HRP960277A2 - Novel compounds, the preparation and use thereof - Google Patents
Novel compounds, the preparation and use thereof Download PDFInfo
- Publication number
- HRP960277A2 HRP960277A2 HR08/472,453A HRP960277A HRP960277A2 HR P960277 A2 HRP960277 A2 HR P960277A2 HR P960277 A HRP960277 A HR P960277A HR P960277 A2 HRP960277 A2 HR P960277A2
- Authority
- HR
- Croatia
- Prior art keywords
- methyl
- acid
- tert
- tumor
- carbonyl
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims description 32
- 238000002360 preparation method Methods 0.000 title description 3
- -1 2-tert.butylglycyl Chemical group 0.000 claims description 52
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 29
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
- 206010028980 Neoplasm Diseases 0.000 claims description 19
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000000741 isoleucyl group Chemical group [H]N([H])C(C(C([H])([H])[H])C([H])([H])C([H])([H])[H])C(=O)O* 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 229950003188 isovaleryl diethylamide Drugs 0.000 claims description 5
- 125000002114 valyl group Chemical group 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 230000000771 oncological effect Effects 0.000 claims description 2
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 claims 3
- 125000001980 alanyl group Chemical group 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
- 239000011347 resin Substances 0.000 description 23
- 229920005989 resin Polymers 0.000 description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 229940024606 amino acid Drugs 0.000 description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 150000001413 amino acids Chemical class 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000012634 fragment Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 235000015165 citric acid Nutrition 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 229920000307 polymer substrate Polymers 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- LQKSHSFQQRCAFW-UHFFFAOYSA-N Dolastatin 15 Natural products COC1=CC(=O)N(C(=O)C(OC(=O)C2N(CCC2)C(=O)C2N(CCC2)C(=O)C(C(C)C)N(C)C(=O)C(NC(=O)C(C(C)C)N(C)C)C(C)C)C(C)C)C1CC1=CC=CC=C1 LQKSHSFQQRCAFW-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 230000005526 G1 to G0 transition Effects 0.000 description 3
- AKCRVYNORCOYQT-YFKPBYRVSA-N N-methyl-L-valine Chemical compound CN[C@@H](C(C)C)C(O)=O AKCRVYNORCOYQT-YFKPBYRVSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- LQKSHSFQQRCAFW-CCVNJFHASA-N [(2s)-1-[(2s)-2-benzyl-3-methoxy-5-oxo-2h-pyrrol-1-yl]-3-methyl-1-oxobutan-2-yl] (2s)-1-[(2s)-1-[(2s)-2-[[(2s)-2-[[(2s)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl]-methylamino]-3-methylbutanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carboxyl Chemical compound C([C@@H]1N(C(=O)C=C1OC)C(=O)[C@@H](OC(=O)[C@H]1N(CCC1)C(=O)[C@H]1N(CCC1)C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C)C(C)C)C(C)C)C1=CC=CC=C1 LQKSHSFQQRCAFW-CCVNJFHASA-N 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- VLNZUSMTOFYNPS-UHFFFAOYSA-N diethylphosphorylformonitrile Chemical compound CCP(=O)(CC)C#N VLNZUSMTOFYNPS-UHFFFAOYSA-N 0.000 description 3
- 108010045552 dolastatin 15 Proteins 0.000 description 3
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 125000001998 leucyl group Chemical group 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 238000010647 peptide synthesis reaction Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 238000005932 reductive alkylation reaction Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- UGNIYGNGCNXHTR-SFHVURJKSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-methylbutanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](C(C)C)C(O)=O)C3=CC=CC=C3C2=C1 UGNIYGNGCNXHTR-SFHVURJKSA-N 0.000 description 2
- CNPSFBUUYIVHAP-WHFBIAKZSA-N (2s,3s)-3-methylpyrrolidin-1-ium-2-carboxylate Chemical compound C[C@H]1CCN[C@@H]1C(O)=O CNPSFBUUYIVHAP-WHFBIAKZSA-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
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- APGLTERDKORUHK-LURJTMIESA-N N,N-dimethyl-L-Valine Chemical compound CC(C)[C@H](N(C)C)C(O)=O APGLTERDKORUHK-LURJTMIESA-N 0.000 description 2
- 108010033276 Peptide Fragments Proteins 0.000 description 2
- 102000007079 Peptide Fragments Human genes 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- IADUEWIQBXOCDZ-UHFFFAOYSA-N azetidine-2-carboxylic acid Chemical compound OC(=O)C1CCN1 IADUEWIQBXOCDZ-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 2
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
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- 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 1
- YCXXXPZNQXXRIG-IBGZPJMESA-N (2s)-2-[9h-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-methylbutanoic acid Chemical compound C1=CC=C2C(COC(=O)N(C)[C@@H](C(C)C)C(O)=O)C3=CC=CC=C3C2=C1 YCXXXPZNQXXRIG-IBGZPJMESA-N 0.000 description 1
- CANZBRDGRHNSGZ-NSHDSACASA-N (2s)-3-methyl-2-(phenylmethoxycarbonylamino)butanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 CANZBRDGRHNSGZ-NSHDSACASA-N 0.000 description 1
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- SZNKRADUZXAHCO-MERQFXBCSA-N (2s)-n-benzylpyrrolidine-2-carboxamide;hydrochloride Chemical compound Cl.O=C([C@H]1NCCC1)NCC1=CC=CC=C1 SZNKRADUZXAHCO-MERQFXBCSA-N 0.000 description 1
- ZIWHMENIDGOELV-DMTCNVIQSA-N (2s,4r)-4-fluoropyrrolidin-1-ium-2-carboxylate Chemical compound OC(=O)[C@@H]1C[C@@H](F)CN1 ZIWHMENIDGOELV-DMTCNVIQSA-N 0.000 description 1
- ZIWHMENIDGOELV-IMJSIDKUSA-N (2s,4s)-4-fluoropyrrolidin-1-ium-2-carboxylate Chemical compound OC(=O)[C@@H]1C[C@H](F)CN1 ZIWHMENIDGOELV-IMJSIDKUSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N 1,1'-Carbonyldiimidazole Substances C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- FNQIGYRDLYROLW-UHFFFAOYSA-N 1-hydroxy-2h-1,2,3-benzotriazine Chemical compound C1=CC=C2N(O)NN=CC2=C1 FNQIGYRDLYROLW-UHFFFAOYSA-N 0.000 description 1
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 1
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- 238000001212 derivatisation Methods 0.000 description 1
- SYZWSSNHPZXGML-UHFFFAOYSA-N dichloromethane;oxolane Chemical compound ClCCl.C1CCOC1 SYZWSSNHPZXGML-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
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- MGHPNCMVUAKAIE-UHFFFAOYSA-N diphenylmethanamine Chemical compound C=1C=CC=CC=1C(N)C1=CC=CC=C1 MGHPNCMVUAKAIE-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
- C07K5/101—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Immunology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Description
Poznato je da peptidi izolirani iz morskih vrsta, kao kao Dolastatin-10 (US 4,816,444) i Dolastatin-15 (EP-A-398558) pokazuju jaku inhibiciju rasta stanica (usporedi: Biochem. Pharmacology 40, br. 8, 1859-64, 1990; J. Natl. Cancer Inst. 85, 483-88, 1993 i tamo citiranu literaturu.) Na temelju zanimljivih rezultata u pokusnim sistemina s tumorima in vivo, daljnja predklinička ocjena tih prirodnih proizvoda sada je na putu početnog kliničkog proučavanja na pacijentima s rakom.
