NO965608L - Vitronectin-reseptor-antagonister - Google Patents
Vitronectin-reseptor-antagonisterInfo
- Publication number
- NO965608L NO965608L NO965608A NO965608A NO965608L NO 965608 L NO965608 L NO 965608L NO 965608 A NO965608 A NO 965608A NO 965608 A NO965608 A NO 965608A NO 965608 L NO965608 L NO 965608L
- Authority
- NO
- Norway
- Prior art keywords
- methyl
- tetrahydro
- oxo
- benzodiazepine
- acetic acid
- Prior art date
Links
- 102100022337 Integrin alpha-V Human genes 0.000 title claims description 30
- 108010048673 Vitronectin Receptors Proteins 0.000 title claims description 30
- 229940044551 receptor antagonist Drugs 0.000 title description 3
- 239000002464 receptor antagonist Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 397
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 217
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 179
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 173
- 238000000034 method Methods 0.000 claims description 127
- -1 methylenedioxy Chemical group 0.000 claims description 120
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 116
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 83
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 74
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 44
- 239000002319 fibrinogen receptor antagonist Substances 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 229910052799 carbon Inorganic materials 0.000 claims description 24
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 23
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 19
- 108010012088 Fibrinogen Receptors Proteins 0.000 claims description 18
- 208000006386 Bone Resorption Diseases 0.000 claims description 16
- 230000024279 bone resorption Effects 0.000 claims description 16
- 229910052794 bromium Inorganic materials 0.000 claims description 16
- 229910052801 chlorine Inorganic materials 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 229910052731 fluorine Inorganic materials 0.000 claims description 15
- 229910052740 iodine Inorganic materials 0.000 claims description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 10
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 10
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 9
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 9
- 125000002883 imidazolyl group Chemical group 0.000 claims description 9
- 229920006395 saturated elastomer Polymers 0.000 claims description 9
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 8
- 201000001320 Atherosclerosis Diseases 0.000 claims description 8
- 208000001132 Osteoporosis Diseases 0.000 claims description 8
- 208000037803 restenosis Diseases 0.000 claims description 8
- 150000001413 amino acids Chemical class 0.000 claims description 7
- 125000003277 amino group Chemical group 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- MLMRQNDTWXKKFK-UHFFFAOYSA-N 2-(2,3,4,5-tetrahydro-1h-1,4-benzodiazepin-2-yl)acetic acid Chemical compound N1C(CC(=O)O)CNCC2=CC=CC=C21 MLMRQNDTWXKKFK-UHFFFAOYSA-N 0.000 claims description 5
