NZ620933B2 - Pharmaceutical compositions of hydrophobic camptothecin derivatives - Google Patents
Pharmaceutical compositions of hydrophobic camptothecin derivatives Download PDFInfo
- Publication number
- NZ620933B2 NZ620933B2 NZ620933A NZ62093312A NZ620933B2 NZ 620933 B2 NZ620933 B2 NZ 620933B2 NZ 620933 A NZ620933 A NZ 620933A NZ 62093312 A NZ62093312 A NZ 62093312A NZ 620933 B2 NZ620933 B2 NZ 620933B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- alkyl
- lower alkyl
- amino
- residue
- halogenated
- Prior art date
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- VSJKWCGYPAHWDS-FQEVSTJZSA-N Camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 title claims abstract description 69
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 67
- 230000002209 hydrophobic Effects 0.000 title claims abstract description 39
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 59
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 59
- 150000003904 phospholipids Chemical class 0.000 claims abstract description 53
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- 239000011780 sodium chloride Substances 0.000 claims abstract description 40
- 150000003839 salts Chemical class 0.000 claims abstract description 39
- 201000011510 cancer Diseases 0.000 claims abstract description 37
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 17
- -1 cyano, nitro, amino Chemical group 0.000 claims description 383
- 125000000217 alkyl group Chemical group 0.000 claims description 332
- 125000003545 alkoxy group Chemical group 0.000 claims description 200
- 229910052739 hydrogen Inorganic materials 0.000 claims description 101
- 239000001257 hydrogen Substances 0.000 claims description 101
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 85
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 79
- 150000002431 hydrogen Chemical group 0.000 claims description 79
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 72
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 64
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 57
- WOAHJDHKFWSLKE-UHFFFAOYSA-N 1,2-Benzoquinone Chemical compound O=C1C=CC=CC1=O WOAHJDHKFWSLKE-UHFFFAOYSA-N 0.000 claims description 50
- 125000000623 heterocyclic group Chemical group 0.000 claims description 48
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 45
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 42
- 239000000203 mixture Substances 0.000 claims description 42
- 125000004414 alkyl thio group Chemical group 0.000 claims description 34
- 239000000693 micelle Substances 0.000 claims description 34
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 31
- 229910052760 oxygen Inorganic materials 0.000 claims description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 31
- 229910052717 sulfur Inorganic materials 0.000 claims description 31
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 27
- 125000003282 alkyl amino group Chemical group 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 23
- 125000002837 carbocyclic group Chemical group 0.000 claims description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N furane Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 125000004665 trialkylsilyl group Chemical group 0.000 claims description 15
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 14
- MENHXVNCWVKFRA-UHFFFAOYSA-N 1,4-oxazin-2-one Chemical group O=C1C=NC=CO1 MENHXVNCWVKFRA-UHFFFAOYSA-N 0.000 claims description 13
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 13
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
- 150000002829 nitrogen Chemical group 0.000 claims description 13
- 239000003002 pH adjusting agent Substances 0.000 claims description 13
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 13
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-Dihydrofuran Chemical group C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 claims description 12
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 claims description 12
- 125000002947 alkylene group Chemical group 0.000 claims description 11
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 11
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 11
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
- 125000005103 alkyl silyl group Chemical group 0.000 claims description 10
- 125000005418 aryl aryl group Chemical group 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 10
- 125000004849 alkoxymethyl group Chemical group 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical group OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 8
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 8
- 239000011975 tartaric acid Substances 0.000 claims description 8
- 235000002906 tartaric acid Nutrition 0.000 claims description 8
- 229960001367 tartaric acid Drugs 0.000 claims description 8
- 239000002246 antineoplastic agent Substances 0.000 claims description 7
- 239000003112 inhibitor Substances 0.000 claims description 6
- 229910003827 NRaRb Inorganic materials 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 239000000546 pharmaceutic aid Substances 0.000 claims description 4
- 229920003013 deoxyribonucleic acid Polymers 0.000 claims description 3
- 239000004052 folic acid antagonist Substances 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- 230000002194 synthesizing Effects 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 239000002168 alkylating agent Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 24
- 125000001475 halogen functional group Chemical group 0.000 claims 20
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 8
- 125000005462 imide group Chemical group 0.000 claims 2
- JTJMJGYZQZDUJJ-UHFFFAOYSA-N Phencyclidine Chemical compound C1CCCCN1C1(C=2C=CC=CC=2)CCCCC1 JTJMJGYZQZDUJJ-UHFFFAOYSA-N 0.000 claims 1
- 230000003115 biocidal Effects 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 230000002503 metabolic Effects 0.000 claims 1
- VMWJCFLUSKZZDX-UHFFFAOYSA-N N,N-dimethylmethanamine Chemical group [CH2]N(C)C VMWJCFLUSKZZDX-UHFFFAOYSA-N 0.000 abstract description 4
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 83
- 125000005843 halogen group Chemical group 0.000 description 64
- 210000004027 cells Anatomy 0.000 description 36
- 150000003254 radicals Chemical class 0.000 description 33
- 125000001424 substituent group Chemical group 0.000 description 29
- 125000004122 cyclic group Chemical group 0.000 description 24
- JCXJVPUVTGWSNB-UHFFFAOYSA-N nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 17
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 125000005842 heteroatoms Chemical group 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000009826 distribution Methods 0.000 description 14
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 13
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 12
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 12
- UCFGDBYHRUNTLO-QHCPKHFHSA-N Topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 12
- 239000000594 mannitol Substances 0.000 description 12
- 235000010355 mannitol Nutrition 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 229960000303 topotecan Drugs 0.000 description 12
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 11
- 229960004106 citric acid Drugs 0.000 description 11
- 125000004429 atoms Chemical group 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 125000004432 carbon atoms Chemical group C* 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 8
- 125000003118 aryl group Chemical group 0.000 description 7
- 238000011156 evaluation Methods 0.000 description 7
- 239000001963 growth media Substances 0.000 description 7
- 229910052751 metal Inorganic materials 0.000 description 7
- 239000002184 metal Substances 0.000 description 7
- 150000002772 monosaccharides Chemical group 0.000 description 7
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 6
- 229920002505 N-(Carbonyl-Methoxypolyethylene Glycol 2000)-1,2-Distearoyl-Sn-Glycero-3-Phosphoethanolamine Polymers 0.000 description 6
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- ZAASRHQPRFFWCS-UHFFFAOYSA-P diazanium;oxygen(2-);uranium Chemical compound [NH4+].[NH4+].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[U].[U] ZAASRHQPRFFWCS-UHFFFAOYSA-P 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- 150000002500 ions Chemical class 0.000 description 6
- 239000002609 media Substances 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 206010060862 Prostate cancer Diseases 0.000 description 5
- 229940035295 Ting Drugs 0.000 description 5
- 235000011054 acetic acid Nutrition 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 5
- 230000027455 binding Effects 0.000 description 5
- 239000007853 buffer solution Substances 0.000 description 5
- 238000000975 co-precipitation Methods 0.000 description 5
- 230000000875 corresponding Effects 0.000 description 5
- 229940079593 drugs Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000000925 erythroid Effects 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 125000005647 linker group Chemical group 0.000 description 5
- DFPAKSUCGFBDDF-UHFFFAOYSA-N nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 5
- 238000001959 radiotherapy Methods 0.000 description 5
- 230000002829 reduced Effects 0.000 description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
- 239000011593 sulfur Substances 0.000 description 5
- 125000004434 sulfur atoms Chemical group 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 206010018338 Glioma Diseases 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000002512 chemotherapy Methods 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 150000003949 imides Chemical group 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- 125000004433 nitrogen atoms Chemical group N* 0.000 description 4
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 4
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- LCTONWCANYUPML-UHFFFAOYSA-N pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 4
- 230000001629 suppression Effects 0.000 description 4
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 3
- MSBZUOIIUNSSRF-UHFFFAOYSA-N 1-oxido-1,2,3-benzotriazin-1-ium Chemical compound C1=CC=C2[N+]([O-])=NN=CC2=C1 MSBZUOIIUNSSRF-UHFFFAOYSA-N 0.000 description 3
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 3
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- 206010073071 Hepatocellular carcinoma Diseases 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 210000002798 bone marrow cell Anatomy 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- MWRBNPKJOOWZPW-CLFAGFIQSA-N dioleoyl phosphatidylethanolamine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(=O)OCCN)OC(=O)CCCCCCC\C=C/CCCCCCCC MWRBNPKJOOWZPW-CLFAGFIQSA-N 0.000 description 3
- 150000002016 disaccharides Chemical class 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 239000001530 fumaric acid Substances 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000007943 implant Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 239000011976 maleic acid Substances 0.000 description 3
- 235000005152 nicotinamide Nutrition 0.000 description 3
- 229920001542 oligosaccharide Polymers 0.000 description 3
- 150000002482 oligosaccharides Polymers 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N oxygen atom Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000011146 sterile filtration Methods 0.000 description 3
- 239000008223 sterile water Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000001384 succinic acid Substances 0.000 description 3
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 3
- 231100000338 sulforhodamine B assay Toxicity 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 150000003852 triazoles Chemical class 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- 238000007738 vacuum evaporation Methods 0.000 description 3
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2R,3R,4S,5R,6S)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2R,3R,4S,5R,6R)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 2
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-Bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 description 2
- CITHEXJVPOWHKC-UUWRZZSWSA-N 1,2-di-O-myristoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCC CITHEXJVPOWHKC-UUWRZZSWSA-N 0.000 description 2
- LVNGJLRDBYCPGB-UHFFFAOYSA-N 1,2-distearoylphosphatidylethanolamine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-UHFFFAOYSA-N 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N 1-[(1S,2R,3R,4S,5R,6R)-3-carbamimidamido-6-{[(2R,3R,4R,5S)-3-{[(2S,3S,4S,5R,6S)-4,5-dihydroxy-6-(hydroxymethyl)-3-(methylamino)oxan-2-yl]oxy}-4-formyl-4-hydroxy-5-methyloxolan-2-yl]oxy}-2,4,5-trihydroxycyclohexyl]guanidine Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N 5-flurouricil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 2
- 241000615866 Antho Species 0.000 description 2
- FTOAOBMCPZCFFF-UHFFFAOYSA-N Barbital Chemical compound CCC1(CC)C(=O)NC(=O)NC1=O FTOAOBMCPZCFFF-UHFFFAOYSA-N 0.000 description 2
- 229960002319 Barbital Drugs 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- 210000001185 Bone Marrow Anatomy 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N Carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N Carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N Coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N Diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
Disclosed herein are pharmaceutical compositions comprising at least one hydrophobic camptothecin derivative, such as the compounds of formula I, or a pharmaceutically acceptable salt of said derivative and a polyethylene glycol (PEG) conjugated phospholipid. Also disclosed are methods for inhibiting cancer cells in a subject in need thereof by administering the pharmaceutical composition of the present invention. An example of the camptothecin derivatives of formula I is the compound (S)-10-[(dimethylamino)methyl]-4-ethyl-9-hydroxy-4-O-[(±)-2-(2",4",5",7"-tetranitro-9"-fluorenylideneaminooxy)propionyl]-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H)-dione. g cancer cells in a subject in need thereof by administering the pharmaceutical composition of the present invention. An example of the camptothecin derivatives of formula I is the compound (S)-10-[(dimethylamino)methyl]-4-ethyl-9-hydroxy-4-O-[(±)-2-(2",4",5",7"-tetranitro-9"-fluorenylideneaminooxy)propionyl]-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H)-dione.
Description
PHARMACEUTICAL COMPOSITIONS OF HYDROPHOBIC
CAMPTOTHECIN TIVES
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Application No. 61/555,084, filed
November 3, 2011, the entire disclosure of which is incorporated herein by reference.
FIELD OF INVENTION
The present invention lly relates to pharmaceutical compositions
comprising one or more hydrophobic camptothecin derivatives. Also described are
methods of their use in inhibiting or suppressing the growth of cancer cells.
BACKGROUND OF THE INVENTION
Camptothecin -ethylhydroxyl-1H-pyrano-[3’4’:6,7]indolizino
[1,2-b]quinoline-3,14(4H,12H)-dione)) (“CPT”) and its derivatives are known as
potent topoisomerase I inhibitors with broad-spectrum anticancer activities.
r, such compounds have low water solubility, reduced bioavailability and
e stability. In on, these compounds have severe adverse reactions such as
bone marrow suppression, which can result in anemia, neutropenia and/or
thrombocytopenia. Therefore, the clinical applications of CPT and its derivatives
are limited.
In view of the deficiencies outlined above, there is a need for providing
pharmaceutical compositions of CPT and its derivatives with ed drug solubility,
extended shelf life and stability and reduced side effects.