Međutim, nedostatak prirodnih proizvoda je slaba topivost u vodenim otapalima i skupa gradnja blokova potrebnih za sintezu.
Ovdje opisan izum osigurava nove peptide i njihove derivate koji nude poboljšanu terapeutsku snagu za liječenje neoplastičnih bolesti slično kao Dolastatin-15. Nadalje, spojevi ovog izuma mogu se uobičajeno sintetizirati kao što je u pojedinostima opisano u nastavku.
Spojevi ovog izuma uključuju nove peptide formule
R1R2N-CHX-CO-A-B-D-E- (F)t-K I
u kojoj
R1je metil, etil ili izopropil;
R2je vodik, metil ili etil;
R1-N-R2mogu zajedno biti pirolidinski prsten;
A je valil, izoleucil, leucil, 2-terc.butil-glicil, 2-etilglicil, norleucil ili norvalil;
B je N-metil-valil, leucil, izoleucil, norvalil, norleucil, -2-terc.butilglicil, -3-terc.butil-alanil, ili -2-etilglicil;
D je 3, 4-dehidroprolil, 4-fluorprolil, 4,4-difluor-prolil, azetidin-2-karbonil, 3-metilprolil, 4-metilprolil ili 5-metilprolil;
E je prolil, homoprolil, hidroksiprolil ili tiazo-lidin-4-karbonil;
F je valil, 2-terc.butilglicil, izoleucil, leucil, 2-cikloceksilglicil, norleucil, norvalil, neopentilglicil,
alanil, β-alanil ili aminoizobutiroil;
X je alkil (ponajprije C2-5), ciklopropil ili ciklopentil;
t je 0 ili 1; i
K je alkoksi (ponajprije C1-4), benziloksi ili supstituirana ili nesupstituirana amino skupina; i njihove soli s fiziološki podnošljivim kiselinama. Ovaj izum također osigurava metode za pripravu spojeva formule I, farmaceutske sastave koji sadrže ove spojeve zajedno s farmaceutski prihvatljivim nosačem i metode za njihovu upotrebu kod liječenja raka kod sisavaca.
Posebno,
K može biti C1-4-alkoksi, benziloksi, -NH2,
-NH-C1-12-alkil, -NH-C (CH3)2CN, -NH-C(CH3)2CCH,
-NH-C(CH3)2C=CH2, -NH-C(CH3)2CH2CH2OH, -NH-C(CH3)2CH2OH,
-NH-C3-8-cikloalkil, -NH-[3,3,0]-biciklooktil, norefedril, norpseudoefedril, -NH-kinolil, -NH-pirazil,
-NH-CH2-benzimidazolil, -NH-adamantil, -NH-CH2-adamantil,
-NH-CH(CH3)-fenil, -NH-CH(CH3)2-fenil,
-N(C1-4-alkoksi) - C1-4-alkil, -N (C1-4-alkoksi)-CH2-fenil,
-N(C1-4-alkoksi) -fenil, -NH-(CH3)-OBzl, -NH-(CH2)v-fenil (v = 0, 1, 2 ili 3), -NH-(CH2)m-naftil (m je 0 ili 1),
-NH-(CH2)w-benzhidril (w je 0, 1 ili 2), -NH-bifenil,
-NH-piridil, -NH-CH2-piridil, -NH-CH2-CH2-piridil,
-NH-benzotiazolil, -NH-benzoizotiazolil, -NH-benzopirazolil, -NH-benzoksazolil, -NH-(CH2)m-fluorenil (m je 0 ili 1), -NH-pirimidil, -NH-(CH2)m-indalil (m je 0 ili 1), -NH-(CH2CH2O)y-CH3 (y = 0, 1, 2, 3, 4 ili 5),
-NH-(CH2CH2O)y-CH2CH3 (y = 0, 1, 2, 3, 4 ili 5),
-(CH2CH2O)y-CH3 (y = 0, 1, 2, 3, 4 ili 5),
-(CH2CH2O)y-CH2CH3 (y = 0, 1, 2, 3, 4 ili 5), -NCH3-NH-C6H5, -NCH3-NH-CH2-C6H5; ili
K je
[image]
[image]
[image]
Spojevi formule I kojima se daje prednost su oni u kojima supstituenti R1, R2, A, B, D, E, X, F i t imaju slijedeća značenja:
R1je metil ili etil;
R2je vodik, metil ili etil;
A je valil, izoleucil, 2-terc.butilglicil;
B je N-metil-valil, izoleucil ili -2-terc.butil-glicil;
D je 3,4-dehidroprolil, 4-fluorprolil, azetidin-2-karbonil, 3-metilprolil ili 5-metilprolil;
E je prolil, homoprolil, hidroksiprolil ili tiazolidin-4-karbonil;
F je ostatak D-valil, 2-terc.butilglicil, D-izo-leucil, D-leucil ili aminoizobutiroil;
X je -CH(CH3)2, -C(CH3)3 ili -CH(CH3) CH2CH3;
t je 0 ili 1.
Značenja za K ponajprije jesu:
-OC(CH3)3, -NHCH3, -NHCH2CH3, -NH (CH2)2CH3, -NH(CH2)3CH3, -NH (CH2)4CH3, -NH (CH2)5CH3, -NH(CH2)6CH3, -NH(CH2)7CH3.
