksy-2-(2,4,6-trimetyl-fenyl)-etyl]-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1 H-quinazolin-2-on; 1-[2-(3,5-Difluor-fenyl)-2-hydroksy-etyl]-4-(4-isopropyl-fenyl)-6-prop-2-yny loksy-1H-quinazolin-2-on; 4-(4-Isopropyl-fenyl)-6-prop-2-ynyloksy-1 -[(E)-2-(2,4,6-trimetyl-fenyl)-vinyl]-1H-quinazolin-2-on;
4-(4-Isopropyl-fenyl)-6-prop-2-ynyloksy-1 -((E)-styryl)-1 H-quinazolin-2-on; l-[(E)-2-(3-klor-4-metoksy-fenyl)-vinyl]-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-lH-quinazolin-2-on; 1-[(E)-2-(3,5-Dimetyl-fenyl)-vinyl]-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1H-quinazolin-2-on; l-[3-(2-Hydroksy-etoksy)-benzyl]-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-lH-quinazolin-2 -tion;
1 -(3-Etoksy-4-metoksy-benzyl)-4-(4-isopropyl-fenyl)-6-prop-2-ynyloksy-1H-quinazolin-2-on; og
1 -(4-Brom-benzyl)-4-(4-isopropyl-fenyl)-6-propargyloksy-1 H-quinazolin-2-on;
eller en farmasøytisk akseptabel og spaltbar ester, eller syreaddisjonssalt derav.
2.
Forbindelse ifølge krav 1, for bruk som et legemiddel.
3.
Anvendelse av en forbindelse ifølge krav 1, for fremstilling av et medikament for å forebygge eller behandle bentilstander som er assosiert med økt kalsiumutarming eller resorpsjon eller hvori stimulering av bendannelse og kalsiumfiksering i benet er ønskelig; eller
for forebyggelse og behandling av osteoporose, juvenil osteoporose, menopausal osteoporose, post-menopausal osteoporose, post-traumatisk osteoporose, frakturerer, osteopati, osteo-malaci, periodontalt bentap eller bentap på grunn av artritt eller osteoartritt eller for behandling av hypoparatyroidisme.
4.
Farmasøytisk sammensetning for å forhindre eller behandle bentilstander som er assosiert med økt kalsiumutarming eller resorpsjon eller hvori stimulering av bendannelse og kalsiumfiksering i benet er ønskelig; eller
for forebyggelse og behandling av osteoporose, juvenil osteoporose, menopausal osteoporose, post-menopausal osteoporose, post-traumatisk osteoporose, frakturerer, osteopati, osteo-malaci, periodontalt bentap eller bentap på grunn av artritt eller osteoartritt eller for behandling av hypoparatyroidisme;
som omfatter en forbindelse ifølge krav 1 i blanding med en farmasøytisk akseptabel eksipient, fortynningsmiddel eller bærer.
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GBGB0230015.0A GB0230015D0 (en) | 2002-12-23 | 2002-12-23 | Organic compounds |
PCT/EP2003/014741 WO2004056365A2 (en) | 2002-12-23 | 2003-12-22 | Derivatives of aryl-quinazoline/aryl-2amino-phenyl methanone which promote the release of parathyroid hormone |
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US (2) | US7696216B2 (no) |
EP (2) | EP1844780A3 (no) |
JP (2) | JP4485956B2 (no) |
KR (2) | KR20070097136A (no) |
CN (2) | CN101445486A (no) |
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Families Citing this family (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AR038658A1 (es) | 2001-06-15 | 2005-01-26 | Novartis Ag | Derivados de 4-aril-2(1h) quinazolinona y 4-aril-quinazolina 2-sustituidas, un proceso para su preparacion, composiciones farmaceuticas y el uso de dichos derivados para la preparacion de un medicamento |
GB0230015D0 (en) * | 2002-12-23 | 2003-01-29 | Novartis Ag | Organic compounds |
PT1663182E (pt) | 2003-09-12 | 2013-03-14 | Amgen Inc | Formulação de dissolução rápida de cinacalcet hcl |
