HRP960257A2 - New compounds, their preparation and use - Google Patents
New compounds, their preparation and use Download PDFInfo
- Publication number
- HRP960257A2 HRP960257A2 HR08/472,453A HRP960257A HRP960257A2 HR P960257 A2 HRP960257 A2 HR P960257A2 HR P960257 A HRP960257 A HR P960257A HR P960257 A2 HRP960257 A2 HR P960257A2
- Authority
- HR
- Croatia
- Prior art keywords
- acid
- methyl
- tert
- methylprolyl
- alkyl
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims description 33
- 238000002360 preparation method Methods 0.000 title description 3
- -1 2-tert.butylglycyl Chemical group 0.000 claims description 84
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 30
- 206010028980 Neoplasm Diseases 0.000 claims description 19
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 5
- 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 5
- 229950003188 isovaleryl diethylamide Drugs 0.000 claims description 5
- 125000002114 valyl group Chemical group 0.000 claims description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 4
- 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 description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[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
- 125000003277 amino 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
- 125000001980 alanyl group Chemical group 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- 125000001424 substituent group Chemical group 0.000 description 25
- 229910052736 halogen Inorganic materials 0.000 description 23
- 150000002367 halogens Chemical class 0.000 description 23
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 23
- 239000011347 resin Substances 0.000 description 23
- 229920005989 resin Polymers 0.000 description 23
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 23
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 22
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 description 22
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 22
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 21
- 239000000243 solution Substances 0.000 description 20
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 19
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 19
- 125000004122 cyclic group Chemical group 0.000 description 18
- 229940024606 amino acid Drugs 0.000 description 15
- 150000001413 amino acids Chemical class 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-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
- 239000000047 product Substances 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 239000012634 fragment Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 6
- 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
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 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
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 235000015165 citric acid Nutrition 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 125000001072 heteroaryl group Chemical group 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
- 229920000307 polymer substrate Polymers 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 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
- 230000037396 body weight Effects 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-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
- 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
- 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 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
- 239000003795 chemical substances by application Substances 0.000 description 3
- 108010045552 dolastatin 15 Proteins 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000007788 liquid 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
- 239000007787 solid Substances 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
- 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
- OMGHIGVFLOPEHJ-UHFFFAOYSA-N 2,5-dihydro-1h-pyrrol-1-ium-2-carboxylate Chemical compound OC(=O)C1NCC=C1 OMGHIGVFLOPEHJ-UHFFFAOYSA-N 0.000 description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-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
- 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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 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
- 230000002378 acidificating effect Effects 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
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- VLNZUSMTOFYNPS-UHFFFAOYSA-N diethylphosphorylformonitrile Chemical compound CCP(=O)(CC)C#N VLNZUSMTOFYNPS-UHFFFAOYSA-N 0.000 description 2
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-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
- 230000000694 effects Effects 0.000 description 2
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 235000011167 hydrochloric acid Nutrition 0.000 description 2
- 238000005984 hydrogenation reaction Methods 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
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 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
- 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
- 239000000843 powder Substances 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
- 239000000725 suspension Substances 0.000 description 2
- 239000003826 tablet Substances 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
- 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
- NNEHOKZDWLJKHP-LBPRGKRZSA-N (2s)-3-methyl-2-[methyl(phenylmethoxycarbonyl)amino]butanoic acid Chemical compound CC(C)[C@@H](C(O)=O)N(C)C(=O)OCC1=CC=CC=C1 NNEHOKZDWLJKHP-LBPRGKRZSA-N 0.000 description 1
- CNPSFBUUYIVHAP-AKGZTFGVSA-N (2s)-3-methylpyrrolidine-2-carboxylic acid Chemical compound CC1CCN[C@@H]1C(O)=O CNPSFBUUYIVHAP-AKGZTFGVSA-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
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 description 1
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
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Classifications
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- 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)
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- Biophysics (AREA)
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- Public Health (AREA)
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- 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-CHK-CO-A-B-D-E-(F)t-K I
u kojoj
R1 je metil, etil ili izopropil;
R2 je vodik, metil ili etil;
R1-N-R2 mogu 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.butilalanil, ili -2-etilglicil;
D je prolil, 3,4-dehidroprolil, 4-fluorprolil, 4,4-difluorprolil, azetidin-2-karbonil, homoprolil, 3-metil-prolil, 4-metilprolil, 5-metilprolil, ili tiazolidin-4-karbonil;
E je 3,4-dehidroprolil, 4-fluorprolil, 3-metil-prolil, 4-metilprolil, azetidin-2-karbonil, ili 4,4-difluorprolil;
F je valil, 2-terc.butilglicil, izoleucil, leucil, 2-cikloceksilglicil, norleucil, norvalil, neopentilglicil, alanil, p-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 araino 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 prihvatijvim nosačem i metode za njihovu upotebu kod liječenja raka kod sisavaca.