- JOJRHLPVZFQAAL-UHFFFAOYSA-N 2-[4-[2-[1h-benzimidazol-2-ylmethyl(methyl)amino]acetyl]-2-(carboxymethoxy)phenoxy]acetic acid Chemical compound N=1C2=CC=CC=C2NC=1CN(C)CC(=O)C1=CC=C(OCC(O)=O)C(OCC(O)=O)=C1 JOJRHLPVZFQAAL-UHFFFAOYSA-N 0.000 claims description 5
- LNTBKZPJLLEDQN-UHFFFAOYSA-N 3-[4-(1H-benzimidazol-2-ylmethylcarbamoyl)anilino]propanoic acid Chemical compound C1=CC(NCCC(=O)O)=CC=C1C(=O)NCC1=NC2=CC=CC=C2N1 LNTBKZPJLLEDQN-UHFFFAOYSA-N 0.000 claims description 5
- 206010061218 Inflammation Diseases 0.000 claims description 5
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 5
- 230000004054 inflammatory process Effects 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- FEFLOAZOBWIBLS-UHFFFAOYSA-N 2-[4-[2-[[1-(1h-benzimidazol-2-ylmethyl)benzimidazol-2-yl]methyl-methylamino]acetyl]phenoxy]acetic acid Chemical compound N=1C2=CC=CC=C2N(CC=2NC3=CC=CC=C3N=2)C=1CN(C)CC(=O)C1=CC=C(OCC(O)=O)C=C1 FEFLOAZOBWIBLS-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- WYYLCRHWQCODSD-QGZVFWFLSA-N 2-[(2r)-7-(1h-benzimidazol-2-ylmethylcarbamoyl)-4-methyl-3-oxo-2,5-dihydro-1h-1,4-benzodiazepin-2-yl]acetic acid Chemical compound N1[C@H](CC(O)=O)C(=O)N(C)CC2=CC(C(=O)NCC=3NC4=CC=CC=C4N=3)=CC=C21 WYYLCRHWQCODSD-QGZVFWFLSA-N 0.000 claims description 3
- WYYLCRHWQCODSD-KRWDZBQOSA-N 2-[(2s)-7-(1h-benzimidazol-2-ylmethylcarbamoyl)-4-methyl-3-oxo-2,5-dihydro-1h-1,4-benzodiazepin-2-yl]acetic acid Chemical compound N1[C@@H](CC(O)=O)C(=O)N(C)CC2=CC(C(=O)NCC=3NC4=CC=CC=C4N=3)=CC=C21 WYYLCRHWQCODSD-KRWDZBQOSA-N 0.000 claims description 3
- WYYLCRHWQCODSD-UHFFFAOYSA-N 2-[7-(1h-benzimidazol-2-ylmethylcarbamoyl)-4-methyl-3-oxo-2,5-dihydro-1h-1,4-benzodiazepin-2-yl]acetic acid Chemical compound N1C(CC(O)=O)C(=O)N(C)CC2=CC(C(=O)NCC=3NC4=CC=CC=C4N=3)=CC=C21 WYYLCRHWQCODSD-UHFFFAOYSA-N 0.000 claims description 3
- LCZBUTQADYURRB-UHFFFAOYSA-N 2-[7-(1h-imidazol-2-ylmethylcarbamoyl)-4-methyl-3-oxo-2,5-dihydro-1h-1,4-benzodiazepin-2-yl]acetic acid Chemical compound C=1C=C2NC(CC(O)=O)C(=O)N(C)CC2=CC=1C(=O)NCC1=NC=CN1 LCZBUTQADYURRB-UHFFFAOYSA-N 0.000 claims description 3
- GIAPXKSBPIKYHI-UHFFFAOYSA-N 2-[7-[2-(1h-benzimidazol-2-yl)ethylcarbamoyl]-4-methyl-3-oxo-2,5-dihydro-1h-1,4-benzodiazepin-2-yl]acetic acid Chemical compound N1C(CC(O)=O)C(=O)N(C)CC2=CC(C(=O)NCCC=3NC4=CC=CC=C4N=3)=CC=C21 GIAPXKSBPIKYHI-UHFFFAOYSA-N 0.000 claims description 3
- PYCLAYQBWVPTTO-UHFFFAOYSA-N 2-[8-[1h-benzimidazol-2-ylmethyl(methyl)carbamoyl]-4-methyl-3-oxo-2,5-dihydro-1h-2-benzazepin-4-yl]acetic acid Chemical compound C1C(C)(CC(O)=O)C(=O)NCC2=CC(C(=O)N(CC=3NC4=CC=CC=C4N=3)C)=CC=C21 PYCLAYQBWVPTTO-UHFFFAOYSA-N 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- RBDLXBRHTIJMGZ-UHFFFAOYSA-N 2-[4-methyl-7-[methyl-[(4-methyl-1h-benzimidazol-2-yl)methyl]carbamoyl]-3-oxo-2,5-dihydro-1h-1,4-benzodiazepin-2-yl]acetic acid Chemical compound N1C(CC(O)=O)C(=O)N(C)CC2=CC(C(=O)N(CC=3NC4=CC=CC(C)=C4N=3)C)=CC=C21 RBDLXBRHTIJMGZ-UHFFFAOYSA-N 0.000 claims description 2