EP1671961A4 (en) * | 2003-09-17 | 2009-04-01 | Sumitomo Chemical Co | CINNAMOYL COMPOUND AND USE THEREOF |
GB0516723D0 (en) * | 2005-08-15 | 2005-09-21 | Novartis Ag | Organic compounds |
WO2008041118A2 (en) * | 2006-10-04 | 2008-04-10 | Pfizer Products Inc. | Pyrido[4,3-d]pyrimidin-4(3h)-one derivatives as calcium receptor antagonists |
EP1956019A1 (en) * | 2007-01-22 | 2008-08-13 | Novartis AG | Benzoquinazoline derivatives |
US7928111B2 (en) * | 2007-06-08 | 2011-04-19 | Senomyx, Inc. | Compounds including substituted thienopyrimidinone derivatives as ligands for modulating chemosensory receptors |
US9603848B2 (en) | 2007-06-08 | 2017-03-28 | Senomyx, Inc. | Modulation of chemosensory receptors and ligands associated therewith |
KR101523126B1 (ko) | 2008-07-31 | 2015-05-26 | 세노믹스, 인코포레이티드 | 단맛 향상제의 제조 방법 및 중간체 |
WO2010136035A2 (en) | 2009-05-27 | 2010-12-02 | Leo Pharma A/S | Novel calcium sensing receptor modulating compounds and pharmaceutical use thereof |
CA2762137A1 (en) | 2009-05-27 | 2010-12-02 | Leo Pharma A/S | Novel calcium sensing receptor modulating compounds and pharmaceutical use thereof |
EP2643291A2 (en) | 2010-11-26 | 2013-10-02 | Leo Pharma A/S | Calcium-sensing receptor-active compounds |
US20130261132A1 (en) | 2010-11-26 | 2013-10-03 | Leo Pharma A/S | Calcium-sensing receptor-active compounds |
CN103391920A (zh) | 2010-11-26 | 2013-11-13 | 利奥制药有限公司 | 钙敏感受体激活化合物 |
RU2013128950A (ru) | 2010-11-26 | 2015-01-10 | Лео Фарма А/С | Замещенные циклопентилазины в качестве casr-активных соединений |
CN104603132B (zh) | 2012-08-06 | 2020-02-21 | 弗门尼舍公司 | 甜味调节剂 |
CN103848781B (zh) * | 2012-11-30 | 2017-06-30 | 重庆华邦制药有限公司 | 高选择性氧化二羟甲基吡啶中一个羟甲基的方法 |
JO3155B1 (ar) | 2013-02-19 | 2017-09-20 | Senomyx Inc | معدِّل نكهة حلوة |
CN104387317B (zh) * | 2014-11-27 | 2017-05-10 | 安徽星宇化工有限公司 | 一种6‑氯烟酸的制备方法及分离纯化方法 |
MX2021001193A (es) | 2018-08-07 | 2021-04-28 | Firmenich Incorporated | 2,2-dioxidos de 4-amino-1h-benzo[c][1,2,6]tiadiazina 5-sustituidos y formulaciones y usos de los mismos. |
WO2021029517A1 (en) * | 2019-08-13 | 2021-02-18 | Dongguk University Industry-Academic Cooperation Foundation | Pharmaceutical composition for improving or treating post-surgical hypoparathyroidism and treatment method using the same |
CN113967249A (zh) * | 2021-12-10 | 2022-01-25 | 深圳先进技术研究院 | 甲状旁腺激素在制备治疗男性抑郁症的药物或保健品中的应用 |
CN116621719B (zh) * | 2022-04-02 | 2024-01-30 | 南京工业大学 | 一种应用于制备聚氨酯的全生物基芳基二胺扩链剂的合成方法 |
Family Cites Families (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB181570A (en) | 1921-05-07 | 1922-06-22 | Malcolm Beresford Bennett | Improvements in building blocks and in walls formed therewith |
US3305553A (en) * | 1965-10-18 | 1967-02-21 | Parke Davis & Co | 2-aminoquinazoline derivatives |
CH487902A (de) | 1966-08-29 | 1970-03-31 | Sandoz Ag | Verfahren zur Herstellung von neuen Chinazolinonen |
FR6001M (no) | 1966-12-02 | 1968-04-29 | ||
US3723432A (en) * | 1968-11-12 | 1973-03-27 | Sandoz Ag | 1-substituted-4-aryl-2(1h)-quinazolinones and their preparation |
BG16442A3 (bg) | 1967-10-30 | 1972-11-20 | Max Denzer | Метод за получаване на нови о-изопропиламинобензофенони |
US3712892A (en) | 1969-08-02 | 1973-01-23 | Sumitomo Chemical Co | Quinazolinone derivatives |
DE2137008A1 (de) * | 1970-10-21 | 1972-04-27 | Zellweger Uster Ag | Verfahren und Vorrichtung zur automatischen Ablesung von Informationsträgern an Gegenständen |