BRIEF SUMMARY OF THE ION
In one aspect, the invention provides a ceutical composition,
comprising:
at least one hydrophobic camptothecin derivative or a ceutically
acceptable salt of said derivative; and
at least one polyethylene glycol (PEG) conjugated phospholipid;
wherein the molar ratio of said PEG conjugated phospholipid to said hydrophobic
camptothecin derivative or said pharmaceutically acceptable salt of said hydrophobic
camptothecin derivative is r than about 0.45:1; wherein said hydrophobic
camptothecin derivative comprises at least one compound of formula (I):
or a pharmaceutically acceptable salt of said derivative;
wherein:
W is alkyl-C(O) , or R1Y-L-C(O), provided that when W is
alkyl-C(O) , at least one of R2, R3, R4, R5, or R6 is nitro;
L is a bond or linear alkylene (1-8) group, optionally substituted with
lower alkyl or tuted lower alkyl, wherein one or two methylene
( CH2 ) units of the linear ne group is optionally replaced with O, S
or NH;
Y is =NO , N(H)O , =N , NR , O, S, or a bond;
R is H, alkyl, or optionally substituted alkyl;
R1 is optionally substituted carbocyclic, heterocyclic, or fused 2-, 3- or
4-ring cyclic;
R2 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RQY,
RQY-L-C(O)O , cyano, nitro, amino, halogenated lower alkyl, halogenated
lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, tri lower
ilyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue,
phosphosugar e residue, O-quinone, substituted lower alkyl
aminomethyl, lower alkylcarbonylamino, lower alkylcarbonyloxy methyl,
optionally substituted lower alkylcarbonyloxy methyl, substituted vinyl,
1-hydroxynitroethyl, alkoxycarbonylethyl, arbonyl, alkylcarbonyl,
benzoylmethyl, benzylcarbonyloxymethyl, lower alkyliminomethyl or lower
alkoxymethyl;
R3 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy,
RQY-L-C(O)O , cyano, nitro, amino, halogenated lower alkyl, halogenated
lower alkoxy, hydroxycarbonyl, , lower alkoxycarbonyl, CH2NR7R8
(where each of R7 and R8 is independently H, alkyl of 1-6 carbons, optionally
substituted phenyl, y lower alkyl, amino lower alkyl, or mono- or
dialkylamino lower alkyl, or R7 and R8 taken together with N represent a
cyclic amino-), CH2R9 (where R9 is lower alkoxy, cyano, amino lower alkoxy,
mono- or di-lower alkylamino lower alkoxy, lower alkylthio, amino lower
alkylthio, or mono- or di-lower alkylamino lower alkylthio), NR10R11 (where
each of R10 and R11 is independently hydrogen, lower alkyl, , hydroxy
lower alkyl, or amino lower alkyl, or R10 and R11 taken together with --N--
represent a cyclic amino), trialkylsilyl, dialkylamino alkyl, lower
alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue, phosphosugar
e, O-quinone, tuted lower alkyl aminomethyl, or lower
alkylcarbonylamino or R3 together with R4 is furan, ofuran or
1,4-oxazineone; and
R4 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy,
RQY-L-C(O)O , cyano, nitro, amino, amino lower alkyl, halogenated lower
alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower
alkoxycarbonyl, carbamoyloxy, lower alkylcarbonyloxy, lower
alkoxycarbonyloxy, sugar residue, phosphosugar residue e, O-quinone,
substituted lower alkyl aminomethyl, or lower alkylcarbonylamino, or R4
together with R3 is furan, dihydrofuran or 1,4-oxazineone, or R4 together
with R5 is methylenedioxy;
R5 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy,
RQY-L-C(O)O , cyano, nitro, amino, trialkylsilyl, halogenated lower alkyl,
halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl,
lower arbonyloxy, lower carbonyloxy, sugar residue,
phosphosugar residue residue, O-quinone, substituted lower alkyl
aminomethyl, or lower alkylcarbonylamino, or R5 together with R4 is
enedioxy;
R6 is en, halo, lower alkyl, lower alkoxy, hydroxy,
RQY-L-C(O)O , cyano, nitro, amino, halogenated lower alkyl, halogenated
lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower
alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue, phosphosugar
residue residue, O-quinone, substituted lower alkyl aminomethyl, or lower
alkylcarbonylamino; and
RQ is ally substituted carbocyclic, heterocyclic, or fused 2-, 3- or
4-ring heterocyclic;
or wherein said hydrophobic camptothecin derivative comprises at
least one compound of formula (II):
(II)
or a pharmaceutically acceptable salt of said derivative;
X is a O, S, —NR—, or a bond;
Y is ═NO—, —N(H)O—, ═N—, —NR—, O, S; or a covalent bond;
T is independently CRR′;
each of R and R′ is ndently selected from hydrogen, C1-4 alkyl,
and substituted C1-4 alkyl;
n is an integer from 0 to 8;
R1 is optionally substituted heterocyclic, aryl, or heteroaryl; provided
that when X is a bond or CH2 and n is 1, 2, or 3, then Y, when bound to R1, is
not oxygen; and provided that when X is a bond or CH2, n is 1, 2, or 3; and R1
is heterocyclic ning at least one nitrogen atom, then Y is not bound
directly to said nitrogen atom;
R2 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy,
RQY-L-C(O)O—, cyano, nitro, amino, halogenated lower alkyl, halogenated
lower alkoxy, hydroxycarbonyl, , lower alkoxycarbonyl, tri lower
alkylsilyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue,
phosphosugar residue residue, O-quinone, substituted lower alkyl
aminomethyl, lower alkylcarbonylamino, lower alkylcarbonyloxy methyl,
optionally substituted lower alkylcarbonyloxy methyl, tuted vinyl,
1-hydroxynitroethyl, alkoxycarbonylethyl, aminocarbonyl, alkylcarbonyl,
alkylcarbonyloxymethyl, benzoylmethyl, carbonyloxymethyl, lower
alkyliminomethyl or lower alkoxymethyl;
R3 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy,
RQY-L-C(O)O—, cyano, nitro, amino, halogenated lower alkyl, halogenated
lower alkoxy, hydroxycarbonyl, formyl, lower carbonyl, CH2NR7R8
(where each of R7 and R8 is independently H, alkyl of 1-6 carbons, ally
substituted phenyl, y lower alkyl, amino lower alkyl, or mono- or
dialkylamino lower alkyl, or and R8 taken together with —N— represent a
cyclic amino-), CH2R9 (where R9 is lower alkoxy, CN, amino lower alkoxy,
mono- or di-lower alkylamino lower alkoxy, lower alkylthio, amino lower
alkylthio, or mono- or di-lower alkylamino lower alkylthio), NR10R11 (where
each of R10 and R11 is independently hydrogen, lower alkyl, phenyl, hydroxy
lower alkyl, or amino lower alkyl, or R10 and R11 taken er with —N—
represent a cyclic amino), trialkylsilyl, dialkylamino alkyl, lower
alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue, phosphosugar
e residue, O-quinone, substituted lower alkyl aminomethyl, or lower
alkylcarbonylamino or R3 together with R4 is furan, dihydrofuran or
1,4-oxazineone;
R4 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy,
RQY-L-C(O)O—, cyano, nitro, amino, amino lower alkyl, halogenated lower
alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower
alkoxycarbonyl, carbamoyloxy, lower alkylcarbonyloxy, lower
carbonyloxy, sugar residue, phosphosugar e residue, O-quinone,
substituted lower alkyl aminomethyl, or lower alkylcarbonylamino, or R4
together with R5 is methylenedioxy;
R5 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy,
RQY-L-C(O)O—, cyano, nitro, amino, halogenated lower alkyl, halogenated
lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower
alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue, phosphosugar
residue residue, O-quinone, substituted lower alkyl aminomethyl, or lower
alkylcarbonylamino; and
R6 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy,
C(O)O—, cyano, nitro, amino, trialkylsilyl, halogenated lower alkyl,
halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl,
lower alkylcarbonyloxy, lower carbonyloxy, sugar residue,
phosphosugar residue, O-quinone, substituted lower alkyl aminomethyl, or
lower arbonylamino; and RQ is an optionally tuted heterocyclic,
aryl, or heteroaryl group, or R1Y er form a NRaRb group, where Ra, Rb,
and the en to which they are attached form a cyclic amine or imide ring.
[0005a] In another aspect, the invention proivdes a plurality of micelles, wherein
each of said micelles comprises a pharmaceutical composition of the invention.
[0005b] In another aspect, the invention provides a pharmaceutical composition,
comprising:
at least one compound selected from the group consisting of
TLC388HCl or a pharmaceutically acceptable salt of TLC388 HCl;
methoxyl PEG-DSPE conjugate; and
citric acid;
wherein the molar ratio of said methoxyl PEG conjugated olipid
to said HCl or a pharmaceutically acceptable salt of TLC388 HCl is
greater than about 0.45: 1 to about 0.9:1.
[0005c] In another aspect, the invention realtes to the use of a pharmaceutical
composition comprising:
at least one hydrophobic camptothecin derivative or a pharmaceutically
acceptable salt of said derivative; and
at least one polyethylene glycol (PEG) conjugated phospholipid; in the
manufacture of a medicament for inhibiting growth of cancer cells, wherein the molar
ratio of said PEG conjugated olipid to said hydrophobic camptothecin
derivative or said pharmaceutically acceptable salt of said hydrophobic thecin
tive is greater than about 0.45:1, wherein said hydrophobic camptothecin
derivative comprises at least one nd of formula (I):
or a pharmaceutically acceptable salt of said derivative;
W is alkyl-C(O) , or R1Y-L-C(O), provided that when W is
alkyl-C(O) , at least one of R2, R3, R4, R5, or R6 is nitro;
L is a bond or linear alkylene (1-8) group, optionally substituted with
lower alkyl or substituted lower alkyl, wherein one or two methylene
( CH2 ) units of the linear alkylene group is optionally replaced with O, S
or NH;
Y is =NO , N(H)O , =N , NR , O, S, or a bond;
R is H, alkyl, or optionally substituted alkyl;
R1 is optionally substituted yclic, heterocyclic, or fused 2-, 3- or
4-ring heterocyclic;
R2 is hydrogen, halo, lower alkyl, lower alkoxy, y, RQY,
RQY-L-C(O)O , cyano, nitro, amino, halogenated lower alkyl, halogenated
lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, tri lower
alkylsilyl, lower arbonyloxy, lower alkoxycarbonyloxy, sugar residue,
phosphosugar residue residue, O-quinone, substituted lower alkyl
aminomethyl, lower alkylcarbonylamino, lower alkylcarbonyloxy methyl,
optionally substituted lower alkylcarbonyloxy methyl, substituted vinyl,
1-hydroxynitroethyl, alkoxycarbonylethyl, aminocarbonyl, alkylcarbonyl,
benzoylmethyl, carbonyloxymethyl, lower alkyliminomethyl or lower
methyl;
R3 is en, halo, lower alkyl, lower , hydroxy,
RQY-L-C(O)O , cyano, nitro, amino, halogenated lower alkyl, nated
lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, CH2NR7R8
(where each of R7 and R8 is independently H, alkyl of 1-6 carbons, optionally
substituted phenyl, hydroxy lower alkyl, amino lower alkyl, or mono- or
dialkylamino lower alkyl, or R7 and R8 taken together with N represent a
cyclic amino-), CH2R9 (where R9 is lower alkoxy, cyano, amino lower alkoxy,
mono- or di-lower alkylamino lower alkoxy, lower alkylthio, amino lower
alkylthio, or mono- or di-lower alkylamino lower hio), NR10R11 (where
each of R10 and R11 is independently en, lower alkyl, phenyl, hydroxy
lower alkyl, or amino lower alkyl, or R10 and R11 taken together with --N--
represent a cyclic amino), ylsilyl, dialkylamino alkyl, lower
alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue, phosphosugar
residue, O-quinone, substituted lower alkyl aminomethyl, or lower
alkylcarbonylamino or R3 together with R4 is furan, dihydrofuran or
1,4-oxazineone; and
R4 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy,
RQY-L-C(O)O , cyano, nitro, amino, amino lower alkyl, halogenated lower
alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower
alkoxycarbonyl, carbamoyloxy, lower alkylcarbonyloxy, lower
alkoxycarbonyloxy, sugar residue, phosphosugar residue residue, O-quinone,
substituted lower alkyl aminomethyl, or lower alkylcarbonylamino, or R4
together with R3 is furan, ofuran or azineone, or R4 together
with R5 is methylenedioxy;
R5 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy,
RQY-L-C(O)O , cyano, nitro, amino, trialkylsilyl, halogenated lower alkyl,
nated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl,
lower alkylcarbonyloxy, lower carbonyloxy, sugar residue,
phosphosugar residue residue, O-quinone, substituted lower alkyl
aminomethyl, or lower alkylcarbonylamino, or R5 together with R4 is
methylenedioxy;
R6 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy,
RQY-L-C(O)O , cyano, nitro, amino, halogenated lower alkyl, halogenated
lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower
alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue, phosphosugar
residue residue, O-quinone, substituted lower alkyl aminomethyl, or lower
alkylcarbonylamino; and
RQ is optionally substituted yclic, heterocyclic, or fused 2-, 3- or
4-ring heterocyclic;
or wherein said hydrophobic thecin derivative comprises at
least one compound of formula (II):
(II)
or a pharmaceutically acceptable salt of said derivative;
wherein:
X is a O, S, —NR—, or a bond;
Y is ═NO—, —N(H)O—, ═N—, —NR—, O, S; or a covalent bond;
T is independently CRR′;
each of R and R′ is independently selected from hydrogen, C1-4 alkyl,
and substituted C1-4 alkyl;
n is an integer from 0 to 8;
R1 is optionally substituted heterocyclic, aryl, or heteroaryl; provided
that when X is a bond or CH2 and n is 1, 2, or 3, then Y, when bound to R1, is
not oxygen; and provided that when X is a bond or CH2, n is 1, 2, or 3; and R1
is heterocyclic containing at least one nitrogen atom, then Y is not bound
directly to said nitrogen atom;
R2 is en, halo, lower alkyl, lower alkoxy, hydroxy,
RQY-L-C(O)O—, cyano, nitro, amino, halogenated lower alkyl, nated
lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, tri lower
alkylsilyl, lower alkylcarbonyloxy, lower carbonyloxy, sugar residue,
phosphosugar residue e, O-quinone, substituted lower alkyl
aminomethyl, lower alkylcarbonylamino, lower alkylcarbonyloxy methyl,
optionally substituted lower alkylcarbonyloxy methyl, substituted vinyl,
1-hydroxynitroethyl, alkoxycarbonylethyl, aminocarbonyl, alkylcarbonyl,
alkylcarbonyloxymethyl, benzoylmethyl, benzylcarbonyloxymethyl, lower
alkyliminomethyl or lower alkoxymethyl;
R3 is hydrogen, halo, lower alkyl, lower , hydroxy,
RQY-L-C(O)O—, cyano, nitro, amino, halogenated lower alkyl, halogenated
lower alkoxy, hydroxycarbonyl, , lower alkoxycarbonyl, CH2NR7R8
(where each of R7 and R8 is independently H, alkyl of 1-6 carbons, ally
substituted phenyl, hydroxy lower alkyl, amino lower alkyl, or mono- or
dialkylamino lower alkyl, or and R8 taken together with —N— represent a
cyclic amino-), CH2R9 (where R9 is lower alkoxy, CN, amino lower alkoxy,
mono- or di-lower alkylamino lower alkoxy, lower alkylthio, amino lower
alkylthio, or mono- or er alkylamino lower alkylthio), 1 (where
each of R10 and R11 is independently hydrogen, lower alkyl, phenyl, hydroxy
lower alkyl, or amino lower alkyl, or R10 and R11 taken together with —N—
represent a cyclic amino), ylsilyl, dialkylamino alkyl, lower
alkylcarbonyloxy, lower carbonyloxy, sugar residue, phosphosugar
residue residue, O-quinone, substituted lower alkyl aminomethyl, or lower
alkylcarbonylamino or R3 together with R4 is furan, dihydrofuran or
azineone;
R4 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy,
RQY-L-C(O)O—, cyano, nitro, amino, amino lower alkyl, halogenated lower
alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower
alkoxycarbonyl, carbamoyloxy, lower alkylcarbonyloxy, lower
carbonyloxy, sugar residue, phosphosugar residue residue, O-quinone,
tuted lower alkyl aminomethyl, or lower alkylcarbonylamino, or R4
together with R5 is methylenedioxy;
R5 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy,
RQY-L-C(O)O—, cyano, nitro, amino, halogenated lower alkyl, halogenated
lower alkoxy, ycarbonyl, formyl, lower alkoxycarbonyl, lower
alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue, phosphosugar
residue residue, O-quinone, substituted lower alkyl aminomethyl, or lower
alkylcarbonylamino; and
R6 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy,
RQY-L-C(O)O—, cyano, nitro, amino, ylsilyl, halogenated lower alkyl,
halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl,
lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue,
phosphosugar residue, O-quinone, substituted lower alkyl aminomethyl, or
lower alkylcarbonylamino; and RQ is an optionally substituted heterocyclic,
aryl, or heteroaryl group, or R1Y together form a NRaRb group, where Ra, Rb,
and the nitrogen to which they are attached form a cyclic amine or imide ring.
