NO320194B1 - Vitronektin reseptor antagonister, anvendelse og fremstilling derav samt farmasoytisk sammensetning - Google Patents

Info

Publication number

NO320194B1

NO320194B1 NO19991590A NO991590A NO320194B1 NO 320194 B1 NO320194 B1 NO 320194B1 NO 19991590 A NO19991590 A NO 19991590A NO 991590 A NO991590 A NO 991590A NO 320194 B1 NO320194 B1 NO 320194B1

Authority

NO

Norway

Prior art keywords

tetrahydro

oxo

benzazepine

propyloxy

acetic acid

Prior art date

1996-10-02

Links

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• 239000008194 pharmaceutical composition Substances 0.000 title claims description 7
• 238000002360 preparation method Methods 0.000 title description 74
• 102100022337 Integrin alpha-V Human genes 0.000 title description 18
• 108010048673 Vitronectin Receptors Proteins 0.000 title description 18
• 239000002464 receptor antagonist Substances 0.000 title 1
• 229940044551 receptor antagonist Drugs 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims description 272
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 123
• 238000000034 method Methods 0.000 claims description 102
• QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 97
• 229910052786 argon Inorganic materials 0.000 claims description 44
• -1 (C1-C4)alkylsulfoxyl Chemical group 0.000 claims description 43
• 238000004519 manufacturing process Methods 0.000 claims description 27
• 229910052739 hydrogen Inorganic materials 0.000 claims description 20
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
• 125000000217 alkyl group Chemical group 0.000 claims description 14
• 150000003839 salts Chemical class 0.000 claims description 12
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 11
• DYNHKJQKKDPTMR-UHFFFAOYSA-N 2-(2,3,4,5-tetrahydro-1h-2-benzazepin-4-yl)acetic acid Chemical compound C1C(CC(=O)O)CNCC2=CC=CC=C21 DYNHKJQKKDPTMR-UHFFFAOYSA-N 0.000 claims description 10
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
• 229910052757 nitrogen Inorganic materials 0.000 claims description 9
• 229910052794 bromium Inorganic materials 0.000 claims description 7
• 229910052801 chlorine Inorganic materials 0.000 claims description 7
• 208000001132 Osteoporosis Diseases 0.000 claims description 6
• 239000003814 drug Substances 0.000 claims description 6
• 229910052731 fluorine Inorganic materials 0.000 claims description 6
• 229910052740 iodine Inorganic materials 0.000 claims description 6
• 125000001424 substituent group Chemical group 0.000 claims description 6
• 229910052799 carbon Inorganic materials 0.000 claims description 5
• 229940079593 drug Drugs 0.000 claims description 5
• 229910052736 halogen Inorganic materials 0.000 claims description 5
• 150000002367 halogens Chemical class 0.000 claims description 5