- OPUQBUMGBDMYAS-UHFFFAOYSA-N 2-[7-(1h-benzimidazol-2-ylcarbamoyl)-4-methyl-3-oxo-2,5-dihydro-1h-1,4-benzodiazepin-2-yl]acetic acid Chemical compound N1C(CC(O)=O)C(=O)N(C)CC2=CC(C(=O)NC=3NC4=CC=CC=C4N=3)=CC=C21 OPUQBUMGBDMYAS-UHFFFAOYSA-N 0.000 claims description 2
- FZAFVZGCFVREAA-UHFFFAOYSA-N 2-[7-(1h-benzimidazol-2-ylmethylcarbamoyl)-3-oxo-4-(2-phenylethyl)-2,5-dihydro-1h-1,4-benzodiazepin-2-yl]acetic acid Chemical compound O=C1C(CC(=O)O)NC2=CC=C(C(=O)NCC=3NC4=CC=CC=C4N=3)C=C2CN1CCC1=CC=CC=C1 FZAFVZGCFVREAA-UHFFFAOYSA-N 0.000 claims description 2
- ZKSIEMHDCDZHLO-UHFFFAOYSA-N 2-[7-(1h-benzimidazol-2-ylmethylcarbamoyl)-3-oxo-4-propan-2-yl-2,5-dihydro-1h-1,4-benzodiazepin-2-yl]acetic acid Chemical compound N1C(CC(O)=O)C(=O)N(C(C)C)CC2=CC(C(=O)NCC=3NC4=CC=CC=C4N=3)=CC=C21 ZKSIEMHDCDZHLO-UHFFFAOYSA-N 0.000 claims description 2
- FJPILIACOVQVRI-UHFFFAOYSA-N 2-[7-(1h-benzimidazol-2-ylmethylcarbamoyl)-9-chloro-4-methyl-3-oxo-2,5-dihydro-1h-1,4-benzodiazepin-2-yl]acetic acid Chemical compound N1C(CC(O)=O)C(=O)N(C)CC2=CC(C(=O)NCC=3NC4=CC=CC=C4N=3)=CC(Cl)=C21 FJPILIACOVQVRI-UHFFFAOYSA-N 0.000 claims description 2
- FDQVMDPICMDAJW-UHFFFAOYSA-N 2-[7-(1h-imidazol-2-ylmethylcarbamoyl)-3-oxo-4-(2-phenylethyl)-2,5-dihydro-1h-1,4-benzodiazepin-2-yl]acetic acid Chemical compound O=C1C(CC(=O)O)NC2=CC=C(C(=O)NCC=3NC=CN=3)C=C2CN1CCC1=CC=CC=C1 FDQVMDPICMDAJW-UHFFFAOYSA-N 0.000 claims description 2
- XBMJVWUOFFUGHP-UHFFFAOYSA-N 2-[7-[(1h-benzimidazol-2-ylmethylamino)methyl]-4-methyl-3-oxo-2,5-dihydro-1h-1,4-benzodiazepin-2-yl]acetic acid Chemical compound N1C(CC(O)=O)C(=O)N(C)CC2=CC(CNCC=3NC4=CC=CC=C4N=3)=CC=C21 XBMJVWUOFFUGHP-UHFFFAOYSA-N 0.000 claims description 2
- JQCFTWVYYDQFDG-UHFFFAOYSA-N 2-[7-[1h-benzimidazol-2-ylmethyl(methyl)carbamoyl]-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-2-yl]acetic acid Chemical compound N1C(CC(O)=O)C(=O)NCC2=CC(C(=O)N(CC=3NC4=CC=CC=C4N=3)C)=CC=C21 JQCFTWVYYDQFDG-UHFFFAOYSA-N 0.000 claims description 2
- BXJLQGWJERMQBC-UHFFFAOYSA-N 2-[7-[1h-benzimidazol-2-ylmethyl(methyl)carbamoyl]-3-oxo-4-(2-phenylethyl)-2,5-dihydro-1h-1,4-benzodiazepin-2-yl]acetic acid Chemical compound N=1C2=CC=CC=C2NC=1CN(C)C(=O)C(C=C1C2)=CC=C1NC(CC(O)=O)C(=O)N2CCC1=CC=CC=C1 BXJLQGWJERMQBC-UHFFFAOYSA-N 0.000 claims description 2
- PIFPXAMHHDLRCN-UHFFFAOYSA-N 2-[7-[2-(1H-indol-3-yl)ethylcarbamoyl]-4-methyl-3-oxo-2,5-dihydro-1H-1,4-benzodiazepin-2-yl]acetic acid Chemical compound N1C(CC(O)=O)C(=O)N(C)CC2=CC(C(=O)NCCC=3C4=CC=CC=C4NC=3)=CC=C21 PIFPXAMHHDLRCN-UHFFFAOYSA-N 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 101000957333 Homo sapiens Muscleblind-like protein 3 Proteins 0.000 claims description 2
- 102100038751 Muscleblind-like protein 3 Human genes 0.000 claims description 2
- 239000007983 Tris buffer Substances 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 2
- ZIAZQJYMSJNRNQ-UHFFFAOYSA-N 2-[4-methyl-7-[[2-(1-methylbenzimidazol-2-yl)-1H-benzimidazol-4-yl]methylcarbamoyl]-3-oxo-2,5-dihydro-1H-1,4-benzodiazepin-2-yl]acetic acid Chemical compound N1C(CC(O)=O)C(=O)N(C)CC2=CC(C(=O)NCC=3C=4N=C(NC=4C=CC=3)C=3N(C4=CC=CC=C4N=3)C)=CC=C21 ZIAZQJYMSJNRNQ-UHFFFAOYSA-N 0.000 claims 1
