EP0850238A1 - Banque combinatoire de 1,4-benzodiazepine-2,5-diones - Google Patents
Banque combinatoire de 1,4-benzodiazepine-2,5-dionesInfo
- Publication number
- EP0850238A1 EP0850238A1 EP96923532A EP96923532A EP0850238A1 EP 0850238 A1 EP0850238 A1 EP 0850238A1 EP 96923532 A EP96923532 A EP 96923532A EP 96923532 A EP96923532 A EP 96923532A EP 0850238 A1 EP0850238 A1 EP 0850238A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- resin
- formula
- linked
- aminoacids
- azidobenzoyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- IAIGWBZFHIEWJI-UHFFFAOYSA-N 1h-1,4-benzodiazepine-2,5-dione Chemical compound N1C(=O)C=NC(=O)C2=CC=CC=C21 IAIGWBZFHIEWJI-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 47
- 239000007787 solid Substances 0.000 claims abstract description 37
- 238000000034 method Methods 0.000 claims abstract description 32
- 238000005447 aza-Wittig reaction Methods 0.000 claims abstract description 9
- 238000006798 ring closing metathesis reaction Methods 0.000 claims abstract description 8
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 212
- 239000011347 resin Substances 0.000 claims description 152
- 229920005989 resin Polymers 0.000 claims description 152
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 82
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 72
- -1 N-(2-azidobenzoyl)amino esters Chemical class 0.000 claims description 46
- 239000000203 mixture Substances 0.000 claims description 37
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical group C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 36
- 239000003153 chemical reaction reagent Substances 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 24
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 18
- NKKFLGZTMQFTCA-UHFFFAOYSA-N 2-azidobenzoyl chloride Chemical class ClC(=O)C1=CC=CC=C1N=[N+]=[N-] NKKFLGZTMQFTCA-UHFFFAOYSA-N 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 16
- 229940049706 benzodiazepine Drugs 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 125000001072 heteroaryl group Chemical group 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 12
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 12
- 150000001413 amino acids Chemical class 0.000 claims description 10
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 9
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 9
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 9
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 9
- 235000001014 amino acid Nutrition 0.000 claims description 9
- 229910052698 phosphorus Inorganic materials 0.000 claims description 9
- 239000011574 phosphorus Substances 0.000 claims description 9
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims description 9
- 239000008096 xylene Substances 0.000 claims description 9
- PWDSJBHSKYBUEX-UHFFFAOYSA-N 1,4-benzodiazepin-5-one Chemical compound O=C1N=CC=NC2=CC=CC=C12 PWDSJBHSKYBUEX-UHFFFAOYSA-N 0.000 claims description 8
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 8
- 235000008206 alpha-amino acids Nutrition 0.000 claims description 8
- 150000001371 alpha-amino acids Chemical class 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 239000000725 suspension Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- 229910004373 HOAc Inorganic materials 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 4
- 239000003929 acidic solution Substances 0.000 claims description 3
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 239000002798 polar solvent Substances 0.000 claims description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims description 3
- 230000002152 alkylating effect Effects 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 claims 6
- 150000001299 aldehydes Chemical class 0.000 claims 2
- 125000003944 tolyl group Chemical group 0.000 claims 2
- 238000003556 assay Methods 0.000 abstract description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 238000003786 synthesis reaction Methods 0.000 description 35
- 239000000243 solution Substances 0.000 description 32
- 230000015572 biosynthetic process Effects 0.000 description 31
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- 239000011324 bead Substances 0.000 description 16
- 239000002243 precursor Substances 0.000 description 16
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
- 235000019439 ethyl acetate Nutrition 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000003818 flash chromatography Methods 0.000 description 8
- 229910052740 iodine Inorganic materials 0.000 description 8
- 125000003342 alkenyl group Chemical group 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 7
- 150000001557 benzodiazepines Chemical class 0.000 description 7
- 229940024606 amino acid Drugs 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 125000004442 acylamino group Chemical group 0.000 description 5
- 125000000304 alkynyl group Chemical group 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 125000005553 heteroaryloxy group Chemical group 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- KQOGTZVMSOJOJQ-UHFFFAOYSA-N 2-[4-(acetyloxymethyl)phenoxy]acetic acid Chemical compound CC(=O)OCC1=CC=C(OCC(O)=O)C=C1 KQOGTZVMSOJOJQ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000000262 chemical ionisation mass spectrometry Methods 0.000 description 4
