AU775090B2 - Antineoplastic peptides - Google Patents
Antineoplastic peptides Download PDFInfo
- Publication number
- AU775090B2 AU775090B2 AU54143/01A AU5414301A AU775090B2 AU 775090 B2 AU775090 B2 AU 775090B2 AU 54143/01 A AU54143/01 A AU 54143/01A AU 5414301 A AU5414301 A AU 5414301A AU 775090 B2 AU775090 B2 AU 775090B2
- Authority
- AU
- Australia
- Prior art keywords
- nhch
- nhc
- xab
- residue
- pro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims description 31
- 102000004196 processed proteins & peptides Human genes 0.000 title claims description 12
- 230000000118 anti-neoplastic effect Effects 0.000 title description 3
- -1 N-methyl-valyl residue Chemical group 0.000 claims description 49
- 150000001875 compounds Chemical class 0.000 claims description 37
- 238000000034 method Methods 0.000 claims description 33
- 150000001413 amino acids Chemical class 0.000 claims description 22
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 20
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 16
- 230000008878 coupling Effects 0.000 claims description 15
- 238000010168 coupling process Methods 0.000 claims description 15
- 238000005859 coupling reaction Methods 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 14
- 206010028980 Neoplasm Diseases 0.000 claims description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims description 11
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 9
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 7
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 150000007513 acids Chemical class 0.000 claims description 5
- 239000012071 phase Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 4
- 239000007821 HATU Substances 0.000 claims description 4
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 4
- 238000010532 solid phase synthesis reaction Methods 0.000 claims description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 3
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 3
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 2
- 102000007079 Peptide Fragments Human genes 0.000 claims description 2
- 108010033276 Peptide Fragments Proteins 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 3
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 claims 2
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 claims 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 2
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 claims 1
- 235000009917 Crataegus X brevipes Nutrition 0.000 claims 1
- 235000013204 Crataegus X haemacarpa Nutrition 0.000 claims 1
- 235000009685 Crataegus X maligna Nutrition 0.000 claims 1
- 235000009444 Crataegus X rubrocarnea Nutrition 0.000 claims 1
- 235000009486 Crataegus bullatus Nutrition 0.000 claims 1
- 235000017181 Crataegus chrysocarpa Nutrition 0.000 claims 1
- 235000009682 Crataegus limnophila Nutrition 0.000 claims 1
- 235000004423 Crataegus monogyna Nutrition 0.000 claims 1
- 240000000171 Crataegus monogyna Species 0.000 claims 1
- 235000002313 Crataegus paludosa Nutrition 0.000 claims 1
- 235000009840 Crataegus x incaedua Nutrition 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 claims 1
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 description 66
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- SBVPYBFMIGDIDX-SRVKXCTJSA-N Pro-Pro-Pro Chemical compound OC(=O)[C@@H]1CCCN1C(=O)[C@H]1N(C(=O)[C@H]2NCCC2)CCC1 SBVPYBFMIGDIDX-SRVKXCTJSA-N 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 229940024606 amino acid Drugs 0.000 description 22
- 239000000243 solution Substances 0.000 description 20
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 18
- 108010077112 prolyl-proline Proteins 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 10
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 7
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 238000010647 peptide synthesis reaction Methods 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 239000002904 solvent 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
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 235000015165 citric acid Nutrition 0.000 description 6
- 238000003776 cleavage reaction Methods 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 239000012634 fragment Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 230000007017 scission Effects 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 4
- RWCOTTLHDJWHRS-YUMQZZPRSA-N Pro-Pro Chemical compound OC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 RWCOTTLHDJWHRS-YUMQZZPRSA-N 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 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 description 4
- 229950003188 isovaleryl diethylamide Drugs 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 230000005526 G1 to G0 transition Effects 0.000 description 3
- 241000124008 Mammalia Species 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
- 108091006629 SLC13A2 Proteins 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 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 3
- 238000010265 fast atom bombardment Methods 0.000 description 3
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 238000005932 reductive alkylation reaction Methods 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 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
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 125000000249 D-isoleucyl group Chemical group N[C@@H](C(=O)*)[C@@H](CC)C 0.000 description 2
- 125000003301 D-leucyl group Chemical group N[C@@H](C(=O)*)CC(C)C 0.000 description 2
- 125000003625 D-valyl group Chemical group N[C@@H](C(=O)*)C(C)C 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-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
- 238000003820 Medium-pressure liquid chromatography Methods 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
- KSPIYJQBLVDRRI-UHFFFAOYSA-N N-methylisoleucine Chemical compound CCC(C)C(NC)C(O)=O KSPIYJQBLVDRRI-UHFFFAOYSA-N 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-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
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000007515 enzymatic degradation Effects 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000008098 formaldehyde solution Substances 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 235000011167 hydrochloric acid Nutrition 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 208000037841 lung tumor Diseases 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000011550 stock solution 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
- QHPXZMZXMVWKAM-ZETCQYMHSA-N (2s)-2-[ethyl(methyl)amino]-3-methylbutanoic acid Chemical compound CCN(C)[C@@H](C(C)C)C(O)=O QHPXZMZXMVWKAM-ZETCQYMHSA-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
- BNUUSRSYNZFTBX-ZETCQYMHSA-N (2s)-n-tert-butylpyrrolidine-2-carboxamide Chemical compound CC(C)(C)NC(=O)[C@@H]1CCCN1 BNUUSRSYNZFTBX-ZETCQYMHSA-N 0.000 description 1
- OQJJVXKMPUJFJK-BQBZGAKWSA-N (2s,3s)-2-(dimethylamino)-3-methylpentanoic acid Chemical compound CC[C@H](C)[C@H](N(C)C)C(O)=O OQJJVXKMPUJFJK-BQBZGAKWSA-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
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-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
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 1
- WFIYPADYPQQLNN-UHFFFAOYSA-N 2-[2-(4-bromopyrazol-1-yl)ethyl]isoindole-1,3-dione Chemical compound C1=C(Br)C=NN1CCN1C(=O)C2=CC=CC=C2C1=O WFIYPADYPQQLNN-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- UIVWXNPUCAHAJX-UHFFFAOYSA-N 4-hydroxy-1,1-dioxo-2,5-diphenylthiophen-3-one Chemical compound O=S1(=O)C(C=2C=CC=CC=2)C(=O)C(O)=C1C1=CC=CC=C1 UIVWXNPUCAHAJX-UHFFFAOYSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- APCGWJOZFJQUGP-UHFFFAOYSA-N C(C)OC(=O)N1C(C=CC2=CC=CC=C12)OCC.C(C)(C)N=C=NC(C)C.C1(CCCCC1)N=C=NC1CCCCC1.Cl.C(C)N=C=NCCCN(C)C Chemical compound C(C)OC(=O)N1C(C=CC2=CC=CC=C12)OCC.C(C)(C)N=C=NC(C)C.C1(CCCCC1)N=C=NC1CCCCC1.Cl.C(C)N=C=NCCCN(C)C APCGWJOZFJQUGP-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- OFDNQWIFNXBECV-UHFFFAOYSA-N Dolastatin 10 Natural products CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)CC)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 OFDNQWIFNXBECV-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 238000002965 ELISA Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- DSLZVSRJTYRBFB-UHFFFAOYSA-N Galactaric acid Natural products OC(=O)C(O)C(O)C(O)C(O)C(O)=O DSLZVSRJTYRBFB-UHFFFAOYSA-N 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 101001095266 Homo sapiens Prolyl endopeptidase Proteins 0.000 description 1
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- OKJIRPAQVSHGFK-UHFFFAOYSA-N N-acetylglycine Chemical compound CC(=O)NCC(O)=O OKJIRPAQVSHGFK-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 102000056251 Prolyl Oligopeptidases Human genes 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 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 1
- 238000002835 absorbance Methods 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- 238000011717 athymic nude mouse Methods 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- SYZWSSNHPZXGML-UHFFFAOYSA-N dichloromethane;oxolane Chemical compound ClCCl.C1CCOC1 SYZWSSNHPZXGML-UHFFFAOYSA-N 0.000 description 1
- VLNZUSMTOFYNPS-UHFFFAOYSA-N diethylphosphorylformonitrile Chemical compound CCP(=O)(CC)C#N VLNZUSMTOFYNPS-UHFFFAOYSA-N 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- OFDNQWIFNXBECV-VFSYNPLYSA-N dolastatin 10 Chemical compound CC(C)[C@H](N(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C=1SC=CN=1)CC1=CC=CC=C1 OFDNQWIFNXBECV-VFSYNPLYSA-N 0.000 description 1
- 108010045524 dolastatin 10 Proteins 0.000 description 1
- 108010045552 dolastatin 15 Proteins 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 208000023965 endometrium neoplasm Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- DSLZVSRJTYRBFB-DUHBMQHGSA-N galactaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O DSLZVSRJTYRBFB-DUHBMQHGSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 230000037219 healthy weight Effects 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- BLWYXBNNBYXPPL-YFKPBYRVSA-N methyl (2s)-pyrrolidine-2-carboxylate Chemical compound COC(=O)[C@@H]1CCCN1 BLWYXBNNBYXPPL-YFKPBYRVSA-N 0.000 description 1
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 230000000771 oncological effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229940116315 oxalic acid Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 208000023958 prostate neoplasm Diseases 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229940032330 sulfuric acid Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000007885 tablet disintegrant Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Landscapes
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Description
P/00/011 28/5/91 Regulation 32(2) 0 r
AUSTRALIA
Patents Act 1990
ORIGINAL
COMPLETE SPECIFICATION STANDARD PATENT Application Number: Lodged: Invention Title: ANTINEOPLASTIC PEPTIDES The following statement is a full description of this invention, including the best method of performing it known to us 4 1 ANTINEOPLASTIC
PEPTIDES
Description The invention described herein provides novel peptides and derivatives thereof which offer potentially improved therapeutic utilities for the treatment of neoplastic diseases as compared to dolastatin -10 and -15 Patent Nos. 4,879,276 and 4,816,444) and the compounds described in WO 93/23424.