- ACQFDANLKVBDHN-UHFFFAOYSA-N 2-[8-(1h-benzimidazol-2-ylmethylcarbamoyl)-2-methyl-3-oxo-4,5-dihydro-1h-2-benzazepin-4-yl]acetic acid Chemical compound C1C(CC(O)=O)C(=O)N(C)CC2=CC(C(=O)NCC=3NC4=CC=CC=C4N=3)=CC=C21 ACQFDANLKVBDHN-UHFFFAOYSA-N 0.000 claims 1
- CKIMFJKYCCXDHI-UHFFFAOYSA-N 2-[8-[[2-(1H-benzimidazol-2-yl)acetyl]amino]-2-methyl-3-oxo-4,5-dihydro-1H-2-benzazepin-4-yl]acetic acid Chemical compound C1C(CC(O)=O)C(=O)N(C)CC2=CC(NC(=O)CC=3NC4=CC=CC=C4N=3)=CC=C21 CKIMFJKYCCXDHI-UHFFFAOYSA-N 0.000 claims 1
- 101100277337 Arabidopsis thaliana DDM1 gene Proteins 0.000 claims 1
- 241000124008 Mammalia Species 0.000 claims 1
- 101150113676 chr1 gene Proteins 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 487
- 239000000243 solution Substances 0.000 description 158
- 238000005481 NMR spectroscopy Methods 0.000 description 147
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 141
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 139
- 239000011541 reaction mixture Substances 0.000 description 136
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 132
- 239000000203 mixture Substances 0.000 description 130
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 108
- 239000000460 chlorine Substances 0.000 description 97
- 239000007787 solid Substances 0.000 description 97
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 90
- 229910001868 water Inorganic materials 0.000 description 83
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 78
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 75
- 238000006243 chemical reaction Methods 0.000 description 75
- 238000002360 preparation method Methods 0.000 description 75
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 70
- 235000019439 ethyl acetate Nutrition 0.000 description 69
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 68
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 64
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 64
- 238000004458 analytical method Methods 0.000 description 60
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 58
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 56
- 239000000741 silica gel Substances 0.000 description 53
- 229910002027 silica gel Inorganic materials 0.000 description 53
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 51
- 239000003921 oil Substances 0.000 description 50
- 235000019198 oils Nutrition 0.000 description 50
- 229960000583 acetic acid Drugs 0.000 description 49
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 43
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 38
- 239000000706 filtrate Substances 0.000 description 38
- IYMAXBFPHPZYIK-BQBZGAKWSA-N Arg-Gly-Asp Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IYMAXBFPHPZYIK-BQBZGAKWSA-N 0.000 description 36
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 34
- 238000004587 chromatography analysis Methods 0.000 description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- 239000002904 solvent Substances 0.000 description 33