Posebno, K može biti C1-4-alkoksi, benziloksi, ili amino dio formule R5-N-R6 u kojoj
R5 je vodik, ili hidroksi, ili C1-4-alkoksi, ili benziloksi (koji može biti supstituiran sa do dva supstituenta koji neovisno mogu biti CF3, nitro, C1-4-alkil-sulfonil, C1-4-alkoksi, halogen, C1-4-alkil, cijano, hidroksi, N(CH3)2, COOMe, COOEt, COOiPr, ili COONH2), ili feniloksi (koji može biti supstituiran sa do dva supstituenta koji neovisno mogu biti CF3, nitro, C1-4-alkil-sulfonil, C1-4-alkoksi, halogen, C1-4-alkil, cijano, hidroksi, N(CH3)2, COOMe, COOEt, COOiPr, ili COONH2);
R6 je vodik, ili C1-12-alkil (koji može biti supstituiran s jednim ili više fluorovih atoma), ili
-C(CH3)2CN, ili -C(CH3)2CCH, ili -C (CH3)2C=CH2, ili
-C(CH3)2CH2OH, ili -C(CH3)2CH2CH2OH, ili
-(CH2)v-C3-7-cikloalkil (v = 0,1 ili 2) (koji može biti supstituiran s metilnom skupinom), ili norefedril, ili norpseudo-efedril, ili kinolil, ili pirazil, ili adamantil, ili -CH2-benzimidazolil, ili -CH2-adamantil, ili alfa-metil-benzil, ili alfa-dimetilbenzil, ili
-(CH2)v-fenil (v = 0,1,2 ili 3; koji može biti supstituiran sa do dva supstituenta koji neovisno mogu biti CF3, nitro, C1-4-alkilsulfonil, C1-4 alkoksi, halogen, C1-4-alkil koji može tvoriti ciklički sistem, cijano, hidroksi, N(CH3)2, COOMe, COOEt, COOiPr, ili COONH2), ili
-(CH2)m-naftil (m = 0 ili 1; koji može biti supstituiran sa do dva supstituenta koji neovisno mogu biti CF3 nitro, C1-4-alkilsulfonil, C1-4-alkoksi, halogen, C1-4-alkil koji može tvoriti ciklički sistem, cijano, hidroksi, N(CH3)2, COOMe, COOEt, COOiPr, ili COONH2), ili
-(CH2)w-benzhidril (w = 0,1 ili 2; koji može biti supstituiran sa do dva supstituenta kej i neovisno mogu biti CF3, nitro, C1-4-alkilsulfonil, C1-4-alkoksi, halogen, C1-4-alkil koji može tvoriti ciklički sistem, cijano, hidroksi, N(CH3)2, COOMe, COOEt, COOiPr, ili COONH2), ili
bifenil (koji može biti supstituiran sa do dva supstituenta koji neovisno mogu biti CF3, nitro, C1-4-alkilsulfonil,
C1-4-alkoksi, halogen, C1-4-alkil koji može tvoriti ciklički sistem, cijano, hidroksi, N(CH3)2, COOMe, COOEt, COOiPr, ili COONH2), ili
piridil (koji može biti supstituiran sa do dva supstituenta koji neovisno mogu biti CF3, nitro, C1-4-alkilsulfonil,
C1-4alkoksi, halogen, C1-4-alkil koji može tvoriti ciklički sistem, cijano, hidroksi, COOMe, COOEt, COOiPr, ili COONH2), ili
pikolil (koji može biti supstituiran sa do dva supstituenta koji neovisno mogu biti CF3, nitro, C1-4-alkilsulfonil, C1-4-alkoksi, halogen, C1-4-alkil koji može tvoriti ciklički sistem, cijano, hidroksi, COOMe, COOEt, COOiPr, ili COONH2), ili
-CH2-CH2-piridil (koji može biti supstituiran sa do dva supstituenta koji neovisno mogu biti CF3, nitro,
C1-4-alkilsulfonil C1-4-alkoksi, halogen, C1-4-alkil koji može tvoriti ciklički sistem, cijano, hidroksi, COOMe, COOEt, COOiPr, ili COONH2), ili
benzotiazolil (koji može biti supstituiran sa do dva supstituenta koji neovisno mogu biti CF3, nitro, C1-4-alkilsulfonil,
C1-4-alkoksi, halogen, C1-4-alkil koji može tvoriti ciklički sistem, cijano, hidroksi, N(CH3)2, COOMe, COOEt, COOiPr, ili COONH2), ili
benzoizotiazolil (koji može biti supstituiran sa do dva supstituenta koji neovisno mogu biti CF3, nitro, C1-4-alkilsulfonil, C1-4-alkoksi, halogen, C1-4-alkil koji može tvoriti ciklički sistem, cijano, hidroksi, N(CH3)2, COOMe, COOEt, COOiPr, ili COONH2), ili