[0005d] Certain statements that appear below are broader than what appears in the
statements of the invention above. These statements are provided in the interests of
providing the reader with a better understanding of the invention and its practice. The
reader is directed to the accompanying claim set which s the scope of the
invention.
[0005e] Also described is a ceutical composition comprising at least one
CPT derivative or a pharmaceutically acceptable salt of said CPT derivative, and a
hylene glycol (PEG) conjugated phospholipid at a molar ratio
(phospholipid:CPT) of more than about 0.45: 1. The CPT tive or the
pharmaceutically acceptable salt of said tive forms micelles with the PEG
ated phospholipid, in which the PEG moiety has a molecular weight in the
range of about 1,000 to about 20,000 Daltons.
Also bed are methods of inhibiting cancer cells in a subject in need
thereof comprising administering to the subject an effective amount of a
pharmaceutical composition as described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying drawings, which are included to provide a further
understanding of the invention and are incorporated in and constitute a part of this
specification, illustrate embodiments of the invention and together with the
description serve to n the principles of the invention. In the drawings:
FIGURE 1 shows the size distribution of CM315 ition.
FIGURE 2 shows the size distribution of CM316 composition.
FIGURE 3 shows the toxic effect of free TLC388 HCl, Topotecan and
Lipotecan® on human hematopoietic progenitors.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
As employed above and throughout the disclosure, the following terms,
unless otherwise indicated, shall be understood to have the following meanings.
As used herein, the singular forms “a,” “an,” and “the” include the plural
reference unless the context clearly indicates otherwise.
As used herein, the term “about,” when ing to a measurable value such
as an amount, a temporal duration, and the like, is meant to encompass variations of ±
%, ably ± 5%, more preferably ± 1%, and even more preferably ± 0.1%
from the specified value, as such variations are appropriate to the dose of CPT
tive , unless otherwise specified. As used herein, the term “about,” when
referring to a range, is meant to encompass variations of ± 10% within the difference
of the range, preferably ± 5%, more preferably ± 1%, and even more preferably ±
0.1% from the specified value, as such ions are riate to, unless other
specified.
[0013a] The term ‘comprising’ as used in this specification and claims means
‘consisting at least in part of’. When interpreting statements in this specification and
claims which es the ‘comprising’, other features besides the features prefaced
by this term in each statement can also be present. Related terms such as ‘comprise’
and ‘comprised’ are to be interpreted in similar manner.
“Micelles” are typically defined as spherical receptacles comprised of a
single yer defining a closed compartment. Generally, amphipathic molecules
such as surfactants and fatty acids spontaneously form micellar structures in polar
solvents. Micelles typically have a spherical shape with the size of nanometer range.
The formation of micelles is driven by decreasing free energy in the system because
of removal of hydrophobic fragments from the aqueous environment and the
ablishment of hydrogen bond network with water molecules. In a micelle,
there is an ement of polar amphipathic molecules, wherein the hydrophilic
portion (i.e. heads) of the structure forms the or e and the hydrophobic
portion (i.e. tails) resides interiorly, away from the medium. Micelles do not have a
bilayer structure and are not considered vesicles or liposomes. The compounds
described herein, when associated with micelles, are either in the compartment, bound
to the micelles ne, or bound to the outside surface of the micelle.
aceutical acceptable salt” includes acid addition salts.
“Pharmaceutically acceptable acid addition salts” refer to those salts which retain the
biological effectiveness and properties of the free bases, which are formed with
inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid and the like, and organic acids such as acetic acid, propionic acid,
pyruvic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid,
citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,
p-toluenesulfonic acid, salicylic acid, trifluoroacetic acid and the like.
An “effective amount,” as used herein, includes a dose of the pharmaceutical
ition that is sufficient to reduce the symptoms and signs of cancer, such as
mass, pain, and weight loss.
The terms “inhibiting” and “suppressing” include slowing or stopping the
growth of.
The term “cancer” is to be considered in the st general definition as a
malignant neoplasm, an abnormal mass of , the growth of which exceeds and is
uncoordinated with that of normal tissues and persists in the same excessive manner
after cessation of the stimuli that evoked the change. Examples of the types of
cancers that may be treated by administrating the ations of the invention
includes, but are not limited to, liver , prostate cancer, colon cancer and glioma.
The term “hydrophobic” includes repelling or tending not to combine with,
or incapable of dissolving in water.
The term “treating,” ed,” or “treatment” as used herein includes
preventative (e.g. prophylactic), tive, and curative uses or results. The term
“subject” includes a rate having cancer or other diseases. ably, the
subject is a warm-blooded animal, including mammals, preferably humans.
The term “ionizing radiation” is the one conventionally adopted in the
therapeutic field of cancer treatment and includes photons having enough energy for
al bond ionization such as, for instance, alpha (α), beta (ß), and gamma (γ) rays
from radioactive nuclei as well as x-rays. The radiation may be high-LET (linear
energy transfer) or low-LET. LET is the energy transferred per unit length of the
distance. High LET is said to be y ionizing radiation and Low LET is said to be
sparsely ionizing radiation. Representative examples of high-LET are neutrons and
alpha particles. Representative examples of T are x-ray and gamma rays.
Low LET radiation including both x-rays and γ rays is most commonly used for
radiotherapy of cancer patients. The radiation may be used for external radiation
therapy that is usually given on an outpatient basis or for internal radiation therapy
that uses radiation that is placed very close to or inside the tumor. In case of internal
radiation therapy, the ion source is usually sealed in a small holder called an
implant. Implants may be in the form of thin wires, plastic tubes called catheters,
s, capsules, or seeds. The implant is put directly into the body. Internal
radiation therapy may require a al stay. The ionizing radiation source is
provided as a unit dose of radiation and is preferably an x-ray tube since it es
many advantages, such as convenient able dosing where the source may be
easily turned on and off, minimal disposal problems, and the like. A unit dose of
radiation is generally measured in gray (Gy). The ionizing radiation source may also
comprise a radioisotope, such as a solid radioisotopic source (e.g., wire, strip, pellet,
seed, bead, or the like), or a liquid radioisotopic filled balloon. In the latter case, the
balloon has been specially configured to prevent leakage of the radioisotopic material
from the balloon into the body lumen or blood stream. Still further, the ionizing
radiation source may comprise a receptacle in the catheter body for receiving
radioisotopic als like pellets or liquids. The radioisotopic material may be
selected to emit α, ß and γ. Usually, α and ß radiations are preferred since they may
be quickly absorbed by the surrounding tissue and will not ate ntially
beyond the wall of the body lumen being treated. Accordingly, incidental irradiation
of the heart and other organs adjacent to the treatment region can be substantially
eliminated. The total number of units provided will be an amount determined to be
therapeutically effective by one skilled in ent using ionizing radiation. This
amount will vary with the subject and the type of malignancy or neoplasm being
treated. The amount may vary but a patient may receive a dosage of about 30-75 Gy
over several weeks.
The term “alkyl” refers to a lent, saturated aliphatic hydrocarbon
radical having the ted number of carbon atoms. For example, a “C1-6 alkyl” or
an “alkyl of 1-6 carbons” or “Alk 1-6” would refer to any alkyl group containing one
to six carbons in the structure. “C1-20 alkyl” refers to any alkyl group having one to
twenty carbons. Alkyl may be a straight chain (i.e. linear) or a branched chain. Lower
alkyl refers to an alkyl of 1-6 carbons. Representative examples of lower alkyl
radicals include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl,
isopentyl, amyl, tyl, tert-butyl, tert-pentyl and the like. Higher alkyl refers to
alkyls of seven carbons and above. These include n-heptyl, n-octyl, n-nonyl, n-decyl,
n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n-eicosyl, and the like, along with
branched variations thereof. The radical may be optionally substituted with
substituents at positions that do not significantly ere with the preparation of
compounds falling within the scope as described herein and that do not significantly
reduce the efficacy of the compounds. The alkyl is optionally substituted with one to
five substituents independently selected from the group consisting of halo, lower
, y, cyano, nitro, phenyl, amino, halogenated lower alkyl, halogenated
lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and
lower arbonylamino.
The term “alkylene” refers to divalent ted aliphatic arbyl groups
preferably having from 1 to 8 carbon atoms that are either straight-chained (linear) or
ed. This term is exemplified by linear groups such as methylene (—CH2—),
ne (—CH2CH2—), n-propylene (—CH2CH2CH2—) and branched groups such
as iso-propylene (—CH2CH(CH3)—) or (—CH(CH3)CH2—) and the like.
The term “alkoxy” refers to a monovalent l of the formula RO—,
where R is an alkyl as defined herein. Lower alkoxy refers to an alkoxy of 1-6 carbon
atoms, with higher alkoxy is an alkoxy of seven or more carbon atoms. Representative
lower alkoxy radicals include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy,
n-hexyloxy, isopropoxy, isobutoxy, isopentyloxy, amyloxy, sec-butoxy, tert-butoxy,
tert-pentyloxy, and the like. Higher alkoxy radicals e those corresponding to the
higher alkyl ls set forth herein. The radical may be optionally substituted with
substituents at positions that do not significantly interfere with the preparation of
compounds falling within the scope as described herein and that do not significantly
reduce the efficacy of the compounds. The alkoxy is ally substituted with one to
five substituents independently selected from the group consisting of halo, lower alkyl,
lower alkoxy, hydroxy, cyano, nitro, phenyl, amino, nated lower alkyl,
halogenated lower , hydroxycarbonyl, lower alkoxycarbonyl, lower
alkylcarbonyloxy, and lower alkylcarbonylamino.
The term “cycloalkyl” refers to a monovalent, alicyclic, saturated
hydrocarbon l having three or more s forming the ring. While known
cycloalkyl compounds may have up to 30 or more carbon atoms, generally there will
be three to seven carbons in the ring. The latter include, for example, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The radical may be optionally
substituted with substituents at positions that do not significantly interfere with the
preparation of compounds falling within the scope as described herein and that do not
significantly reduce the efficacy of the compounds. The cycloalkyl is optionally
substituted with one to five substituents independently selected from the group
consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, phenyl, amino,
halogenated lower alkyl, nated lower alkoxy, hydroxycarbonyl, lower
alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino.
The term “hydroxycarbonyl” is a monovalent radical having the
a —C(O)OH.
The term “lower carbonyl” is a lent radical having the
formula —C(O)OAlk, where Alk is lower alkyl.
The term “lower alkoxycarbonyloxy” is a monovalent radical having the
formula —OC(O)OAlk, where Alk is lower alkyl.
The term “sugar” or “sugar residue” refers to a monovalent radical formed
by removal of a hydrogen from any hydroxy group of a charide, disaccharide,
oligosaccharide or ccharide. The monosaccharide unit that is a part of a
disaccharide, accharide or polysaccharide may be a D or L isomer existing as a
embered cyclic form (furanose) or a 6-membered cyclic form (pyranose).