- 239000002244 precipitate Substances 0.000 description 31
- 229910052786 argon Inorganic materials 0.000 description 28
- 210000004027 cell Anatomy 0.000 description 26
- 238000001035 drying Methods 0.000 description 26
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 24
- 238000001914 filtration Methods 0.000 description 23
- 238000010898 silica gel chromatography Methods 0.000 description 22
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 21
- 239000002253 acid Substances 0.000 description 21
- 239000000843 powder Substances 0.000 description 21
- 239000012044 organic layer Substances 0.000 description 20
- 239000011734 sodium Substances 0.000 description 20
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 20
- 238000003818 flash chromatography Methods 0.000 description 19
- 239000006260 foam Substances 0.000 description 19
- 210000002997 osteoclast Anatomy 0.000 description 19
- 235000002639 sodium chloride Nutrition 0.000 description 19
- 239000000725 suspension Substances 0.000 description 19
- 108010072041 arginyl-glycyl-aspartic acid Proteins 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- 238000004809 thin layer chromatography Methods 0.000 description 18
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 17
- 239000012267 brine Substances 0.000 description 17
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
- 239000012362 glacial acetic acid Substances 0.000 description 16
- 239000011521 glass Substances 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- 239000010410 layer Substances 0.000 description 16
- 101000781681 Protobothrops flavoviridis Disintegrin triflavin Proteins 0.000 description 15
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 15
- 238000010992 reflux Methods 0.000 description 15
- DPVHGVQSAWATDG-UHFFFAOYSA-N 2-(2-methoxy-2-oxoethyl)-4-methyl-3-oxo-2,5-dihydro-1h-1,4-benzodiazepine-7-carboxylic acid Chemical compound C1N(C)C(=O)C(CC(=O)OC)NC2=CC=C(C(O)=O)C=C21 DPVHGVQSAWATDG-UHFFFAOYSA-N 0.000 description 14
- 101001068640 Nicotiana tabacum Basic form of pathogenesis-related protein 1 Proteins 0.000 description 14
- 239000000872 buffer Substances 0.000 description 14
- 239000003054 catalyst Substances 0.000 description 14
- 238000001816 cooling Methods 0.000 description 14
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 14
- 239000000463 material Substances 0.000 description 13
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- 229960002180 tetracycline Drugs 0.000 description 1
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- 150000003522 tetracyclines Chemical class 0.000 description 1
- ZXLDQJLIBNPEFJ-UHFFFAOYSA-N tetrahydro-beta-carboline Natural products C1CNC(C)C2=C1C1=CC=C(OC)C=C1N2 ZXLDQJLIBNPEFJ-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/14—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Vascular Medicine (AREA)
- Pain & Pain Management (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US26769594A | 1994-06-29 | 1994-06-29 | |