- 238000003776 cleavage reaction Methods 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 230000007017 scission Effects 0.000 description 4
- 238000012216 screening Methods 0.000 description 4
- 238000010532 solid phase synthesis reaction Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 101150041968 CDC13 gene Proteins 0.000 description 3
- 239000004793 Polystyrene Substances 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229920002223 polystyrene Polymers 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
- ZPGDWQNBZYOZTI-SFHVURJKSA-N (2s)-1-(9h-fluoren-9-ylmethoxycarbonyl)pyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 ZPGDWQNBZYOZTI-SFHVURJKSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- GBROUWPNYVBLFO-QHCPKHFHSA-N (2s)-2-[9h-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-phenylpropanoic acid Chemical compound C([C@H](N(C)C(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C(O)=O)C1=CC=CC=C1 GBROUWPNYVBLFO-QHCPKHFHSA-N 0.000 description 2
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 description 2
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 2
- IBXNCJKFFQIKKY-UHFFFAOYSA-N 1-pentyne Chemical compound CCCC#C IBXNCJKFFQIKKY-UHFFFAOYSA-N 0.000 description 2
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- KDKYADYSIPSCCQ-UHFFFAOYSA-N but-1-yne Chemical compound CCC#C KDKYADYSIPSCCQ-UHFFFAOYSA-N 0.000 description 2
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000013058 crude material Substances 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 230000005264 electron capture Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 125000005059 halophenyl group Chemical group 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 125000005647 linker group Chemical group 0.000 description 2
- BVWTXUYLKBHMOX-UHFFFAOYSA-N methyl vanillate Chemical compound COC(=O)C1=CC=C(O)C(OC)=C1 BVWTXUYLKBHMOX-UHFFFAOYSA-N 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
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- 239000012071 phase Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 229960002429 proline Drugs 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 2
- 230000003252 repetitive effect Effects 0.000 description 2
- SZQVMUPTZFMHQT-UHFFFAOYSA-N rhodium;2,2,2-trifluoroacetic acid Chemical compound [Rh].[Rh].OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.OC(=O)C(F)(F)F SZQVMUPTZFMHQT-UHFFFAOYSA-N 0.000 description 2
- 238000005556 structure-activity relationship Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- WMSUFWLPZLCIHP-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 9h-fluoren-9-ylmethyl carbonate Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)ON1C(=O)CCC1=O WMSUFWLPZLCIHP-UHFFFAOYSA-N 0.000 description 1
- FLGAHXWKUMCISQ-XIFFEERXSA-N (2s)-6-amino-2-[bis(9h-fluoren-9-ylmethoxycarbonyl)amino]hexanoic acid Chemical group C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)N([C@@H](CCCCN)C(O)=O)C(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 FLGAHXWKUMCISQ-XIFFEERXSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- SUNMBRGCANLOEG-UHFFFAOYSA-N 1,3-dichloroacetone Chemical compound ClCC(=O)CCl SUNMBRGCANLOEG-UHFFFAOYSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
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- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- 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
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
Definitions
- the present invention relates to a method of synthesizing a combinatorial library of 1 ,4-benzodiazepin-5-ones on solid supports via an aza-Wittig ring closure, said compounds optionally encoded with tags, and to the use of this library in assays to discover biologically active compounds, and, optionally, to cleave l,4-benzodiazepin-2,5- diones therefrom.
- R 1 is H, lower alkyl, c-lower alkyl, -or (CH2) R 4 , or R 1 and R 2 , together with the atoms to which they are attached, join to form a 5-, or 6-membered heterocyclic ring, optionally monosubstituted with OH, alkoxy, or arylalkoxy;
- R 2 is H, loweralkyl, arylR 6 R 7 R8, or heteroarylR 6 R 7 R8, or R 1 and R 2 , together with the atoms to which they are attached, join to form a 5- or 6-membered heterocyclic ring, optionally monosubstituted with OH, alkoxy, or arylalkoxy;
- R 3 is H or loweralkyl;
- R 4 is aryl, substituted aryl, heteroaryl, substituted heteroaryl,
- R5 is H, lower alkyl, -CNHR3R3, or -C(0)R3;
- R 6 , R 7 , and R 8 is each, independently, H, lower alkyl, lower alkoxy, halogen, aryl, lower alkylthio, X-aryl, X-substituted aryl, lower alkylaryl, C(hal)3, -(CH2) m NR3R5, or -X-CH(C ⁇ 2R 3 )2, or R6 and R 7 , together with the atoms to which they are attached, join to form a 5- or 6-membered heterocyclic ring; and X is O or S.
- the ligands of Formula II may be detached by photolytic, oxidative, acidic, basic, or other cleavage techniques.
- acidic cleavage may be represented by:
- An embodiment of the invention is the solid phase synthesis of l,4-benzodiazepin-2,5-diones via aza-Wittig ring closure.