Representative examples of monosaccharides include glucose, fructose, mannose, and
ose. Representative examples of disaccharides include lactose, maltose, and
sucrose. Oligosaccharides may contain 3-20 monosaccharide units linked together,
more preferably 3-15 monosaccharide units linked together. Representative examples
of oligosaccharides include maltotetraose and cyclodextrin. Representative examples
of polysaccharides include amylose, starch and cellulose.
The term “phosphosugar” or “phosphosugar residue” refers to a monovalent
radical formed by removal of a hydrogen from any hydroxy group of either a
monsaccharide or a phosphoric acid wherein the monosaccharide is linked to the
phosphoric acid via an ether linkage. The monosaccharide may be a D or L isomer
existing as a five-membered cyclic form ose) or a 6-membered cyclic form
(pyranose). Representative examples of monosaccharides are set forth above.
The term “lower alkylcarboxyloxy” is a monovalent radical having the
formula —OC(O)Alk, where Alk is lower alkyl.
The term “lower alkylcarbonylamino” is a monovalent radical having the
a —NHC(O)Alk, where Alk is lower alkyl.
The term “substituted lower alkyl ethyl” is a monovalent radical
having the formula —CH2NHAlk, where Alk is a substituted lower alkyl.
Representative examples of substituted lower alkyl aminomethyl include
(tris(hydroxymethyl)methylamino)methyl, (bis(hydroxymethyl)methylamino)methyl,
and (2-hydroxyethylamino)methyl.
A “halo” substituent is a lent halogen radical chosen from chloro,
bromo, iodo, and fluoro. A “halogenated” compound is one substituted with one or
more halo substituents. Chloro is generally preferred.
A “1-naphthyl” or “2-naphthyl” is a radical formed by removal of a
en from the 1- or 2-position of a naphthalene structure, respectively. It is
optionally substituted with from one to four substituents independently selected from
the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, ,
amino, halogenated lower alkyl, formyl, halogenated lower alkoxy, hydroxycarbonyl,
lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino.
A l” is a radical formed by removal of a hydrogen from a benzene
ring. The phenyl is optionally substituted with from one to five substituents
independently selected from the group ting of halo, lower alkyl, lower alkoxy,
hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy,
carbonyl, hydroxycarbonyl, lower alkylcarbonyloxy, benzyloxy, optionally substituted
piperidino, lower alkoxycarbonyl, and lower alkylcarbonylamino.
A “cyclic amino” is a monovalent radical of a saturated 5-, 6-, or
ered cyclic amine ring having no more than one additional hetero atom such
as en, oxygen, or sulfur. Representative examples include, e.g., olidino,
1-piperidino, morpholino, piperazino, and the like. These may be substituted or
unsubstituted. If substituted, generally they will have no more than 2 substituents
chosen from lower alkyl, lower cycloalkyl, hydroxy lower alkyl, phenyl (substituted
or unsubstituted), benzyl (substituted or tituted), aminocarbonylmethyl, lower
alkylaminocarbonylmethyl, amino, mono- or di-lower alkylamino, or cyclic amino.
“Monovalent l” refers to attachment of the radical via a single bond.
“Divalent radical” refers to attachment of the radical via a double bond.
oatom” refers to nitrogen, oxygen, , or any oxidized form of
nitrogen or sulfur.
“Cyano” refers to a monovalent —CN radical.
“Nitro” refers to a monovalent —NO2 radical.
“Amino” refers to a monovalent —NH2 radical.
“Formyl” refers to a lent —CHO radical.
“Tri loweralkylsilyl”, refers to a monovalent silyl radical substituted with
three loweralkyl groups, where the lower alkyl groups may be the same or different.
“Loweralkylcarbonyloxy methyl” refers to a monovalent — CH2C(O)
(loweralkyl) radical.
“Substituted vinyl” refers to a substituted –CH═CH2 group where one or
more the CH groups are replaced with one to three substituents independently selected
from the group consisting of alkyl, halo, lower alkoxy, hydroxy, cyano, nitro, phenyl,
amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower
alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino.
“Hydroxy” refers to a monovalent OH radical.
“Carbocyclic” refers to a 3-18 membered ring monovalent or divalent l
where all the ring atoms are carbon and may be fully saturated, partially saturated, or
unsaturated (i.e., aromatic in nature). The carbocyclic radical is bonded through a
ted, partially saturated, or unsaturated ring via a single or double bond.
Carbocyclic groups may be fused, containing 2, 3, or 4 rings where the fused rings are
independently saturated, partially saturated, or unsaturated. Examples of yclic
groups include phenyl, yl, fluorenyl, and tetracenyl. The radical may be
optionally substituted with substituents at positions that do not significantly interfere
with the ation of compounds falling within the scope as described herein and
that do not significantly reduce the efficacy of the compounds. The radical is
optionally substituted with one to five substituents independently selected from the
group ting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino,
halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower
alkoxycarbonyl, lower alkylcarbonyloxy, lower alkylcarbonylamino, sugar residue
and phosphosugar residue.
A “carbamoyloxy” is a monovalent radical of the formula R13R14NC(O)O—
(i.e. an aminocarbonyloxy) where R13 and R14 together form a cyclic amino with the
nitrogen atom, or each of R13 and R14 is independently hydrogen, lower alkyl,
hydroxy lower alkyl, amino lower alkyl, lower cycloalkyl, phenyl (substituted or
unsubstituted), or benzyl (substituted or unsubstituted). Examples include
aminocarbonyloxy, methylaminocarbonyloxy, dimethyl aminocarbonyloxy,
[4-(1-piperidino)piperidino]carbonyloxy, 1-morpholinocarbonyloxy, 1-pyrrolidinyl,
1-piperazinecarbonyloxy, and others recognized by one skilled in the art or delineated
herein.
ocyclic” is a monovalent or divalent radical of a 3-10 membered ring
group containing at least one heteroatom in the ring and may be fully ted,
partially saturated, or unsaturated (i.e. ic in nature). The cycle is bonded
through a carbon atom or atom via a single or double bond. The heteroatom in
the heterocycle such as N can optionally exist as an N-oxide or S can ally exist
as a sulfoxide or a sulfone.
A “5-membered heterocyclic ring” is a monovalent or a divalent radical of a
ered ring containing at least one heteroatom in the ring and may be fully
saturated, partially saturated, or unsaturated (i.e. aromatic in nature). lly the
heterocycle will contain no more than two hetero atoms. The heterocycle is bonded
through a carbon atom or heteroatom via a single or double bond. Representative
examples of unsaturated 5-membered heterocycles with only one hetero atom include
2- or 3-pyrrolyl, 2- or 3-furanyl, and 2- or 3-thiophenyl. Corresponding partially
ted or fully saturated radicals e 3-pyrrolinyl, 2- or 3-pyrrolidinyl, 2- or
3-tetrahydrofuranyl, and 2- or 3-tetrahydrothiophenyl. Representative unsaturated
ered heterocyclic ls having two hetero atoms include imidazolyl,
oxazolyl, thiazolyl, pyrazolyl, and the like. The corresponding fully saturated and
partially saturated radicals are also included. The radical may be optionally
substituted with substituents at positions that do not significantly interfere with the
preparation of compounds g within the scope as described herein and that do not
significantly reduce the efficacy of the compounds. The ring is optionally substituted
with one or two tuents selected from the group consisting of halo, lower alkyl,
lower alkoxy, hydroxy, cyano, nitro, phenyl, amino, halogenated lower alkyl,
halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower
alkylcarbonyloxy, lower alkylcarbonylamino, sugar residue and phosphosugar
residue.
A bered heterocyclic ring” is a monovalent or a divalent l of a
6-membered ring containing at least one heteroatom and may be fully saturated,
partially saturated, or unsaturated (i.e., aromatic in nature). Generally the heterocycle
will contain no more than two hetero atoms. The heterocycle is bonded through a
carbon atom or atom via a single or double bond. Representative examples of
unsaturated 6-membered heterocycles with only one hetero atom include 2-, 3-, or
4-pyridinyl, 2H-pyranyl, and 4H-pyranyl. Corresponding partially saturated or fully
saturated ls include 2-, 3-, or 4-piperidinyl, 2-, 3-, or 4-tetrahydropyranyl and
the like. Representative unsaturated 6-membered heterocyclic radicals having two
hetero atoms include 3- or 4-pyridazinyl, 2-, 4-, or 5-pyrimidinyl, zinyl, and the
like. The corresponding fully saturated and partially saturated ls are also
ed, e.g. razine. The radical may be optionally substituted with
substituents at positions that do not significantly interfere with the preparation of
nds falling within the scope as described herein and that do not icantly
reduce the efficacy of the compounds. The ring is optionally tuted with one or
two substituents selected from the group ting of halo, lower alkyl, lower alkoxy,
hydroxy, cyano, nitro, phenyl, amino, halogenated lower alkyl, halogenated lower
alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower
alkylcarbonylamino, sugar residue and phosphosugar residue.
A “fused 2-, 3-, or 4-ring heterocyclic” is a monovalent or a divalent radical
that is polynuclear in that the adjacent rings share a pair of atoms, generally carbon
atoms. At least one of the rings will be heterocyclic in that it will have a noncarbon
atom such as nitrogen, oxygen, or sulfur. The ring system may contain from 9 to 18
atoms. The heterocycle is bonded through a carbon atom or heteroatom of one of the
rings via a single or double bond. A 2-ring heterocyclic system will generally have 9
or 10 atoms included in the ring. Examples of such a 2-ring system include quinoline,
isoquinoline, purine, indolizine, 4H-quinolizine, 3H-pyrrolizine, coumaran, coumarin,
isocoumarin, 4-methylcoumarin, 3-chloro-H-methylcoumarin, chromone, benzofuran,
benzothiophene, benzothiazole, indole, and the like. A 3-ring system will generally
have 12 to 14 atoms included in the ring. Examples of such a 3-ring system include
carbazole, acridine, and the like. A 4-ring fused system will generally have 16 to 18
atoms included in the chain. Examples of such a 4-ring system include isothebaine
and the like. The radical may be optionally substituted with tuents at ons
that do not significantly interfere with the preparation of compounds falling within the
scope as described herein and that do not significantly reduce the efficacy of the
compounds. The radical is optionally substituted with one to five substituents
ndently selected from the group consisting of halo, lower alkyl, lower alkoxy,
hydroxy, cyano, nitro, phenyl, amino, halogenated lower alkyl, halogenated lower
alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower
alkylcarbonylamino, sugar residue and phosphosugar residue.
Other al terms are given their standard meaning as tood by one
of skill in the art with guidance from standard texts and dictionaries. Under standard
nomenclature used throughout this sure, the terminal portion of the substituent
is described first, followed by adjacent functionality toward the point of attachment.
Thus, for example, a carbonyl” group refers to a —C(O)NH2 group, a
“loweralkoxymethyl” group refers to a —CH2(loweralkoxy) group, a “amino lower
alkoxy” group refers to a -(loweralkoxy)amino group, etc.
Described is a ceutical composition comprising a hydrophobic CPT
derivative or a pharmaceutically acceptable salt of said CPT derivative, and a
polyethylene glycol (PEG) conjugated phospholipid. The PEG moiety has a
lar weight from about 1,000 to about 20,000 daltons and is conjugated to the
phospholipid moiety. The PEG conjugated phospholipid is mixed with the CPT
derivative or a pharmaceutically acceptable salt of said derivative, at a molar ratio of
more than about 0.45: 1 to form micelles. The pharmaceutical composition of CPT
derivatives of the present invention have uniform micellar size, narrow size
distribution, extended storage ity, improved solubility and reduced side effects.
Another embodiment is directed to methods in inhibiting the growth of
cancer cells in a subject, comprises the administration of an effective amount of the
ceutical composition described herein to the subject, whereby the symptoms
and signs of the cancer in the subject are reduced. The cancer cells in the subject is
optionally exposed to one or more anti-cancer agents, include but are not limited to,
one or more units dose of radiation, tional chemotherapy, and targeted cancer
therapy.
Camptothecin derivatives
The camptothecin tives, which are suitable for use in the present
invention, are hydrophobic camptothecin tives. A hydrophobic campthothecin
derivative may be formed in a convention , for example, by adding a polymer
to one or more functional groups of camptothecin ((S)ethylhydroxyl- 1H-
pyrano - [3’4’:6,7] indolizino [1,2-b]quinoline-3,14(4H,12H)-dione)). The
hydrophobic camptothecin derivative can be more or less active than camptothecin.
Examples of the CPT derivative include compounds of formulae (I) and (II) in U.S.
Patent No. 7,875,602, which is incorporated herein by reference in its entirety.