US42893395A | 1995-04-25 | 1995-04-25 | |
PCT/US1995/008306 WO1996000730A1 (en) | 1994-06-29 | 1995-06-29 | Vitronectin receptor antagonists |
Publications (2)
Publication Number | Publication Date |
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NO965608D0 NO965608D0 (no) | 1996-12-27 |
NO965608L true NO965608L (no) | 1997-02-27 |
Family
ID=26952569
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO965608A NO965608L (no) | 1994-06-29 | 1996-12-27 | Vitronectin-reseptor-antagonister |
Country Status (13)
Country | Link |
---|---|
EP (1) | EP0767792A4 (hu) |
JP (1) | JPH10504808A (hu) |
CN (1) | CN1156995A (hu) |
AU (1) | AU702661B2 (hu) |
BR (1) | BR9508178A (hu) |
CA (1) | CA2193966A1 (hu) |
CZ (1) | CZ382496A3 (hu) |
HU (1) | HUT76344A (hu) |
MX (1) | MX9700041A (hu) |
NO (1) | NO965608L (hu) |
NZ (3) | NZ290008A (hu) |
PL (1) | PL318199A1 (hu) |
WO (1) | WO1996000730A1 (hu) |
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MX9801716A (es) * | 1995-08-30 | 1998-05-31 | Searle & Co | Derivados de meta-guanidina, urea, tiourea o acido aminobenzoico azaciclico, como antagonistas de integrina. |
US6100423A (en) * | 1995-08-30 | 2000-08-08 | G. D. Searle & Co. | Amino benzenepropanoic acid compounds and derivatives thereof |
US6011029A (en) * | 1996-02-26 | 2000-01-04 | Bristol-Myers Squibb Company | Inhibitors of farnesyl protein transferase |
EP0796855B1 (de) | 1996-03-20 | 2002-02-06 | Hoechst Aktiengesellschaft | Inhibitoren der Knochenresorption und Vitronectinrezeptor-Antagonisten |
DE19629816A1 (de) | 1996-07-24 | 1998-01-29 | Hoechst Ag | Neue Cycloalkyl-Derivate als Inhibitoren der Knochenresorption und Vitronectinrezeptor-Antagonisten |
DE19629817A1 (de) * | 1996-07-24 | 1998-01-29 | Hoechst Ag | Neue Imino-Derivate als Inhibitoren der Knochenresorption und Vitronectinrezeptor-Antagonisten |
UA60311C2 (uk) * | 1996-10-02 | 2003-10-15 | Смітклайн Бічам Корпорейшн | Антагоністи рецептора вітронектину, спосіб одержання цих сполук та фармацевтична композиція |
JP2001501951A (ja) * | 1996-10-07 | 2001-02-13 | スミスクライン・ビーチャム・コーポレイション | 骨形成刺激方法 |
DE19653647A1 (de) * | 1996-12-20 | 1998-06-25 | Hoechst Ag | Vitronectin - Rezeptorantagonisten, deren Herstellung sowie deren Verwendung |
DE19653646A1 (de) * | 1996-12-20 | 1998-06-25 | Hoechst Ag | Substituierte Purinderivate, Verfahren zu deren Herstellung, sie enthaltende Mittel und deren Verwendung |
US6218387B1 (en) | 1996-12-20 | 2001-04-17 | Hoechst Aktiengesellschaft | Vitronectin receptor anatagonists, their preparation and their use |
DE19653645A1 (de) * | 1996-12-20 | 1998-06-25 | Hoechst Ag | Vitronectin - Rezeptorantagonisten, deren Herstellung sowie deren Verwendung |
US6482821B2 (en) | 1996-12-20 | 2002-11-19 | Hoechst Aktiengellschaft | Vitronectin receptor antagonists, their preparation and their use |
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US6548663B1 (en) | 1998-03-31 | 2003-04-15 | Bristol-Myers Squibb Pharma Company | Benzodiazepine vitronectin receptor antagonist pharmaceuticals |