- the process comprises: a) attaching a set of suitably protected oc-aminoacids or N- alkyl- ⁇ -aminoacids to solid supports to form resin linked N-alkyl- ⁇ - aminoacids; or b) attaching a set of suitably protected N-unsubstitued- ⁇ - aminoacids to solid supports to form resin linked N-unsubstitued- ⁇ - aminoacids and reductively alkylating said resin linked aminoacids with a set of aldehydes to form resin linked N-arylalkyl or heteroarylalkyl- ⁇ -aminoacids; c) acylating the resin linked N-alkyl- ⁇ -aminoacids or the N-arylalkyl or heteroarylalkyl- ⁇ -a
- a preferred embodiment of the invention is the solid phase synthesis of l,4-benzodiazepin-2,5-diones via aza-Wittig ring closure, wherein the process comprises: a) reacting a set of suitably protected ⁇ -aminoacids of the formula:
- step (b) reacting the resin linked aminoacids of step (a), suspended in DMF and acetic acid, with a set of aldehydes of the formula HC(0)R 2 in HOAc/DMF and sodium cyanoborohydride in THF to form resin linked N-alkyl- ⁇ -aminoacids of the formula:
- step (c) treating the resin linked N-(2-azidobenzoyl)amino esters of step (c), suspended in an involatile solvent (i.e., a non-protic, organic solvent with a boiling point of 80-140 C) such as toluene, xylene, or chlorobenzene, with an excess of a trivalent phosphorus reagent such as triphenylphosphine or tributylphosphine at 80-150°C and then cooling said mixture to room temperature to form resin linked benzodiazepines of formula:
- an involatile solvent i.e., a non-protic, organic solvent with a boiling point of 80-140 C
- a trivalent phosphorus reagent such as triphenylphosphine or tributylphosphine at 80-150°C
- step (d) suspending the resin linked benzodiazepines of step (d) in TF A/water at room temperature for 1-24 hours to form 1,4- benzodiazepin-2,5-diones of formula:
- a second preferred embodiment of the invention is the solid phase synthesis of l,4-benzodiazepin-2,5-diones and l,3-cyclo-l,4- benzodiazepin-2,5-diones via aza-Wittig ring closure, wherein the process comprises: a) reacting a set of suitably protected ⁇ -aminoacids of the formula:
- step (b) reacting the resin linked N-alkyl- ⁇ -aminoacids of step (b), in methylene chloride and diisopropylethylamine, with 2- azidobenzoyl chlorides of formula: to form resin linked N-(2-azidobenzoyl)amino esters of formula:
- step (b) treating the resin linked N-(2-azidobenzoyl)amino esters of step (b), suspended in an involatile solvent (i.e., a non-protic, organic solvent with a boiling point of 80-140 C) such as toluene, xylene, or chlorobenzene, with an excess of a trivalent phosphorus reagent such as triphenylphosphine or tributylphosphine at 80-150°C and then cooling said mixture to room temperature to form resin linked benzodiazepines of formula:
- an involatile solvent i.e., a non-protic, organic solvent with a boiling point of 80-140 C
- a trivalent phosphorus reagent such as triphenylphosphine or tributylphosphine at 80-150°C
- step (c) suspending the resin linked benzodiazepines of step (c) in TF A/water at room temperature for 1-24 hours to form 1,4- benzodiaze ⁇ in-2,5-diones of formula:
- an aspect of the invention is a method of identifying a compound having a desired characteristic which comprises synthesizing a combinatorial library of Formula I and testing the library of Formula I, either attached to the solid support or detached therefrom, in an assay which identifies compounds of Formula II having the desired characteristic.
- Another embodiment of the invention is a method of identifying a compound having a desired characteristic which comprises testing the library of Formula I, either attached to the solid support or detached therefrom, in an assay which identifies compounds of Formula II having the desired characteristic.
- a further embodiment of the invention is determining the structure of any compound so identified.
- the determination of the structures of compounds having the desired characteristic can be accomplished by decoding the tags (represented by T'-L- in Formula I) or, alternatively, by deconvolution of the library (Smith et al., BioMed. Chem. Lett., 4, 2821 (1994); Kurth et aL, . Org. Chem., 59, 5862 (1994); Murphy et ah, J. Am. Chem. Soc, 111, 7029 (1995); Cambell et aL, J. Am. Chem. Soc, 111, 5381 (1995); and Erb et aL, Proc Nat. Acad. Sci. USA, 91, 11422 (1994)).
- Another embodiment of the invention is the use of divinylbenzene-cross-linked, polyethyleneglycol-grafted polystyrene beads optionally functionalized with amino groups (for example, TentaGel® S NH2, Rapp Polymere) as the solid supports for constructing a combinatorial library of Formula I or I'.
- amino groups for example, TentaGel® S NH2, Rapp Polymere
- Alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof.
- “Lower alkyl” means alkyl groups of from 1 to 8 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t- butyl, pentyl, hexyl, octyl, cyclopropylethyl, and the like.
- “Lower cycloalkyl” includes cycloalkyl groups of from 3 to 8 carbon atoms. Examples of lower cycloalkyl groups include c-propyl, c-butyl, c- pentyl, 2-methylcyclopropyl, cyclopropylmethyl, norbornyl, and the like.
- Alkenyl is C2-C8 alkenyl of a linear, branched, or cyclic (C5-C6) configuration and combinations thereof.
- alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, c-hexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.
- Alkynyl is C2-C8 alkynyl of a linear or branched configuration and combinations thereof.
- alkenyl groups examples include ethyne, propyne, butyne, pentyne, 3-methyl-l-butyne, 3,3- dimethyl-1-butyne, and the like.
- Alkoxy means alkoxy groups of from 1 to 8 carbon atoms of a straight, branched, or cyclic configuration and combinations thereof. Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like.
- Acylamino means acylamino groups of from 1 to 8 carbon atoms of a straight, branched or cyclic configuration and combinations thereof. Examples of acylamino groups are acetylamino, butylamino, cyclohexylamino, and the like.