JPS5118423B1 (no) * | 1970-12-08 | 1976-06-09 | ||
BE790804A (fr) * | 1971-11-18 | 1973-04-30 | Sandoz Sa | Procede de preparation de derives de la quinazoline |
US3812257A (en) * | 1972-04-07 | 1974-05-21 | Sumitomo Chemical Co | Uricosuric agent |
JPS5418269B2 (no) * | 1972-07-20 | 1979-07-06 | ||
JPS555506B2 (no) * | 1972-09-07 | 1980-02-07 | ||
US4067868A (en) * | 1973-04-17 | 1978-01-10 | Sumitomo Chemical Company, Limited | Production of quinazolinone compounds |
JPS5046680A (no) * | 1973-08-20 | 1975-04-25 | ||
US3923003A (en) * | 1974-05-06 | 1975-12-02 | Southwire Co | Production of flooded multistrand cable |
JPS518287A (en) | 1974-07-13 | 1976-01-23 | Sumitomo Chemical Co | Kinazorinonjudotaioyobi sonoenno seizoho |
JPS5251379A (en) * | 1975-10-24 | 1977-04-25 | Sumitomo Chem Co Ltd | Preparation 3,4-dihydro-2(1h)-quinazoline derivates |
JPS5271483A (en) * | 1975-12-11 | 1977-06-14 | Sumitomo Chem Co Ltd | Synthesis of 2(1h)-quinazolinone derivatives |
CH625512A5 (no) * | 1976-12-13 | 1981-09-30 | Sandoz Ag | |
US4171441A (en) * | 1977-09-06 | 1979-10-16 | Sandoz, Inc. | Preparation of quinazolin-2(1H)-ones |
JPS55143959A (en) * | 1979-04-26 | 1980-11-10 | Shionogi & Co Ltd | 2-acylbenzcyanamide derivative |
JPS5795966A (en) | 1980-12-04 | 1982-06-15 | Sumitomo Chem Co Ltd | Novel 2(1h)-quinazolinone derivative |
JP3142638B2 (ja) * | 1991-06-21 | 2001-03-07 | 三井化学株式会社 | 感熱記録材料およびフェノール化合物 |
DE69422450T2 (de) | 1993-06-29 | 2000-06-08 | Takeda Chemical Industries Ltd | Chinoline oder Chinazolin-Derivate und deren Verwendung zur Herstellung eines Medikaments für die Behandlung von Osteoporose |
DE69533948T2 (de) * | 1994-10-21 | 2005-12-15 | NPS Pharmaceuticals, Inc., Salt Lake City | Kalzium-Rezeptor aktive Verbindungen |
US5773663A (en) * | 1996-05-01 | 1998-06-30 | American Cyanamid Company | Fungicidal methods, compounds and compositions containing benzophenones |
CN1244091C (zh) * | 1995-08-22 | 2006-03-01 | 松下电器产业株式会社 | 光盘记录和/或重放装置及设定记录功率及清除功率的方法 |
US6008230A (en) * | 1995-10-16 | 1999-12-28 | Fujisawa Pharmaceutical Co., Ltd. | Quinoline compounds as H+ -ATPases |
CA2190708A1 (en) * | 1995-12-08 | 1997-06-09 | Johannes Aebi | Aminoalkyl substituted benzo-heterocyclic compounds |
JPH11209350A (ja) | 1998-01-26 | 1999-08-03 | Eisai Co Ltd | 含窒素複素環誘導体およびその医薬 |
US6358959B1 (en) | 1999-01-26 | 2002-03-19 | Merck & Co., Inc. | Polyazanaphthalenone derivatives useful as alpha 1a adrenoceptor antagonists |
JP2001302515A (ja) | 2000-04-18 | 2001-10-31 | Sumitomo Pharmaceut Co Ltd | ポリ(adp−リボース)ポリメラーゼ阻害剤 |
AU2001293829A1 (en) * | 2000-09-25 | 2002-04-02 | Janssen Pharmaceutica N.V. | Farnesyl transferase inhibiting 6-((substituted phenyl)methyl)-quinoline and quinazoline derivatives |
DE10058347A1 (de) | 2000-11-23 | 2002-06-13 | Petra Bauersachs | Konvergenz-Boxen-Set |
AR038658A1 (es) * | 2001-06-15 | 2005-01-26 | Novartis Ag | Derivados de 4-aril-2(1h) quinazolinona y 4-aril-quinazolina 2-sustituidas, un proceso para su preparacion, composiciones farmaceuticas y el uso de dichos derivados para la preparacion de un medicamento |
GB0230015D0 (en) * | 2002-12-23 | 2003-01-29 | Novartis Ag | Organic compounds |
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2002
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2003
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