benzopirazolil (koji može biti supstituiran sa do dva supstituenta koji neovisno mogu biti CF3, nitro, C1-4-alkilsulfonil, C1-4-alkoksi, halogen, C1-4-alkil koji može tvoriti ciklički sistem, cijano, hidroksi, N(CH3)2, COOMe, COOEt, COOiPr, ili COONH2), ili
benzoksazolil (koji može biti supstituiran sa do dva supstituenta koji neovisno mogu biti CF3, nitro, C1-4-alkilsulfonil, C1-4-alkoksi, halogen, C1-4-alkil koji može tvoriti ciklički sistem, cijano, hidroksi, N(CH3)2, COOMe, COOEt, COOiPr, ili COONH2), ili
-(CH2)m-fluorenil (m = 0 ili 1; koji može biti supstituiran sa do dva supstituenta koji neovisno mogu biti CF3, nitro,
C1-4-alkilsulfonil, C1-4-alkoksi, halogen, C1-4-alkil koji može tvoriti ciklički sistem, cijano, hidroksi, N(CH3)2, COOMe, COOEt, COOiPr, ili COONH2), ili
pirimidil (koji može biti supstituiran sa do dva supstituenta koji neovisno mogu biti CF3, nitro,
C1-4-alkilsulfonil, C1-4-alkoksi, halogen, C1-4-alkil koji može tvoriti ciklički sistem, cijano, hidroksi, N(CH3)2, COOMe, COOEt, COOiPr, ili COONH2), ili
-(CH2)m,-indanil (m = 0 ili 1; koji može biti supstituiran sa do dva supstituenta koji neovisno mogu biti CF3, nitro,
C1-4-alkilsulfonil, C1-4-alkoksi, halogen, C1-4-alkil koji može tvoriti ciklički sistem, cijano, hidroksi, N(CH3)2, COOMe, COOEt, COOiPr, ili COONH2), ili
-(CH2CH2O)y-CH3 (y = 0, 1, 2, 3, 4, ili 5) ili
-(CH2CH2O)y-CH2CH3 (y = 0, 1, 2, 3, 4, ili 5) ili
-NH-C6H5 (koji može biti supstituiran sa do dva supstituenta koji neovisno mogu biti CF3, nitro, C1-4-alkilsulfonil,
C1-4-alkoksi, halogen, C1-4-alkil koji može tvoriti ciklički sistem, cijano, hidroksi, COOMe, COOEt, COOiPr, ili COONH2), ili
-NCH3-C6H5 (koji može biti supstituiran sa do dva supstituenta koji neovisno mogu biti CF3, nitro, C1-4-alkilsulfonil,
C1-4-alkoksi, halogen, C1-4-alkil koji može tvoriti ciklički sistem, cijano, hidroksi, COOMe, COOEt, COOiPr, ili COONH2), ili
-NH-CH2-C6H5 (koji može biti supstituiran sa do dva supstituenta koji neovisno mogu biti CF3, nitro, C1-4-alkilsulfonil, C1-4-alkoksi, halogen, C1-4-alkil koji može tvoriti ciklički sistem, cijano, hidroksi, COOMe, COOEt, COOiPr, ili COONH2), ili -NCH3-CH2-C2H5 (koji može biti supstituiran sa do dva supstituenta koji neovisno mogu biti CF3, nitro,
C1-4-alkilsulfonil, C1-4-alkoksi, halogen, C1-4-alkil koji može tvoriti ciklički sistem, cijano, hidroksi, COOMe, COOEt, COOiPr, ili COONH2), ili
peteročlani heteroaril koji može biti supstituiran sa do dva supstituenta koji neovisno mogu biti CF3, nitro, C1-4-alkilsulfonil, C1-4-alkoksi, tiometil, tioetil pikolil, acetil, C3-6-cikloalkil, tiofenil, -CH2-COOEt, C3-4-alkilenska skupina koja tvori biciklički sistem s heterociklom, fenil (koji može biti supstituiran sa do dva supstituenta koji neovisno mogu biti nitro, CF3, CN, halogen ili C1-4-alkil) , benzil (koji može biti supstituiran sa do dva supstituenta koji neovisno mogu biti nitro, CF3, halogen, C1-4-alkil, C1-4-alkilsulfonil, cijano, hidroksi, C1-4-dialkilamino) ili -CHR7 -peteročlani heteroaril (koji može biti supstituiran sa do dva supstituenta koji neovisno mogu biti CF3, nitro, cijano, halogen, COOMe, COOEt, COOiPr, CONH2, C1-4-alkil, C1-4-alkoksi, fenil, benzil, naftil, ili C1-4-alkilsulfonil (R7=vodik, linearni ili razgranati C1-4-alkil, benzil).