• 125000006239 protecting group Chemical group 0.000 claims description 5
• QPYGAAZQEFGBCP-UHFFFAOYSA-N 2-[2-[(4-aminophenyl)methyl]-3-oxo-8-[3-(pyridin-2-ylamino)propoxy]-4,5-dihydro-1h-2-benzazepin-4-yl]acetic acid Chemical compound C1=CC(N)=CC=C1CN1C(=O)C(CC(O)=O)CC2=CC=C(OCCCNC=3N=CC=CC=3)C=C2C1 QPYGAAZQEFGBCP-UHFFFAOYSA-N 0.000 claims description 4
• UIEMONZKDPCLPU-UHFFFAOYSA-N 2-[3-oxo-8-[3-(pyridin-2-ylamino)propoxy]-1,2,4,5-tetrahydro-2-benzazepin-4-yl]acetic acid Chemical compound C1=C2CNC(=O)C(CC(=O)O)CC2=CC=C1OCCCNC1=CC=CC=N1 UIEMONZKDPCLPU-UHFFFAOYSA-N 0.000 claims description 4
• URDYMLIOCMVKKV-UHFFFAOYSA-N 2-[8-[2-(1h-benzimidazol-2-yl)ethoxy]-3-oxo-1,2,4,5-tetrahydro-2-benzazepin-4-yl]acetic acid Chemical compound C1=C2CNC(=O)C(CC(=O)O)CC2=CC=C1OCCC1=NC2=CC=CC=C2N1 URDYMLIOCMVKKV-UHFFFAOYSA-N 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
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• 230000008569 process Effects 0.000 claims description 4
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
• CBJLRYOFGHMYQK-UHFFFAOYSA-N 2-[8-[3-(1h-imidazol-2-ylamino)propoxy]-3-oxo-1,2,4,5-tetrahydro-2-benzazepin-4-yl]acetic acid Chemical compound C1=C2CNC(=O)C(CC(=O)O)CC2=CC=C1OCCCNC1=NC=CN1 CBJLRYOFGHMYQK-UHFFFAOYSA-N 0.000 claims description 3
• HYQHGAJNOBGSCA-UHFFFAOYSA-N N1=CC=C(CC2=C1C=CC=C2)CC(=O)O Chemical compound N1=CC=C(CC2=C1C=CC=C2)CC(=O)O HYQHGAJNOBGSCA-UHFFFAOYSA-N 0.000 claims description 3
• 230000033115 angiogenesis Effects 0.000 claims description 3
• LGYHUVHIIJSDMP-UHFFFAOYSA-N 2-[3-oxo-8-[3-(pyrimidin-2-ylamino)propoxy]-1,2,4,5-tetrahydro-2-benzazepin-4-yl]acetic acid Chemical compound C1=C2CNC(=O)C(CC(=O)O)CC2=CC=C1OCCCNC1=NC=CC=N1 LGYHUVHIIJSDMP-UHFFFAOYSA-N 0.000 claims description 2
• DTUVSXXKDCPWGN-UHFFFAOYSA-N 2-[8-[3-(4,5-dihydro-1h-imidazol-2-ylamino)propoxy]-2-methyl-3-oxo-4,5-dihydro-1h-2-benzazepin-4-yl]acetic acid Chemical compound C=1C=C2CC(CC(O)=O)C(=O)N(C)CC2=CC=1OCCCNC1=NCCN1 DTUVSXXKDCPWGN-UHFFFAOYSA-N 0.000 claims description 2
• NSMTUKNNHXHRIB-UHFFFAOYSA-N 2-[8-[3-[(4,6-dimethylpyridin-2-yl)amino]propoxy]-2-methyl-3-oxo-4,5-dihydro-1h-2-benzazepin-4-yl]acetic acid Chemical compound C=1C=C2CC(CC(O)=O)C(=O)N(C)CC2=CC=1OCCCNC1=CC(C)=CC(C)=N1 NSMTUKNNHXHRIB-UHFFFAOYSA-N 0.000 claims description 2
• JYFKEXVYPPVSLX-UHFFFAOYSA-N 2-[8-[3-[(4-methoxypyridin-2-yl)amino]propoxy]-3-oxo-1,2,4,5-tetrahydro-2-benzazepin-4-yl]acetic acid Chemical compound COC1=CC=NC(NCCCOC=2C=C3CNC(=O)C(CC(O)=O)CC3=CC=2)=C1 JYFKEXVYPPVSLX-UHFFFAOYSA-N 0.000 claims description 2
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
• 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 claims description 2
• 230000002401 inhibitory effect Effects 0.000 claims description 2