The camptothecin tive of formula (I) is as s:
wherein:
W is alkyl-C(O) , or R1Y-L-C(O), provided that when W is alkyl-C(O) , at
least one of R2, R3, R4, R5, or R6 is nitro;
L is a bond or linear ne (1-8) group, optionally substituted with lower
alkyl or substituted lower alkyl, n one or two methylene ( CH2 ) units of the
linear alkylene group is optionally replaced with O, S or NH;
Y is =NO , N(H)O , =N , NR , O, S, or a bond;
R is H, alkyl, or substituted alkyl;
R1 is optionally substituted carbocyclic, cyclic, or fused 2-, 3- or 4-ring
heterocyclic;
R2 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RQY,
RQY-L-C(O)O , cyano, nitro, amino, halogenated lower alkyl, halogenated lower
alkoxy, hydroxycarbonyl, , lower alkoxycarbonyl, tri lower alkylsilyl, lower
alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue, phosphosugar e
residue, O-quinone, substituted lower alkyl aminomethyl, lower alkylcarbonylamino,
lower arbonyloxy methyl, optionally substituted lower alkylcarbonyloxy methyl,
substituted vinyl, 1-hydroxynitroethyl, alkoxycarbonylethyl, aminocarbonyl,
alkylcarbonyl, benzoylmethyl, benzylcarbonyloxymethyl, lower alkyliminomethyl or
lower alkoxymethyl;
R3 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RQY-L-C(O)O ,
cyano, nitro, amino, nated lower alkyl, halogenated lower alkoxy,
hydroxycarbonyl, formyl, lower alkoxycarbonyl, CH2NR7R8 (where each of R7 and
R8 is independently H, alkyl of 1-6 carbons, optionally substituted phenyl, hydroxy
lower alkyl, amino lower alkyl, or mono- or dialkylamino lower alkyl, or R7 and R8
taken together with N represent a cyclic amino-), CH2R9 (where R9 is lower
alkoxy, cyano, amino lower alkoxy, mono- or di-lower mino lower alkoxy,
lower alkylthio, amino lower alkylthio, or mono- or di-lower alkylamino lower
alkylthio), NR10R11 (where each of R10 and R11 is independently hydrogen, lower
alkyl, , hydroxy lower alkyl, or amino lower alkyl, or R10 and R11 taken
together with --N-- represent a cyclic amino), trialkylsilyl, dialkylamino alkyl, lower
alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue, osugar residue
residue, O-quinone, substituted lower alkyl aminomethyl, or lower
alkylcarbonylamino or R3 together with R4 is furan, dihydrofuran or
1,4-oxazineone; and
R4 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RQY-L-C(O)O ,
cyano, nitro, amino, amino lower alkyl, halogenated lower alkyl, halogenated lower
, ycarbonyl, formyl, lower alkoxycarbonyl, carbamoyloxy, lower
alkylcarbonyloxy, lower carbonyloxy, sugar residue, phosphosugar residue
residue, O-quinone, substituted lower alkyl aminomethyl, or lower
alkylcarbonylamino, or R4 together with R3 is furan, dihydrofuran or
1,4-oxazineone, or R4 together with R5 is methylenedioxy;
R5 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RQY-L-C(O)O ,
cyano, nitro, amino, ylsilyl, halogenated lower alkyl, halogenated lower alkoxy,
hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower
carbonyloxy, sugar residue, phosphosugar residue, O-quinone, substituted
lower alkyl aminomethyl, or lower alkylcarbonylamino, or R5 together with R4 is
methylenedioxy;
R6 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RQY-L-C(O)O ,
cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy,
hydroxycarbonyl, , lower alkoxycarbonyl, lower alkylcarbonyloxy, lower
alkoxycarbonyloxy, sugar residue, phosphosugar residue residue, O-quinone,
tuted lower alkyl aminomethyl, or lower alkylcarbonylamino; and
RQ is optionally substituted carbocyclic, heterocyclic, or fused 2-, 3- or 4-ring
cyclic, or fused 2-, 3- or 4-ring heterocyclic.
In some embodiments, W is R1Y-L-(O) .
R1 groups that may be incorporated into the active camptothecin derivative
as described by a (I) include phenyl optionally substituted with from one to
five substituents independently selected from the group consisting of halo, lower alkyl,
lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated
lower alkoxy, formyl, lower alkyl carbonyl, ycarbonyl, lower alkylcarbonyloxy,
benzyloxy, optionally substituted piperazino, lower alkoxycarbonyl, and lower
alkylcarbonylamino; a fused, 2-, 3-, or 4-ring cyclic system optionally
substituted with one to five substituents independently selected from the group
consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino,
halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower
alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino; 1- or
2-naphthyl ally substituted with from one to four substituents independently
selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano,
nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl,
lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino; or a 5
or 6 membered heterocyclic ring containing one or two nitrogen atoms, which ring is
optionally substituted with one or two substituents selected from the group consisting
of halo, lower alkyl, lower alkoxy, y, cyano, nitro, amino, halogenated lower
alkyl, halogenated lower , hydroxycarbonyl, lower alkoxycarbonyl, lower
alkylcarbonyloxy, and lower alkylcarbonylamino. In a red embodiment, R1 is
substituted with at least one carbonyl, amido, trifluoromethyl, halogen, nitro, nitroso,
sulfonyl, sulfinyl, oryl, or oxo group. In other embodiments, R1 is selected
from the group consisting of O-quinone, semiquinone, fluorene, imidazole, triazole,
ne, benzamide, nicotinamide, benzotriazine oxide, furan, thiophene, oxazole, or
thiazole, where each of the aforementioned groups may be substituted or
unsubstituted.
In other embodiments, R1 is aromatic.
Preferably at least one of R1, R2, R3, R4, R5, or R6 comprises an
electron-affinic , wherein the electron-affinic moiety is a (i) nitro; (ii)
carbocyclic or heterocyclic ic moiety possessing one or more carbonyl,
trifluoromethyl, halogen, nitro, sulfonyl, sulfinyl, phosphoryl, oxide or cyano groups;
(iii) cyclic ic moiety containing two or more heteroatoms; (iv) metal
complex; or (v) organo-metallic group in which the metal is covalently bonded to
carbon.
Carbocyclic or heterocyclic aromatic electron-affinic moieties n one to
three rings with a total of 5 to 15 ring atoms. The heteroatoms are selected from the
group consisting of N, S, O and P. Preferably, the carbocyclic or heterocyclic aromatic
electron-affinic moieties contain one to two rings with one ring being presently most
preferred. entative carbocyclic aromatic electron-affinic moieties include
phenyl and naphthyl groups containing one or more nitro, halogen, carbonyl or
sulfonyl substituents, with nitro-substituted phenyl being a preferred carbocyclic
aromatic electron-affinic moiety. Representative heterocyclic aromatic on-affinic
moieties include imidazoles, triazoles, pyridines, ides, nicotinamides,
benzotriazine oxides, furans, thiophenes, oxazoles and thiozoles possessing one or
more carbonyl, trifluoromethyl, halogen, nitro, sulfonyl, sulfinyl, phosphoryl, oxide or
cyano groups, and preferably at least one nitro group.
Metal x on-affinic moieties preferably comprise Pt2+, Co3+, Fe2+,
Fe3+, Pd2+, Cu2+, Ti4+, or Zr4+ as the metal and generally fall into two subgroups: (a)
metal complexes of the carbocyclic and heterocyclic aromatic electron-affinic
moieties discussed above, and (b) metal complexes of bidentate ligands comprising
nitrogen, carbon or sulfur. In general, metal complexes of bidentate ligands
correspond to the formula –BMLXK wherein B is a bidentate ligand containing
nitrogen, carbon or sulfur, ML is a metal, X is an c ligand such as Cl- or -OAc,
and k is 1-4.
Organometallic electron-affinic moieties are aliphatic or ic mercury
radicals. The preparation and use of ensitizing agents incorporating mercury
ning entities is described in Shenoy et al., Cancer Investigation, 533-551
(1992) and Bruce et al., Radiation Res., 24:473-481 (1965).
Electron-affinic moieties that are particularly suitable for inclusion in the
compound of Formula (I) include one, semiquinone, fluorene, imidazole,
triazole, pyridine, benzamide, nicotinamide, benzotriazine oxide, furan, thiophene,
oxazole, and thiazole, where each of the aforementioned groups may be tuted or
unsubstituted. In a preferred embodiment, R1 is selected from this group.
In a particularly preferred embodiment, the method of sensitizing tumor cells
to radiation is using a camptothecin-based compound selected from the group
consisting of:
3434
3535
In other embodiments, the electron-affinic moiety includes an R1 that is a
2-nitroimidazolyl or 3-nitro-1,2,4-triazolyl group having the following structure:
wherein R20 is halo, alkyl, or substituted alkyl.
The electron-affinic moieties may be directly ed to one of the s
at the C5, C7, C9, C10, C11, C12 or C20 position of thecin or indirectly
attached via a linker. While the linker, L, may be any alkylene group of 1 to 8 carbons,
optionally upted by one or more oxygen, sulfur or nitrogen atoms, a preferred
linker is (CH2)m or -(T)n-X--, wherein X is O, S, --NR--, or a bond; T is independently
CRR'; m is an integer from 0 to 3; n is an integer from 1 to 3, and each of R and R' is
independently selected from hydrogen, lower alkyl, and substituted lower alkyl.
In a particularly preferred embodiment, WO--, comprised in the substitution
at the -20 position of the camptothecin derivative, is selected from the group
consisting of:
3737
The thecin derivative of formula (II) is as follows:
(II)
wherein
X is a O, S, —NR—, or a bond;
Y is ═NO—, —N(H)O—, ═N—, —NR—, O, S; or a covalent bond;
T is ndently CRR′;
each of R and R′ is independently selected from hydrogen, C1-4 alkyl, and
substituted C1-4 alkyl;
n is an integer from 0 to 8;
R1 is optionally substituted heterocyclic, aryl, or heteroaryl;
provided that when X is a bond or CH2 and n is 1, 2, or 3, then Y, when bound
to R1, is not oxygen; and
provided that when X is a bond or CH2, n is 1, 2, or 3; and R1 is heterocyclic
containing at least one nitrogen atom, then Y is not bound ly to said nitrogen
atom;
R2 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RQY-L-C(O)O—,
cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy,
hydroxycarbonyl, formyl, lower alkoxycarbonyl, tri lower ilyl, lower
alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue, phosphosugar residue,
O-quinone, substituted lower alkyl aminomethyl, lower alkylcarbonylamino, lower
alkylcarbonyloxy methyl, optionally substituted lower alkylcarbonyloxy methyl,
substituted vinyl, 1-hydroxynitroethyl, alkoxycarbonylethyl, aminocarbonyl,
alkylcarbonyl, alkylcarbonyloxymethyl, benzoylmethyl, benzylcarbonyloxymethyl,
lower alkyliminomethyl or lower alkoxymethyl;
R3 is hydrogen, halo, lower alkyl, lower , hydroxy, RQY-L-C(O)O—,
cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy,
hydroxycarbonyl, formyl, lower alkoxycarbonyl, CH2NR7R8 (where each of R7 and
R8 is independently H, alkyl of 1-6 carbons, optionally substituted phenyl, hydroxy
lower alkyl, amino lower alkyl, or mono- or lamino lower alkyl, or and R8 taken
together with the nitrogen to which it is attached represent a cyclic amino-), CH2R9
(where R9 is lower alkoxy, CN, amino lower alkoxy, mono- or di-lower alkylamino
lower alkoxy, lower alkylthio, amino lower alkylthio, or mono- or di-lower
mino lower alkylthio), NR10R11 (where each of R10 and R11 is independently
hydrogen, lower alkyl, phenyl, hydroxy lower alkyl, or amino lower alkyl, or R10 and
R11 taken together with the nitrogen to which they are ed represent a cyclic
, trialkylsilyl, dialkylamino alkyl, lower alkylcarbonyloxy, lower
alkoxycarbonyloxy, sugar residue, phosphosugar residue, O-quinone, tuted
lower alkyl aminomethyl, or lower alkylcarbonylamino or R3 together with R4 is furan,
dihydrofuran or 1,4-oxazineone;
R4 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, C(O)O—,
cyano, nitro, amino, amino lower alkyl, halogenated lower alkyl, halogenated lower
alkoxy, hydroxycarbonyl, , lower alkoxycarbonyl, carbamoyloxy, lower
alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue, phosphosugar residue,
O-quinone, substituted lower alkyl aminomethyl, or lower alkylcarbonylamino, or R4
together with R5 is methylenedioxy;
R5 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RQY-L-C(O)O—,
cyano, nitro, amino, halogenated lower alkyl, nated lower alkoxy,
hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower
alkoxycarbonyloxy, sugar residue, phosphosugar residue, O-quinone, substituted
lower alkyl aminomethyl, or lower alkylcarbonylamino;
R6 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RQY-L-C(O)O—,
cyano, nitro, amino, trialkylsilyl, halogenated lower alkyl, nated lower alkoxy,
hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower
alkoxycarbonyloxy, sugar residue, phosphosugar residue, O-quinone, substituted
lower alkyl aminomethyl, or lower alkylcarbonylamino; and RQ is an optionally
substituted heterocyclic, aryl, or heteroaryl group, or R1Y er form a NRaRb
group, where Ra, Rb, and the nitrogen to which they are attached form a cyclic amine
or imide ring.
In one embodiment, one of the R2, R4, or R5 is selected from the group
consisting of (tris(hydroxymethyl)methylamino)methyl, (bis(hydroxymethyl)
methylamino)methyl, and (2-hydroxyethylamino)methyl.
In a preferred embodiment, R2 is ed from the group consisting of
(tris(hydroxymethyl)methylamino)methyl, (bis(hydroxymethyl)methylamino)methyl,
and (2-hydroxyethylamino)methyl.
In another embodiment, R2 is ed from the group consisting of
(tris(hydroxymethyl)methylamino)methyl, (bis(hydroxymethyl)methylamino)methyl,
and (2-hydroxyethylamino)methyl; R3 is hydrogen, dimethylamino, amino, or nitro;
R4 is hydrogen, hydroxy, or 4-(1-piperidino)piperidinocarbonyloxy; or R4 together
with R5 is enedioxy; R5 is en; or R5 together with R4 is methylenedioxy;
and R6 is hydrogen. In another embodiment, R2 is ed from the group consisting
of (tris(hydroxymethyl)methylamino)methyl, (bis(hydroxymethyl)methylamino)
methyl, and (2-hydroxyethylamino)methyl; R3 is en; R4 together with R5 is
methylenedioxy and R6 is hydrogen.
