IL129243A

IL129243A - Vitronectin receptor antagonists, a process for their preparation, pharmaceutical preparations containing them and their use in the preparation of drugs in the treatment of bone thinning and prevention of vascular formation

Vitronectin receptor antagonists, a process for their preparation, pharmaceutical preparations containing them and their use in the preparation of drugs in the treatment of bone thinning and prevention of vascular formation

Info

Publication number: IL129243A
Authority: IL; Israel
Prior art keywords: benzazepine; oxo; tetrahydro; acetic acid; propyloxy
Prior art date: 1996-10-02

Application number

IL12924397A

Other languages

English (en)

Hebrew (he)

Other versions

IL129243A0 (en

Original Assignee

Smithkline Beecham Corp

Priority date

1996-10-02

Filing date

1997-10-01

Publication date

2004-07-25

1997-10-01 Application filed by Smithkline Beecham Corp filed Critical Smithkline Beecham Corp

2000-02-17 Publication of IL129243A0 publication Critical patent/IL129243A0/xx

2004-07-25 Publication of IL129243A publication Critical patent/IL129243A/en

Links

238000000034 method Methods 0.000 title claims description 110
238000011282 treatment Methods 0.000 title claims description 22
208000001132 Osteoporosis Diseases 0.000 title claims description 11
239000003814 drug Substances 0.000 title claims description 11
239000008194 pharmaceutical composition Substances 0.000 title claims description 9
230000008569 process Effects 0.000 title claims description 9
230000014399 negative regulation of angiogenesis Effects 0.000 title claims description 4
238000002360 preparation method Methods 0.000 title description 97
102100022337 Integrin alpha-V Human genes 0.000 title description 22
108010048673 Vitronectin Receptors Proteins 0.000 title description 22
239000002464 receptor antagonist Substances 0.000 title description 2
229940044551 receptor antagonist Drugs 0.000 title description 2
150000001875 compounds Chemical class 0.000 claims abstract description 312
-1 -OR11 Chemical group 0.000 claims abstract description 67
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 32
150000003839 salts Chemical class 0.000 claims abstract description 20
229910052757 nitrogen Inorganic materials 0.000 claims abstract description 17
229910052736 halogen Inorganic materials 0.000 claims abstract description 16
150000002367 halogens Chemical class 0.000 claims abstract description 16
102100025248 C-X-C motif chemokine 10 Human genes 0.000 claims abstract description 12
101000858088 Homo sapiens C-X-C motif chemokine 10 Proteins 0.000 claims abstract description 12
125000003118 aryl group Chemical group 0.000 claims abstract description 10
125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 claims abstract description 10
125000000623 heterocyclic group Chemical group 0.000 claims abstract description 10
229910052760 oxygen Inorganic materials 0.000 claims abstract description 10
125000001424 substituent group Chemical group 0.000 claims abstract description 10
229910052799 carbon Inorganic materials 0.000 claims abstract description 8
229910052717 sulfur Inorganic materials 0.000 claims abstract description 5
125000003831 tetrazolyl group Chemical group 0.000 claims abstract description 5
125000001475 halogen functional group Chemical group 0.000 claims abstract 8
QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 141