Značenja za K kojima se daje prednost jesu:
-OC(CH3)3, -NHCH3, -NHCH2CH3, -NH (CH2)2CH3, -NH(CH2)3CH3, -NH(CH2)4CH3, -NH(CH2)5CH3, -NH(CH2)6CH3, -NH(CH2)7CH3, -NHCH (CH3)2, -NHCH (CH3) CH2CH3, -NHCH(CH3)CH2CH2CH3, -NHCH(CH2CH3)2, -NH (CH2CH2CH3)2, -NHC(CH3)3, -NHCH(CH2CH3) CH2CH2CH3, -NHCH(CH3) CH(CH3)2, -NHCH (CH2CH3) CH(CH3)2, -NHCH(CH3) C(CH3)3, -NH-ciklopropil, -NH-ciklobutil, -NH-ciklopentil, -NH-cikloheksil, -NH-cikloheptil, -NH- ciklooktil, -NH-biciklo[3,3,0]-oktil, -N(CH3)OCH3, -N(CH3)OCH2CH3, -N(CH3) OCH2CH2CH3, -N(CH3)OCH(CH3)2, -N(CH2CH3)OCH3, -N (CH2CH3) OCH2CH3,
-N (CH (CH3)2) OCH3, -N (CH3) OCH2C6H5, -N (OCH3) CH2-C6H5, -N (CH3) OC6H5, -NH-CH2-C6H5, -N (CH2)2C6H5, -N(CH2)3C6H5, -NHCH (CH3) C6H5, -NHC (CH3)2C6H5, -NHC (CH3)2CH2CH3, -NHCH (CH3) (CH2CH3)2, -NHCH (CH3) CH (OH) C6H5, -NHCH2-ciklo-heksil, -NH-CH2CF3, -NHCH (CH2F)2, -NHC (CH3)2CH2CH2OH,
-NH(CH2CH2O)2CH2CH3, -NHC (CH3)2 (CH3)2, -NHC (CH3)2CN,
-NHC(CH3)2, norefedril, norpseudoefedril, -NH-kinolil,
-NH-pirazil, -NH-adamantil(2), -NH-CH2-adamantil(1),
-NH-CH2-adamantil, -NH-CH2-naftilf -NH-benzhidril,
-NH-bifenil, -NH-piridil, -NH-CH2-piridil,
-NH-CH2-CH2-piridilr -NH-benzotiazolil,
-NH-benzoizotiazolil, -NH-benzopirazolil,
-NH-benzoksazolil, -NH-fluorenil, -NH-pirimidil,
-NH-CH2-(4-metil)-tiazolil (2), -NH-CH2-furanil(2),
-NH-CH2 tienil (2), -NH-CH2- (5-metil) tienil (2),
-NH-tiazolil (2), -NH-izoksazolil(3),
-NH-(3-metil)izoksazolil(5), -NH-(3-metil)izotiazolil(5),
-NH-(2-trifluormetil)-tiadiazolil (5),
-NH-(2-ciklopropil)-tiadiazolil(5),
-NHC (CH3)2 =CH2, ili
K može biti
[image]
Ovi primjeri ilustriraju ali ne ograničavaju svrhu predloženog izuma.
Peptidi formule I sastavljeni su od L-amino kiselina, ali F također može biti i D-amino kiselina.
Novi spojevi mogu postojati kao soli s fiziološki podnošljivim kiselinama kao što su klorovodična kiselina, limunska kiselina, vinska kiselina, mliječna kiselina, fosforna kiselina, metansulfonska kiselina, octena kiselina, mravlja kiselina, maleinska kiselina, fumarna kiselina, jabučna kiselina, sukcinska kiselina, malonska kiselina, sumporna kiselina, L-glutaminska kiselina, L-asparatinska kiselina, piruvunska kiselina, mukoidna kiselina, benzojeva kiselina, glukuronska kiselina, oksalna kiselina, askorbinska kiselina i acetilglicin.
Novi spojevi mogu se proizvesti po poznatim metodama kemije peptida. Peptidi se tako mogu sastaviti slijedom od amino kiselina ili povezivanjem prikladnih malih peptidnih fragmenata. Kod slijednog povezivanja, počevši na C završetku peptidni lanac se postupno povećava svaki puta za jednu amino kiselinu. Kod spajanja fragmenata mogu se zajedno povezati fragmenti različitih duljina, a fragmenti se jedan za drugim mogu dobiti slijednim sastavljanjem od amino kiselina ili spajanjem njih samih s fragmentom.
U oba slučaja, kod slijednog sastavljanja i kod spajanja fragmenata, potrebno je povezati jedinice tvorbom amidne veze. Za to su prikladne enzimatske i kemijske metode.
Kemijske metode za tvorbu amidne veze opisane su u pojedinostima u Mueller, Methoden der organischen Chemie, Vol. XV/2, str. l do 364, Thieme Verlag, Stuttgart, 1974; Stewart, Young, Solid Phase Peptide Svnthesis, str. 31 do 34, 71 do 82, Pierce Chemical Company, Rockford, 1984; Bodanszky, Klausner, Ondetti, Peptide Synthesis, str. 85 do 128, John Wiley & Sons, New York, 1976 i u drugim standardnim radovima kemije peptida.
Posebnu prednost daje se metodi azida, simetričnoj i kombiniranoj metodi anhidrida, in situ stvaranjem ili pretvorbom aktivnih estera, upotrebi uretanom zaštićenih N-karboksi anhidrida amino kiselina i tvorbi amidne veze povezivanjem reagenata/aktivatora, a to su naročito dicikloheksilkarbo-diimid (DCC), diizopropilkarbodiimid (DIC), 1-etoksi-karbonil -2-etoksi-1,2-dihidrokinolin (EEDQ), 1-etil-3-(3-dimetil-aminopropil)karbodiimid-hidroklorid (EDCI), anhidrid n-propanfosfonske kiseline (PPA), N,N-bis-(2-okso-3-oksazoldinil)-amidofosforil klorid (BOP-C1), brom- tris- pirolidinofosfonijev heksafluorfosfat (PyBrop), difenilfosforil azid (DPPA), Castrov reagens (BOP, PyBop), O-benzotriazolil-N,N,N’,N’-tetrametiluronijeve soli (HBTU), O-azabenzotriazolil-N,N,N’,N’-tetrametiluronijeve soli (HATU), dietilfosforil cijanid (DEPCN), 2,5-difenil-2,3-dihidro-3-okso-4-hidroksitiofen dioksid (Steglichov reagens; HOTDO) i 1,1'-karbonildiimidazol (CDI). Reagensi za povezivanje inogu se upotrijebiti sami ili u kombinaciji s dodacima kao što su N,N-dimetil-4-amino-piridln (DMAP), N-hidroksi-benzotriazol (HOBt), N-hidroksi-benzotriazin (HOOBt), azabenzotriazol (HOAt), N-hidroksi-sukcinimid (HOSu) ili 2-hidroksipiridin.
Budući da se normalno u enzimatskoj sintezi peptida može izbjeći rad sa zaštitnim skupinama, reverzibilna zaštita reaktivnih skupina, koje nisu uključene u tvorbu amidne veze, nužna je u kemijskoj sintezi za oba reaktanta. Za kemijsku sintezu peptida prednost imaju tri uobičajena postupka sa zaštitnim skupinama: postupci s benziloksikarbonilom (Z), t-butoksikarbonilom (Boe) i 9-fluorenilmetoksikarbonilom (Fmoc). U svakom slučaju identificirana je zaštitna skupina na alfa amino skupini jedinice produženja lanca. Detaljan pregled zaštitnih skupina za amino kiseline dao je Mueller, Methoden der organischen Chemie Vol. XV/1, str. 20 do 906, Thieroe Verlag, Stuttgart, 1974. Jedinice koje se upotrebljavaju za sastavljanje peptidnog lanca mogu reagirati u otopini, u suspenziji ili metodom sličnom onoj koju je opisao Merrifield u J. Amer. Chem. Soc. 85 (1963) 2149. Posebno se preporučaju metode po kojima se peptidi sastavljaju slijedno ili povezivanjem fragmenata primjenom postupka Z, Boe ili Fmoc zaštitne skupine. Jedan od reaktanata u spomenutom Merrifieldovom postupku vezan je na netopivu polimernu podlogu (koja se u nastavku naziva također i smola). Ona tipično prenosi peptid, koji se sastavlja slijedom, na polimernu podlogu primjenom postupka sa zaštitnom skupinom Boe ili Emoc, pri čemu se rastući peptidni lanac uobičajeno povezuje na C kraju na čestice netopive smole (usporedi slike l i 2). Taj postupak omogućuje uklanjanje reagenata i sporednih proizvoda filtracijom, i stoga je nepotrebna prekristalizacija intermedijata.