Compounds of this invention include novel peptides of the f ormula 1 R1R2NCHXCOABD-E- sK
I
where
R
1 is hydrogen, methyl, or ethyl;
R
2 is methyl; or ethyl; or
R
1
-N-R
2 together are a pyrrolidine ring; A is a valyl, isoleucyl, allo-isoleucYl, 2-tert-butylglycyl, 2-ethyiglycyl, norleucyl or norvalyl residue; B is a N-methyl-valyl, N-methyl-florvalyl, N-methyl-leucyls N-methyl-isoleucyl, N-ehl2trtbtllcl N-methyl- 2-ethyiglycyl, or N-methyl-norleucyl residue; is a prolyl, homoprolyl, hydroxyprolYl, or thiazolidine-4-carbonyl residue; *E is a prolyl, homoprolyl, hydroxyprolyl, thiazolidine-4 carbonyl, trans-4-fluoro-L-prolyl, cis-4-fluoro-L-prolyl, '00. trans-4-chloro-L-prolyl or cis-4-chloro-L-prolyl residue; X is ethyl-, propyl, butyl, isopropyl, sec. butyl, tert. butyl, cyclopropyl, or cyclopentyl; :G is a L-2-tert.butylglycyl, D-2-tert.butylglycyl', D-valyl, D-isoleucyl, D-leucyl, D-norvalyl, I-amirlopeftyl-l 49; carbonyl, or 2,2-dimethylglycyl residue; 2 is 0 or .i: is -NH-Cl.8 -alkyl, -NH-C 3 8 -alkenyl,
-NH-C
3 8 -alkilyl,
-NH-C
6 8 -cycloalkYl, -NH-Cl 1 4 .alkene.C3.8-cycloalkyl,
C
1 4 -alkyl-N-Cl.6-alkYl, in which residues one CH 2 group may be replaced by 0 or S, one H by phenyl or cyano, or 1, 2 or 3 H by F, except the Nrnethoxy-N-methYlamilo,
N-
benzylamino, or N-methyl-N-benzylamiflo residue, or K is
S
~N -N /\0N
NH-O
CH
3 NH 0
H
3
C
-NH\/
H
NH
-NH-01Z1 NH
CH
3
CH
-N-Q N
CH
3
,-NH
4 2J CH3 -NH
-O,
CH
3
CH
3
~NH\
CONH
2
NH
0N 2
H
NCO
CH
3 or -NH +CO -NH -CH 2 CH2 CH3
CH
3 40 and the salts thereof with physiologically tolerated acids.
Specifically K may be -NHCH3, *NHCH 2 CH3, -NH(CH 2 2 CH3,
-NH(CH
2 3 CH3, -NH(CH 2 4
CH
3
-NH(CH
2 5 CH3, -NH(CH 2 6 CH3,
-NHCH(CH
2 )7CH3, -NHCH(CH 3 2 -NHCH(CH3)CH2CH3,
-NHCH(CH
2 CH3)2, -NHCH (CH 2
CH
2
CH
3 2, -NHC (CH 3 3, -NHCH (CH 2
CH
3
)CH
2
CH
2
CHJ.
-NHCH(CH
3 )CH(CH3)2,
-NHCH(CH
2 CH3)CH(CH3)2s
-NHCH(CH
3 )C(CH3)3, -NH-cyclohexyl, -NH-cycloheptyl, -NH-cyclooctyl,
-N(CH
3
)OCH
2 CH3, 3 -N(CH3)OCH 2 CH2CI3, -N(CH 3 )QCH(CH3)2,
-N(CH
3
)O(CH
2 3 CH3, -N(CH3)OCH2C6H5,
-NH(CH
2 2
C
6 HS, -NH(CH 2 3
C
6
H
5 -NHCH(CH3)C6H5,
-NHC(CH
3 )2C6H5, -NHC(CH3) 2
CH
2 CH3i -NHC(CH 3
(CH
2
CH
3 2 -NHCH[CH(CH3)2]2,
-NHC(CH
3 2 CN, -NHCH(CH 3 )CH(OH)C6H5, -NHCH2-CYClOhexyl, -NHCH 2 C(CH3)3, -NHCH 2 CH(CH3)2,
-N(CH
3 2
-N(CH
2
CH
3 )2, -N (CH 2
CH
2
CH
3 2' -NHCH 2
CF
3 -NHCH (CH 2 F) 2' -NHCH 2
CH
2 F, -NHCH 2
CH
2 OCH3,
.NHCH
2
CH
2 SH,-CHHH 2 -NH-C (CH 3 2
CH=CH
2 -NHC (CH 3 2 C' CH, -NHC (CH 2 CH3) 2 C-CH, NHC (CH3) 2
CH
2
CH
2 OH, -NH (CH 2
CH
2 O) 2
CH
2 CH3, -NHC (CH 3 2
CH(CH
3 2 NHC (CH 3 2
CH
2
CH
2 CH3, -NHC (CH 3 2
CH
2
C
6
-N(OCH
3 )CH(CH3)2,
-N(OCH
3
)CH
2 CH3, -N(OCH 3
)CH
2
CH
2
CH
3
.N(OCH
3
)CH
2 C6H5, -N(OCH.
3
)C
6 Hs, -N(CH 3 )0C 6
H
5
-NHCH[CH(CH
3 )2]2, -N (OCH 3
CH
2
CH
2
CH
2 CH3, or the special ring systems mentioned above.
Preferred are compounds of the formula I where the substituents
R
1
R
2 A, B, D, E, X, G and s have the following meanings:
R
1 hydrogen, methyl, or ethyl, especially methyl;
R
2 methyl or ethyl, especially methyl; A valyl, isoleucyl, 2-tert-butylglycyl, 2-ethylglycyl, norleucyl or norvalyl, especially valyl, isoleucyl, 2-tertbutylglycyl, 2-ethylglycyl, B N-methyl-valyl, N-methyl-norvalyl, N-methyl-isoleucyl, N-mnethyl-2-tert-.butylglycyl, N-methyl-2-ethylglycyl, or N-methyl-norleucyl, especially N-methyl-valyl, N-methyl-2-ethylglycyle N-methyl-norleucyl, N-methylisoleucyl, or N-methyl-2-tert.butyl-glycyl; D prolyl, homoprolyl or thjazolidine-4carboflyl, especially :prolyl or thiazolidine-4carbflyl; E prolyl, homoprolyl, thiazolidife-4carboflyl, trans -4 -f luoro-L-prolyl, cis-4-fluoro-Lprolyl, trans-4-chloro-L-prolyl or cis-4-chloro-L-prolyl, especially prolyl, trans-4 fluoro-prolyl, cis-4-fluoroprolyl, trans -4 -chloro-prolyl, or cis-4-chloro-prolyl; x ethyl, propyl, isopropyl, sec.butyl, tert.butyl or cyclopropyl, especially ethyl, isopropyl, sec.butyl or tert -butyl; G L-2-tert.butylglycyl, D-2-tert.butylglycyl, D-valyl, D-isoleucyl, D-leucyl or 2,2-dimethylglycyl residue; 0 or 1.