• PVDGZHKJXXVONO-MRXNPFEDSA-N 2-[(4r)-3-oxo-8-[3-(pyridin-2-ylamino)propoxy]-2-(2,2,2-trifluoroethyl)-4,5-dihydro-1h-2-benzazepin-4-yl]acetic acid Chemical compound C([C@@H](C(N(CC(F)(F)F)CC1=C2)=O)CC(=O)O)C1=CC=C2OCCCNC1=CC=CC=N1 PVDGZHKJXXVONO-MRXNPFEDSA-N 0.000 claims 1
• CUDGZLBNJBIXMF-KRWDZBQOSA-N 2-[(4s)-8-[3-[(4-methylpyridin-2-yl)amino]propoxy]-3-oxo-2-(2,2,2-trifluoroethyl)-4,5-dihydro-1h-2-benzazepin-4-yl]acetic acid Chemical compound CC1=CC=NC(NCCCOC=2C=C3CN(CC(F)(F)F)C(=O)[C@H](CC(O)=O)CC3=CC=2)=C1 CUDGZLBNJBIXMF-KRWDZBQOSA-N 0.000 claims 1
• JUJDYKKIXFJQKW-UHFFFAOYSA-N 2-[3-oxo-8-[3-(1,4,5,6-tetrahydropyrimidin-2-ylamino)propoxy]-1,2,4,5-tetrahydro-2-benzazepin-4-yl]acetic acid Chemical compound C1=C2CNC(=O)C(CC(=O)O)CC2=CC=C1OCCCNC1=NCCCN1 JUJDYKKIXFJQKW-UHFFFAOYSA-N 0.000 claims 1
• PVDGZHKJXXVONO-UHFFFAOYSA-N 2-[3-oxo-8-[3-(pyridin-2-ylamino)propoxy]-2-(2,2,2-trifluoroethyl)-4,5-dihydro-1h-2-benzazepin-4-yl]acetic acid Chemical compound C1=C2CN(CC(F)(F)F)C(=O)C(CC(=O)O)CC2=CC=C1OCCCNC1=CC=CC=N1 PVDGZHKJXXVONO-UHFFFAOYSA-N 0.000 claims 1
• QXOPVSRJPCOUCJ-UHFFFAOYSA-N 2-[8-[3-[3,3-dimethylbutanoyl(pyridin-2-yl)amino]propoxy]-3-oxo-2-[[4-(trifluoromethyl)phenyl]methyl]-4,5-dihydro-1h-2-benzazepin-4-yl]acetic acid Chemical compound C=1C=CC=NC=1N(C(=O)CC(C)(C)C)CCCOC(C=C1C2)=CC=C1CC(CC(O)=O)C(=O)N2CC1=CC=C(C(F)(F)F)C=C1 QXOPVSRJPCOUCJ-UHFFFAOYSA-N 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 242
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 239
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 166
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 159
• 239000000243 solution Substances 0.000 description 151
• 235000019439 ethyl acetate Nutrition 0.000 description 107
• 238000006243 chemical reaction Methods 0.000 description 102
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 100
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 89
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 82
• 239000000203 mixture Substances 0.000 description 80
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• WYMBGZKYOCPSPU-OAHLLOKOSA-N methyl 2-[(4r)-8-[3-[(4-aminopyridin-2-yl)amino]propoxy]-3-oxo-1,2,4,5-tetrahydro-2-benzazepin-4-yl]acetate Chemical compound C([C@@H](C(NCC1=C2)=O)CC(=O)OC)C1=CC=C2OCCCNC1=CC(N)=CC=N1 WYMBGZKYOCPSPU-OAHLLOKOSA-N 0.000 description 1
• DNVBCJYLEUWACC-SECBINFHSA-N methyl 2-[(4r)-8-hydroxy-3-oxo-1,2,4,5-tetrahydro-2-benzazepin-4-yl]acetate Chemical compound C1NC(=O)[C@@H](CC(=O)OC)CC2=CC=C(O)C=C21 DNVBCJYLEUWACC-SECBINFHSA-N 0.000 description 1
• KHBKKNFOOBMFDN-DEOSSOPVSA-N methyl 2-[(4s)-3-oxo-2-(2-phenylethyl)-8-[3-(pyridin-2-ylamino)propoxy]-4,5-dihydro-1h-2-benzazepin-4-yl]acetate Chemical compound C([C@H](C(N(CCC=1C=CC=CC=1)CC1=C2)=O)CC(=O)OC)C1=CC=C2OCCCNC1=CC=CC=N1 KHBKKNFOOBMFDN-DEOSSOPVSA-N 0.000 description 1