-CHR7-peteročlani heteroaril može se na primjer predstaviti s jednim od slijedećih ostataka:
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Peteročlani heteroaril može se na primjer predstaviti s jednim od slijedećih ostataka:
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R5-N-R6 zajedno mogu tvoriti strukture odabrane iz skupine koja se sastoji od
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Spojevi formule I kojima se daje prednost su oni u kojima supstituienti R1, R2, A, B, D, E, X, F i t imaju slijedeća značenja:
R1 je metil ili etil;
R2 je vodik, metil ili etil;
A je valil, izoleucil, 2-terc.butilglicil;
B je N-metil-valil, -izoleucil ili -2-terc.butilglicil;
D je prolil, 3,4-dehidroprolil, 4-fluorprolil, 3-metilprolil ili tiazolidin-4-karbonil;
E je 3,4-dehidroprolil, 4-fluorprolil, 3-metilprolil ili azetidin-2-karbonil;
F je D-valil, 2-terc.butilglicil, D-izoleucil, D-leucil ili aminoizobutiroil;
X je -CH(CH3)2, -(CH3)3, ili -CH(CH3) CH2CH3;
t je 0 ili 1;
Prednostna značenja za K jesu:
-OC(CH3)3, -NH2, -NH-C1-12-alkil, -NH-C3-8-cikloalkil,
-NH-[3,3,0]-biciklooktil, norefedril, norpseudoefedril,
-NH-kinolilf -NH-pirazil, -NH-CH2-benzimidazolil,
-NH-adamantil, -NH-CH2-adamantil, -NH-CH(CH3)-fenil,
-NH-C(CH3)2-fenil, -N(C1-4-alkoksi) C1-4-alkil,
-N (C1-4-alkoksi) -CH2-fenil, -N(C1-4-alkoksi) -fenil,
-N(CH3)OBzl, -NH-(CH2)v-fenil (v = 0, 1, 2 ili 3),
-NH-(CH2)m-naftil (m = 0 ili 1), -NH- (CH2)-benzhidril (w = 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 = 0 ili 1),
-NH-pirimidil, -NH-(CH2)m-indalil (m = 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),
-NH-(peteročlani heteroaril) (kao što je prikazano na stranama 8-10)
-NH-CHR7-peteročlani heteraril (R1 je vodik, linearni ili razgranati C1-5-alkil, benzil)
(kao što je prikazano na stranama 7-8); ili K je
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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, piruvinska 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 aniidne veze. Za to su prikladne enziraatske 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 Svnthesis, 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 s 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-l,2-dihidrokinolin (EEDQ), 1-etil-3-(3-dimetilaminopropil)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), 0-benzotriazolil-N,N, NN -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 mogu se upotrijebiti sami ili u kombinaciji s dodacima kao što su N,N-dimetil-4-aminopiridin (DMAP), N-hidroksi-benzotriazol (HOBt), N-hidroksibenzotriazin (HOOBt), azabenzotriazol (HOAt), N-hidroksisukcinimid (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, Thieme 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 Fmoc, 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 nepotreba prekristalizacija intermedijata.
Zaštićene amino kiseline mogu se povezati na bilo koje prikladne polimere, koji jedino moraju biti netopivi u upotrijebljenom 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- (2,4-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 inertna pod uvjetima reakcije, naročito voda, N,N-dimetilformamid (DMF), dimetil sulfoksid, (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 provesti 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 alkiliranjem veze smola-peptid u DMF/1% octenoj kiselini s NaCNBH3 i odgovarajećim 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 mogu se upotrijebiti za inhibiciju ili za drugačiji način liječenja čvrstih tumoa (npr. tumora pluća, dojke, debelog crijeva, prostate, bubrega, rektuma ili unutrašnjih tumora) ili hematoloških malignacija (npr. 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 davanja. 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 koji uključuju biološku aktivnost dotičnog upotrijebljenog spoja, način davanja, starost, zdravstveno stanje i tjelesnu težinu primaoca, prirodu i opseg simptoma, učestalosti liječenja, davanje 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-Verlag, 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.