Preferred meanings for K are: -NH-Ci.e -alkyl, -NH-C 6 8 -cycloalkyl,
*NH-CH
2 -cyclohexyl,
SC
1 4 -alkyl-N-Cl6-alkyl, in which residues one CH 2 group may be replaced by 0, one H by phenyl or 1 or 2 H by F, except the N-methoxy-N-methylamilo, N-benzylamino, or N-methyl-N-benzylaminlo residue, or K is
NH-
CH
3 -NH N
-NH-C
NH==
NH
~~NH
CH
3 -NH 1Q, NH -S3 CH3
CH
3 H NH-tj or
N
4 4*
-N
CH
3 or -NH +CO-NH-CH 2 -CH2-CH3
CH
3 More preferred K is
-NHCH
3
-NHCH
2
CH
3
-NH(CH
2 2
CH
3
-NH(CH
2 3 CH3, *NH(CH 2 )4CH 3
-NH(CM
2 SCH3, -NH(CH 2 )rCH 3
-NH(CH
2 7 CH3, -NHCHCCH 3 )2, -NHCH(CH3)CH2CH3,
-NHCH(CH
2 CH3)2, -NHCH(CH 2 CH2CH3)2, -NHC(CH 3 )3, NHCH (CH 2
CH
3
CH
2
CH
2
CH
3 D NHCH (CH 3
CH(CH
3 2' NHCH(CH 2
CH
3 CE(CH3) 2' -NHCH(CH3)C(CH3)3, -NH-cyclohexyl, -NE-cycloheptyl, -NE-cyclooc- 40 tyl, -N(CH3)OCH 2 CH3, -N(CH3)OCH 2
CH
2 CH3, -N(CH 3 OCH (CH3) 2.
N(OCH)CH(CH3)2, -N(CH3)OCH 2 CrHS, -NH(CH 2 )2C6H5, -NH(CH 2 3 -;VHCH(CH3)C6H5, -NHC(CH3) 2
C
6
H
5 -NHC(CH3)2CH2CH3,
-NHC(CH
3
(CH
2 CH3)2, .NHCH(CH3)CH(OH)C6HS,
-NHCH
2 -cyclohexyl, -N(CH3) 2
-N(CH
2 CH3) 2
-N(CH
2
CH
2 CH3)2, -NHCH(CH 2
F)
2 -NHC(CH3) 2 CH2CH2OH,
.NH(CH
2
CH
2 0) 2 CH2CH3, -NHC(CH 3 2 CH(CH3)2, -NHC(CH 3
)CH=CH
2 NHC(CH3) 2 CN, -NHC(CH3) 2 C -CH, -NHC(CH3) 2 CONH2, -N(OCH3)C 6
H
5 NHCH(CH(CH3)2)2, -N(OCH 3 )CH2C6H5, -N(OCH3)CH2CH3, r4(OCH3
)CH
2
CH
2 CH3,
N(OCH
3
CH
2
CH
2 CH2CH3, NH 3 N CH3 CR3 CH3 HNH~l
H
3
CH
3 NHkD ~NHO
NH
Especially preferred are compounds of the formula I where R1 and R 2 are methyl, A is a valyl, isoleucyl, or 2-tert. .butylglycyl residue B is a N-rnethylvalyl, N-methyl-isoleucyl, or Nmethyl tert. .butylglycyl residue, D is a prolyl or thiazolidife4carbonyl residue, E is a prolyl, cis-4.fluoro-Lprolyl, or cis-4-chloro- L-prolYl residue, X is a isopropyl, seC. -butyl, or tert. -butyl residue, s is 0, and K is -NHCH
(CH
3 2. *NHCH
(CH
3
CH
2 CH3, -NHCH
(CH
2 CH3) 2' -NHCH
(CH
2
CH
2 CH3) 2' NHC (CH 3 -NHCH(CH 2
CH
3 )CH2CH2CH3D NHCH(CH3)CH(CH3)2, -NHCH(CH 2 CH3)CH(CH3)2, -NHCH
(CH
3 )C(CH3)3e -NHcycloheptyl, .NH-cyclooctyl, -N (CH 3 )OCH2CH3. -N(CH3)
OCH
2
CH
2 CH3, -N(CH 3 OCH(CH3) 2' -N(OCH 3 )CH(CH3)2. -N(CH 3 )OCH2C6H5, -NH(CH 2 2 -NH(CH 2 3 C6,H5. .NHCH(CH 3 )C6HSe -NHC(CH3)2C6H5, 4IHC (CH 3 2
CH
2 CH3, NHC(CH3)
(CH
2 CH3) 2' -NHCH(CH3) CR(OH)
C
6
HS,
.NHCH(CH2F)2, NHC(CH 3 2
CH
2 CH20, .NH(CH 2
CH
2 O)CH2CH3I -NHC(CH 3 )2CH=CH2, -NHC(CH 3 2 CH(CH3)21 -N(OCH 3 )CH2CH3.
-N (OCR 3
CR
2
CH
2 CH3, -N(OCR 3
CR
2
CH
2 CH2CH3. -NHC (CR 3 2
CN,
6
-NHC(CH
3 )2C=CH, -NHCH[CH(CH3)22, -NHC(CH3) 2 CONH2,
-NHC(CH
3 2
CH
2 C6Hs, -N(OCH3)C 6 Hs, -N(OCH3)CH2 H3C CH3 CH3 CH3
H
3
C
CH
3 CH3
CH
3
-NH
3 NHC -NH or
CH
3 -NH CO--NH-CH2-CH2--CH3
CH
3 This invention also provides methods for preparing the compounds of formula I, pharmaceutical compositions containing such compounds together with a pharmaceutically acceptable carrier and methods for using same for treating cancer in mammals.
The new compounds may be present as salts with physiologically tolerated acids such as: hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, malic acid, succinic acid, malonic acid, sulfuric acid, L-glutamic acid, L-aspartic acid, pyruvic acid, mucic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbic acid and acetylglycine.
The novel compounds can be prepared by known methods of peptide chemistry. Thus, the peptides can be assembled sequentially from 35 amino acids or by linking suitable small peptide fragments. In the sequential assemblage, starting at the C terminus the peptide chain is extended stepwise by one amino acid each time. In fragment coupling it is possible to link together fragments of different lengths, and the'fragments in turn can be obtained by sequential assemblage from amino acids or themselves by fragmentcoupling.
Both in the sequential assemblage and in the fragment coupling it S. is necessary to link the units by forming an amide linkage. Enzymatic and chemical methods are suitable for this.
7 Chemical methods for forming the amide linkage are described in detail by Mueller, Methoden der organischen Chemie Vol. XV/2, pp 1 to 364, Thieme Verlag, Stuttgart, 1974; Stewart, Young, Solid Phase Peptide Synthesis, pp 31 to 34, 71 to 82, Pierce Chemical Company, Rockford, 1984; Bodanszky, Klausner, Ondetti, Peptide Synthesis, pp 85 to 128, John Wiley Sons, New York, 1976; The Practice of Peptide Synthesis, M. Bodanszky, A. Bodanszky, Springer-Verlag, 1994, and other standard works on peptide chemistry. Particular preference is given to the azide method, the symmetric and mixed anhydride method, in situ generated or preformed active esters, the use of urethane protected N-carboxy anhydrides of amino acids and the formation of the amide linkage using coupling reagents, especially dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC l-ethoxycarbonyl-2-ethoxy- 1,2-dihydroquinoline (EEDQ), pivaloylchloride, 1-ethyl-3-(3dimethylaminopropyl)carbodiimide hydrochloride (EDCI), n-propanephosphonic anhydride (PPA), N,N-bis(2-oxo-3-oxazolodinyl)-amidophosphoryl chloride (BOP-C1), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop), diphenylphosphoryl azide (DPPA), Castro's reagent (BOP, PyBop), O-benzotriazolyl-N,NN',N'-tetramethyluronium salts (HBTU), O-azabenzotriazolyl-N,N,N',N'-tetramethyluronium salts (HATU), diethylphosphoryl cyanide
(DEPCN),
2,5-diphenyl-2,3-dihydro-3-oxo-4-hydroxythiophene dioxide (Steglich's reagent; HOTDO) and 1,1'-carbonyldiimidazole
(CDI).
The coupling reagents can be employed alone or in combination with additives such as N,N-dimethyl-4-aminopyridine
(DMAP),
N-hydroxy-benzotriazole (HOBt), N-hydroxybenzotriazine (HOOBt), Azabenzotriazole, N-hydroxysuccinimide (HOSu) or 2-hydroxypyridine.
Whereas it is normally possible to dispense with protective groups in enzymatic peptide synthesis, reversible protection of :"reactive groups not involved in formation of the amide linkage is necessary for both reactants in chemical synthesis. Three conven- 35 tional protective group techniques are preferred for the chemical peptide synthesis: the benzyloxycarbonyl the t-butoxycarbonyl (Boc) and the 9-fluorenylmethoxycarbonyl (Fmoc) techniques.