- Hal means halogen, which includes F, Cl, Br, and I.
- Halophenyl means phenyl substituted by 1-5 halogen atoms. Halophenyl includes pentachlorophenyl, pentafluorophenyl, and 2 ,4,6-trichlorophenyl.
- the aromatic 6- to 14-membered carbocyclic rings include benzene, naphthalene, indane, tetralin, and fluorene and the 5- to 10- membered aromatic heterocyclic rings include imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole, and pyrazole.
- Substituted alkyl, alkenyl, or alkynyl means alkyl, alkenyl, or alkynyl wherein up to three H atoms on each C therein are replaced by halogen, hydroxy, loweralkoxy, carboxy, carboalkoxy, carboxamido, cyano, carbonyl, NO2, NR 3 R3, alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, heteroaryloxy, and substituted phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, and heteroaryloxy.
- the linkers may be any component capable of being selectively cleaved to release both T and II from the solid support. See, e.g., Greene and Wuts, "Protective Groups in Organic Synthesis", 2nd ed., Wiley, 1991.
- the left-hand bond is the point of attachment to the solid support (via -C(O)- for L' and -C(O)- or -CH2C(0)- for L) and the right-hand bond is the point of attachment to either T or II.
- the tags of this invention, T are chemical entities which possess several properties: they must be detachable from the solid supports, preferably by photolysis or oxidation; they must be individually differentiable, and preferably separable; they must be stable under the synthetic conditions; they must be capable of being detected at very low concentrations, e.g., IO -18 to IO -9 mole; they should be identifiable with readily-available equipment which does not require sophisticated technical capabilities to operate; and they should be relatively economical.
- the tags may be structurally related or unrelated, e.g., a homologous series, repetitive functional groups, related members of the Periodic Chart, different isotopes, combinations thereof, and the like.
- each solid support there will usually be attached at least 0.01 femtomol, usually 0.001-50 pmol, of each tag.
- the tags may be aliphatic, alicyclic, aromatic, heterocyclic, or combinations thereof.
- Distinguishing features may be the number of repetitive units, such as methylene groups in an alkyl moiety; alkyleneoxy groups in a polyalkyleneoxy moiety; halo groups in a polyhalo compound; ⁇ - and/or ⁇ -substituted ethylene groups where the substituents may be alkyl groups, oxy, carboxy, amino, halo, or the like; isotopes; etc.
- the materials upon which the combinatorial syntheses of the invention are performed are referred to as solid supports, beads, and resins.
- beads, pellets, disks, fibers, gels, or particles such as cellulose beads, pore-glass beads, silica gels, polystyrene beads optionally cross-linked with divinylbenzene and optionally grafted with polyethylene glycol and optionally functionalized with amino, hydroxy, carboxy, or halo groups, grafted co-poly beads, poly-acrylamide beads, latex beads, dimethylacrylamide beads optionally cross-linked with N,N'-bis-acryloyl ethylene diamine, glass particles coated with hydrophobic polymer, etc., i.e., material having a rigid or semi-rigid surface; b) soluble supports such as low molecular weight non- cross-linked polystyrene; and.
- Suitable aminoacid protecting groups are well known in the art and include Fmoc, Alloc (allyloxycarbonyl), etc.
- R H or lower alkyl
- B O or NH
- Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisometric forms which may be defined in terms of absolute stereochemistry as (R) or (S), or as (D) or (L) for amino acids.
- the present invention is meant to include all such possible diastereomers as well as their racemic and optically pure forms.
- Optically active (R) and (S), or (D and L), isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
- the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are intended to be included.
- the library of the present invention is useful as a screening tool for discovering new lead structures by evaluation across an array of biological assays, including the discovery of selective inhibition patterns across isozymes.
- the library is thus a tool for drug discovery; i.e., as a means to discover novel lead compounds by screening the library against a variety of biological targets and to develop structure- activity relationships (SAR) in large families of related compounds.
- the library may be tested with the ligands attached to the solid supports as depicted in Formula I or I', or the compounds II may be detached prior to evaluation. With the compounds of Formula I or I', screening assays such as FACS sorting and cell lawn assays may be used.
- tags attached to solid support associated with bioactivity may then be decoded to reveal the structural or synthetic history of the active compound (Ohlmeyer et al., Proc. Natl. Aca ⁇ Sci. USA, 90, 10922-10926, Dec. 1993 and Still et al., Complex Combinatorial Chemical Libraries Encoded with Tags, WO 94/08051) or, alternatively, the structures may be determined by deconvolution.
- the compounds of the present invention can be prepared according to the following methods.
- each solid support upon which a compound is being synthesized may be uniquely tagged to define the particular chemical event(s) occurring during that step.
- the tagging is accomplished using identifiers such as those of Formula IV, which record the sequential events to which the support is exposed during the synthesis, thus providing a reaction history for the compound produced on each support.
- the identifiers are used in combination with one another to form a binary or higher order encoding scheme permitting a relatively small number of identifiers to encode a relatively large number of reaction products. For example, when used in a binary code, N identifiers can encode up to 2N different compounds and/or conditions.