In yet another embodiment, R2 is selected from the group consisting of
hydroxymethyl)methylamino)methyl, (bis(hydroxymethyl)methylamino)methyl,
and (2-hydroxyethylamino)methyl and each of R3, R4, R5, and R6 is hydrogen.
In a preferred embodiment R1 is aromatic.
In a preferred embodiment X is a covalent bond. onally it is preferred
that Y is ═NO— or —N(H)O— and even more preferably that n is 1 and each of R
and R' is independently methyl or en. In a further preferred embodiment, R1 is
a substituted or unsubstituted carbocyclic, preferably having 1 to 4 ic rings.
The substituted or unsubstituted carbocyclic may be 9-fluorenyl, preferably
substituted with at least one nitro group. In one embodiment of the compound, R1 is
In a preferred embodiment, the hydrophobic camptothecin derivative is
selected from the group consisting of
4343
()3N
4444
In another preferred embodiment, the compound of a (II) includes an
R1 or RQ that is
wherein R20 is halo, alkyl, or substituted alkyl.
In yet another preferred embodiment of Formula (II), R1Y-(T)n-X
C—(O)O — is
4646
Certain CPT derivatives are particularly desirable, for example, a compound
of the a (II), wherein R2 is hydrogen; R3 is CH2NR7R8 (where each of R7 and
R8 is ndently H, alkyl of 1-6 s, optionally substituted phenyl, hydroxy
lower alkyl, amino lower alkyl, or mono- or dialkylamino lower alkyl, or R7 and R8
taken together with —N— represent a cyclic ), NR10R11 (where each of R10
and R11 is ndently hydrogen, lower alkyl, phenyl, hydroxy lower alkyl, or
amino lower alkyl, or R10 and R11 taken together with —N— represent a cyclic
amino), or dialkylamino alkyl; R4 is lower alkoxy, hydroxy, halogenated lower alkyl,
halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl,
carbamoyloxy, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue,
phosphosugar residue, or R4 together with R5 is methylenedioxy; R5 is en or
together with R4 is methylenedioxy; and R6 is hydrogen.
More preferably, R3 is CH2NR7R8 (where each of R7 and R8 is lower alkyl),
R4 is hydroxy, alkoxy, or alkylcarbonyloxy, and R5 is hydrogen. In a ularly
preferred embodiment of this compound, R3 is CH2N(CH3) 2 and/or R4 is hydroxy.
Similarly, a preferred compound of Formula (II) has the following features:
R2 is hydrogen, lower alkyl or halogenated lower alkyl; R3 is hydrogen or lower alkyl;
R4 is lower alkoxy, hydroxy, halogenated lower alkoxy, hydroxycarbonyl,
carbamoyloxy, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue,
phosphosugar residue, or R4 together with R5 is methylenedioxy; R5 is hydrogen or
together with R4 is methylenedioxy; and R6 is hydrogen.
ably, R3 is hydrogen, R4 is carbamoyloxy, and R5 is hydrogen. Even
more preferably, R2 is lower alkyl, especially ethyl, and R4 is 4-(1-piperidino)
piperidinocarbonyloxy.
In other embodiments, R2 is hydrogen and R4 is 4-(1-piperidino)
piperidinocarbonyloxy.
In other embodiments, R2 is hydrogen, R3 is en and R4 is
tert-butoxycarbonyloxy.
Yet r preferred compound is of Formula (II), n R2 is lower alkyl;
R3 is hydrogen; R4 is hydroxy, lower alkoxy, halogenated lower alkoxy,
hydroxycarbonyl, , lower alkoxycarbonyl, lower alkoxycarbonyloxy, sugar
residue, phosphosugar residue, or lower alkylcarbonyloxy; R5 is hydrogen; and R6 is
hydrogen.
Preferably, R2 is ethyl and R4 is hydroxy.
Yet another preferred compound is of Formula (II) where R2, R4, R5 and R6
are hydrogen and R3 is amino or nitro. An alternative compound of a (II) has
the following substituents: R2 is tri-lower alkylsilyl; R3 is hydrogen; R4 is y,
lower alkoxy, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower
alkoxycarbonyl, lower alkoxycarbonyloxy, sugar residue, phosphosugar residue,
carbamoyloxy or lower alkylcarbonyloxy; R5 is hydrogen; and R6 is hydrogen.
Preferably, R2 is t-butyldimethylsilyl and R4 is hydroxy.
While the linker, L, may be any alkylene group of 1 to 8 carbons, optionally
upted by one or more oxygen, sulfur or nitrogen atoms, a preferred linker is
(CH2)m or X—, wherein X is O, S, —NR—, or a bond; T is independently
CRR'; m is an integer from 0 to 3; n is an integer from 1 to 3, and each of R and R' is
independently selected from hydrogen, alkyl, and substituted alkyl.
In yet another preferred embodiment, the camptothecin derivative known as
TLC388HCl, comprises the following isomers:
NO2 NO2
HO HO
N N
N O N O
N O N O
NO2 NO2
HCl Et HCl Et
O NO2 O
N NO2
O NO2 O NO2
O O O O
(III) (IV)
TLC388HCl is a diastereomer and comprises (S,S) and (S,R) isomers in
approximately 2:1 molar ratio. As used herein, the term “S” or “R” is a way to name
an optical isomer by its configuration, without involving a reference molecule, which
is called the R/S system. It labels each chiral center R or S according to a system by
which its ligands are each assigned a priority, according to the Cahn Ingold Prelog
priority rules, based on atomic number. This system labels each chiral center in a
molecule (and also has an extension to chiral molecules not involving chiral centers).
If the compound has two chiral centers, it can be labeled, for example, as an (S,S)
isomer versus an (S,R) isomer.
The hydrophobic CPT derivatives sed herein are prepared by reacting a
known camptothecin-based compound having a free hydroxyl or an amine group with
an appropriate electron-affinic moiety, by linking the electron-affinic group to any of
the C5, C7, C9, C10, C11, C12 or C20 carbons of CPT using a variety of methods.
Preparation processes of the CPT derivative useful in the t invention are
described in U.S. Patent No. 7,875,602, which is incorporated herein in its entirety.
In a preferred embodiment, the camptothecin derivative is selected from the
group consisting of TLC388HCl, TLC1988HCl, and mixtures thereof.
In another group of embodiment, the CPT tives include compounds of
formula (V), which are sed in U.S. Patent No. 6,350,756, and is incorporated
herein by reference in its entirety.
wherein R is R1 O (CH2)m , m is an integer of 1-10 and R1 is
phenyl optionally tuted with from one to five substituents ndently
selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano,
nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, formyl, lower alkyl
carbonyl, hydroxycarbonyl, lower alkylcarbonyloxy, benzyloxy, optionally substituted
piperazino, lower alkoxycarbonyl, and lower alkylcarbonylamino;
a fused, 2-, 3-, or 4-ring heterocyclic system optionally substituted with one to
five tuents independently selected from the group consisting of halo, lower alkyl,
lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated
lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and
lower alkylcarbonylamino;
1- or 2-naphthyl ally substituted with from one to four substituents
independently selected from the group consisting of halo, lower alkyl, lower alkoxy,
hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy,
ycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower
arbonylamino;
a 5 or 6 membered heterocyclic ring containing one or two nitrogen atoms,
which ring is optionally substituted with one or two substituents selected from the
group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino,
halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower
alkoxycarbonyl, lower arbonyloxy, and lower alkylcarbonylamino;
R2 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R is
defined hereinbefore), cyano, nitro, amino, halogenated lower alkyl, halogenated
lower alkoxy, hydroxycarbonyl, formyl, lower carbonyl, tri lower alkylsilyl,
lower alkylcarbonyloxy, lower alkylcarbonylamino, lower alkylcarbonyloxy methyl,
substituted vinyl, 1-hydroxynitroethyl, alkoxycarbonylethyl, aminocarbonyl,
alkylcarbonyl, alkylcarbonyloxymethyl, benzoylmethyl, benzylcarbonyloxymethyl, or
lower methyl;
R3 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R is
defined hereinbefore) cyano, nitro, amino, halogenated lower alkyl, halogenated
lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, CH2NR7R8 (where
each of R7 and R8 is independently H , alkyl of 1-6 carbons, optionally substituted
phenyl, hydroxy lower alkyl, amino lower alkyl, or mono- or dialkylamino lower
alkyl, or R7 and R8 taken together with N represent a cyclic amino-), CH2R9
(where R8 is lower alkoxy, CN, amino lower alkoxy, mono- or di-lower alkylamino
lower alkoxy, lower alkylthio, amino lower hio, or mono- or er
alkylamino lower alkylthio), or NR10R11 (where each of R10 and R11 is independently
hydrogen, lower alkyl, phenyl, hydroxy lower alkyl, or amino lower alkyl, or R10 and
R11 taken together with N represent a cyclic , dialkylamino alkyl, lower
alkylcarbonyloxy lower alkylcarbonylamino; and
R4 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R is
defined before) cyano, nitro, amino, amino lower alkyl, halogenated lower alkyl,
halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl,
carbamoyloxy, lower alkylcarbonyloxy, or lower alkylcarbonylamino, or R4 together
with R5 is methylenedioxy;
R5 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R is
defined hereinbefore) cyano, nitro, amino, halogenated lower alkyl, halogenated
lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower
arbonyloxy, or lower alkylcarbonylamino; and
R6 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R is
defined hereinbefore) cyano, nitro, amino, halogenated lower alkyl, halogenated
lower alkoxy, hydroxycarbonyl, , lower alkoxycarbonyl, lower
arbonyloxy, or lower alkylcarbonylamino.
In yet another group of embodiment, the CPT derivatives e
compounds of formula (VI), which are disclosed in U.S. Patent No. 6,403,604, and is
incorporated herein by reference in its entirety.
(VI)
n R is RaRbN (CH2)m, m is 2,
RaRb together with N form (a) a 5-, 6-, or 7-membered cyclic amine having no
more than one additional nitrogen, oxygen, or sulfur atom in the ring, which ring is
fused to another, carbocyclic ring or rings which resulting fused ring system is
optionally substituted with up to two substituents chosen from lower alkyl, lower
cycloalkyl, hydroxy lower alkyl, phenyl, substituted phenyl (substituted with one to
five substituents independently ed from the group consisting of halo, lower alkyl,
lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated
lower alkoxy, carbonyl, hydroxycarbonyl, lower alkylcarbonyloxy, benzyloxy,
optionally substituted piperidino, lower alkoxycarbonyl, and lower
alkylcarbonylamino), benzyl, substituted benzyl (substituted with one to five
substituents independently selected from the group consisting of halo, lower alkyl,
lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, nated
lower alkoxy, carbonyl, hydroxycarbonyl, lower alkylcarbonyloxy, benzyloxy,
optionally substituted piperidino, lower alkoxycarbonyl, and lower
alkylcarbonylamino), aminocarbonylmethyl, lower alkylaminocarbonylmethyl, amino,
mono- or di-lower alkyl amino, cyclic amino, or a 5- or 6-membered cyclic ring
optionally substituted with one or two tuents selected from the group consisting
of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower
alkyl, nated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower
alkylcarbonyloxy, and lower alkylcarbonylamino or (b) a 5- or ered cyclic
imide ring;
R2 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R is
defined hereinbefore), cyano, nitro, amino, halogenated lower alkyl, halogenated
lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, tri lower alkylsilyl,
lower alkylcarbonyloxy, lower alkylcarbonylamino, lower alkylcarbonyloxymethyl,
substituted vinyl, oxynitroethyl, alkoxycarbonylethyl, aminocarbonyl,
arbonyl, alkylcarbonyloxymethyl, benzoylmethyl, benzylcarbonyloxymethyl, or
lower alkoxymethyl,
R3 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R is
d hereinbefore) cyano, nitro, amino, halogenated lower alkyl, halogenated
lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, R8 (where
each of R7 and R8 is independently H , alkyl of 1-6 carbons, optionally substituted
phenyl, hydroxy lower alkyl, amino lower alkyl, or mono- or dialkylamino lower
alkyl, or R7 and R8 taken together with N represent a saturated 5-, 6-, or 7
membered cyclic amine ring having no more than one additional en, oxygen or
sulfur atom that is optionally fused to another carbocyclic ring or rings), CH2R9
(where R9 is lower alkoxy, CN, amino lower alkoxy, mono- or di-lower alkylamino
lower alkoxy, lower alkylthio, amino lower alkylthio, or mono- or di-lower
alkylamino lower alkylthio), or NR10R11 (where each of R10and R11 is independently
hydrogen, lower alkyl, , hydroxy lower alkyl, or amino lower alkyl, or R10 and
R11 taken together with N represent a ted 5-, 6, or 7 membered cyclic
amine ring having no more than one additional nitrogen, oxygen or sulfur atom that is
optionally fused to another carbocyclic ring or rings), dialkylamino alkyl, lower
alkylcarbonyloxy, or lower alkylcarbonylamino; and
R4 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R is
defined hereinbefore) cyano, nitro, amino, amino lower alkyl, halogenated lower alkyl,
nated lower alkoxy, hydroxycarbonyl, formyl, lower carbonyl,
oyloxy, lower alkylcarbonyloxy, or lower alkylcarbonylamino, or R4 together
with R5 is methylenedioxy;
R5 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R is
defined hereinbefore) cyano, nitro, amino, halogenated lower alkyl, halogenated
lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower
alkylcarbonyloxy, or lower arbonylamino; and
R6 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R is
defined hereinbefore) cyano, nitro, amino, halogenated lower alkyl, halogenated
lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower
alkylcarbonyloxy, or lower arbonylamino.