Identified in each case is the protective group on the alpha- 40 amino group of the chain-extending unit. A detailed review of amino-acid protective groups is given by Mueller, Methoden der organischen Chemie Vol. XV/1, pp 20 to 906, Thieme Verlag, Stutt- S: gart, 1974. The units employed for assembling the peptide chain can be reacted in solution, in suspension or by a method similar to that described by Merrifield in J. Amer. Chem. Soc. 85 (1963) 2149.
8 Suitable for peptide synthesis in solution are all solvents which are inert under the reaction conditions, especially water, N,Ndimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dichloromethane (DCM), ethyl acetate, 1,4-dioxane, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP) and mixtures of the said solvents.
Peptide synthesis on the polymeric support can be carried out in all inert organic solvents in which the amino-acid derivatives used are soluble. However, preferred solvents additionally have resin-swelling properties, such as DMF, DCM, NMP, acetonitrile and DMSO, and mixtures of these solvents. After synthesis is complete, the peptide is cleaved off the polymeric support. The conditions under which cleavage off the various resin types is possible are disclosed in the literature. The cleavage reactions most commonly used are acid- and palladium-catalyzed, especially cleavage in liquid anhydrous hydrogen fluoride, in anhydrous trifluoromethanesulfonic acid, in dilute or concentrated trifluoroacetic acid, palladium-catalyzed cleavage in THF or THF-DCM mixtures in the presence of a weak base such as morpholine or cleavage in acetic acid/dichloromethane/trifluoroethanol mixtures. Depending on the chosen protective groups, these may be retained or likewise cleaved off under the cleavage conditions.
Partial deprotection of the peptide may also be worthwhile when certain derivatization reactions are to be carried out.
Peptides dialkylated at the N-terminus can be prepared either by coupling on the appropriate N,N-di-alkylamino acids in solution 30 or on the polymeric support, by reductive alkylation of the resin-bound peptide in DMF/1% acetic acid with NaCNBH 3 and the appropriate aldehydes, by hydrogenation of the peptide in solution *in the presence of aldehyde or ketone and Pd/C.
The various non-naturally occurring amino acids as well as the various non-amino acid moieties disclosed herein may be obtained from commercial sources or synthesized from commercially-available materials using methods known in the art. For example, amino acids building blocks with R 1 and R 2 moieties can be prepared according to E. wuensch, Houben Weyl, Meth. d. Org. Chemie, Bd. XV, 1, p. 306 following, Thieme Verlag Stuttgart 1974 and Literature cited therein.
The compounds of this invention may be used to inhibit or otherwise treat solid tumors tumors of the lung, breast, colon, prostate, bladder, rectum, or endometrial tumors) or hematological malignancies leukemias, lymphomas) by administration of the compound to the mammal.
It is a special advantage of the new compounds that they are very resistant to enzymatic degradation and can also be administered orally.
Administration may be by any of the means which are conventional for pharmaceutical, preferably oncological, agents, including oral and parenteral means such as subcutaneously, intravenously, intramuscularly and intraperitoneally.
The compounds may be administered alone or in the form of pharmaceutical compositions containing a compound of formula I together with a pharmaceutically accepted carrier appropriate for the desired route of administration. Such pharmaceutical compositions may be combination products, may also contain other therapeutically active ingredients.
The dosage to be administered to the mammal will contain an effective tumor-inhibiting amount of active ingredient which will depend upon conventional factors including the biological activity of the particular compound employed; the means of administration; the age, health and body weight of the recipient; the nature and extent of the symptoms; the frequency of treatment; the administration of other therapies; and the effect desired. A typical daily dose will be about 0.05 to 50 milligrams per kilogram of body weight on oral administration and about 0.01 to 20 milli- S.:grams per kilogram of body weight on parenteral administration.
30 The novel compounds can be administered in conventional solid or liquid pharmaceutical administration forms, e.g. uncoated or (film-)coated tablets, capsules, powders, granules, suppositories or solutions. These are produced in a conventional manner. The 35 active substances can for this purpose be processed with conventional pharmaceutical aids such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, sustained release compositions, antioxidants and/or propellant gases (cf. H.
Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The administration forms obtained in this way normally contain 1-90% by weight of the active substance.
The following examples are intended to illustrate the invention.
The proteinogenous amino acids are abbreviated in the examples using the known three-letter code. Other abbreviations used: Me 2 Val N,N-dimethylvaline, MeVal N-methylvaline.
A. General procedures I. The peptides claimed in claim 1 are either synthesized by classical solution synthesis using standard Z- and Bocmethodology as described above or by standard methods of solid-phase synthesis using Boc and Fmoc protective group techniques.
In the case of solid phase synthesis, the N,N-dialkylpenta- or hexapeptide acids are liberated from the solid support and further coupled with the corresponding C-terminal amines in solution. BOP-C1 and PyBrop were used as reagents for coupling of the amino acid following the Nmethylamino acids. The reaction times were correspondingly increased. For reductive alkylation of the N-terminus, the peptide-resin was deprotected at the N terminus and then reacted with a 3-fold molar excess of aldehyde or ketone in DMF/1% acetic acid with addition of 3 equivalents of NaCNBH 3 After the reaction was complete (negative Kaisertest) the resin was washed several times with water, isopropanol, DMF and dichloromethane.
In solution synthesis, the use of either Boc-protected amino acid NCAs (N-tert.-butyloxycarbonyl-amino acid-Ncarboxy-anhydrides), Z-protected amino acid NCAs (N-benzyloxycarbonyl-amino acid-N-carboxy-anhydrides), or the use of pivaloylchloride as condensing agent respectively is most advantageous for coupling of the amino acid following the N-methylamino acids. Reductive alkylation of 30 the N terminus can e.g. be achieved by reaction of the N-terminally deprotected peptides or amino acids with the corresponding aldehydes or ketones using NaCNBH 3 or hydrogen, Pd/C.
II. Purification and characterization of the peptides Purification was carried out by gel chromatography (SEPHADEX G-10, G-15/10% HOAc, SEPHADEX LH20/MeOH), medium pressure chromatography (stationary phase: HD-SIL C-18, 20-45 mikron, 100 Angstrom; mobile phase: gradient with A 0.1% TFA/ MeOH, B 0.1% TFA/water), or preparative HPLC (stationary phase: Waters Delta-Pak C-18, mikron, 100 Angstrom; mobile phase: gradient with A 0.1 TFA/MeOH, B 0.1 TFA/water).
The purity of the resulting products was determined by analytical HPLC (stationary phase: 100 2.1 mm VYDAC C-18, 1, 300 A; mobile phase: acetonitrile-water gradient, buffered with 0.1% TFA, 400C).
Characterization was by amino-acid analysis and fast atom bombardment mass spectroscopy.
B. Specific procedures EXAMPLE 1 (SEQ ID NO: 1) Me 2 Val-Val-MeVal-Pro-Pro-NHCH(CH3 )2 a) Z-MeVal-Pro-OMe 66.25 g (250 mmol) Z-MeVal-OH were dissolved in 250 ml dry dichloromethane. After addition of 36.41 ml (262.5 mmol) triethylamine, the reaction mixture was cooled to -250 C and 32.27 ml (262.5 mmol) pivaloyl chloride were added. After stirring for 2,5 h, 41.89 g (250 mmol) H-Pro-OMe x HC1 in 250 ml dichloromethane, neutralized with 36.41 ml (262.5 mmol) triethylamine at 0°C, were added to the reaction mixture.
Stirring continued for 2 h at -250 C and overnight at room temperature. The reaction mixture was diluted with dichloromethane and thoroughly washed with saturated aqueous NaHCO3 solution water 5 citric acid (3x) and saturated NaC1 solution. The organic phase was dried over sodium sulfate and evaporated to dryness. The residue (91.24 g) was 30 stirred with petroleum ether overnight and filtered. 62.3 g of product were obtained.
b) H-MeVal-Pro-OMe 35 48.9 g (130 mmol) Z-MeVal-Pro-OMe were dissolved in 490 ml methanol. After addition of 10.9 ml (130 mmol) concentrated hydrochloric acid and 2.43 g 10 Palladium/charcoal, the reaction mixture was hydrogenated. Filtration and evaporation :o dryness yielded 36.43 g of the product.
c) Z-Val-MeVal-Pro-OMe 18.1 g (65 mmol) H-MeVal-Pro-OMe, 21.6 g (78 mmol) Z-Val- S" N-carboxyanhydride and 22.8 ml (130 mmol) diisopropylethylarine were stirred in 110 ml DMF at 400 C for 2 d. After evaporation of DMF, dichloromethane was added and the organic phase washed with saturated aqueous NaHCO3 solution (3x), water 5 citric acid (3x) and saturated NaCI solution.