A. Opći postupak
I. Naznačeni peptidi u patentnom zahtjevu 1 sintetizirani su 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 1x1 min
2. 20%-tni piperidin u DMF-u 1x4 min
3. 20% piperidin u DMF-u l x 16 min
4. Ispiranje s DMF-pm 5x1 min
5. Dodavanje prethodno aktivirane zaštićene amino kiseline (aktivacija s l ekvivalentom TBTU-a i 5 ekvivalenata DIPEA-a u DMF-u) l x 61 min
6. Ispiranje s DMF-ora 3x1 min
7. Ako pretvorba nije potpuna, ponavljanje povezivanja (ponovno od 5.)
8. 10%-tni acetanhidrid u DMF-u 1x8 min
9. Ispiranje s DMF-om 3x1 min
10. Ponavljanje od 2.
BOP-C1 i PvBrop upotrijebljeni su kao reagensi za povezivanje amino kiseline i zatim 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-zaštićenih amino kiselinskih NCA (N-karboksi anhidridi), Z-zaštićnih amino kiselinskih NCA (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/1%-tnoj octenoj kiselini s dodatkom 3 ekvivalenta NaCNBH3. Po završetku reakcije (Kaiserov test negativan) smola se ispere nekoliko puta s vodom, izopropanoloin, DMF-om i diklormetanom.
Reduktivno alkiliranje u otopini može se provesti npr. pomoću reakcije N-terminalno nezaštićenih peptida, peptidnih fragmenata, ili amino kiselina s odgovarajućim aldehidima ili ketonima upotrebom NaCNBH3 ili vodika-Pd/C.
III. Obrada peptidne smole dobivene u lb i II Peptidna smola osuši se pod smanjenim tlakom i zatim se 1,5 sata obraduje s mješavinom TFA/vode (95:5) (Wade, 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 odvoji 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-voda, 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 TD NO:1)
Me2Val-Val-MeVal-Pro-L-azetidin-2-karboksamid
0,53 g smole Fraoc-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-L-azetidin-2-karboksilne kiseline,
Fmoc-Pro-OH
Fmoc-MeVal-OH
Fmoc-Val-OH
Fmoc-Val-OH
Amino kiselina iza N-metilamino kiseline bila je povezana dvostrukim povezivanjem sa PyBrop kao sredstvom za povezivanje. Po završetku ponovljenih ciklusa sinteze ciklusa, peptidna smola podvrgnuta je deprotekciji N-završetka (postupci 2-4 u AIa), i dalje je reagirala s vodenom otopinom formaldehida kao u AII, a 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 od 5 mg željenog čistog peptida (10-40 % A u 10’;
40-90% A u 200’). Spoj je također karakteriziran pomoću masene spektrometrije bombardiranjem s brzim atomima ([M+K]+ = 537,37).
Primjer 2
(SEQ ID NO: 1)
Me2Val-Val-MeVal-Pro-3,4-dehidroprolilbenzilamid
a) Z-MeVal-Pro-OMe
66,25 g (250 mmola) Z-MeVal-OH otopi se u 250 ml suhog diklormetana. Nakon dodatka 36,41 ml (262,5 mmola) trietilamina reakcijsku smjesu se ohladi na -25°C i doda se 32,27 ml (262,5 mmol) pivaloil klorida. Miješa se 2,5 sata, i zatim se k rekacijskoj smjesi doda se 41,89 g (250 mmola) H-Pro-OMe x HCl u 250 ml diklormetana, neutralizira se s 36,41 ml (262,5 mrnola) trietilamina pri 0°C. Nastavi se miješati još 2 sata pri -25°C i preko noći pri sobnoj temperaturi. Reakcijsku smjesu se razrijedi s diklor-metanom i temeljito ispere sa zasićenom vodenom otopinom NaHCO3 (3 x), s vodom (1x), a 5%-tnom limunskom kiselinom (3 x) i sa zasićenom otopinom NaCl. Organsku fazu se osuši preko natrijevog sulfata i ispari do suhog. Ostatak (91,24 g) se miješa s petrol eterom preko noći i filtrira. Dobije se 62,3 g proizvoda.
b) H-MeVal-Pro-Ome
48,9 g (130 mmola) 2-MeVal-Pro-OMe otopi se u 490 ml metanola. Doda se 10,9 ml (130 ml) koncentrirane solne kiseline i 2,43 g 10%-tnog Pd/C i reakcijsku smjesu se hidrogenira. Filtracijora i isparavanjem do suhog dobije se 36,43 g proizvoda.