Zaštićene amino kiseline mogu se povezati na bilo koje prikladne polimere, koji jedino moraju biti netopivi u upotrijebljenim otapalima i moraju imati fizički postojan oblik koji omogućuje laganu filtraciju. Polimer mora sadržavati funkcionalnu skupinu na koju se prva zaštićena amino kiselina može čvrsto pripojiti kovalentnom vezom. Za tu svrhu prikladno je veliko mnoštvo polimera, npr. celuloza, polivinil alkohol, polimetakrilat, sulfonirani polistiren, kopolimer klorometiliranog stirena i divinilbenzena (Merrifieldova smola), 4-metilbenzil-hidrilaminska smola (MBHA-smola), fenilacetamidometilna smola (Pam-smola), p-benziloksi-benzil-alkoholna smola, benzhidril-aminska smola (BHA-smola), 4-(hidroksimetil)-benziloksi-metilna smola, smola Breipohla i sur. (Tetrahedron Letters 28 (1987) 565; (koju isporučuje BACHEM), 4-(2r4-dimetoksifenilamino-metil)fenoksi smola (koju isporučuje Novabiochem) ili o-klorotritilna smola (koju isporučuje Biochellas).
Za sintezu peptida u otopini prikladna su sva otapala koja su inertni pod uvjetima reakcije, naročito voda. N, N-d ime ti l formaini d (DMF), dimetilsulfoksid, (DMSO) , aceto-nitril, diklormetan (DCM), 1,4-dioksan, tetrahidrofuran (THF), N-metil-2-pirolidon (NMP) i mješavine spomenutih otapala. Sinteza peptida na polimernoj podlozi može se prevesti u svim inertnim organskim otapalima u kojima su topivi upotrijebljeni derivati amino kiselina. Međutim, prednost se daje otapalima koja imaju dodatno svojstvo da u njima smola bubre, kao DMF, DCM, NMP, acetonitril i DMSO, i mješavine tih otapala. Po završetku sinteze, peptid se odvaja od polimerne podloge. Uvjeti pod kojima je moguće odvajanje različitih tipova smola obznanjeni su u literaturi. Reakcije odvajanja koje se općenito najčešće koriste su kiselo katalizirane i s paladijem kao katalizatorom, naročito odvajanje u tekućem bezvodnom fluorovodiku, u anhidridu trifluormetansulfonkse kiseline, u razrijeđenoj ili koncentriranoj trifluoroctenoj kiselini, odvajanje s paladijem kao katalizatorom u THF-u ili mješavini THF-DCM u prisutnosti slabe baze kao što je morfolin ili odvajanje u mješavini octene kiseline i diklormetana i trifluoretanola. Ovisno o odabranim zaštitnim skupinama, one se mogu zadržati ili također odcijepiti pod uvjetima odvajanja.
Djelomična deprotekcija peptida može tako biti korisna kad se provode određene reakcije derivatizacije. Peptidi dialkilirani na N-završetku mogu se pripremiti
a) povezivanjem odgovarajućih N,N-dialkilamino kiselina u otopini ili na polimernoj podlozi,
b) reduktivnim alkilranjem veze smola-peptid u DMF/1% octenoj kiselini s NaCNBH3 i odgovaraječim aldehidom ili ketonom,
c) hidrogeniranjem peptida u otopini u prisutnosti aldehida ili ketona i Pd/C.
Ovdje obznanjene razne amino kiseline, nastale neprirodnim putem, mogu se dobiti od komercijalnih izvora ili se mogu sintetizirati od komercijalno dostupnih materijala primjenom metoda poznatih u struci. Azetidin-2-karboksilna kiselina, 3-metil-L-prolin, 5-metil-L-prolin, i Boe- ili Fmoc-zaštićeni 3,4-dihidroprolin komercijalno su dostupni polazni materijali (ACROS, NOVABIOCHEM, BACHEM), Cis- i trans-4-fluorprolin mogu se pripremiti metodom koju su opisali Panasik i sur. (N. Panasik, E. S. Eberhardt, A. S Edison, D. R. Powell, R. T. Raines, Int. J. Peptide Protein Res. 44, 1994, 262-269) od hidroksi-prolina.
Spojevi ovog izuma inogu se upotrijebiti za inhibiciju ili za drugačiji način liječenja čvrstih tumora (tj. tumora pluća, dojke, debelog crijeva, bubrega, rektuma ili unutrašnjih tumora) ili hematoloških malignacija (tj. leukemije, limfoma) davanjem spoja sisavcima.
Naročita prednost novih spojeva je to da su oni u usporedbi s Dolastatinom-15 mnogo otporniji prema enzimatskoj razgradnji.
Lijek se može dati na bilo koji način uobičajen za farmaceutska, ponajprije onkološka sredstva, uključiv oralno, parenteralno kao subkutano, intravenski, intramuskularno i intraperitonealno.
Spojevi se mogu dati sami ili u obliku farmaceutskih sastava koji sadrže spoj formule I zajedno s farmaceutski prihvatljivim nosačem prikladnim za željeni način nadanja. Takovi farmaceutski sastavi mogu biti kombinirani proizvodi, tj. mogu također sadržavati i druge terapeutski aktivne sastojke.
Doza koja se daje sisavcima sadrži učinkovitu količinu aktivnog sastojka koji inhibira tumor ovisi o uobičajenim faktorima uključiv biološku aktivnost dotičnog upotrijebljenog spoja, načinu davanja, starosti, zdravstvenom stanju i tjelesnoj težini primaoca, prirodi i opsegu simptoma, učestalosti liječenja, davanju druge terapije i željenom učinku. Tipična dnevna doza bit će približno 0,5 do 50 miligrama po kilogramu tjelesne težine kod oralnog davanja ili 0,05 do 20 mg kod parenteralnog davanja.
Novi spojevi mogu se dati u čvrstim ili tekućim uobičajenim farmaceutskim oblicima, npr. neprevučene ili s filmom prevučene tablete, kapsule, puderi, granule, čepići ili otopine. Oni se proizvode na uobičajen način. U tu svrhu aktivne tvari mogu se preraditi s uobičajenim farmaceutskim pomoćnim sredstvima kao što su veziva za tablete, punila, konzervansi, sredstva za razaranje tableta, regulatori tecivosti, plastifikatori, kvasila, dispergatori, emulgatori, otapala, sastavi za potpomaganje oslobađanja, antioksidanti i/ili potisni plinovi (vidi H. Sucker i sur.: Pharmazeutische Technologie, Thieme-Verlagf Stuttgart, 1978). Oblici za davanje dobiveni na taj način normalno sadrže 1-90% mase aktivne tvari.
Slijedeći primjeri imaju svrhu objasniti izum. Proteinogene amino kiseline pisane su u primjerima u kraticama pri čemu se koristi poznati kod od tri slova. Ostale upotrijebljene kratice jesu: Me2Val = N,N-dimetil-valin, MeVal = N-metilvalin, Z = benziloksikarbonil.