The organic phase was dried over sodium sulfate and evaporated to dryness. The product (29.3 g) was obtained as a viscous oil.
d) H-Val-MeVal-Pro-OMe 29.3 g (61.6 mmol) of Z-Val-MeVal-Pro-OMe were dissolved in 230 ml methanol. After addition of 1.15 g 10 Palladium/ charcoal, the reaction mixture was hydrogenated. Filtration and evaporation to dryness yielded 21.96 g of the product.
e) Z-Val-Val-MeVal-Pro-OMe 15.29 g (61 mmol) Z-Val-OH and 21.96 g (61 mmol) H-Val-MeVal- Pro-OMe were dissolved in 610 ml dichloromethane and cooled to 0°C. After addition of 8.16 ml (73.2 mmol) N-Methylmorpholine, 2.77 g (20.3 mmol) HOBt and 11.74 g (61 mmol) EDCI, the reaction mixture was stirred overnight at room temperature, diluted with dichloromethane and thoroughly washed with saturated aqueous NaHCO 3 solution water 5 citric acid (3x) and saturated NaC1 solution. The organic phase was dried over sodium sulfate and evaporated to dryness to yield 31.96 g of the product.
f) Z-Val-Val-MeVal-Pro-OH 31.96 g (57 mmol) Z-Val-Val-MeVal-Pro-OMe were dissolved in 250 ml methanol. 102.6 ml of a 1 N LiOH solution was added 30 and the mixture stirred overnight at room temperature. After addition of 500 ml water, the aqueous phase was washed three times with ethyl acetate, adjusted to pH 2 at 00 C and extracted three times with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated to dryness yielding 30.62 g of the desired product as a white solid.
g) Z-Val-Val-MeVal-Pro-Pro-NHCH (CH 3 2 2 g (3.35 mmol) Z-Val-Val-MeVal-Pro-OH and 0.664 g (3.35 40 mmol) H-Pro-NHCH(CH 3 2 were dissolved in 34 ml of dry dichloromethane. After cooling to o0C, 1.35 ml (12.1 mmol) N-methylmorpholine, 0.114 g (0.84 mmol) HOBt and 0.645 g (3.35 mmol) EDCI were added and the reaction mixture stirred overnight at room temperature. 80 ml dichloromethane were added and the organic phase thoroughly washed with saturated aqueous NaHC03 solution water 5 citric acid (3x) and saturated NaCl solution The organic phase was 13 dried over sodium sulfate and evaporated to dryness to yield 1.96 g of the product which was used in the next reaction without further purification.
h) Me 2 Val-Val-MeVal-Pro-Pro-NHCH(CH3)2 1.96 g Z-Val-Val-MeVal-Pro-Pro-NHCH(CH3)2 were dissolved in 11 ml methanol. 0.054 g 10 Pd/C were added under nitrogen atmosphere and the reaction mixture hydrogenated at room temperature for 4 h. After addition of 0.86 ml (11.24 mmol) of a 37 aqueous formaldehyde solution and 0.281 g 10 Pd/C, hydrogenation was continued for 5 h. Filtration and evaporation of the solvent gave rise to 2.77 g of crude product. Further purification was achieved by dissolving the peptide in water, adjusting the pH to 2 and extracting the aqueous phase three times with ethyl acetate. The aqueous phase was then adjusted to pH 8-9 and extracted four times with dichloromethane. The organic phase was dried over sodium sulfate to yield 1.37 g of purified product as a white foam.
The compound was further purified using medium pressure liquid chromatography (10 50 A in 10 min.; 50 90 A in 320 min.). Fractions containing the product were combined, lyophilized, redissolved in water and the pH adjusted to 9 with 1 N LiOH. After extraction with dichloromethane, the organic phase was dried over sodium sulfate and evaporated to dryness. Lyophilization led to 500 mg of pure product, which was characterized by fast atom bombardment mass spectrometry 593).
30 EXAMPLE 2 (SEQ ID NO: 1) Me 2 Val-Val-MeVal-Pro-Pro-NHC
(CH
3 3 i) Z-Val-Val-MeVal-Pro-Pro-NHC
(CH
3 3 2 g (3.35 mmol) Z-Val-Val-MeVal-Pro-OH and 0.692 g (3.35 mmol) H-Pro-NHC(CH3)3 were dissolved in 34 ml of dry dichloromethane. After cooling to 0°C, 1.35 ml (12.1 mmol) N-methylmorpholine, 0.114 g (0.84 mmol) HOBt and 0.645 g (3.35 mmol) EDCI were added and the reaction mixture stirred overnight at room temperature. 80 ml dichloromethane were added and the organic phase thoroughly washed with saturated aqueous NaHCO3 solution water 5 citric acid (3x) and saturated NaC1 solution The organic phase was dried over sodium sulfate and evaporated to dryness to yield 1.8 g of the product which was used in the next reaction without further purification.
14 k) Me 2 Val-Val-MeVal-Pro-Pro-NHC(CH3)3 1.8 g Z-Val-Val-MeVal-Pro-Pro-NHC(CH 3 3 were dissolved in ml methanol. 0.049 g 10 Pd/C were added under nitrogen atmosphere and the reaction mixture hydrogenated at room temperature for 4 h. After addition of 0.86 ml (11.24 mmol) of a 37 aqueous formaldehyde solution and 0.252 g 10 Pd/C, hydrogenation was continued for 5 h. Filtration and evaporation of the solvent gave rise to 1.82 g of crude product. The compound was further purified using medium pressure liquid chromatography (10 50 A in 10 min.; 50 90 A in 320 min.). Fractions containing the product were combined, lyophilized, redissolved in water and the pH adjusted to 9 with 1 N LiOH. After extraction with dichloromethane, the organic phase was dried over sodium sulfate and evaporated to dryness. Lyophilization led to 547 mg of pure product, which was characterized by fast atom bombardment mass spectrometry 607).
The following compounds were prepared or can be prepared according to examples 1 and 2: a.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xdd val Xaa Val Xaa Val Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Pro Xac Pro Xad Pro Xae Pro Xaf Pro Xag Pro Xah Pro Xai Pro Xak Pro Xal Pro Xam Pro Xan Pro Xao Pro Xap Pro Xaq Pro Xar Pro Xas Pro Xat Pro Xau Pro Xav Pro Xaw Pro Xax Pro Xay Pro Xaz Pro Xba 27. Xaa val Xab Pro Xbb 28.
29.
31.
32.
33.
34.
36.
37.
38.
39.
41.
42.
43.
44.
46.
47.
48.
49.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
35 62.
63.
64.
66.
40 67.
68.
69.
70.
71.
72.
73.
74.
Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val.
Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Xdf Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xcw Val Xcx Val Xaa Val Xaa Val XbC Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab X ab Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Xay Xbd Xbe Xbf Xbg Xbh Xb i Xbk Xbl Xbm Xbn Xbo Xbp Xbq Xbr Xbs Xb t Xbu Xbv Xbw Xbx Xby Xb z Xca Xcb Xcc Xcd Xce Xcf Xay Xch Xci xck Xci Xcm Xcrl Xco Xcp Xcq Xcr Xcs Xc t Xcu Xcv Xcv Pro Xcy Pro Xcz Xaa Val 76. Xaa Xdb 77. Xdc Val 78. Xaa Ile 79. Xdd Val Xde Val 81. Xaa Xdf 82. Xaa Val 83. Xaa Val 84. Xaa Val Xaa Val 86. Xaa Val 87. Xaa Val 88. Xde Val.
89. Xaa Val Xaa Val 91. Xaa Val 92. Xaa Val.
93. Xaa Val 94. Xaa Val Xaa Val.
96. Xaa Val.
97. Xaa Val.
98. Xaa Ile 99. Xcw Val 100. Xaa Val.
101.Xaa Val.
102.Xaa Xdf 103.Xaa Ile 30 104. Xdd Val.
105. Xde Val.
106.Xcx Val.
107.Xcw Val.
108. Xcx Val.
109. Xcw Val.
110. Xcx Val 11:1.Xcw Val 1:12.Xcx Val 113. Xab Va].
40 114. Xab Val.