c) Z-Val-MeVal-Pro-OMe
18,1 g (65 mmola) H-MeVal-Pro-OMe, 21,6 g (78 mmola) Z-Val~N~karboksanhidrida i 22,8 ml (130 mmola) diizo-propiletilamina miješa se u 110 ml DMF-a dva dana pri 40°C. Nakon isparavanja DMF-a doda se diklorraetan i organsku fazu se ispere sa zasićenom vodenom otopinom NaHCO3 (3 x), s vodom (l x), a 5%-tnom limunskom kiselinom (3 x) i sa zasićenom otopinom NaCl. Organsku fazu se osuši preko natrijevog sulfata i ispari do suhog. Proizvod (29,3 g) dobije se kao viskozno ulje.
d) H-Val-MeVal-Pro-Ome
29,3 g (61,6 mola) Z-Val-MeVal-Pro-OMe otopi se u 230 ml metanola. Doda se 1,15 g 10%-tnog Pd/C i reakcijsku smjesu se hidrogenira. Filtracijom i isparavanjem do suhog dobije se 21,96 g proizvoda.
e) Z-Val-Val-MeVal-Pro-OMe
15,29 g (61 mmola) Z-Val-OH i 21,96 g (61 mmol) H-Val-MeVal-Pro-OMe otopi se u 610 ml diklormetana i ohladi na 0°C. Doda se 8,16 ml (73,2 mmola) N-metil-morfolina, 2,11 g (20,3 ramola) HOBt i 11,74 g (61 mmol) EDCI i reakcijsku smjesu miješa se preko noći pri sobnoj temperaturi, razrijedi s diklormetanom i temeljito ispere sa zasićenom vodenom otopinom NaHCO3 (3x), s vodom (1x), a 5%-tnom limunskom kiselinom (3x) i sa zasićenom otopinom NaCl. Organsku fazu se osuši preko natrijevog sulfata i ispari do suhog. Dobije se 31,96 g proizvoda.
f) Z-Val-Val-MeVal-Pro-OH
31,96 g (57 mmola) d) Z-Val-Val-MeVal-Pro-OMe otopi se u 250 ml metanola i doda se 102,6 ml (102,6 mmola) 1 M LiOH u vodi. Miješa se 24 sata pri sobnoj temperaturi, doda se vodu i metanol se ispari pod smanjenim tlakom. Vodenu fazu se ekstrahira tri puta s etilacetatom, namjesti se pH na 2 i ekstrahira se 3 puta s etilacetatom. Sjedinjeni organski ekstrakti se osuše preko natrijevog sulfata i otapalo se ispari pod smanjenim tlakom. Dobije se 30,6 g bijele čvrste tvari.
g) Me2Val-Val-MeVal-Pro-OH
N,N-dimetilirana tetrapeptidna kiselina pripremi se od Z-zaštićene tetrapeptidne kiseline hidrogeniranjem Z zaštitne skupine i zatim dodatkom vodene otopine formaldehida k mjesi za hidrogeniranje. Željeni proizvod se dobije s gotovo kvantitativnim iskorištenjem.
h) Me2Val-Val-MeVal-Pro-3,4-dehidroprolin metilester
3,38 g Me2Val-Val-MeVal-Pro-OH (7,27 mmola) i 0,925 g 3,4-dehidroprolin metilester-hidrokloirda (7,27 mmola) otopi se u 75 ml suhog diklormetana. Pri 4°C doda se 0,975 ml N-metilmorfolina (8,72 mmola), 0,332 g HOBt-a (2,43 mmnola) i 1,4 g EDCI (1,21 iranola). Miješa se preko noći pri sobnoj temperaturi, doda se diklormetan i organsku fazu se ispere 3 puta s otopinom natrijevog hidrogen-karbonata i jednom s vodom. Organski spoj se ekstrahira s 5%-tnom vodenom limunskom kiselinom. pH kiselog vodenog sloja namjesti se zatim s 1 N NaOH na pH 8 i ekstrahira se 4 puta s diklormetanom. Nakon sušenja preko natrijevog sulfata i isparavanja pod smanjeim tlakom dobije se 2, 82 g pentapeptid- metilestera.