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 121
229910052786 argon Inorganic materials 0.000 claims description 42
229910052739 hydrogen Inorganic materials 0.000 claims description 25
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
125000006239 protecting group Chemical group 0.000 claims description 7
125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
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 5
238000004519 manufacturing process Methods 0.000 claims description 5
125000000524 functional group Chemical group 0.000 claims description 4
KSSPHFGIOASRDE-HNNXBMFYSA-N 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]acetic acid Chemical compound CNC1=CC=CC(CCOC=2C=C3CN(CC(F)(F)F)C(=O)[C@H](CC(O)=O)CC3=CC=2)=N1 KSSPHFGIOASRDE-HNNXBMFYSA-N 0.000 claims description 3
LTUYANUSXTXRJD-QFIPXVFZSA-N 2-[(4s)-8-[2-[6-(methylamino)pyridin-2-yl]ethoxy]-3-oxo-2-(2-phenylethyl)-4,5-dihydro-1h-2-benzazepin-4-yl]acetic acid Chemical compound CNC1=CC=CC(CCOC=2C=C3CN(CCC=4C=CC=CC=4)C(=O)[C@H](CC(O)=O)CC3=CC=2)=N1 LTUYANUSXTXRJD-QFIPXVFZSA-N 0.000 claims description 3
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 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
239000003937 drug carrier Substances 0.000 claims description 3
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 description 2
ALBSDNWEUVWZEI-FQEVSTJZSA-N 2-[(4s)-3-oxo-8-[3-(1,4,5,6-tetrahydropyrimidin-2-ylamino)propoxy]-2-[[4-(trifluoromethyl)phenyl]methyl]-4,5-dihydro-1h-2-benzazepin-4-yl]acetic acid Chemical compound C([C@H](C(N(CC=1C=CC(=CC=1)C(F)(F)F)CC1=C2)=O)CC(=O)O)C1=CC=C2OCCCNC1=NCCCN1 ALBSDNWEUVWZEI-FQEVSTJZSA-N 0.000 claims description 2
WKDQPUWEMPFLGV-FQEVSTJZSA-N 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]acetic acid Chemical compound CNC1=CC=CC(CCOC=2C=C3CN(CC=4C=CC(=CC=4)C(F)(F)F)C(=O)[C@H](CC(O)=O)CC3=CC=2)=N1 WKDQPUWEMPFLGV-FQEVSTJZSA-N 0.000 claims description 2
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 2
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 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
CUDGZLBNJBIXMF-UHFFFAOYSA-N 2-[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(CC(O)=O)CC3=CC=2)=C1 CUDGZLBNJBIXMF-UHFFFAOYSA-N 0.000 claims description 2
125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
JBWATVMHTWVORX-UHFFFAOYSA-N CC1NC(C(CC2=C1C=CC=C2)CC(=O)O)=O Chemical compound CC1NC(C(CC2=C1C=CC=C2)CC(=O)O)=O JBWATVMHTWVORX-UHFFFAOYSA-N 0.000 claims 1
125000004744 butyloxycarbonyl group Chemical group 0.000 claims 1
125000000217 alkyl group Chemical group 0.000 abstract description 23
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 abstract description 3
125000003545 alkoxy group Chemical group 0.000 abstract description 2
125000005021 aminoalkenyl group Chemical group 0.000 abstract description 2
125000005188 oxoalkyl group Chemical group 0.000 abstract description 2
125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 8
125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
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125000005014 aminoalkynyl group Chemical group 0.000 abstract 1
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125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 182
239000000243 solution Substances 0.000 description 155
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229960000583 acetic acid Drugs 0.000 description 104
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238000006243 chemical reaction Methods 0.000 description 102