115. Xab Val.
116. Xab Val.
117. Xab Val 118. Xab Val.
119. Xab Val.
120. Xab Val.
121. Xab Val.
Xda Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xd 1 Xab Xd 1 Xab Xab Xab Xab Xab Xab Xab Xbc Xab Xab Xbc Xdl Xab Xab Xab Xab Xab Xab xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Pro Xcv Pro Xcv Pro Xcv Pro Xcv Pro Xcv Pro Xcv Pro Xcv Pro Xcg Pro Pro Xdg Pro Pro Xdh Pro Pro Xdi Pro Pro Xdk Pro Xcv Pro Xay Pro Xay Pro Xdm Pro Xdn Pro Xdo Pro Xdp Pro Xdq Pro Pro Xdr Pro Xds Pro Xcv Pro Xay Pro Xay Pro Xal Pro Xal Pro Xal Pro Xal Pro Xal Pro Xal Pro Xcy Pro Xal Pro Xal Pro Xav Pro Xav Pro Xaw Pro Xaw Pro Xay Pro Xcv Pro Xal Pro Xam Pro Xan Pro Xao Pro Xav Pro Xaw Pro Xat
S
S S
S
S
S
S
S
S S S
S
S5* 5* 9
*S
S.
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
132.
133.
134.
135.
136.
137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
147.
148.
149.
150.
151.
Xab Val Xab Val Xab Val Xab Val Xab Val Xab Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xaa Val Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Xab Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Xau Xb f Xbm Xbn Xbo Xch Xd t Xdu Xdv Xdw Xdx Xdy Xdz Xea Xeb Xec Xed Xe f Xeg Xeh Xe i Xek Xe 1 Xem Xen Xeo Xep Xecj Xer Xcg 0..
1 7a The following is a list of protecting groups and coupling reagents, and their abbreviated names, that may be used in methods to prepare compounds of formula 1.
Protecting Group Z benzyloxycarbonyl Boc t-butoxycarbonyl Fmoc N-alpha-(9-f luorenylmethyloxycarbonyl) Coupling Reagent
EDCI
DCC
DIC
EEDQ
PPA
BOP-CI
PyBrop
BOP
PyBop 4*
OS*@
-D 6 6
S
S
,v
S
S S 6SS S 6*@S
S
S
555* 4*e.~
S
DPPA
HBTU
HATU
1 -ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride 1 ,3-dicyclohexylcarbodiimide N, N'-Diisopropylcarbodiimide 1 -ethoxycarbonyl-2-ethoxy-1 ,2-dihydroquinoline 1 -propane phosphonic acid cyclic anhydride Bis(2.-oxo-3-oxozonilidyl)-phosphonic chloride bromo-tris-pyrrolidino-phosphonium hexafluorophosphate benzotriazol-1 -yloxytris(di-methylamino)phosphonium hexafluorophosphate 1 -benzotriazol- 1 -yl-oxytris(pyrrolidino)phosphonium hexafluorophosphate dipalmitoylphosphatidic acid 2-(1 H-benzotriazol- 1 -yl)-1 ,1 ,3,3-tetramethylu ronium hexafluorophosphate O-(7-azabenzotriazol-1 1,1 ,3,3-tetramethylu ronium hexafluorophosphate diethylphosphoryl cyanide 2 ,5-diphenyl 2,3-dihydro-3-oxo-4-hydroxythiophene dioxide N, N'-Carbonyldiimidazole (Dimethylamino)pyridine N-Hydroxybenzotriazole monohydrate 3,4-dihyd ro-3-hydroxy-4-oxo-1 ,2,3-benzotriazine N-hyd roxysuccinimide palladium on carbon
DEPCN
HOTDO
CDI
DMAP
HOBt
HOOBI
HOSu Pd/C Examples ror L1t ris-characterization of the compounds are given in the following table.
Fast atom bombardment MS analysis.
(Mol.-Weight (measured)] 3. 565 4. 579 5. 593 6. 607 7. 621 8. 635 1-607 12. 607 13. 621 14. 649 635 16. 635 17. 635 18. 635 19. 621 20. 621 21. 635 22. 635 V0625. 633 030 26. 647 661 31. 623 32. 671 33. 667 se*:34. 681 655 36. 655 .00 4 37. 669 4038. 621 39. 635 41. 649 42. 621 .0 45 43. 633 44 667 19 EXAMPLE Fast atom bombardment MS analysis.
607 46. 647 47. 668 48. 655 49. 669 685 51. 629 52. 625 53. 721 579 58. 623 61. 597 62. 621 63. 609 64. 625 635 66. 591 67. 715 68. 685 69. 685 591 71. 607 72. 621 30 74. 706 579 579 76. 579 77. 579 78. 607 79. 607 80. 607 81. 607 82. 637 83. 692 84. 706 85. 706 S 86. 706 87. 607 635 EXAMPLE Fast atom bombardment MS analysis.
92. 659 93. 617 94. 636 678 128. 671 131. 625 139 625 151. 637 Table I Sequence Identification of Compounds Prepared According to Examples 1 and 2 Compound Number(s) Sequence ID Number 1-56, 58-72, 75, 77, 79, 80, 82, 1 87-94, 96, 97, 99-101, 104-151 73, 74, 83-86, 95, 2 57, 76, 81, 102 3 78, 98, 103 4 The symbols Xaa in the summary have the following meanings: Xaa: N,N-Dimethylvaline Xab: N-Methylvaline
C*
oo N rNH CH 0 Xad: NN CH 3 0H Xae: NNH .CH 0
H
200 200 Xag: NH
CH
3 400 Xah:N N NH
CH
3 0 Xai: Xk Xa: H
CH
3 Xal: NH CH 3 o H 3
C
Xam:
NH
0 H 3
C
.Xan: Nl~ 1 N
H
CH
3 *A r N NH CH3 0
H
3
C
Xap: N N o CH 3 Xaq: ,N NH CH 3 Xar:
CH
3 NH CH 3 0 CH 3 1 X a :NN H C H- 3 0 CH 3
CH
3 XtNNHCH 3 0
H
3
C
CH
3 Xau: INNq I L CH 3 o H 3
C
iXav: HC CE 3 IlII NH I <CE 3 o H 3
C
Xaw:HC o NH
CH
3 0 H 3
C
Xax: NC H N NE CH =C
CH
3 Xay: NNH CH o CH 3 Xaz: Xba: N
NH
Xbb:
NN
250 Xbc: N-Methyl- isoleucine CH3 0 Xbd:I 400
CH
3 Xbe:0
H
I
CH
3 0
CH
3 0Xbg:N
CH
3 0 Xbh:
NN
1 Xbi:N *Xbk: N N
H
3
C
Al Xb 1: ~(rHNI~~h o H 3
C
H
3
C
Xbm: N NH C u CH 3
CH
3 Xbn: ~IVN CH 3 CH3
CH
3 *Xbo: q
CH
3 CH3
CH
3 *.Xbp: N NH H H *40 28
CH
3 Xbq: N NH CH 3 Xbr: C:H3 0N CH 3 Xb s: N NH ~,CF 3 Xb t: 0 Xbu: N CH 3 30 0CH 3 Xbv:
NHNI
400 Xbw
NH
Xbx: N NH K
OH
Xb z: u hI~. H3 I Xca: ~NH F o F Xcb: u CH 3 XCC: Proline adarnantyl amide 0 CH3 Xce: 1K 0 CM3 Xcf: 30CM 0
H
NN
0 CH3
OH
.0.0 Xch:
NN
Xci: 0
CH
3 Xck: Xcl:
,N
F
.NNH 00 0
XCM:
Xcn:
CH
3 0
XCO:
5~3N
CH
3 N
NH
0 Xcq:
NH
0 200 Xcs: O C 40 N
OH
Xc t: NN Xcu: Xcv: N N -CH 3 N o CH 3 Xcw: N-Methyl -N-ethyl -valine Xcx: N, N-Diethylvalile
CH
3 N NH
H
0 Xcz:
H
3 C' H N N H C H 3 0 34 Xda: N-Metnyi-2-aminobutyroyl Xdb: 2-aminobutyroyl Xdc: N, N-Dirnethyl-2-aminobutyroyl Xdd: N,N-Dimethyl-2-tert.butylglycine Xde: N, N-Dimethyl-isoleucine Xdf: 2-tert.butylglycine Xdg: HCl,,,-H -N NH %(CH 3 0
CH
3
CH
3 Xdh: H 3
CH
3 0 CH 3 V.
CH
3 Xdi: 3-, NH -CH3 0
CH
3 4Xdk:HC NH T..CH3 *0
CH
3 Xdl: N-Methyl-2-tert.butylglycile
CR
3 Xdm: NN,
CH
3 a CH 3
CR
3 Xdn:
CR
3 NH3 Xdo: 200 Xdp:
H
NH,, C~ CH S.