k) Me2Val-Val-MeVal-Pro-3f 4-dehidroprolin benzilarnid
Otopinu od 2,0 g dehidroprolina koja sadrži pentapeptid" metilester u 20 ml metanola pomiješa se pri sobnoj temperaturi s 4, 6 ml l N otopine LiOH. Po završetku reakcije (TLC kontrola) doda se vodu, metanol se ispari i spoj se liofilizira iz vode. Dobiveni bijeli prah otopi se u 36 ml diklormetana i doda se 0,388 ml (3,55 mmola) benzilamina. Pri 4°C doda se 0,476 ml N-metilmorfolina (4,26 mmola), 0,163 g HOBt (1,19 mmol) i 0,684 g (EDCI (3,55 mmola) i zatim se reakcijsku smjesu miješa preko noći pri sobnoj temperaturi. Doda se diklormetan i organsku fazu ispere se 3 puta sa zasićenom vodenom otopinom natrijevog karbonata i jednom s vodom. Organski sloj se ekstrahira 2 puta s 5%-tnom limunskom kiselinom. Kiselom vodenom sloju namjesti se s 5 N NaOH pH na 9 i ekstrahira se 4 puta s diklormetanom. Osuši se preko natrijevog sulfata i otapalo se ispari pod smanjenim tlakom. Dobije se 600 mg sirovog pentapeptid-benzilamida. 300 mg ovog sirovog peptida Čisti se dalje pomoću srednjetlačne tekućinske kromatografije (0-10% A u 5, 10-25% A u 10’, 25-90% A u 450'). Dobije se 92 mg analitički čistog proizvoda. Spoj je dalje karakteriziran pomoću masene kromatografije bombardiranjem s brzim atomima.
([M+H]+ = 639,4).
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 1 i 2.
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Simboli Xaa u sažetku imaju slijedeća značenja:
Xaa: N,N-dimetilvalin Xab: N-metilvalin
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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 raka debelog crijeva ili LX-1 tumora pluća. U 96-jamičnu ploču (u 150 μl medija) zasađeno je 5000-20.000 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 jxl 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 ud 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 za + /- 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
S obzirom in vivo djelovanja, koje je indikacija kliničke upotrebljivosti, spojevi ovog izuma bili su nadalje podvrgnuti predkliničkim ispitivanjima. 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 atiraičkim bezdlakim miševima transplantirani su u nove recipijentne 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
R1 je metil, etil ili izopropil;
R2 je vodik, metil ili etil;
R1-N-R2 mogu 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 prolil, 3,4-dehidroprolil, 4-fluorprolil, 4,4-difluorprolil, azetidin-2-karbonil, homoprolil, 3-metilprolil, 4-metilprolil, 5-metilprolil ili tiazolidin-4-karbonil;
E je 3,4-dehidroprolil, 4-fluorprolil, 3-inetilprolil, 4-metilprolil, azetidin-2-karbonil ili 4,4-difluorprolil;
F je valil, 2-terc.butilglicil, izoleucil, leucil, 2-cikloheksilglicil, norleucil, norvalil, neopentilglicil,
alanil, p-alanil ili aminoizobutiroil;
X je alkil (ponajprije C2-5), ciklopropil il: ciklopentil;
t je 0 ili 1; i
K je alkoksi (ponajprije C1-4), benziloksi il: 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, naznačen 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 l, 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 |
|---|---|
| HRP960257A2 true HRP960257A2 (en) | 1998-02-28 |
Family
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Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| 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 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR08/472,453A HRP960277A2 (en) | 1995-06-07 | 1996-06-06 | Novel compounds, the preparation and use thereof |
Country Status (33)
| Country | Link |
|---|---|
| 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) |
| HU (2) | HU228071B1 (hr) |
| IL (2) | IL122215A (hr) |
| MX (2) | MX9709147A (hr) |
| 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) |
| WO (2) | WO1996040751A1 (hr) |
| ZA (2) | ZA964710B (hr) |
Families Citing this family (30)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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. |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
1995
- 1995-06-07 US US08/472,453 patent/US5831002A/en not_active Expired - Lifetime
-
1996
- 1996-06-03 TR TR97/01545T patent/TR199701545T1/xx unknown
- 1996-06-03 WO PCT/EP1996/002392 patent/WO1996040751A1/en active IP Right Grant
