IL128610A - Cryptophycin compound and its use as a medicament for treating neoplasm - Google Patents

Info

Publication number

IL128610A

IL128610A IL12861097A IL12861097A IL128610A IL 128610 A IL128610 A IL 128610A IL 12861097 A IL12861097 A IL 12861097A IL 12861097 A IL12861097 A IL 12861097A IL 128610 A IL128610 A IL 128610A

Authority

IL

Israel

Prior art keywords

cryptophycin

group

mmol

alkyl

boc

Prior art date

1996-08-30

Links

• Espacenet
• Global Dossier
• Discuss

• 206010028980 Neoplasm Diseases 0.000 title claims abstract description 29
• -1 Cryptophycin compound Chemical class 0.000 title claims description 56
• 229930188224 Cryptophycin Natural products 0.000 title claims description 38
• PSNOPSMXOBPNNV-UHFFFAOYSA-N cryptophycin-327 Natural products C1=C(Cl)C(OC)=CC=C1CC1C(=O)NCC(C)C(=O)OC(CC(C)C)C(=O)OC(C(C)C2C(O2)C=2C=CC=CC=2)CC=CC(=O)N1 PSNOPSMXOBPNNV-UHFFFAOYSA-N 0.000 title claims description 33
• 108010006226 cryptophycin Proteins 0.000 title claims description 28
• 239000003814 drug Substances 0.000 title claims description 16
• 208000035269 cancer or benign tumor Diseases 0.000 title claims description 6
• PSNOPSMXOBPNNV-VVCTWANISA-N cryptophycin 1 Chemical class C1=C(Cl)C(OC)=CC=C1C[C@@H]1C(=O)NC[C@@H](C)C(=O)O[C@@H](CC(C)C)C(=O)O[C@H]([C@H](C)[C@@H]2[C@H](O2)C=2C=CC=CC=2)C/C=C/C(=O)N1 PSNOPSMXOBPNNV-VVCTWANISA-N 0.000 claims abstract description 57
• 150000001875 compounds Chemical class 0.000 claims description 178
• MXZDFWPOJAPNJL-VIVUCZJBSA-N (3s,10r,13e,16s)-16-[(2r,3r,4s)-4-chloro-3-hydroxy-4-phenylbutan-2-yl]-10-[(3-chloro-4-methoxyphenyl)methyl]-6,6-dimethyl-3-(2-methylpropyl)-1,4-dioxa-8,11-diazacyclohexadec-13-ene-2,5,9,12-tetrone Chemical compound C1=C(Cl)C(OC)=CC=C1C[C@@H]1C(=O)NCC(C)(C)C(=O)O[C@@H](CC(C)C)C(=O)O[C@H]([C@H](C)[C@@H](O)[C@@H](Cl)C=2C=CC=CC=2)C/C=C/C(=O)N1 MXZDFWPOJAPNJL-VIVUCZJBSA-N 0.000 claims description 126
• 108010083682 cryptophycin 55 Proteins 0.000 claims description 121
• 229910052739 hydrogen Inorganic materials 0.000 claims description 110
• 238000002360 preparation method Methods 0.000 claims description 82
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 67
• 239000001257 hydrogen Substances 0.000 claims description 57
• 229910052757 nitrogen Inorganic materials 0.000 claims description 48
• 125000000217 alkyl group Chemical group 0.000 claims description 43
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 34
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 33
• 150000003839 salts Chemical class 0.000 claims description 33
• 125000003118 aryl group Chemical group 0.000 claims description 23
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 21
• 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 20
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
• 229910052736 halogen Inorganic materials 0.000 claims description 18
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
• 125000005843 halogen group Chemical group 0.000 claims description 15
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
• DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical group NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 claims description 11
• 241000124008 Mammalia Species 0.000 claims description 11
• 150000001413 amino acids Chemical class 0.000 claims description 11
• 150000002367 halogens Chemical class 0.000 claims description 11
• WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims description 11
• 229940024606 amino acid Drugs 0.000 claims description 10
• 150000001720 carbohydrates Chemical class 0.000 claims description 10
• 125000001072 heteroaryl group Chemical group 0.000 claims description 10
• 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 8
• 229910052708 sodium Inorganic materials 0.000 claims description 8
• KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 8
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 7
• IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 claims description 7
• 235000014633 carbohydrates Nutrition 0.000 claims description 7
• 229940049953 phenylacetate Drugs 0.000 claims description 7
• 229910006069 SO3H Inorganic materials 0.000 claims description 6
• 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 6
• 229910018830 PO3H Inorganic materials 0.000 claims description 5
• 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
• 101100516559 Caenorhabditis elegans nhr-65 gene Proteins 0.000 claims description 4
• PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 4
• 125000006307 alkoxy benzyl group Chemical group 0.000 claims description 4
• 229940067621 aminobutyrate Drugs 0.000 claims description 4
• 150000002576 ketones Chemical class 0.000 claims description 4
• 239000008194 pharmaceutical composition Substances 0.000 claims description 4
• 229940009098 aspartate Drugs 0.000 claims description 3
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
• 150000002337 glycosamines Chemical class 0.000 claims description 3
• 125000006498 halo alkoxy benzyl group Chemical group 0.000 claims description 3
• 125000006289 hydroxybenzyl group Chemical group 0.000 claims description 3
• KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 3
• MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 2
• 125000006710 (C2-C12) alkenyl group Chemical group 0.000 claims description 2
• 125000006711 (C2-C12) alkynyl group Chemical group 0.000 claims description 2
• HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 2
• MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 2
• 239000012453 solvate Substances 0.000 claims description 2
• 150000002431 hydrogen Chemical class 0.000 claims 6
• PQBAWAQIRZIWIV-UHFFFAOYSA-N N-methylpyridinium Chemical compound C[N+]1=CC=CC=C1 PQBAWAQIRZIWIV-UHFFFAOYSA-N 0.000 claims 2
• PECYZEOJVXMISF-REOHCLBHSA-O 3-ammonio-L-alanine(1+) Chemical compound [NH3+]C[C@H](N)C(O)=O PECYZEOJVXMISF-REOHCLBHSA-O 0.000 claims 1
• CKLJMWTZIZZHCS-UWTATZPHSA-N D-aspartic acid Chemical compound OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 claims 1
• KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 claims 1
• ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims 1
• QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims 1
• KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims 1
• COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims 1
• UCMIRNVEIXFBKS-UHFFFAOYSA-M beta-alaninate Chemical compound NCCC([O-])=O UCMIRNVEIXFBKS-UHFFFAOYSA-M 0.000 claims 1
• 229940065734 gamma-aminobutyrate Drugs 0.000 claims 1
• RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims 1
• 239000000203 mixture Substances 0.000 abstract description 143
• 238000011282 treatment Methods 0.000 abstract description 26
• 239000002246 antineoplastic agent Substances 0.000 abstract description 22
• 229940034982 antineoplastic agent Drugs 0.000 abstract description 17
• 201000011510 cancer Diseases 0.000 abstract description 8
• 238000009472 formulation Methods 0.000 abstract description 4
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 360
• 239000000243 solution Substances 0.000 description 306
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• VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 145
• 238000003756 stirring Methods 0.000 description 138
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 123
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 109
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 104
• 229910052799 carbon Inorganic materials 0.000 description 98
• 238000002451 electron ionisation mass spectrometry Methods 0.000 description 98
• PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 90
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• 229910002027 silica gel Inorganic materials 0.000 description 68
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 67
• 210000004027 cell Anatomy 0.000 description 63
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 61
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 59
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• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 54
• OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical class CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 53
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• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 51
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 50
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 50
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
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• 150000002118 epoxides Chemical group 0.000 description 43
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• QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 39
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 39
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