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238000005481 NMR spectroscopy Methods 0.000 description 42
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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
OMPLBDGZJCWSQL-NRFANRHFSA-N methyl 2-[(4s)-3-oxo-8-[3-(1,4,5,6-tetrahydropyrimidin-2-ylamino)propoxy]-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=C2OCCCNC1=NCCCN1 OMPLBDGZJCWSQL-NRFANRHFSA-N 0.000 description 1
ZOWZGDYEHSINRS-KRWDZBQOSA-N methyl 2-[(4s)-3-oxo-8-[3-(pyridin-2-ylamino)propoxy]-2-(2,2,2-trifluoroethyl)-4,5-dihydro-1h-2-benzazepin-4-yl]acetate Chemical compound C([C@H](C(N(CC(F)(F)F)CC1=C2)=O)CC(=O)OC)C1=CC=C2OCCCNC1=CC=CC=N1 ZOWZGDYEHSINRS-KRWDZBQOSA-N 0.000 description 1
YWIRXTSRPYKJNO-NRFANRHFSA-N methyl 2-[(4s)-3-oxo-8-[3-(pyrimidin-2-ylamino)propoxy]-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=C2OCCCNC1=NC=CC=N1 YWIRXTSRPYKJNO-NRFANRHFSA-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
JUMCWOYFXDBBTI-SFHVURJKSA-N methyl 2-[(4s)-8-(3-aminopropoxy)-3-oxo-2-[[4-(trifluoromethyl)phenyl]methyl]-4,5-dihydro-1h-2-benzazepin-4-yl]acetate Chemical compound C([C@H](C1=O)CC(=O)OC)C2=CC=C(OCCCN)C=C2CN1CC1=CC=C(C(F)(F)F)C=C1 JUMCWOYFXDBBTI-SFHVURJKSA-N 0.000 description 1
DZDXMIPOOKZPKF-SFHVURJKSA-N methyl 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]acetate Chemical compound C([C@H](C(N(CC(F)(F)F)CC1=C2)=O)CC(=O)OC)C1=CC=C2OCCCNC1=CC(C)=CC=N1 DZDXMIPOOKZPKF-SFHVURJKSA-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
YVSMCLJLBFLFGK-KRWDZBQOSA-N methyl 2-[(4s)-8-hydroxy-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(O)C=C2CN1CCC1=CC=CC=C1 YVSMCLJLBFLFGK-KRWDZBQOSA-N 0.000 description 1
NDWSPVHHOTWHFE-NSHDSACASA-N methyl 2-[(4s)-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@H](CC(=O)OC)CC2=CC=C(OC)C=C21 NDWSPVHHOTWHFE-NSHDSACASA-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
YFKZIVYLONRCAV-UHFFFAOYSA-N methyl 2-[3-oxo-8-[3-(pyridin-2-ylamino)propoxy]-1,2,4,5-tetrahydro-2-benzazepin-4-yl]acetate Chemical compound C1=C2CNC(=O)C(CC(=O)OC)CC2=CC=C1OCCCNC1=CC=CC=N1 YFKZIVYLONRCAV-UHFFFAOYSA-N 0.000 description 1
ZOWZGDYEHSINRS-UHFFFAOYSA-N methyl 2-[3-oxo-8-[3-(pyridin-2-ylamino)propoxy]-2-(2,2,2-trifluoroethyl)-4,5-dihydro-1h-2-benzazepin-4-yl]acetate Chemical compound C1=C2CN(CC(F)(F)F)C(=O)C(CC(=O)OC)CC2=CC=C1OCCCNC1=CC=CC=N1 ZOWZGDYEHSINRS-UHFFFAOYSA-N 0.000 description 1
ACBRKNJCMOEUGV-UHFFFAOYSA-N methyl 2-[3-oxo-8-[3-(pyrimidin-2-ylamino)propoxy]-1,2,4,5-tetrahydro-2-benzazepin-4-yl]acetate Chemical compound C1=C2CNC(=O)C(CC(=O)OC)CC2=CC=C1OCCCNC1=NC=CC=N1 ACBRKNJCMOEUGV-UHFFFAOYSA-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
FZJXJGONQXSZKU-UHFFFAOYSA-N methyl 2-[8-[2-(1h-benzimidazol-2-yl)ethoxy]-3-oxo-1,2,4,5-tetrahydro-2-benzazepin-4-yl]acetate Chemical compound C1=C2CNC(=O)C(CC(=O)OC)CC2=CC=C1OCCC1=NC2=CC=CC=C2N1 FZJXJGONQXSZKU-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
LZHYQCLBPYYOLS-UHFFFAOYSA-N methyl 2-[8-[3-(4,5-dihydro-1h-imidazol-2-ylamino)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=NCCN1 LZHYQCLBPYYOLS-UHFFFAOYSA-N 0.000 description 1
JILRDIJMUXXSCC-UHFFFAOYSA-N methyl 2-[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 compound C1=C2CN(CC=3C=CC(=CC=3)C(F)(F)F)C(=O)C(CC(=O)OC)CC2=CC=C1OCCCN(C(=O)OC(C)(C)C)C1=CC=CC=N1 JILRDIJMUXXSCC-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
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