- 1996-06-03 PT PT96918661T patent/PT871656E/pt unknown
- 1996-06-03 NZ NZ310444A patent/NZ310444A/xx not_active IP Right Cessation
- 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
- 1996-06-03 EP EP96918660A patent/EP0832104B1/en not_active Expired - Lifetime
- 1996-06-03 MY MYPI96002155A patent/MY119042A/en unknown
- 1996-06-03 MX MX9709147A patent/MX9709147A/es unknown
- 1996-06-03 CN CNB961944676A patent/CN1182154C/zh not_active Expired - Fee Related
- 1996-06-03 DK DK96918660T patent/DK0832104T3/da active
- 1996-06-03 AT AT96918661T patent/ATE224910T1/de active
- 1996-06-03 IL IL12221596A patent/IL122215A/xx not_active IP Right Cessation
- 1996-06-03 BR BR9609423A patent/BR9609423A/pt not_active Application Discontinuation
- 1996-06-03 AU AU61242/96A patent/AU725170B2/en not_active Ceased
- 1996-06-03 HU HU9801817A patent/HU228073B1/hu not_active IP Right Cessation
- 1996-06-03 AU AU61241/96A patent/AU725164B2/en not_active Ceased
- 1996-06-03 CZ CZ19973763A patent/CZ293682B6/cs not_active IP Right Cessation
- 1996-06-03 ES ES96918660T patent/ES2186783T3/es not_active Expired - Lifetime
- 1996-06-03 DK DK96918661T patent/DK0871656T3/da active
- 1996-06-03 KR KR1019970709063A patent/KR100437985B1/ko not_active IP Right Cessation
- 1996-06-03 CZ CZ19973765A patent/CZ293683B6/cs not_active IP Right Cessation
- 1996-06-03 SI SI9630539T patent/SI0832104T1/xx unknown
- 1996-06-03 AT AT96918660T patent/ATE223431T1/de active
- 1996-06-03 PT PT96918660T patent/PT832104E/pt unknown
- 1996-06-03 RO RO97-02264A patent/RO118953B1/ro unknown
- 1996-06-03 RO RO97-02254A patent/RO119783B1/ro unknown
- 1996-06-03 JP JP50013297A patent/JP4221062B2/ja not_active Expired - Fee Related
- 1996-06-03 NZ NZ310443A patent/NZ310443A/en not_active IP Right Cessation
- 1996-06-03 UA UA98010070A patent/UA46776C2/uk unknown
- 1996-06-03 JP JP50013197A patent/JP3957751B2/ja not_active Expired - Fee Related
- 1996-06-03 WO PCT/EP1996/002393 patent/WO1996040752A1/en active IP Right Grant
- 1996-06-03 PL PL96323723A patent/PL185762B1/pl unknown
- 1996-06-03 SK SK1653-97A patent/SK282466B6/sk not_active IP Right Cessation
- 1996-06-03 CA CA002219818A patent/CA2219818C/en not_active Expired - Fee Related
- 1996-06-03 DE DE69623992T patent/DE69623992T2/de not_active Expired - Lifetime
- 1996-06-03 ES ES96918661T patent/ES2188759T3/es not_active Expired - Lifetime
- 1996-06-03 PL PL96323726A patent/PL185763B1/pl unknown
- 1996-06-03 CA CA002219819A patent/CA2219819C/en not_active Expired - Fee Related
- 1996-06-03 DE DE69623472T patent/DE69623472T2/de not_active Expired - Lifetime
- 1996-06-03 TR TR97/01544T patent/TR199701544T1/xx unknown
- 1996-06-03 KR KR1019970709064A patent/KR100437986B1/ko not_active IP Right Cessation
- 1996-06-03 SI SI9630550T patent/SI0871656T1/xx unknown
- 1996-06-03 IL IL12221696A patent/IL122216A/en not_active IP Right Cessation
- 1996-06-03 CN CNB961944684A patent/CN1182153C/zh not_active Expired - Fee Related
- 1996-06-03 UA UA98010069A patent/UA46775C2/uk unknown
- 1996-06-03 MX MX9709146A patent/MX9709146A/es unknown
- 1996-06-03 BR BR9609424-9A patent/BR9609424A/pt not_active Application Discontinuation
- 1996-06-04 MY MYPI96002170A patent/MY124487A/en unknown
- 1996-06-06 ZA ZA9604710A patent/ZA964710B/xx unknown
- 1996-06-06 HR HR08/472,453A patent/HRP960257A2/hr not_active Application Discontinuation
- 1996-06-06 AR ARP960102981A patent/AR003427A1/es active IP Right Grant
- 1996-06-06 HR HR08/472,453A patent/HRP960277A2/hr not_active Application Discontinuation
- 1996-06-06 AR ARP960102980A patent/AR003136A1/es active IP Right Grant
- 1996-06-06 ZA ZA9604711A patent/ZA964711B/xx unknown
- 1996-06-07 TW TW085106866A patent/TW508357B/zh not_active IP Right Cessation
- 1996-06-07 CO CO96029751A patent/CO4700527A1/es unknown
- 1996-06-07 CO CO96029749A patent/CO4700526A1/es unknown
- 1996-10-02 TW TW085106867A patent/TW424096B/zh not_active IP Right Cessation
-
1997
- 1997-12-05 NO NO19975710A patent/NO318384B1/no not_active IP Right Cessation
- 1997-12-05 NO NO19975711A patent/NO317670B1/no not_active IP Right Cessation
- 1997-12-18 BG BG102125A patent/BG102125A/xx unknown
- 1997-12-29 BG BG102152A patent/BG102152A/xx unknown
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