PEG-conjugated Phospholipid
As described herein, a PEG conjugated phospholipid, comprising a PEG
moiety, preferably having a molecular weight from about 1,000 to about 20,000
daltons and conjugated to a phospholipid moiety, is used as a micelle-forming
amphipathic lipid. The PEG conjugated phospholipid is mixed with the CPT
derivative to form micelles and izes the CPT derivative, or the pharmaceutically
acceptable salt of said derivative. ably, the PEG moiety of the PEG
conjugated phospholipid has a molecular weight from about 1,000 to about 10,000
s. More preferably, the PEG moiety of the PEG conjugated phospholipid has a
molecular weight from about 2,000 to about 5,000 daltons. The PEG moiety may be
linear, branched (including “dendrimeric” or “star”), and may be derivatized with
amino, carboxyl, acyl, sulfonyl, or lower alkoxyl ends e.g. methoxyl polyethylene
glycol (mPEG). Combinations of different types of PEG (e.g., branched PEG and
linear PEG) may also be used.
The phospholipid moiety of the PEG conjugated phospholipid as used herein
may include natural or synthesized phospholipid, for example,
phosphatidylethanolamine (such as roylphosphatidylethanolamine (DSPE),
itoylphosphatidylethanolamine (DPPE), dioleoylphosphatidylethanolamine
(DOPE), 1-palmitoyloleyl, phosphatidylethanolamine (POPE), and
dimyristoylphosphatidylethanolamine ); phosphatidylcholine (such as yolk
phosphatidylcholine, soy phosphatidylcholine, dipalmitoylphosphatidylcholine
(DPPC), roylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine
(DMPC), and dioleoylphosphatidylcholine (DOPC)); phosphatidylserine;
phosphatidylinositol; sphingophospholipid; hydrogenated olipid (such as
hydrogenated phosphatidylcholine (HSPC)); and the like; and ations thereof.
Particularly preferred phospholipid for conjugation to PEG as used herein is selected
from the group consisting of DSPE, DPPE, DMPE, DOPE, and POPE and
combinations thereof.
In one embodiment, the PEG conjugated phospholipid is a PEG-DSPE
conjugate, preferably a methoxyl PEG-DSPE conjugate such as
1,2-distearoyl-phosphatidylethanolamine-methyl-polyethyleneglycol-2000
(mPEG2000-DSPE). The chemical ure of mPEG2000-DSPE is shown below:
Pharmaceutical Compositions
The pharmaceutical composition of the present invention comprises at least
one CPT derivative or the pharmaceutically acceptable salt of said tive; and at
least one PEG-conjugated phospholipid. The molar ratio of said PEG ated
olipid to said hydrdophobic camptothecin derivative or said pharmaceutically
acceptable salt of said hydrophobic camptothecin derivative is greater than about
0.45:1.
Molar Ratio of Phospholipid to CPT
The molar ratio of the phospholipid to CPT tive plays an important
role in improving the stability of the CPT derivative in the pharmaceutical
composition. In a preferred embodiment, the PEG conjugated phospholipid is mixed
with the CPT derivative at a molar ratio (lipid: CPT derivative) more than about 0.45:
1. In a more preferred embodiment, the molar ratio of the phospholipid to CPT
derivative is from about 0.60:1 to about 1.00: 1 and even more preferably, from about
0.70:1 to about 0.90:1 In other embodiments, the molar ratio of the lipid to
CPT derivative is greater than about 0.75 to 1, preferably, from about 0.75:1 to about
1:00:1. By mixing the olipid with the CPT derivative at the molar ratio as
described herein, the micelles thus formed have an average diameter below about 40
nm, more particularly below about 20 nm, and even more particularly about 15 nm.
pH Adjusting Agent
The pharmaceutical composition of the present ion is preferably acidic.
Certain CPT derivatives useful in the t invention, such as TLC388HCl, may be
unstable in an alkaline environment. In a preferred embodiment, the pharmaceutical
composition of the present invention has a pH less than about 4.0. In a more
preferred embodiment, the pH of the pharmaceutical composition is between about 3
to about 4. The pharmaceutical composition may contain one or more pH ing
agents to maintain an acidic pH and izing the CPT derivatives. The pH
adjusting agent can be any ceutical acceptable buffer, which includes one or
more of the following: oxalic acid, ethylenediamine tetraacetic acid, maleic acid,
aspartic acid, phosphate, asparagine buffer, glycine, pyruvic acid, pyrophosphate,
malonic acid, phthalate, fumaric acid, ic acid, citrate, furancarboxylic acid, β
-alanine buffer, β : β '-dimethyl glutaric acid, formic acid, lactic acid, γ
-aminobutyric acid, barbituric acid, benzoic acid, succinic acid, E-aminocaproic
acid, acetic acid, propionic acid, malic acid, pyridine, histidine, cacodylic acid,
carbonic acid, hydroxyimidazole, glycerol phosphate, ethylenediamine, imidazole,
arsenic acid, collidine, 1-, 2-, or 4-methyl ole, N-ethyl morpholine,
veronal, barbital, 2,4-dimethyl imidazole, morpholine, N-ethyl morpholine,
2-aminomethyl-1,3-propanediol, 2-aminoethyl-1,3-propanediol,
diethanolamine, 4-aminopyridine, serine, boric acid, ammonia, lamine,
ephedrine, hydroxyproline, 2-aminomethylpropanol, leucine, trimethyl, αalanine
, n-propyl alcohol, methylamine, ethylamine, n-butylamine, triethylamine,
dimethylamine, thylenediamine, piperidine, p-toluenesulfonic acid,
tris(hydroxymethyl)aminomethane (Tris), glycine, GTA buffer, Good buffer
such as MES buffer, Bis-Tris buffer, ADA buffer, PIPES buffer, ACES buffer,
MOPSO buffer, BES buffer, MOPS buffer, TES buffer, HEPES buffer, DIPSO buffer,
TAPSO , POPSO buffer, HEPPSO , EPPS buffer, Tricine buffer, Bicine
buffer, TAPS buffer, CHES buffer, CAPSO buffer, and CAPS buffer. Preferably, the
pH adjusting agent comprises one or more of the ing: e, fumaric acid,
diethanolamine, Tris, glycine, acetic acid, succinic acid, ic acid, carbonic acid,
imidazole and maleic acid.
The pharmaceutical composition of the ion may further comprise at
least one cryoprotectant such as mannitol, glycerol, dextrose, e, and/or trehalose.
One preferred cryoprotectant is mannitol.
In some embodiments, this invention also provides a pharmaceutical
composition further comprising at least one pharmaceutically acceptable excipient,
diluent, vehicle, medium for the active ingredient, or a combination.
In one embodiment, the pharmaceutical composition comprising
TLC388HCl or the pharmaceutically acceptable salt of TLC388 HCL; methoxyl
PEG-DSPE conjugate; and citric acid, wherein the methoxyl PEG conjugated
phospholipid is mixed with the TLC388HCl or the ceutically acceptable salt of
TLC388 HCL at a molar ratio of between about 0.45: 1 to about 0.9:1.
Methods for preparing micelles are known in the art, such as the
methanol-evaporation method and the co-precipitation method. In the
methanol-evaporation method, the CPT derivative and the PEG conjugated
phospholipid at a suitable molar ratio, as described herein, are dissolved in methanol.
The mixture is then mixed with a suitable buffer solution and the methanol is removed
by vacuum evaporation or vice versa; and the mixture is optionally sterilized and/or
lyophilized. In the co-precipitation method, the CPT derivative and the PEG
conjugated phospholipid at a le molar ratio, as bed herein, are ved in
a suitable organic solvent; the mixture is then injected into an anti-solvent to form
itate and the organic t is d by vacuum drying; the powder thus
obtained is dissolved in a suitable buffer solution; and the resulting aqueous solution
is optionally sterilized by filtration and/or lyophilized. Details of the preparation are
described in the examples below.
The pharmaceutical compositions of the invention may be used in methods
to inhibit cancer cells in a subject suffering from a cancer disorder. It is found that
the pharmaceutical compositions of the ion inhibit cancer cells and reduce
toxicity to normal s or cells, particularly bone marrow cells.
The method of inhibiting cancer cells and treating cancer
Another embodiment is directed to methods of inhibiting or retarding the
growth of cancer cells in a subject, which comprises the administration of an effective
amount of the pharmaceutical composition as described herein to the subject, whereby
the symptoms and signs of the cancer in the subject are reduced. The method may
optionally include the step of exposing the t’s cancer cells to one or more
anti-cancer agents, such as ionizing radiation, conventional chemotherapy, or targeted
cancer y.
The pharmaceutical composition may be constituted into any form suitable
for the mode of administration selected. Preferably, the pharmaceutical composition
is formulated for al administration, such as intravenous, intramuscular,
subcutaneous and intraperitoneal injection. For example, the pharmaceutical
ition of the invention may be in the form of lyophilized powders and further
diluted or reconstituted in an aqueous on such as sterile water, saline or other
suitable fluid for injection. Other medically acceptable route of administration
includes oral, transdermal, rectal or tion and the like.
The dosage of the pharmaceutical composition or the compound as described
herein can be determined by the skilled person in the art according to the
embodiments. Unit doses or multiple dose forms are contemplated, each offering
ages in certain clinical settings. The actual amount of the compound or
pharmaceutical ition to be administered can vary in accordance with the age,
weight, condition of the subject to be treated and other co-morbidity, and depends on
the discretion of medical professionals.
In one embodiment, the method comprises co-administering the
pharmaceutical composition with one or more anti-cancer agents, such as ionized
radiation, targeted cancer therapy such as EGFR and VEGF antagonists, or
convention chemotherapy.
Examples of convention chemotherapy include, but are not d to
anthracycline antibiotic, DNA synthesis inhibitor, alkylating agent, antifolate agent,
lic inhibitor or the like.
Examples of anthracycline antibiotic include, but are not limited to,
doxorubicin, Epirubicin, Mitoxantrone and the like.
Examples of DNA synthesis inhibitor include, but are not limited to,
mitomycin C, 5-FU (5-fluorouracil), tabine, ecan hydrochloride, thymitaq
and the like.
Examples of ting agent include, but are not limited to, cisplatin,
carboplatin, oxaliplatin, mitoxantrone and the like.
Examples of lic inhibitor include, but are not limited to, ide,
rottlerin and the like.
Examples of antifolate agent include, but are not limited to, Nolatrexed and
the like.
The following examples further illustrate the present invention. These
examples are intended merely to be illustrative of the present invention and are not to
be construed as being limiting.
In this specification where reference has been made to patent specifications,
other external documents, or other sources of information, this is generally for the
purpose of providing a context for sing the es of the invention. Unless
specifically stated otherwise, reference to such external documents is not to be
ued as an admission that such documents, or such sources of information, in any
jurisdiction, are prior art, or form part of the common general knowledge in the art.
Example 1: Preparation of the pharmaceutical compositions of camptothecin
derivatives
1.1 Camptothecin derivatives
TLC388 base, with the following a was used to prepare the
pharmaceutical composition:
The al name of the TLC388 base is (S)[(dimethylamino)methyl]
ethylhydroxyO-[(±)(2’’,4’’,5’’,7’’-tetranitro-9’’-fluorenylideneaminooxy)
propionyl]-1H-pyrano[3’,4’:6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H)-dione.
TLC388 base was used to prepare the pharmaceutical compositions e of its
fixed molecular weight, which is 850.7. This allowed for the exact quantitation of
the CPT derivative by mole.
TLC1988HCl, with the following formula, was used to prepare the CM1901
and 1903 pharmaceutical compositions:
HO O
N HCl
TLC-1988
FW = 864.20
900.18 (as HCl salt)
The chemical name of TLC1988HCl is
(S)[(dimethylamino)methyl]-4–ethylhydroxyO-[2-methyl(2’’,4’’,5’’,7’’-
tetranitro-9’’-fluorenylideneaminooxy)propionyl]-1H-pyrano[3’,4’:6,7]indolizino
[1,2-b]quinoline-3,14-(4H,12H)-dione, monohydrochloride.
1.2 Methanol-evaporation method
The pharmaceutical compositions were prepared by methanol-evaporation
method, as illustrated below:
1. TLC388 base (or TLC1988HCl) and mPEG2000-DSPE at various molar ratios,
as shown in Table 1, were dissolved in methanol;
2. The mixture in Step 1 was mixed with a buffer solution containing mannitol
and tartaric acid, at the volume ratio of 1 to 1;
3. The methanol in the mixture in Step 2 was removed by vacuum evaporation,
using a rotor bottle in the 50-55oC water bath (pressure 11-21 cm Hg) for at
least 30 minutes;
4. The mixture in Step 3 underwent sterile filtration using a 0.22 mm membrane,
ed by lyophilization for uent analyses.
An alternative route was d out in the following order:
1. TLC388 base (or 8HCl) and mPEG2000-DSPE at various molar ratios
were dissolved in methanol;
2. The ol in the mixture in Step 1 was removed by vacuum evaporation
using a rotor bottle in the 50-55oC water bath ure 11-21cmHg) for at
least 30 minutes;
3. The mixture in Step 2 was mixed with a buffer solution containing mannitol
and tartaric acid, at the volume ratio of 1 to 1;
4. The mixture in Step 3 underwent sterile filtration using a 0.22 mm membrane,
followed by lyophilization for subsequent analyses.