A. Opći postupak
I. Naznačeni peptidi u patentnom zahtjevu 1 su ili sintetizira! klasičnom sintezom iz otopine primjenom standardne Z- ili Boe-metodologije, kako je gore opisano, ili primjenom standardnih metoda sinteze iz čvrste faze primjenom postupka sa Boe ili Fmoc zaštitnom skupinom.
a) Ciklus sinteze za postupak sa Fmoc zaštitnom skupinom:
1. Ispiranje s DMF-om 1 x 1 min
2. 20%-tni piperidin u DMF-u 1 x 4 min
3. 20% piperidin u DMF-u 1 x 16 min
4. Ispiranje s DMF-pm 5 x 1 min
5. Dodavanje prethodno aktivirane
zaštićene amino kiseline (aktivacija s 1 ekvivalentom TBTU-a i
5 ekvivalenata DIPEA-a u DMF-u) 1 x 61 min
6. Ispiranje s DMF-om 3x1 min
7. Ako pretvorba nije potpuna, ponavljanje povezivanja (ponovno od 5.)
8. Ispiranje s DMF-om 3 x l min
9. Ponavljanje od 2.
BOP-Cl i PyBrop upotrijebljeni su kao reagensi za povezivanje amino kiseline iza N-metilamino kiselina. Vremena reakcija odgovarajuće su rasla s uključenjem dvostrukog povezivanja. Kod sinteze u otopini za taj tip povezivanja najveću prednost ima upotreba Boc-zaštićene amino kiseline NCA-a (N-karboksi anhidridi) , Z-zaštićenih amino kiselinskih NCA-a (N-karboksi anhidrida) ili upotreba pivaloilklorida kao sredstva za kondenzaciju.
II. Reduktivno alkiliranje N-završetka
Peptidna smola pripremljena kao u Ala oslobodi se zaštite na N-završetku (postupci 2-4 u Ala) i zatim reagira s trostrukim molskim suviškom aldehida ili ketona u DMF/-% octenoj kiselini s dodatkom 3 ekvivalenta NaCNBH3. Po završetku reakcije (Kaiserov test negativan) smola se ispere nekoliko puta s vodom, izopropanolom, DMF-om i diklormetanom.
Reduktivno alkiliranje u otopini može se provesti npr. pomoću reakcije N-terminalno zaštićenih peptida, peptidnih fragmenata/ ili amino kiselina s odgovarajućim aldehidima ili ketonima upotrebom NaCNBH3 ili vodika-Pd/C.
III. Obrada peptidne smole dobivene u 1b i II
Peptidna smola osuši se pod smanjenim tlakom i zatim se 1,5 sata obraduje s mješavinom TFA/vode (95:5) (Wadef Treager, Howard Florey Fmoc Workshop Manual, Melbourne 1985) . Zatim se smola odfiltrira i ispere s TFA i DCM. Filtrat i eluati se koncentriraju, peptid se istaloži dodatkom dietiletera. Nakon hlađenja na ledenoj kupelji talog se odfiltrira, preuzme u 30%-tnu octenu kiselinu i liofilizira.
IV, Kod upotrebe o-klortritilne smole (isporučuje ju Biohellas) suspenziju peptidne smole u mješavini octena kiselina/trifluoretanol/diklometana (1:1:3) miješa se 1 sat pri sobnoj temperaturi. Smolu se zatim odfiltrira odsisavanjem i temeljito ispere s otopinom za odvajanje. Sjedinjeni filtrati se koncentriraju u vakuumu i obrade s eterom. Istaložena čvrsta tvar se odstrani filtracijom ili centrifugiranjem, ispere s dietileterom i osuši pod smanjenim tlakom.
V. Čišćenje i karakterizacija peptida
Čišćenje se provodi pomoću gel kromatografije (SEPHADEX G-10, G-15/10% HOAc, SEPHADEX LH20/MeOH) i/ili kromatografijom srednjeg pritiska (stacionarna faza: HD-SIL C-8, 20-45 mikrona, 100 angstrema; mobilna faza: gradijent s A = 0,1% TFA/voda, B = 0,1% TFA/MeOH) , ili preparativna HPLC (stacionarna faza: Waters Delta-Pak C-18, 15 mikrona, 100 angstrema; mobilna faza: gradijent s A = 0,1% TFA/voda, B = 0,1% TFA/MeOH).
Čistoća dobivenih proizvoda određena je pomoću analitičke HPLC (stacionarna faza: 100 2, 1 mm VYDAC C-18, 300 angstrema; mobilna faza: gradijent acetonitril-vode, puferiran s 0,1% TFA, 40°C). Karakterizacija je provedena pomoću masene spektroskopije bombardiranjem s brzim atomima i NMR spektroskopije.
B. Posebni postupci
Primjer 1
(SEQ 1D NO: 1)
Me2Val-Val-MeVal-3,4-dehidroprolil-Pro-amid
0,53 g smole Fmoc-RINK (supstitucija 0,46 mmol/g), koja odgovara veličini šarže od 0,25 mmola, reagirala je kao u Ala s 0,4 mmola svakog od
Fmoc-Pro-OH
Fmoc-3,4-dehidroprolin
Fmoc-MeVal-OH
Fmoc-Val-OH
Fmoc-Val-OH
Amino kiselina iza N-metilamino kiseline bila je povezana dvostrukim povezivanjem. Po završetku ponovljenih ciklusa sinteze ciklusa, peptidna smola podvrgnuta je deprotekciji N-završetka (postupci 2-4 u Ala), i dalje je reagirala s vodenom otopinom formaldehida kao u Ala i zatim je osušena pod smanjenim tlakom. Dobivena smola podvrgnuta je odvajanju Tfa kao u AIII. Sirov proizvod (132 mg) očišćen je preparativnom kromatografijom srednjeg pritiska s iskorištenjem 32 mg željenog čistog peptida (10-40 % A u 10' ; 40-90% A u 140') . Spoj je nadalje karakteriziran pomoću masene spektrometrije bombardiranjem s brzim atomima ([M+H]+ = 548).