CH
3 Ndq NH., CONH 2 0S**: 0
CR
3 535
H
se@Xdr:
CONHCH
2
CH
2 CR3 Xds :.HCR 400 Xdt:N Xdu: NNH 0H Xdv: Nc NH -\CQ
F
Xdw: N R
CH
3
F
Xdx: NNH,,CH. CH 3 0
CH
3 F 0 06 ee Xdy: N NH
\CR
3 0 0dz CR 3 0000 NN 0 a 0CH 3 0 CR 3 Xea:N H
F
Xeb:
.KN
150 OCH 3 2 Xec:
CH
3
ICH
3
F
H
Xed: .A
IN
300
NH
F 0
CH
3 ANSNH
CH
3 j Xef:
H
cl Xeg: ,A Cl0 200 1AN NH
CH
3 15Xi:0ANN
CH
3 Cl Xe:
NH
NH, CH NH CH 3 0 CH 3 rH *l
CH
3 Xen:
NCH
3 0
CH
3 Cl Xeo: N NH-s 0 C1 CH3 Xep: N~ NH 0
CH
3 0 Cl N
NCH
3 NH CH 3 Xeq: l x Xeq:
CH
3 0 Compounds of this invention may be assayed for anti-cancer activity by conventional methods, including for example, the methods *described below.
A. In vitro methodology Cytotoxicity was measured using a standard methodology for adherent cell lines such as the microculture tetrazolium 35 assay (MTT). Details of this assay have been published "(Alley, MC et al, Cancer Research 48:589-601, 1988). Exponentially growing cultures of tumor cells such as the HT-29 colon carcinoma or LX-1 lung tumor are used to make microtiter plate cultures. Cells are seeded at 3000 cells per well in 96-well plates (in 150 gl of media), and grown overnight at 37°C. Test compounds are added, in 10-fold dilutions varying from 10- 4 M to 10-10 M. Cells are then incubated for 72 hours. To determine the number of viable cells in each well, the MTT dye is added (50 il of 3 mg/ml solution of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide in saline) This mixture is incubated at 37 0 C for 5 hours, and then 50 Vi of 25 SDS, pH2 is added to each well. After an overnight incubation, the absorbance of each well at 550 nm is read using an ELISA reader. The values for the mean SD of data from replicated wells are calculated, using the formula T/C viable cells treated/control).
OD of treated cells x 100 T/C OD of control cells The concentration of test compound which gives a T/C of growth inhibition was designated as the ICso value.
B. In vivo methodology Compounds of this invention were further tested in pre-clinical assay for in vivo activity which is indicative of clinical utility. Such assays were conducted with nude mice into which tumor tissue, preferably of human origin, had been transplanted (xenografted), as is well known in this field.
Test compounds were evaluated for their anti-tumor efficacy following administration to the xenograft-bearing mice.
More specifically, human breast tumors (MX-1) which had been grown in athymic nude mice were transplanted into new recipient mice, using tumor fragments which were about 50 mg in size. The day of transplantation was designated as day 0. Six to ten days later, mice were treated with the test compounds given as an intravenous injection or orally, in groups of 5-10 mice at each dose. Compounds were given every other day, 30 for 3 weeks, at doses from 1-200 mg/kg body weight.
Tumor diameters and body weights were measured twice weekly.
Tumor volumes were calculated using the diameters measured with Vernier calipers, and the formula i (length x width 2 mm 3 of tumor volume Mean tumor volumes are calculated for each treatment group, and T/C values determined for each group relative to the untreated control tumors.
The new compounds possess good tumor inhibiting properties.
*09 e 41 Compounds of this invention were assayed for resistance to enzymatic degradation and compared to known compounds treated under the same conditions.
Assay Conditions 100gl of a 1.35gM stock solution of commercially available enzyme (prolyloligopeptidase, (CN) were added to 1 ml 0.1 M phosphate buffer (pH 7) and 250 gl of an 810 gM stock solution of the compound at 37 0 C. After the various time points, small samples were taken, quenched with 0.3% aqueous TFA and analysed with analytical HPLC.
The compounds of the present invention demonstrated a high level of resistance to degradation relative to the comparative examples (Table 2).
.42 TABLE 2 Example K Metabolism Number 1 h 2 h .4h 2 NHC(CH 3 3 2 11 NHCH(CH3)C 2 Hs 12 12 NHCd(CH 3
)C
2 Hs 13 NHCH(C 2 Hs) 2 8 14 NHCH(C 3 Hy) 2
NHCH(C
2 Hs)C 1
H
7 16 NHCH(C 2 ;Hs)C 3 !i 7 6 17 NHCH(C 2 Hs)CH(GH 3 2 3 18 NH-CH(C 2 Hs)CH (CH 3 2 1 19 NHCH(CH 3
)CH(CH
3 2 8
NHCH(CH
3
)CII(CH
3 2 8 21 NHCH(CH3)CCH 3 3 1 22 NHCH(CH 3
)C(SIH
3 3 NH ccohe I 14 26 NH cydloheptyt 8 31 fN(CH 3 )0C 3
V-
7 1 37 NHd OH 3 2 Ph 0 38 NHC(C1 1).
2 1 39 NHC(PH 3
)(C
2 Hs) 2 1.
41 .NHCH[CH(CH 3 1 52 NHC(CH 3 3 4r--~ 53 NH adamant-i -yl 4 60 1 _4* 62- Mofleholino 82 1NHC(CH 3 2
CH
2
CH
2 0H 1 *83 NHCJ-i(CH 3 4 t0 fi IfI& (Ctf 3 2 1 92 12 .1 ,.93 RumH~CC 1 4 9 Example K Metabolism 1h 2h 4 h 128 N(OCH 3
)CH
2 Ph 132 NHCCH 3 2
C
2 Hs 129 N H(1 -methyl-i -cydlopentyl) 130 NH(1 -methyl-l-cydohexyI) COMPARATIVE EXAMPLES Example K Metabolism Nube1h 2h 4h A. NHCH2Ph 38- 70 B NH(CH 2 CH, 14 25 4 C NHLCH2)CH 3 14 22 D NI-f(CH 2 )sCHf 112 122 44: =after 24 hours
K=
2. K -NH -13 SEQUENCE
LISTING
GENERAL INFORMATION
APPLICANT:
BASF Aktiengesellschaft STREET: Carl-Bosch-Strasse 38 CITY: Ludwigshafen COUNTRY: Bundesrepublik Deutschland ZIP: D-67056 TELEPHONE: 0621/6048526 TELEFAX: 0621/6043123 TELEX: 1762175170 (ii) TITLE OF INVENTION: Novel peptides, the preparation and use thereof (iii) NUMBER OF SEQUENCES: 4 (iv) COMPUTER READABLE FORM: MEDIUM TYPE: Diskette, 3.5 inch, 2 DD COMPUTER: IBM AT-compatible, 80286 processor OPERATING SYSTEM: MS-DOS version SOFTWARE: WordPerfect INFORMATION FOR SEQ ID NO: 1: SEQUENCE CHARACTERISTICS: LENGTH: 5 amino acids TYPE: amino acid TOPOLOGY: linear 30 (ii)MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1: Xaa Val Xaa Pro Xaa 35 INFORMATION FOR SEQ ID NO: 2: S(i) SEQUENCE CHARACTERISTICS: LENGTH: 6 amino acids TYPE: amino acid TOPOLOGY: linear 40 (ii)MOLECULE TYPE: peptide (xi)SEQUENCE DESCRIPTION: SEQ ID NO: 2: .o*e Xaa Val Xaa Pro Pro Xaa S..e 45 INFORMATION FOR SEQ ID NO: 3: SEQUENCE CEARACTERISTICS LENGTH: 5 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3: Xaa Xaa Xaa Pro Xaa INFORMATION FOR SEQ ID NO: 4: SEQUENCE CHARACTERISTICS: LENGTH: 5 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 4: Xaa Ile Xaa Pro Xaa
Claims (12)
1. A peptide of the formula I R 1 R'N-CHX-CO-A-B-D-E- (G)s-K where R 1 A B D is methyl; is methyl; is a valyl residue; is a N-methyl-valyl residue; is a prolyl residue; E is a prolyl residue; X is isopropyl; s isO0; K is -NHC(CH 3 3 -NHCH(CH 2 CH 3 )CH(CH 3 2 -NHCH(CH 3 )C(CH 3 3 -N(CH 3 )OCH 2 CH 3 -N(CH 3 )OCH 2 CH 2 CH 3 -N(CH 3 )OCH(CH 3 2 -N(CH 3 )O(CH 2 3 0H 3 -N(CH 3 )OCH 2 C 6 H 5 -NHC(CH 3 2 C 6 H 5 -NHC(CH 3 2 CH 2 CH 3 -NHC(CH 3 )(CH 2 CH 3 2 -NHCH[CH(CH 3 2 2 -NHC(CH 3 2 CN, -NHCH(CH 3 )CH(OH)C 6 H 5 -NH-C(CH 3 2 CH=CH 2 -NHC(CH 3 2 C-=CH, -NHC(CH 2 CH 3 2 C-=CH, -NHC(CH 3 2 CH 2 CH 2 OH, -NHC(0H 3 2 CH(CH 3 2 -NHC(CH 3 2 CH 2 CH 2 CH 3 -NHC(CH 3 2 CH 2 0 6 H 5 -N(OCH 3 )CH(CH 3 2 -N(OCH 3 )CH 2 CH 3 -N(OCH 3 )CH 2 CH 2 CH 3 -N(00H 3 )CH 2 C 6 H 5 -N(OCH 3 )C 6 H 5 -N(CH 3 )0C 6 H 5 or -N(OCH 3 )CH 2 CH 2 CH 2 CH 3 or K is -NHCH(C 2 H 5 2 -NHCH(C 2 H 5 )CH(CH 3 2 -NHCH(CH 3 )CH(CH 3 2 -NHCH(CH 3 )C 2 Hs5, -NH cyclohexyl, -NH cycloheptyl, -NHC(CH 3 2 0 2 H 5 25 -NHC(CH 3 2 CH(CH 3 2 -NHCH(C 3 H 7 2 -NHCH(C 2 H 5 )C 3 H 7 or -NHCH(CH 3 2 or K is -N 0 -NH HGC -N b H 3 C -Ni H 3 c or K is -N H N -N-N -N -N) H H H- CH H 3 C CH 3H 3 -N-N 1 or CO-NHCH 2 CH 2 CH 3 -NH CONH 2 HI D I CH 3 and the salts thereof with physiologically tolerated acids.