- each variable or combination of variables at each step of the synthesis By associating each variable or combination of variables at each step of the synthesis with a combination of identifiers which uniquely define the chosen variables such as reactant, reagent, reaction conditions, or combinations of these, one can use the identifiers to define the reaction history of each solid support.
- identifiers By associating each variable or combination of variables at each step of the synthesis with a combination of identifiers which uniquely define the chosen variables such as reactant, reagent, reaction conditions, or combinations of these, one can use the identifiers to define the reaction history of each solid support.
- the syntheses one begins with at least IO 4 , desirably at least IO 7 , and generally not exceeding IO 15 solid supports.
- IO 15 IO 15 solid supports.
- the supports Depending on the pre-determined number of choices for the first step, one divides the supports accordingly into as many containers.
- the appropriate reagents and reaction conditions are applied to each container and the combination of identifier
- the tagging may be done prior to, concomitantly with, or after the reactions which comprise each choice.
- sample supports may be picked at any stage and a portion of their tags detached and decoded to verify that the correct tags are bound to the sample supports.
- one may wash the beads free of any excess reagents or by ⁇ products before proceeding.
- the supports are combined, mixed, and again divided, this time into as many containers as pre-determined for the number of choices for the second step in the synthesis. This procedure of dividing, reacting, tagging, and remixing is repeated until the combinatorial synthesis is completed.
- A is suspended in an aprotic, polar solvent such methylene chloride, DMF,
- the resin is filtered and washed and then suspended in an involatile solvent (i.e., a non-protic, organic solvent with a boiling point of 80-140 C) such as toluene, xylene, or chlorobenzene and treated with an excess of a trivalent phosphorus reagent such as triphenylphosphine or tributylphosphine.
- an involatile solvent i.e., a non-protic, organic solvent with a boiling point of 80-140 C
- a trivalent phosphorus reagent such as triphenylphosphine or tributylphosphine.
- Compounds 4, 8, 11, and 16 have been synthesized by the aza-Wittig method of the present invention.
- Compound 4 is a known intermediate useful in the synthesis of antitumor antibiotics (Kaneko et aL, Tet. Lett., 1983, p. 5165; Kaneko et al., J. Med. Chem., 1985, p. 388).
- Compound 8 is a novel compound useful as an intermediate in the synthesis of the antibiotic 5-thioabbeymycin (Kamal et aL, Bioorg. Med. Chem. Lett., 3, p. 743, 1993) and abbeymycin.
- Compound 11 is a novel compound useful as an intermediate in the synthesis of antitumor antibiotics (Hurley et al., Chem. Res. Toxicol, 1, p. 258, 1988.
- Compound 16 is a natural product isolated from Penicillium cyclopium with potential antibiotic properties (Framm et al., Eur. J. Biochem, 37, p. 78, 1973.)
- Resin-linked ⁇ -amino ester, A is suspended in an aprotic, polar solvent such methylene chloride, DMF, THF or ethyl acetate.
- An excess (2-50 equivalents) of a soluble organic base such as triethylamine, N,N-diisopropylethylamine, or pyridine is added to the suspended resin.
- an acylation catalyst such as 4- dimethylaminopyridine may be added. This mixture is treated with an excess (2-10 equivalents) of an appropriately substituted 2-azidobenzoyl chloride and agitated at room temperature for 2-24 hr.
- Resin linked N-(2-azidobenzoyl)ami ⁇ o ester, B is suspended in an involatile solvent such as toluene, xylene, or chlorobenzene and treated with an excess (2-10 equivalents) of a trivalent phosphorus reagent such as triphenylphosphine or tributylphosphine.
- Resin-linked 1,4- benzodiazepin-5-one, C is suspended in an acidic solution such as trifluoroacetic acid/methylene chloride (50-90% TFA/CH2C12) or hydrogen chloride/dioxane (1-4M HCl/dioxane) and agitated at room temperature for 1-24 hr.
- an acidic solution such as trifluoroacetic acid/methylene chloride (50-90% TFA/CH2C12) or hydrogen chloride/dioxane (1-4M HCl/dioxane)
- the resin is filtered and washed with appropriate solvents such as methylene chloride or dioxane.
- appropriate solvents such as methylene chloride or dioxane.
- the filtrate and washings are combined and evaporated to give the crude l,4-benzodiazepin-2,5-dione, D, which may be purified and characterized by standard techniques.
- a) Methyl vanillate (0.729 g, 4.0 mmole), l-hydroxy-9- (2,3,4,5,6-pentachlorophenoxy)nonane (1.634 g, 4.0 mmole) and triphenylphosphine (1,258 g, 4.8 mmole) were dissolved in 20 mL dry toluene under argon.
- the diazoketone (0.85 g, 1.4 mmole, 82% yield over three steps) was obtained as a pale yellow solid.
- purification by flash chromatography was no longer necessary, which in some cases had resulted in significant acid-catalyzed decomposition of the identifier.
- Example 5 the 12 identifiers were used to encode the combinatorial library.
- N-Fmoc-c ⁇ -4-benzoyloxy-L-proline p-alkoxybenzyl resin was prepared by routine methods as outlined below.