• KIWDZMAJDQPBPT-NRFANRHFSA-N methyl 2-[(4s)-3-oxo-8-[[4-(trifluoromethyl)phenyl]methoxy]-2-[[4-(trifluoromethyl)phenyl]methyl]-4,5-dihydro-1h-2-benzazepin-4-yl]acetate Chemical compound C([C@H](C(N(CC=1C=CC(=CC=1)C(F)(F)F)CC1=C2)=O)CC(=O)OC)C1=CC=C2OCC1=CC=C(C(F)(F)F)C=C1 KIWDZMAJDQPBPT-NRFANRHFSA-N 0.000 description 1
• SCGBFQUOTIZFLZ-INIZCTEOSA-N methyl 2-[(4s)-8-[2-[6-(methylamino)pyridin-2-yl]ethoxy]-3-oxo-2-(2,2,2-trifluoroethyl)-4,5-dihydro-1h-2-benzazepin-4-yl]acetate Chemical compound CNC1=CC=CC(CCOC=2C=C3CN(CC(F)(F)F)C(=O)[C@H](CC(=O)OC)CC3=CC=2)=N1 SCGBFQUOTIZFLZ-INIZCTEOSA-N 0.000 description 1
• QXECIBGVADGKOC-QHCPKHFHSA-N methyl 2-[(4s)-8-[2-[6-(methylamino)pyridin-2-yl]ethoxy]-3-oxo-2-(2-phenylethyl)-4,5-dihydro-1h-2-benzazepin-4-yl]acetate Chemical compound CNC1=CC=CC(CCOC=2C=C3CN(CCC=4C=CC=CC=4)C(=O)[C@H](CC(=O)OC)CC3=CC=2)=N1 QXECIBGVADGKOC-QHCPKHFHSA-N 0.000 description 1
• YQGKSHJEPSPUAN-NRFANRHFSA-N methyl 2-[(4s)-8-[2-[6-(methylamino)pyridin-2-yl]ethoxy]-3-oxo-2-[[4-(trifluoromethyl)phenyl]methyl]-4,5-dihydro-1h-2-benzazepin-4-yl]acetate Chemical compound CNC1=CC=CC(CCOC=2C=C3CN(CC=4C=CC(=CC=4)C(F)(F)F)C(=O)[C@H](CC(=O)OC)CC3=CC=2)=N1 YQGKSHJEPSPUAN-NRFANRHFSA-N 0.000 description 1
• JILRDIJMUXXSCC-VWLOTQADSA-N methyl 2-[(4s)-8-[3-[(2-methylpropan-2-yl)oxycarbonyl-pyridin-2-ylamino]propoxy]-3-oxo-2-[[4-(trifluoromethyl)phenyl]methyl]-4,5-dihydro-1h-2-benzazepin-4-yl]acetate Chemical class C([C@H](C(N(CC=1C=CC(=CC=1)C(F)(F)F)CC1=C2)=O)CC(=O)OC)C1=CC=C2OCCCN(C(=O)OC(C)(C)C)C1=CC=CC=N1 JILRDIJMUXXSCC-VWLOTQADSA-N 0.000 description 1
• IWUCMTSBIKTGIS-DEOSSOPVSA-N methyl 2-[(4s)-8-[3-[(4-nitrophenyl)methoxycarbonylamino]propoxy]-3-oxo-2-[[4-(trifluoromethyl)phenyl]methyl]-4,5-dihydro-1h-2-benzazepin-4-yl]acetate Chemical compound C([C@H](C(N(CC=1C=CC(=CC=1)C(F)(F)F)CC1=C2)=O)CC(=O)OC)C1=CC=C2OCCCNC(=O)OCC1=CC=C([N+]([O-])=O)C=C1 IWUCMTSBIKTGIS-DEOSSOPVSA-N 0.000 description 1
• SFFLORBVBCOJJW-JTQLQIEISA-N methyl 2-[(4s)-8-hydroxy-2-methyl-3-oxo-4,5-dihydro-1h-2-benzazepin-4-yl]acetate Chemical compound C1N(C)C(=O)[C@H](CC(=O)OC)CC2=CC=C(O)C=C21 SFFLORBVBCOJJW-JTQLQIEISA-N 0.000 description 1
• QNNFQRACPNCRIL-SFHVURJKSA-N methyl 2-[(4s)-8-methoxy-3-oxo-2-(2-phenylethyl)-4,5-dihydro-1h-2-benzazepin-4-yl]acetate Chemical compound C([C@H](C1=O)CC(=O)OC)C2=CC=C(OC)C=C2CN1CCC1=CC=CC=C1 QNNFQRACPNCRIL-SFHVURJKSA-N 0.000 description 1
• KCKAGGQLHRMFEB-UHFFFAOYSA-N methyl 2-[8-(3-aminopropoxy)-3-oxo-1,2,4,5-tetrahydro-2-benzazepin-4-yl]acetate Chemical compound C1NC(=O)C(CC(=O)OC)CC2=CC=C(OCCCN)C=C21 KCKAGGQLHRMFEB-UHFFFAOYSA-N 0.000 description 1
• WSAHLSDLTJSZRT-UHFFFAOYSA-N methyl 2-[8-(3-aminopropoxy)-3-oxo-1,2,4,5-tetrahydro-2-benzazepin-4-yl]acetate 2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1NC(=O)C(CC(=O)OC)CC2=CC=C(OCCCN)C=C21 WSAHLSDLTJSZRT-UHFFFAOYSA-N 0.000 description 1