Primjer 2
(SEQ ID NO: 1)
Me2Val-Val-MeVal-[(2S,3S)-3-metil-pirolidin-2-karbonil]-Pro-benzilamid
a) Z- (2S,3S)-3-metil-pirolidin-2-karboksilna kiselina
1,5 g (2S,3S)-3-metil-pirolidin-2-karboksilne kiseline (11, 6 mmola) otopi se u 4 ml vode i 2, 33 ml 5N NaOH. Pri 4°C tijekom l sata doda se 2,12 ml benzil-kloroformata (Z-Cl; 12,8 mmola) i 6,5 ml 2N NaOH. Reakcijsku smjesu miješa se preko noći pri sobnoj temperaturi i zatim se pH namjesti na 10. Vodeni sloj se ekstrahira s diklormetanom (4 x), s 5N HCl namjesti pH na 2 i ekstrahira se s diklormetanom (2 x). Sjedinjeni organski ekstrakti se osuše preko natrijevog sulfata i ispare u vakuumu. Dobije se 1,75 g željenog proizvoda kao ulja.
b) Z-(2S,3S)-3-metil-pirolidin-2-karbonil-L-prolil benzilamid
1, 75 g (2S,3S)-3-metil-pirolidin-2-karboksilne kiseline (6,62 mmola) i 1,59 g prolin benzilamid-hidro-klorida (6,62 mmola) otopi se u 66 ml diklormetana i ohladi na 4°C. Nakon dodatka 0,89 ml N-metilmorfolina (7,94 mmola), 0,304 g HOBt (2,21 mmola) i 1,28 g EDCI (6,62 mmola) reakcijsku smjesu miješa se preko noći pri sobnoj temperaturi, razrijedi se sa 150 ml diklormetana i ispere sa zasićenom otopinom natrijevog hidrogen-karbonata (3 x), s vodom (1x), 5%-tnom limunskom kiselinom (3 x), vodom (1x) i zasićenom otopinom NaCl (1x). Organski sloj se osuši iznad natrijevog sulfata i zgusne pod smanjenim tlakom. Dobije se 2,63 g visoko viskoznog ulja.
c) (2S,3S)-metil-pirolidin-2-karbonil-L-prolil benzilamid
2,63 g Z-(2S,3S)-3-metil-pirolidin-2-karbonil-L-prolil benzilamida (5,8 mmola) otopi se u 43 ml metanola. Doda se 105 mg 10%-tnog paladij/ugljena i reakcijsku smjesu hidrogenira se preko noći. Nakon filtracije i sušenja dobije se 1,88 g dipeptida bez zaštite.
d) Z-MeVal-[(2S, 3S)-3-metil-pirolidin-2-karbonil]-Pro-benzilainid
1,54 g Z-MeVal-OH (5,8 mmola) i l, 88 g (2S,3S)-3-metil-pirolidin-2-karbonil-L-prolil benzilamida (5, 8 mmola) otopi se u 58 ml diklormetana i ohladi na 4°C. Doda se 0,78 ml N-metilmorfolina (6,96 mmola) , 0,266 g HOBt (1,93 mmola) i 1,12 g EDCI (5,8 mmola) i reakcijsku smjesu miješa se preko noći pri sobnoj temperaturi, razrijedi se sa 120 ml diklormetana, ispere sa zasićenom otopinom natrijevog hidrogen-karbonata, jednom (3 x), s vodom (1x), 5%-tnom limunskom kiselinom (3 x) , vodom (1x) i sa zasićenom otopinom NaCl (1x). Organski sloj se osuši preko natrijevog sulfata i zgusne pod smanjenim tlakom. Dobije se 3,01 g proizvoda kao suhe bijele pjene.
e) MeVal-[(2S,3S)-3-metil-pirolidin-2-karbonil]-Pro-benzilamid
3,01 g Z-MeVal-[(2S, 3S)-3-metil-pirolidin-2-karbonil]-Pro-benzilamida (5,33 mmola) otopi se u 39 ml metanola. Doda se 96 mg 10%-tnog paladij/ugljena i reakcijsku smjesu hidrogenira se 3 sata. Nakon filtracije i sušenja dobije se 2, 18 g tripeptida bez zaštite kao bistro ulje.
f) Z-Val-MeVal-[(2S,3S)-3-metil-pirolidin-2-karbonilj-Pro-benzilamid
1,28 g Z-Val-OH (5,11 mmola) otopi se u 10 ml diklormetana. Doda se 0,73 ml trietilamina (5,37 mmola) i ohladi se na -10°C. Polako se doda 0,66 ml pivaloilklorida (5,37 mmola). Smjesu se miješa l sat pri -10°C i zatim se doda otopinu od 2,8 g MeVal-[(2S, 3S)-3-metil-pirolidin-2-karbonil]-Pro-benzilamida (5,11 mmola) i 0,73 ml trietilamina (5,37 mmola) u 10 ml diklormetana. Reakcijsku smjesu miješa se l sat pri -10°C i preko noći pri sobnoj temperaturi. Razrijedi se s diklormetanom i ispere sa zasićenom otopinom natrijevog hidrogen-karbonata, (3 x) , s vodom (1x), 5%-tnom limunskom kiselinom (3 x), vodom (1x) i sa zasićenom otopinom NaCl (1x). Organski sloj se osuši preko natrijevog sulfata i zgusne. Dobije se 2,75 g proizvoda kao suhe pjene.
g) Val-MeVal-[ (2S,3S)-3-metil-pirolidin-2-karbonil]-Pro-benzilamid
2,75 g Z-Val-MeVal-[(2S,3S)-3-metil-pirolidin-2-karbonil]-Pro-benzilamida (4,13 mmola) otopi se u 30 ml metanola. Doda se 0,34 ml konc. HC1 (4,13 mmola) i 78 mg 10%-tnog paladij/ugljena i reakcijsku smjesu hidrogenira se 3 sata. Nakon filtracije i isparavanja do suhog dobije se 2,23 g tripeptida bez zaštite kao suhe bijele pjene. Sirov proizvod otopi se dalje u 50 ml vode i pH se namjesti na 2-3 s 1N HCl. Vodeni sloj se ekstrahira s diklormetanom (3 x), s 5N NaOH namjesti se pH na 5 i dalje se ekstrahira s diklormetanom (3 x). Sjedinjeni organski ekstrakti se osuše preko natrijevog sulfata i zgusnu pod smanjenim tlakom. Dobije se 1, 74 g nezaštićenog tripeptidnog benzilamida.
h) Me2Val-Val-MeVal-[(2S,3S)-3-metil-pirolidin-2-karbonil] -Pro-benzilarnid
0,47 Me2Val-OH (3,24 mmola) i 1,71 g Val-MeVal-[(2S, 3S)-3-metil-pirolidin-2-karbonil]-Pro-benzilamida (3,24 mmola) otopi se u 32 ml suhog DMF-a. Ohladi se na 4°C i doda se 1,07 ml DEPCN (6,48 mmola) i 1,88 ml trietilamina (12,96 mmola). Reakcijsku smjesu miješa se preko noći pri sobnoj temperaturi i DMF se ispari pod smanjnim tlakom. Ostatak se otopi u 100 ml diklormetana i ispere sa zasićenom otopinom natrijevog hidrogen-karbonata, (3 x) , s vodom (1x), 5%-tnom limunskora kiselinom (3 x), vodom (1x) i sa zasićenom otopinom NaCl (4x). Organski sloj se osuši preko natrijevog sulfata i zgusne pod smanjenim tlakom. Dobije se 0, 88 g proizvoda kao kao bezbojnog ulja. Sirov proizvod otopi se u ključajućem diizopropileteru i istaloži se nakon hlađenja. Talog se skupi i osuši. Dobije se 0,56 g čistog proizvoda. Spoj je dalje karakteriziran masenom spektroskopijom bombardiranjem s brzim atomima
([M+H]+ = 655,6).
Proizvedeni su slijedeći spojevi i mogu se proizvesti sukladno primjerima 1 i 2:
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Primjeri MS-karakterizacije sintetiziranih novih spojeva dati su u slijedećoj tablici.