- TentaGel resin may be modified with bis-Fmoc lysine to increase the available reaction sites for ligand attachment.
- the schemes elsewhere herein do not show the use of this modification with lysine.
- the resulting mixture was treated with 4-dimethylamino- pyridine (92 mg, 0.75 mmol, 0.1 equiv.), followed by N,N'- diisopropylcarbodiimide (4.73 g, 37.5 mmol, 5 equiv.), and the reaction mixture was shaken at ambient temperature. After 6 hours, the solvent was removed by filtration, and the beads were washed successively with 5 x 150 mL DMF, and 5 x 150 mL methylene chloride. A small portion of the resin was checked by the Kaiser test for disappearance of free NH2, and found to be negative.
- the resin was treated with a 30% solution of piperidine in DMF (100 mL), and shaken at 25 °C for 1 hr.
- the resin was filtered and washed successively with 5 x 150 mL DMF and 5 x 150 mL methylene chloride A small portion of the resin was checked with the Kaiser test to assure removal of the Fmoc groups, and found to be positive.
- the solvent was removed by filtration, and the resin was washed successively with 5 x 150 mL DMF and 5 x 150 mL CH2C12 to afford the acetate protected resin. A small aliquot of the resin was checked for disappearance of free NH2 with the Kaiser test, and found to be negative.
- the acetate protected resin from above was treated with a solution of 10% hydrazine hydrate in methanol (100 mL), and shaken at ambient temperature. After 6 hr., the solvent was removed by filtration, and the resin was washed successively with 5 x 150 mL MeOH and then re-treated with 10% hydrazine hydrate in MeOH (100 mL) and shaken at 25 C for 16 hr. The solvent was removed by filtration, and the resin was washed successively with 5 xl50 mL DMF and 5 x 150 mL CH2CI2 to afford the hydroxy resin A.
- N-Fmoc-L-proline p-alkoxybenzyl resin, 1 (Bachem) (0.34 mmole/g, 2.0 g, 0.68 mmole) was suspended in 30 mL DMF, then filtered. The resin was then shaken with 50% piperidine/DMF for 2 hr. then filtered and washed with DMF (5 x 30 mL) and methylene chloride (10 x 30 mL). The resin was suspended in 20 mL methylene chloride, and 2 mL (14 mmole) triethylamine was added, followed by 1.0 g (5.5 mmole, 8 equiv.) 2-azidobenzoyl chloride.
- the mixture was shaken at 25°C for 3 hr. and then the resin was washed with methylene chloride (10 x 30 mL) followed by toluene (10 x 30 mL).
- the resin, 2 was suspended in 20 mL toluene and 0.3 g (1.14 mmole, 1.7 equiv.) triphenylphosphine was added and the mixture was shaken until the triphenylphosphine had dissolved.
- the mixture was shaken and heated to 80°C for 3 hr. then cooled and washed with methylene chloride (10 x 30 mL).
- the pale brown resin, 3, was dried under vacuum.
- the resin, 3 (2.0 g, 0.68 mmole), prepared as described above, was suspended in 20 mL methylene chloride and 20 mL trifluoroacetic acid was added. The resin was shaken at 25 °C for 30 min then filtered and washed with methylene chloride (2 x 20 mL). The filtrate and washings were collected and combined, then evaporated to give the crude product.
- the benzodiazepine was purified by flash chromatography, eluting with 60% ethyl acetate/hexane to give the product, 4, as a white solid.
- N-Fmoc-c5-4-benzoyloxy-L-proline p-alkoxybenzyl resin, 5, (400 mg) was suspended in 10 mL DMF, then filtered. The resin was then shaken with 50% piperidine/DMF, 10 mL, for 2 hr. then filtered and washed with DMF (5 x 10 mL) and methylene chloride (10 x 10 mL). The resin was suspended in 10 mL methylene chloride, 0.4 mL ( ⁇ 3 mmole) triethylamine was added, followed by 0.2 g (1.1 mmole) 2-azido-benzoyl chloride. The mixture was shaken at 25°C for 12 hr.
- N-Fmoc-L-proline p-alkoxybenzyl resin, 1 (0.34 mmole/g, 5.0 g, 1.8 mmole) was suspended in 50 mL DMF, then filtered. The resin was then shaken with 50% piperidine/DMF for 2 hr. then filtered and washed with DMF (5 x 50 mL) and methylene chloride (10 x 50 mL). The resin was suspended in 50 mL methylene chloride, 3 mL (21 mmole) triethylamine was added, followed by 0.75 g (3 mmole, 1.7 equiv.) 2-azido-4,5-dimethoxybenzoyl chloride as a solid.
- the mixture was shaken at 25 °C for 12 hr. and then the resin was washed with methylene chloride (10 x 50 mL), followed by toluene (10 x 50 mL).
- the resin, 9, was suspended in 50 mL toluene and 1.26 g (4.8 mmole 2.6 equiv.) triphenylphosphine was added and the mixture was shaken until the triphenylphosphine had dissolved.
- the mixture was shaken and heated to 80°C for 2 hr. then cooled and washed with toluene (10 x 50 mL), alternately with methanol and methylene chloride (5 x 50 mL each) and finally methylene chloride (5 x 50 mL).