EP1054871A2 (en) | 1998-04-01 | 2000-11-29 | Du Pont Pharmaceuticals Company | Pyrimidines and triazines as integrin antagonists |
US6228985B1 (en) | 1998-05-21 | 2001-05-08 | Schering Corporation | Derivatives of aminobenzoic and aminobiphenylcarboxylic acids useful as anti-cancer agents |
CZ20004568A3 (cs) * | 1998-06-12 | 2001-11-14 | Societe De Conseils De Recherches Et D'application | Sloučenina imidazolylu, farmaceutický prostředek a způsob výroby |
KR20010086355A (ko) * | 1998-08-07 | 2001-09-10 | 스튜어트 알. 수터, 스티븐 베네티아너, 피터 존 기딩스 | 비트로넥틴 수용체 길항제 |
DE19842415A1 (de) | 1998-09-16 | 2000-03-23 | Merck Patent Gmbh | Pharmazeutische Zubereitung |
US6160099A (en) * | 1998-11-24 | 2000-12-12 | Jonak; Zdenka Ludmila | Anti-human αv β3 and αv β5 antibodies |
US6204282B1 (en) | 1998-11-30 | 2001-03-20 | Schering Corporation | Benzimidazole compounds that are vitronectin receptor antagonists |
CN1161340C (zh) * | 1998-11-30 | 2004-08-11 | 先灵公司 | 为玻连蛋白受体拮抗剂的苯并咪唑化合物 |
US6339083B1 (en) | 1998-12-14 | 2002-01-15 | Bayer Aktiengesellschaft | Multiheterocyclic pharmAceuticals |
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US6271241B1 (en) | 1999-04-02 | 2001-08-07 | Neurogen Corporation | Cycloalkyl and aryl fused aminoalkyl-imidazole derivatives: modulators and GLP-1 receptors |
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-
1995
- 1995-06-29 JP JP8503462A patent/JPH10504808A/ja not_active Ceased
- 1995-06-29 BR BR9508178A patent/BR9508178A/pt not_active Application Discontinuation
- 1995-06-29 PL PL95318199A patent/PL318199A1/xx unknown
- 1995-06-29 CZ CZ963824A patent/CZ382496A3/cs unknown
- 1995-06-29 CA CA002193966A patent/CA2193966A1/en not_active Abandoned
- 1995-06-29 EP EP95926152A patent/EP0767792A4/en not_active Withdrawn
- 1995-06-29 NZ NZ290008A patent/NZ290008A/en unknown
- 1995-06-29 CN CN95194853A patent/CN1156995A/zh active Pending
- 1995-06-29 MX MX9700041A patent/MX9700041A/es unknown
- 1995-06-29 AU AU30010/95A patent/AU702661B2/en not_active Ceased
- 1995-06-29 HU HU9603525A patent/HUT76344A/hu unknown
- 1995-06-29 WO PCT/US1995/008306 patent/WO1996000730A1/en not_active Application Discontinuation
-
1996
- 1996-12-27 NO NO965608A patent/NO965608L/no unknown
-
1998
- 1998-01-28 NZ NZ329656A patent/NZ329656A/xx unknown
- 1998-02-23 NZ NZ329822A patent/NZ329822A/en unknown
Also Published As
Publication number | Publication date |
---|---|
NZ329656A (en) | 2000-01-28 |
CA2193966A1 (en) | 1996-01-11 |
MX9700041A (es) | 1997-04-30 |
AU3001095A (en) | 1996-01-25 |
HU9603525D0 (en) | 1997-02-28 |
NZ329822A (en) | 2000-02-28 |
EP0767792A1 (en) | 1997-04-16 |
NZ290008A (en) | 1998-08-26 |
NO965608D0 (no) | 1996-12-27 |
WO1996000730A1 (en) | 1996-01-11 |
HUT76344A (en) | 1997-08-28 |
CZ382496A3 (en) | 1997-12-17 |
AU702661B2 (en) | 1999-02-25 |
PL318199A1 (en) | 1997-05-26 |
JPH10504808A (ja) | 1998-05-12 |
CN1156995A (zh) | 1997-08-13 |
BR9508178A (pt) | 1997-11-18 |
EP0767792A4 (en) | 2002-11-20 |
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