• HCOAGHSXSNNRLI-UHFFFAOYSA-N methyl 2-[8-[2-(2-amino-1,3-thiazol-4-yl)ethoxy]-2-methyl-3-oxo-4,5-dihydro-1h-2-benzazepin-4-yl]acetate Chemical compound C1=C2CN(C)C(=O)C(CC(=O)OC)CC2=CC=C1OCCC1=CSC(N)=N1 HCOAGHSXSNNRLI-UHFFFAOYSA-N 0.000 description 1
• SAYVBDJYDMVNKE-UHFFFAOYSA-N methyl 2-[8-[3-[(4-aminopyridin-2-yl)amino]propoxy]-2-methyl-3-oxo-4,5-dihydro-1h-2-benzazepin-4-yl]acetate Chemical compound C1=C2CN(C)C(=O)C(CC(=O)OC)CC2=CC=C1OCCCNC1=CC(N)=CC=N1 SAYVBDJYDMVNKE-UHFFFAOYSA-N 0.000 description 1
• WYMBGZKYOCPSPU-UHFFFAOYSA-N methyl 2-[8-[3-[(4-aminopyridin-2-yl)amino]propoxy]-3-oxo-1,2,4,5-tetrahydro-2-benzazepin-4-yl]acetate Chemical compound C1=C2CNC(=O)C(CC(=O)OC)CC2=CC=C1OCCCNC1=CC(N)=CC=N1 WYMBGZKYOCPSPU-UHFFFAOYSA-N 0.000 description 1
• OZOXAGROOHQETK-UHFFFAOYSA-N methyl 2-[8-[3-[(4-methoxypyridin-2-yl)amino]propoxy]-3-oxo-1,2,4,5-tetrahydro-2-benzazepin-4-yl]acetate Chemical compound C1=C2CNC(=O)C(CC(=O)OC)CC2=CC=C1OCCCNC1=CC(OC)=CC=N1 OZOXAGROOHQETK-UHFFFAOYSA-N 0.000 description 1
• DZDXMIPOOKZPKF-UHFFFAOYSA-N methyl 2-[8-[3-[(4-methylpyridin-2-yl)amino]propoxy]-3-oxo-2-(2,2,2-trifluoroethyl)-4,5-dihydro-1h-2-benzazepin-4-yl]acetate Chemical class C1=C2CN(CC(F)(F)F)C(=O)C(CC(=O)OC)CC2=CC=C1OCCCNC1=CC(C)=CC=N1 DZDXMIPOOKZPKF-UHFFFAOYSA-N 0.000 description 1
• YVJPNBILAQNTNW-UHFFFAOYSA-N methyl 2-[8-[3-[2-methylpropoxycarbonyl(pyridin-2-yl)amino]propoxy]-3-oxo-2-[[4-(trifluoromethyl)phenyl]methyl]-4,5-dihydro-1h-2-benzazepin-4-yl]acetate Chemical class C1=C2CN(CC=3C=CC(=CC=3)C(F)(F)F)C(=O)C(CC(=O)OC)CC2=CC=C1OCCCN(C(=O)OCC(C)C)C1=CC=CC=N1 YVJPNBILAQNTNW-UHFFFAOYSA-N 0.000 description 1
• HBWGJDYATCLISW-UHFFFAOYSA-N methyl 2-[8-[3-[benzoyl(pyridin-2-yl)amino]propoxy]-3-oxo-2-[[4-(trifluoromethyl)phenyl]methyl]-4,5-dihydro-1h-2-benzazepin-4-yl]acetate Chemical compound C1=C2CN(CC=3C=CC(=CC=3)C(F)(F)F)C(=O)C(CC(=O)OC)CC2=CC=C1OCCCN(C=1N=CC=CC=1)C(=O)C1=CC=CC=C1 HBWGJDYATCLISW-UHFFFAOYSA-N 0.000 description 1
• NDWSPVHHOTWHFE-UHFFFAOYSA-N methyl 2-[8-methoxy-3-oxo-2-(2,2,2-trifluoroethyl)-4,5-dihydro-1h-2-benzazepin-4-yl]acetate Chemical compound C1N(CC(F)(F)F)C(=O)C(CC(=O)OC)CC2=CC=C(OC)C=C21 NDWSPVHHOTWHFE-UHFFFAOYSA-N 0.000 description 1
• DCSIJTCHDZCROE-UHFFFAOYSA-N methyl 3-[4-methoxy-2-[[(2-methylpropan-2-yl)oxycarbonyl-(2,2,2-trifluoroethyl)amino]methyl]phenyl]prop-2-enoate Chemical compound COC(=O)C=CC1=CC=C(OC)C=C1CN(CC(F)(F)F)C(=O)OC(C)(C)C DCSIJTCHDZCROE-UHFFFAOYSA-N 0.000 description 1
• MGPZFOCWWJCGED-UHFFFAOYSA-N methyl 3-[4-methoxy-2-[[(2-methylpropan-2-yl)oxycarbonyl-[[4-(trifluoromethyl)phenyl]methyl]amino]methyl]phenyl]prop-2-enoate Chemical compound COC(=O)C=CC1=CC=C(OC)C=C1CN(C(=O)OC(C)(C)C)CC1=CC=C(C(F)(F)F)C=C1 MGPZFOCWWJCGED-UHFFFAOYSA-N 0.000 description 1
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