- the pale brown resin, 1 was dried under vacuum.
- N-Fmoc-N-methyl-L- phenylalanine, 3.0 g (7.5 mmole, 3 equiv.), DMAP, 1.0 g (0.82 mmole, 0.3 equiv.), and DIC 1.74 mL (1.26 g, 10 mmole, 4 equiv.) were added and the mixture was agitated for 2 hr.
- the resin was filtered and washed with methylene chloride, (10 x 30 mL), then dried.
- the mixture was shaken at 25 C for 1 hr and then the resin was washed with methylene chloride (10 x 30 mL) followed by toluene (10 x 30 mL).
- the resin, 14, was suspended in 20 mL toluene and 0.52 g (2.0 mmole) triphenylphosphine was added and the mixture was shaken until the triphenylphosphine had dissolved.
- the mixture was shaken and heated to 9 C for 3 hr then cooled and washed with toluene (5 x 20 mL) and methylene chloride (10 x 20 mL) to give the resin linked 1,4- benzodiazepine-5-one, 15.
- the resin, 15, was suspended in 10 mL methylene chloride and 10 mL trifluoroacetic acid was added. The resin was shaken at 25 ° C for 2 hr, then filtered and washed with methylene chloride (2 x 20 mL). The filtrate and washings were collected and combined, then evaporated to give the crude product which was purified by flash chromatography eluting with 50% ethyl acetate/hexane to give the product, 16.
- Rhodium (II) trifluoroacetate dimer 2 mL of 1 mg/mL in methylene chloride, was added to each vessel in turn with - 30 sec agitation of the vessels after each addition.
- the resin batches, tag precursor and catalyst were agitated for 12 hr, then filtered and washed with 5 x 40 mL methylene chloride.
- the 62 resin batches were encoded with six tags as follows.
- the resin batches were suspended in 30 mL methylene chloride. Aliquots, 2 mL of 37 mg/mL (74 mg tag precursor/vessel -8.7 % by mass of resin), of C6CI5 tag precursor solution in methylene chloride were added to the appropriate vessels from 3 to 62 and the vessels were shaken for 2 min. A 3 mL aliquot of 37 mg/mL C6CI5 tag precursor solution was added to vessel 1 (111 mg tag precursor in vessel 1, 6.3% by mass of resin).
- a collection of 51 319 l,4-benzodiazepine-2,5-diones was prepared as follows. Resin batches 3C-62C were combined and mixed thoroughly in a seperatory funnel, then divided as a slurry in methylene chloride into nineteen equal portions (-2.7 g, 1.4 mmole) in 100 mL synthesis vessels. The resin was suspended in 30 mL methylene chloride and diisopropylethylamine, 2.5 mL (1.8 g, 14 mmole, 10 equiv), was added followed by 5 mmole of the appropriate o- azidobenzoyl chloride (Reagent Set 3).
- Tributylphosphine 1.8 mL (1.45 g, 7.2 mmole, 5 equiv), was added to each flask and the mixtures were heated to 140- 150°C for 6 hr, then cooled, filtered, and washed with 2 x 30 mL toluene and 5 x 30 mL methylene chloride to give the resin linked benzodiazepines, E.
- the product 1 ,4-benzodiazepine-2,5-diones, F were cleaved from the resin support by suspending the resin, 20 beads, in 100 ⁇ L of 70 % TFA/water for 4 hours and filtering the solution.
- a second collection of 1 170 l,4-benzodiazepine-2,5-diones was prepared as follows. Resin batches 1C and 2C were combined and mixed thoroughly in a seperatory funnel. The resin was dried in vacuo and divided into thirteen equal portions (-0.27 g, 0.14 mmole) then placed in 20 mL synthesis vessels. The resin was suspended in 10 mL methylene chloride and diisopropylethylamine, 0.25 mL (0.18 g, 1.4 mmole, 10 equiv), was added followed by 0.5 mmole of thirteen o- azidobenzoyl chlorides.
- Tributylphosphine 0.14 mL (0.11 g, 0.55 mmole, 4 equiv), was added to each flask and the mixtures were heated to 140-150°C for 6 hr, then cooled, filtered, and washed with 2 x 10 mL toluene and 5 x 10 mL methylene chloride to give the resin batches E, from which the product l,4-benzodiazepine-2,5-diones, F, may be cleaved as described above.
- the GC analysis is performed with a Hewlett Packard 5890 plus gas chromatograph. On column injection into a 5 m, 0.32 mm retention gap connected to a 25 m, 0.2 mm crosslinked 5% phenylmethyl silicone column is used.
- the temperature and pressure programs for the analysis are 200-320°C, 15°C/min, then 320°C for 10 min and 20-40 psi at 2 psi/min, then 40 psi for 10 min.
- the EC detector is maintained at 400°C and the auxiliary gas is set at 35 psi.