2. A peptide of formula I according to claim 1 in which R' is methyl R 2 is methyl; A is a valyl residue; B is a N-methyl-valyl residue; D is a prolyl residue; E is a prolyl residue; X is isopropyl; K is -NHC(CH 3 3 -NHCH(CH 3 )C 2 H 5 -NHCH(C 2 H 5 2 -NHCH(C 2 H 5 )CH(CH 3 2 -NHCH(0H 3 )CH(CH 3 2 -NHCH(CH 3 )C(CH 3 3 -NHC(CH 3 2 C 2 H 5 NHCH[CH(CH 3 2 2 -NHC(CH 3 2 CH(CH 3 2 -NHCH(C 3 H 7 2 -NHCH(0 2 H 5 )C 3 H 7 -NH cyclohexyl, -NH cycloheptyl, -N(0H 3 )0C 3 H 7 -NHC(CH 3 2 Ph, -NHC (CH 3 )(C 2 H 5 2 -NHC(CH 3 2 G=-CH, -NHC(CH 3 2 CH 2 CH 2 OH, -NHCH(CH 3 2 or N(OCH 3 )CH 2 Ph or K is or K is -N O CH 3 -N- H -N H -NCO
3. R' R 2 A B D E X s K A is is is is is is is is is peptide according to claim 1 in which methyl; methyl; a valyl residue; a N-methyl-valyl residue; a prolyl residue; a prolyl residue; isopropyl; 0; NI-C(CH 3 3
4. The use of a compound of formula I according to claim 1, or a 15 pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of disease.
5. The use according to claim 4, wherein the disease is cancer.
6. A method of preparing a compound of formula I according to claim 1, wherein the method comprises solution synthesis or solid phase synthesis as described herein.
7. A peptide according to claim 1, as specifically set forth herein. 49
8. A method according to claim 6, substantially as herein described with reference to Example 1 or Example 2.
9. The method of preparing a peptide of formula I according to claim 1, wherein the peptides are assembled sequentially from amino acids by starting at the C terminus of the peptide with R'R 2 N-CHX-CO and extending the chain stepwise by coupling the C terminus carbonyl with the A residue, followed by the B residue, the D residue, and the E residue, wherein the C-terminus of the E residue maybe derivatized with the K group before or after coupling; or by linking suitable small peptide fragments, wherein A, B, D, E, K, X, R' and R 2 are as defined in claim 1. A method according to claim 9, wherein the method comprises solution phase synthesis and utilizes an amino acid protecting group selected from the group consisting of Z, Boc, and Fmoc.
11. A method according to claim 10, wherein the coupling reagents are selected from the group consisting of EDCI, DCC, DIG, EEDQ, PPA, BOP-CI, PyBrop, BOP and PyBop, DPPA, HBTU, HATU, DEPCN, HOTDO, CDI, and pivaloylchloride.
12. A method according to claim 11 further comprising a coupling reagent selected from the group consisting of DMAP, HOBt, HOOBt, azobenzotriazole 20 HOSu, and 2-hydroxypyridine.
13. A method according to claim 10, wherein the method comprises solution phase synthesis and utilizes a Z amino acid protecting group, EDCI and HOBt as the coupling reagents, and the compound is deprotected using Pd/C under a nitrogen atmosphere. *0 25 14. A method according to claim 9, wherein the method comprises solid phase synthesis and utilizes an amino acid protecting group selected from the group consisting of Z, Boc, and Fmoc. o A method according to claim 14, wherein the coupling reagents are selected from the group consisting of EDCI, DCC, DIC, EEDQ, PPA, BOP-CI, PyBrop, BOP and PyBop, DPPA, HBTU, HATU, DEPCN, HOTDO, CDI, and pivaloylchloride. DATED this 14th day of May 2004 ABBOTT GMBH CO. KG WATERMARK PATENT TRADE MARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA P2550AU01 CJH/BJDVRH
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU54143/01A AU775090B2 (en) | 1995-12-15 | 2001-06-29 | Antineoplastic peptides |
| AU2004220772A AU2004220772B2 (en) | 1995-12-15 | 2004-10-15 | Antineoplastic peptides |
| AU2005203729A AU2005203729B2 (en) | 1995-12-15 | 2005-08-19 | Outer surface proteins, their genes, and their use |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/573422 | 1995-12-15 | ||
| AU54143/01A AU775090B2 (en) | 1995-12-15 | 2001-06-29 | Antineoplastic peptides |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU11925/97A Division AU731458B2 (en) | 1995-12-15 | 1996-12-11 | Antineoplastic peptides |
Related Child Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2004220772A Division AU2004220772B2 (en) | 1995-12-15 | 2004-10-15 | Antineoplastic peptides |
| AU2005203729A Division AU2005203729B2 (en) | 1995-12-15 | 2005-08-19 | Outer surface proteins, their genes, and their use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU5414301A AU5414301A (en) | 2001-08-30 |
| AU775090B2 true AU775090B2 (en) | 2004-07-15 |
Family
ID=3740146
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU54143/01A Ceased AU775090B2 (en) | 1995-12-15 | 2001-06-29 | Antineoplastic peptides |
| AU2005203729A Expired - Fee Related AU2005203729B2 (en) | 1995-12-15 | 2005-08-19 | Outer surface proteins, their genes, and their use |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2005203729A Expired - Fee Related AU2005203729B2 (en) | 1995-12-15 | 2005-08-19 | Outer surface proteins, their genes, and their use |
Country Status (1)
| Country | Link |
|---|---|
| AU (2) | AU775090B2 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993023424A1 (en) * | 1992-05-20 | 1993-11-25 | Basf Aktiengesellschaft | Derivatives of dolastatin |
-
2001
- 2001-06-29 AU AU54143/01A patent/AU775090B2/en not_active Ceased
-
2005
- 2005-08-19 AU AU2005203729A patent/AU2005203729B2/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993023424A1 (en) * | 1992-05-20 | 1993-11-25 | Basf Aktiengesellschaft | Derivatives of dolastatin |
Also Published As
| Publication number | Publication date |
|---|---|
| AU5414301A (en) | 2001-08-30 |
| AU2005203729B2 (en) | 2008-06-12 |
| AU2005203729A1 (en) | 2005-09-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU725164B2 (en) | Novel dolastatin derivatives, their preparation and use | |
| EP0674652B1 (en) | Dolastatin analog | |
| AU2004220772B2 (en) | Antineoplastic peptides | |
| US8440626B2 (en) | Antineoplastic peptides | |
| AU775090B2 (en) | Antineoplastic peptides | |
| HK1080871A (en) | Antineoplastic peptides |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PC1 | Assignment before grant (sect. 113) |
Owner name: ABBOTT GMBH AND CO. KG Free format text: THE FORMER OWNER WAS: BASF AKTIENGESELLSCHAFT |
|
| FGA | Letters patent sealed or granted (standard patent) |