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Tablica I. Identifikacija sekvence spojeva proizvedenih sukladno primjerima l i 2.
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Simboli Xaa u sažetku imaju slijedeća značenja:
Xaa: N, N-dimetilvalin
Xab: N-metilvalin
Xac: 3,4-dehidroprolin
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Spojevi ovog izuma mogu se ocijeniti glede anti-kancernog djelovanja konvencionalnim metodama, uključiv na primjer, metode opisane u nastavku.
A. Metodologija in vitro
Citotoksičnost je izmjerena primjenom standardne metodologije na adherentnim staničnim linijama kao što je ispitivanje na mikrokulturi tetrazolija (MTT, mickroculture tetrazolium assay). Pojedinosti ovog ispitivanja bile su objavljene (Alley, Me i sur., Cancer Research 48 : 589-601, 1988). Za pripravu mikrotitarske ploče kultura upotrijebljene su eksponencijalno rastuće kulture stanica tumora kao što je HT-29 rak debelog crijeva ili LX-1 tumora pluća. U 96-jamičnu ploču (u 150 μl medija) zasađeno je 500-20.000 stanica po jamici i stanice su rasle preko noći pri 37°C. Ispitni spojevi su dodani u deseterostrukom razredenju varirajanjući od 10-4 do 10-10 M. Stanice su zatim inkubirane 48 sati.
Za određivanje broja za život sposobnih stanica u svakoj jamici dodana je MTT boja (50 μl otopine od 3 mg/ml od 3-(4, 5-diemtiltiazol-2-il)-2,5-difeniltetrazolijevog bromida u otopini soli). Smjesa je inkubirana 5 sati pri 37°C i zatim je u svaku jamicu dodano po 50 μl od 25%-ne SDS, pH 2. Nakon inkubacije preko noći, pomoću ELISA čitača očitana je apsorbancija svake jamice kod 550 nm. Izračunate su srednje vrijednosti +/- standardno odstupanje podataka iz ponovljenih jamica pomoću formule % T/C (% za život sposobnih obrađenih stanica /kontrolnih).
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Koncentracija ispitnog spoja koja daje T/C od 50% inhibicije rasta označena je kao vrijednost IC50.
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B. Metodologija in vivo
Spojevi ovog izuma bili su nadalje ispitani u predkliničkim ispitivanjima glede in vivo djelovanja koje je indikacija kliničke upotrebljivosti. Takovi pokusi provedeni su s bezdlakim miševima u koje je transplantirano (ksenografirano) tkivo tumora, ponajprije humanog podrijetla, što je dobro poznato u tom području. Dati miševima koji nose ksenografirani tumor ispitni spojevi bili su ocijenjeni glede njihove anti-tumorske učinkovitosti.
Potanje, humani tumori dojke (MX-1) koji su rasli u atimičkim bezdlakim miševima transplantirani su u nove jiecipijentne miševe, koristeći fragmente tumora koji su bili veličine približno 50 mg. Dan presađivanja bio je označen kao dan 0. Šest dana kasnije miševi, u skupina od po 5-10 miševa, obrađeni su s ispitnim spojevima datim intravenskom injekcijom. Spojevi su davani svaki drugi dan tijekom 3 tjedna dozom od 1-100 mg/kg tjelesne težine. Promjeri tumora i tjelesne težine mjerene su dva puta tjedno. Volumeni tumora izračunati su pomoću promjera izmjerenog s Vernerovim šestarom i formule
(duljina x širina2)/2 = mm3 volumena tumora
Prosječni volumeni tumora izračunati su za svaku liječenu skupinu, a T/C vrijednosti određene su za svaku skupinu prema kontrolnim neobrađenim tumorima.
Novi spojevi imaju dobra svojstva inhibicije tumora.
Claims (5)
1. Novi peptidi formule I
R1R2N-CHK-CO-A-B-D-E- (F)t-K I
naznačeni time, da
R1je metil, etil ili izopropil;
R2je vodik, metil ili etil;
R1-N-R2mogu zajedno biti pirolidinski prsten;
A je valil, izoleucil, leucil, 2~terc.butilglicil, 2-etilglicil, norleucil ili norvalil;
B je N-metil-valil, leucil, izoleucil, norvalil, norleucil, -2-terc.butilglicil, -3-terc.butilalanil, ili -2-etilglicil;
D je 3,4-dehidroprolil, 4-fluorprolil, 4,4-difluor-prolil, azetidin-2-karbonil, 3-metilprolil, 4-metilprolil ili 5-metilprolil;
E je prolil, homoprolil, hidroksiprolil ili tiazolidin-4-karbonil;
F je valil, 2-terc.butilglicil, izoleucil, leucil, 2-cikloheksilglicil, norleucil, norvalil, neopentilglicil, alanil, β-alanil ili aminoizobutiroil;
X je alkil (ponajprije C2-5), ciklopropil ili ciklopentil;
t je 0 ili 1; i
K je alkoksi (ponajprije C1-4), benziloksi ili supstituirana ili nesupstituirana amino skupina; i njihove soli s fiziološki podnošljivim kiselinama.
2. Spojevi formule I ili njihove soli, naznačeni time, da se upotrebljavaju u medicini, a posebno za liječenje onkoloških bolesti.
3. Farmaceutski sastav, naznačeni time, da sadrži farmakološki prihvatljivu noseću tvar i terapeutski učinkovitu količinu spoja prema zahtjevu 1.
4. Metoda liječenja tumora kod sisavaca, naznačena time, da se sisavcima koji nose takav tumor daje spoj formule I, kako je definiran u zahtjevu 1, količinom koja inhibira tumor.