- the identity of the library compound attached to the bead is ascertained based on the reagents utilized in the synthesis of such compound, which are readily determined from the binary codes associated, respectively, with each of the identifiers for such reagents, as characterized through the above procedure.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Applications Claiming Priority (3)
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US65795P | 1995-06-29 | 1995-06-29 | |
US657P | 1995-06-29 | ||
PCT/US1996/011070 WO1997001560A1 (fr) | 1995-06-29 | 1996-06-28 | Banque combinatoire de 1,4-benzodiazepine-2,5-diones |
Publications (2)
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EP0850238A1 true EP0850238A1 (fr) | 1998-07-01 |
EP0850238A4 EP0850238A4 (fr) | 1998-10-07 |
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EP96923532A Withdrawn EP0850238A4 (fr) | 1995-06-29 | 1996-06-28 | Banque combinatoire de 1,4-benzodiazepine-2,5-diones |
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EP (1) | EP0850238A4 (fr) |
JP (1) | JPH11508563A (fr) |
AU (1) | AU6402096A (fr) |
CA (1) | CA2225914A1 (fr) |
WO (1) | WO1997001560A1 (fr) |
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US5191404A (en) * | 1989-12-20 | 1993-03-02 | Digital Equipment Corporation | High density memory array packaging |
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US5874064A (en) * | 1996-05-24 | 1999-02-23 | Massachusetts Institute Of Technology | Aerodynamically light particles for pulmonary drug delivery |
WO2000012508A2 (fr) | 1998-08-27 | 2000-03-09 | Spirogen Limited | Composes |
GB9818732D0 (en) | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Collection of compounds |
GB9818730D0 (en) | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Collections of compounds |
US6939712B1 (en) | 1998-12-29 | 2005-09-06 | Impedagen, Llc | Muting gene activity using a transgenic nucleic acid |
US6909006B1 (en) | 1999-08-27 | 2005-06-21 | Spirogen Limited | Cyclopropylindole derivatives |
US20030215871A1 (en) * | 2002-05-01 | 2003-11-20 | Pharmacopeia, Inc. | Chemically inert molecular tags |
GB0226593D0 (en) | 2002-11-14 | 2002-12-24 | Consultants Ltd | Compounds |
GB0321295D0 (en) | 2003-09-11 | 2003-10-15 | Spirogen Ltd | Synthesis of protected pyrrolobenzodiazepines |
US8088759B2 (en) * | 2005-11-01 | 2012-01-03 | The Regents Of The University Of Michigan | 1,4-benzodiazepine-2,5-diones with therapeutic properties |
CA2915237C (fr) | 2009-11-17 | 2017-10-10 | The Regents Of The University Of Michigan | 1,4-benzodiazepine-2,5-diones et composes apparentes presentant des proprietes therapeutiques |
Citations (1)
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WO1994008051A1 (fr) * | 1992-10-01 | 1994-04-14 | The Trustees Of Columbia University In The City Of New York | Banques chimiques combinatoires complexes codees avec des etiquettes |
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US3173912A (en) * | 1961-10-02 | 1965-03-16 | Olin Mathieson | Benzodiazepines |
US3860600A (en) * | 1972-07-10 | 1975-01-14 | Sterling Drug Inc | Octahydropyrrido{8 2,1-c{9 {8 1,4{9 benzodiazepines |
-
1996
- 1996-06-28 EP EP96923532A patent/EP0850238A4/fr not_active Withdrawn
- 1996-06-28 AU AU64020/96A patent/AU6402096A/en not_active Abandoned
- 1996-06-28 JP JP9504592A patent/JPH11508563A/ja active Pending
- 1996-06-28 WO PCT/US1996/011070 patent/WO1997001560A1/fr not_active Application Discontinuation
- 1996-06-28 CA CA002225914A patent/CA2225914A1/fr not_active Abandoned
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WO1994008051A1 (fr) * | 1992-10-01 | 1994-04-14 | The Trustees Of Columbia University In The City Of New York | Banques chimiques combinatoires complexes codees avec des etiquettes |
Non-Patent Citations (4)
Title |
---|
B BUNIN ET AL: "A general and expedient method for the solid-phase synthesis of 1,4-benzodiazepine derivatives" JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 114, no. 27, 1992, pages 10997-10998, XP002072683 * |
BUNIN B A ET AL: "Synthesis and evaluation of 1,4-benzodiazepine libraries" METHODS ENZYMOL. (MENZAU,00766879);96; VOL.267 (COMBINATORIAL CHEMISTRY); PP.448-465, UNIV. CALIFORNIA;DEP. CHEM.; BERKELEY; 94720; CA; USA (US), XP002072681 * |
S EGUCHI ET AL: "Facile synthesis of 1,4-benzodiazepin-5-ones via inramolecular aza-wittig reaction" SYNLETT, 1992, pages 295-296, XP002072682 * |
See also references of WO9701560A1 * |
Cited By (1)
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US5191404A (en) * | 1989-12-20 | 1993-03-02 | Digital Equipment Corporation | High density memory array packaging |
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EP0850238A4 (fr) | 1998-10-07 |
AU6402096A (en) | 1997-01-30 |
WO1997001560A1 (fr) | 1997-01-16 |
CA2225914A1 (fr) | 1997-01-16 |
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