5. Metoda za pripravu spojeva formule I prema zahtjevu 1, naznačena time, da se oni pripremaju sukladno poznatim metodama kemije peptida.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/472,453 US5831002A (en) | 1992-05-20 | 1995-06-07 | Antitumor peptides |
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| Publication Number | Publication Date |
|---|---|
| HRP960277A2 true HRP960277A2 (en) | 1997-10-31 |
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| HR08/472,453A HRP960257A2 (en) | 1995-06-07 | 1996-06-06 | New compounds, their preparation and use |
| HR08/472,453A HRP960277A2 (en) | 1995-06-07 | 1996-06-06 | Novel compounds, the preparation and use thereof |
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| US (1) | US5831002A (hr) |
| EP (2) | EP0871656B1 (hr) |
| JP (2) | JP4221062B2 (hr) |
| KR (2) | KR100437985B1 (hr) |
| CN (2) | CN1182154C (hr) |
| AR (2) | AR003427A1 (hr) |
| AT (2) | ATE224910T1 (hr) |
| AU (2) | AU725170B2 (hr) |
| BG (2) | BG102125A (hr) |
| BR (2) | BR9609423A (hr) |
| CA (2) | CA2219818C (hr) |
| CO (2) | CO4700527A1 (hr) |
| CZ (2) | CZ293682B6 (hr) |
| DE (2) | DE69623992T2 (hr) |
| DK (2) | DK0832104T3 (hr) |
| ES (2) | ES2186783T3 (hr) |
| HR (2) | HRP960257A2 (hr) |
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| MY (2) | MY119042A (hr) |
| NO (2) | NO318384B1 (hr) |
| NZ (2) | NZ310444A (hr) |
| PL (2) | PL185762B1 (hr) |
| PT (2) | PT871656E (hr) |
| RO (2) | RO118953B1 (hr) |
| SI (2) | SI0832104T1 (hr) |
| SK (1) | SK282466B6 (hr) |
| TR (2) | TR199701545T1 (hr) |
| TW (2) | TW508357B (hr) |
| UA (2) | UA46776C2 (hr) |
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| US5807984A (en) * | 1995-11-09 | 1998-09-15 | Basf Aktienegesellschaft | Oligopeptides, the preparation and use thereof |
| TW474946B (en) * | 1995-12-15 | 2002-02-01 | Basf Ag | Novel compounds, the preparation and use thereof |
| US20010009901A1 (en) * | 1996-12-11 | 2001-07-26 | Basf Aktiengesellschaft Germany | Antineoplastic peptides |
| US5965537A (en) * | 1997-03-10 | 1999-10-12 | Basf Aktiengesellschaft | Dolastatin 15 derivatives with carbonyl and heterocyclic functionalities at the C-terminus |
| US6103698A (en) * | 1997-03-13 | 2000-08-15 | Basf Aktiengesellschaft | Dolastatin-15 derivatives in combination with taxanes |
| US6143721A (en) * | 1997-07-18 | 2000-11-07 | Basf Aktiengesellschaft | Dolastatin 15 derivatives |
| US6015790A (en) * | 1997-10-06 | 2000-01-18 | Basf Aktiengesellschaft | Methods and compositions for treating rheumatoid arthritis |
| US5985837A (en) * | 1998-07-08 | 1999-11-16 | Basf Aktiengesellschaft | Dolastatin 15 derivatives |
| US6395897B1 (en) | 1999-03-02 | 2002-05-28 | Boehringer Ingelheim Pharmaceuticals, Inc. | Nitrile compounds useful as reversible inhibitors of #9 cathepsin 5 |
| US6420364B1 (en) | 1999-09-13 | 2002-07-16 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compound useful as reversible inhibitors of cysteine proteases |
| AU775373B2 (en) | 1999-10-01 | 2004-07-29 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
| US7018642B2 (en) | 2001-04-27 | 2006-03-28 | The Procter & Gamble Company | Compounds, compositions, and methods for controlling biofilms |
| AU2002359792A1 (en) * | 2001-12-18 | 2003-06-30 | Proteologics, Inc. | Methods and compositions for the inhibition of viral release |
| WO2003072754A2 (en) * | 2002-02-27 | 2003-09-04 | The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Conjugates of ligand, linker and cytotoxic agent and related compositions and methods of use |
| WO2006013552A2 (en) | 2004-08-02 | 2006-02-09 | Ramot At Tel Aviv University Ltd. | Articles of peptide nanostructures and method of forming the same |
| CA2607940C (en) | 2005-05-18 | 2009-12-15 | Aegera Therapeutics Inc. | Bir domain binding compounds |
| EP1924245A2 (en) * | 2005-08-19 | 2008-05-28 | Government of the United States of America, Represented by the Secretary, Department of Health and Human Services | Topical formulations of histone deacetylase inhibitors and methods of using the same |
| EP1973928A2 (en) * | 2005-10-11 | 2008-10-01 | Ramot at Tel-Aviv University Ltd. | Self-assembled fmoc-ff hydrogels |
| US8163792B2 (en) | 2006-05-16 | 2012-04-24 | Pharmascience Inc. | IAP BIR domain binding compounds |
| JP5452223B2 (ja) * | 2006-07-24 | 2014-03-26 | テトラロジック ファーマシューティカルズ コーポレーション | Ｉａｐ阻害剤 |
| CN101674835B (zh) * | 2007-04-12 | 2013-12-11 | 台湾神隆股份有限公司 | 制备加兰他敏的方法 |
| UY32099A (es) | 2008-09-11 | 2010-04-30 | Enanta Pharm Inc | Inhibidores macrocíclicos de serina proteasas de hepatitis c |
| US8283372B2 (en) | 2009-07-02 | 2012-10-09 | Tetralogic Pharmaceuticals Corp. | 2-(1H-indol-3-ylmethyl)-pyrrolidine dimer as a SMAC mimetic |
| SG10201501095WA (en) | 2010-02-12 | 2015-04-29 | Pharmascience Inc | Iap bir domain binding compounds |
| CA2822556A1 (en) | 2010-12-30 | 2012-07-05 | Enanta Pharmaceuticals, Inc | Macrocyclic hepatitis c serine protease inhibitors |
| CN103380132B (zh) | 2010-12-30 | 2016-08-31 | 益安药业 | 菲啶大环丙型肝炎丝氨酸蛋白酶抑制剂 |
| US10201584B1 (en) | 2011-05-17 | 2019-02-12 | Abbvie Inc. | Compositions and methods for treating HCV |
| EA201391756A1 (ru) * | 2011-05-27 | 2014-05-30 | Амбркс, Инк. | Композиции, содержащие, способы, включающие, и применение производных доластатина, связанных с неприродными аминокислотами |
| WO2015103490A1 (en) | 2014-01-03 | 2015-07-09 | Abbvie, Inc. | Solid antiviral dosage forms |
| MX2024002571A (es) | 2021-09-03 | 2024-03-20 | Toray Industries | Composicion farmaceutica para tratamiento y/o prevencion de cancer. |
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| US4816444A (en) * | 1987-07-10 | 1989-03-28 | Arizona Board Of Regents, Arizona State University | Cell growth inhibitory substance |
| US4879278A (en) * | 1989-05-16 | 1989-11-07 | Arizona Board Of Regents | Isolation and structural elucidation of the cytostatic linear depsipeptide dolastatin 15 |
| DK0934950T3 (da) * | 1991-08-09 | 2002-07-29 | Teikoku Hormone Mfg Co Ltd | Tetrapeptidderivat |
| CZ292612B6 (cs) * | 1992-05-20 | 2003-11-12 | Abbott Gmbh & Co. Kg | Peptid s protirakovinnou aktivitou, jeho použití a farmaceutický prostředek s obsahem takového peptidu |
| US5530097A (en) * | 1994-08-01 | 1996-06-25 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Human cancer inhibitory peptide amides |
| US5504191A (en) * | 1994-08-01 | 1996-04-02 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Human cancer inhibitory pentapeptide methyl esters |
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1995
- 1995-06-07 US US08/472,453 patent/US5831002A/en not_active Expired - Lifetime
-
1996
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- 1996-06-03 WO PCT/EP1996/002392 patent/WO1996040751A1/en active IP Right Grant
- 1996-06-03 PT PT96918661T patent/PT871656E/pt unknown
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- 1996-06-03 HU HU9801910A patent/HU228071B1/hu not_active IP Right Cessation
- 1996-06-03 EP EP96918661A patent/EP0871656B1/en not_active Expired - Lifetime
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- 1996-06-03 CN CNB961944676A patent/CN1182154C/zh not_active Expired - Fee Related
- 1996-06-03 DK DK96918660T patent/DK0832104T3/da active
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