1.3 cipitation method
The pharmaceutical compositions were prepared by co-precipitation method,
as illustrated below:
1A. TLC388 base and mPEG2000-DSPE at various molar ratios were dissolved in
a suitable organic solvent, such as methanol;
2A. The mixture in Step 1A was injected into an olvent to form precipitation;
3A. The mixture in Step 2A underwent filtration and vacuum drying to remove
solvent, and intermediate powder was formed;
4A. The intermediate powder in Step 3A was dissolved in a buffer solution
containing mannitol and citric acid;
5A. The mixture in Step 4A underwent sterile filtration, ed by
lyophilization.
Example 2: The Solubility of the Pharmaceutical Composition
The solubility of the pharmaceutical composition in the t invention
was evaluated in term of the micellar size and the distribution.
An evaluation of the pharmaceutical composition with s phospholipid
to CPT derivative molar ratios was med. The results of the study are
summarized in Table 1.
Table 1. The characteristics of the various pharmaceutical compositions with
various phospholipid to CPT derivative molar ratios.
Pharmaceutical Phospholipid/CPT Size (nm) PI*
Composition derivative
CM317a 0.09/1 67.4 0.364
CM316a 0.29/1 87.2 0.824
CM315a 0.45/1 21.9 0.263
CM314 a 0.68/1 13.4 0.105
CM391b 0.46/1 13.2 0.314
CM392 b 0.52/1 11.5 0.136
CM386 b 0.65/1 15.2 0.142
CM381 b 0.71/1 15.1 0.106
CM382 b 0.70/1 15.2 0.099
CM387 b 0.75/1 15.2 0.106
CM388 b 0.85/1 14.8 0.075
CM389 b 0.95/1 14.7 0.069
CM390 b 1.05/1 15.3 0.118
CM1901 a 1.25/1 15.8 0.427
CM1903 a 1.5/1 16.4 0.236
a. The pharmaceutical composition was prepared by the methanol-evaporation method.
b. The pharmaceutical composition was prepared by the co-precipitation method.
* PI= Polydispersity, a measure of distribution of particles. High PI means wide size distribution
and low PI reflects a good monodispersed particle size.
The micellar size (hydrodynamic diameter) of the pharmaceutical
composition was measured by c light ring (DLS) using a Zetasizer
NANO-ZS90 with zer Software 6.20 (Malvern Instruments). The
pharmaceutical ition was diluted with normal saline at ambient temperature to
a concentration to provide a Count Rate of 50 to 200 kcps. The Z-average diameter
was obtained from three measurements.
The results in Table 1 show that to obtain a micelle size less than 40 nm, the
minimum phospholipids to CPT derivative molar ratio is more than about 0.45.
In addition, the s solubility of TLC1988HCl increased to 10 mg/mL
with mPEG2000-DSPE ation.
An evaluation of the size distribution of the pharmaceutical compositions
with various phospholipid to CPT derivative molar ratios was performed. The
results are shown in FIGURES 1 and 2.
FIGURE 1 shows the size distribution graph of the CM315 Composition.
The micellar size of the CM315 Composition is less than 40 nm, and the size
distribution graph shows CM315 Composition has a narrow size distribution with one
major peak at about 15 nm.
FIGURE 2 shows the size distribution graph of the CM316 Composition.
The micellar size of the CM316 Composition is over 40 nm, and the size distribution
graph shows a wide size bution with multiple peaks. The main peak is at more
than 200 nm.
These results show that the ceutical composition with a phospholipid
to CPT derivative molar ratio of more than about 0.45 has a micelle size less than 40
nm and narrower size distribution.
Example 3: Effect of pH Adjusting Agent and pH on Stability
TLC388 HCl and TLC1988HCl are known to be unstable in an alkaline
condition. An evaluation of s pH ing agents and the pH was performed
to determine the suitable pH range and the pH adjusting agent for the ceutical
composition.
Tartaric acid or citric acid was added to the pharmaceutical compositions and
incubated the mixture at 40°C for 2 weeks. The stability of the pharmaceutical
compositions after 2 weeks of incubation is summarized in Tables 2-4.
Table 2. The effect of the pH Adjusting Agents and pH on the Stability of the
ceutical Compositions
Pharmaceutical Excipient pH Stability at 40°C for
Composition 2 weeks
Drug %c Size(nm)
CM314-3a 1.2% mannitol & 2.95 96% 424.0
CM314-4a 0.5% tartaric 3.78 75% 260.0
acid/ NaOH
CM348-3b 5% mannitol & 3.10 93% 16.0
CM348-4b 0.2% tartaric acid/ 4.00 86% 15.6
CM348-5b NaOH 5.01 76% 180.0
CM347-3b 5% mannitol & 3.14 92% 24.5
CM347-4 b 0.2% citric acid/ 3.99 85% 14.6
CM347-5 NaOH 4.94 78% 225.0
CM381 b 1.5% mannitol & 3.0 99% 15.2
CM382 b 0.1% citric acid/ 3.5 97% 15.0
NaOH
CM1901 a 2% mannitol & 2.5~3.5 N/A N/A
0.2% ic acid/ 2.5~3.5
CM1903 a
NaOH N/A N/A
a. The pharmaceutical composition was prepared by the methanol-evaporation method.
b. The pharmaceutical composition was prepared by the co-precipitation method.
c. Percentage of ing TLC388 base with respect to the initial content.
Table 3: rated ity Evaluation of the CM381 Composition
(1.5%mannitol + 0.08% sodium citric, PEG Phospholipid/TLC388=0.71)
40±2oC
CM381 Initial
14 days 28days
Appearance of cake light yellow cake light yellow cake light yellow cake
Clarity Clear Clear Clear
pH 3.10 3.11 3.30
Size (nm) 15.1 15.2 15.2
bution (PdI) 0.106 0.064 0.037
Conc. (mg/mL) 8.61 8.57 8.61
Drug ing (%)a 100.0% 99.5% 100.0%
a Percentage TLC388 remaining with respect to initial content of TLC388
Table 4: Accelerated Stability Evaluation of CM382 Composition (1.5%mannitol
+ 0.11% sodium citric, PEG phospholipid/TLC388=0.7).
40±2oC
CM382 Initial
14 days 28days
Appearance of cake light yellow cake light yellow cake light yellow cake
Clarity Clear Clear Clear
pH 3.56 3.58 3.61
Size (nm) 15.2 15.0 15.1
Distribution (PdI) 0.099 0.085 0.069
Conc. (mg/mL) 8.61 8.42 8.44
Drug remaining (%)a 100.0% 97.8% 98.0%
a Percentage TLC388 remaining with respect to initial content of TLC388.
The results show that the suitable pH range for the pharmaceutical
itions of the invention is lower than about pH 4.0. In addition, citric acid and
tartaric acid are suitable pH adjusting agents for the pharmaceutical compositions in
the present invention.
Example 4: Cytotoxicity Assay
4.1 Cell lines and culture conditions
Human hepatoma cell lines Hep3B, HepG2, HepG2/2.2.15, Huh-7 and
-1, human glioblastoma cell line RG-2, and human prostate cancer cell line
DU145 were maintained in DMEM (HyClone Laboratories, Logan, Utah, USA).
Human prostate cancer cell line LNCap was maintained in RPMI-1640 culture
medium (Sigma-Aldrich, St. Louis, MO, USA). Culture medium was supplemented
with 10 % heat-inactive fetal bovine serum (HyClone tories, Logan, Utah,
USA), 1 % penicillin/streptomycin (Invitrogen, Carlsbad, CA, USA), 1 mM sodium
pyruvate (HyClone tories, Logan, Utah, USA) and 1 mM L-Glutamine
(HyClone Laboratories, Logan, Utah, USA). Human prostate cancer cell line PC-3
was maintained in the Ham’s F-12K medium (Invitrogen, Carlsbad, CA, USA) with
the same medium supplements described in the culture medium except that the fetal
bovine serum concentration was d to 7 % by . Cancer cells were
maintained at 37 C in a humidified incubator (Nuaire, USA) ning 5 % CO2.
4.2 Sulforhodamine B assay (SRB assay)
The SRB assay was used for measuring cancer cell viability. The cancer
cells in the plate wells were rinsed with 1· PBS and d with 1· trypsin-EDTA
(Invitrogen, Carlsbad, CA). The culture medium was added to dilute the
trypsin-EDTA. The detached cancer cells were harvested by centrifugation and
suspended in the 1 ml culture medium. Ten μl of the cell suspension was dispensed
into counting chambers and the cell density was determined microscopically. The
cells in 198 μl suspensions were seeded onto a 96-well cell plate (Nunc, Rochester, NY)
at the appropriate cell density per well and incubated in the cell culture incubator
overnight.
4.3 Testing Compositions
We evaluated the ncer activity of the following CPT tives
pharmaceutical compositions:
1. TLC388 HCl, a non-water soluble CPT derivative (obtained from ScinoPharm
Taiwan Ltd., Taiwan);
2. Topotecan, a water-soluble CPT derivative and is used as positive control
(Commercially available from Wuhan Yuancheng Technology Development
Co., Ltd, China); and
3. Lipotecan® (CM382 Composition in Table 1, ses PEG conjugated
phospholipid and CPT derivative at a molar ratio of 0.7).
TLC388 HCl and Topotecan were dissolved in DMSO (Sigma-Aldrich, St. Louis, MO,
USA) and diluted with 5 mM of citric acid (J.T. Baker, NJ, USA) to desired
concentrations. Lipotecan® was ved with sterile ddH2O and diluted with 5 mM
of citric acid to desired tration.
The intermediate plate was set up for the drug dilution. 5 mM of citric acid
was used for free TLC388 HCl and Topotecan dilution and ddH2O was used for
Lipotecan® dilution. Two μl of free TLC388 HCl or can® of the following
concentrations were then added to the cells: 0, 0.0008, 0.003, 0.012, 0.049, 0.195,
0.781, 3.125, 12.5 and 50 μmole/ml. Each concentration was tested in triplicate and
was incubated at 37 oC with the cancer cells for 24 h, 48 h and 72 h. The highest
concentration of DMSO was 0.05 % in this test.
At the end of the incubation period, cells were fixed by adding 50 ml of cold
50 % TCA (w/v) (Sigma, St Louis, MO, USA) to a final concentration of 10 % TCA
and further incubated at 4 C for 60 minutes. The supernatants were discarded, and the
plates were washed five times with sterile water and air-dried. 100 ml of
Sulforhodamine B solution (SRB, Sigma, St. Louis, MO, USA) at 0.4 % (w/v) in 1 %
acetic acid (Fluka, Seelze, Germany) was uently added to each well and
ted at room temperature for 30 minutes. After staining, unbound dye was
removed by 1 % acetic acid and the plates were again air-dried. Bound stain in each
well was solubilized with 100 ml of 10 mM trizma base (Bioshop, gton, ON,
Canada), and the absorbance was measured using an automated plate reader (Anthos
2001, Anthos Labtec Instrument) at 540 nm.
4.3 Data Analysis
The graph and data were analyzed by SigmaPlot 10.0 software and
Microsoft® Excel 2002.
4.4 s
Tables 5 and 6 show the 50 % inhibitory concentration (IC50) values for
Lipotecan®, TLC388 HCl and Topotecan as well as the enhancement factor (IC50
TLC388 HCl/IC50 Lipotecan®).
Table 5. In Vitro xic Effect of Lipotecan®, TLC388 HCl and Topotecan
Against Selected Cancer Cell Lines
Table 6. in vitro cytotoxic effect of Lipotecan®, TLC388 HCl and Topotecan in
RG-2 glioma cell line.
Incubation IC50 (mM)
Cell line
Time Topotecan TLC388 HCl Lipotecan® Ratio*
24 h 7.23 7 1.23 5.7
RG-2 48 h 2.78 2.1 0.53 4
72 h 3 2.12 0.24 8.8
* Note: The IC50 ratios are calculated to indicate enhancement in cytotoxicity of TLC388 HCl
over Lipotecan® (IC50 TLC388 HCl/ IC50 Lipotecan®)
As shown in Tables 5 and 6, Lipotecan® is more effective in ting
hepatoma, prostate and glioma cancer cells than TLC388 HCl. In addition,
Lipotecan® is ive in inhibiting the colon cancer cells.
e 5: Bone Marrow Suppression Evaluation
An in vitro evaluation of the effect of the pharmaceutical compositions on
human bone marrow cells was performed.
Protocol: Clonogenic progenitors of the erythroid , ,
granulocyte- monocyte (CFU-GM) and multipotential lineages (CFU-GEMM) were
set up in methylcellulose-based medium (R&D Systems) containing recombinant
rhSCF (50 ng/mL), rhIL-3 (10 ng/mL), rhGM-CSF (10 ng/mL),and rhEpo (3 U/mL).
TLC388 HCl and Topotecan were diluted in DMSO and Lipotecan® was
diluted in sterile water to provide the appropriate working stock concentrations.
These working stock solutions were subsequently added to the methylcellulose-based
colony assay medium described above. The colony assay mediums were set up in
triplicate at 2x104 cells per culture medium.
The replicate culture s were incubated at 37oC in 5% CO2 for 14-16
days. After this time, the resultant colonies in the culture medium were evaluated by
a senior ist in term of size and morphology.
FIGURE 3 shows the toxicity of TLC388HCl, Topotecan and Lipotecan®
(TLC388 HCl composition) on human erythroid and myeloid progenitor. The IC50
values of the free TLC388 HCl were 9.3 nM for oid Colony Forming Cells
(CFCs) and 9.8 nM for myeloid CFCs. The IC50 values of Topotecan were 11.8 nM
for erythroid CFCs and 8.7 nM for myeloid CFCs. The IC50 values of can®
were 12.5 nM for erythroid CFCs and 11.5 nM for myeloid CFCs. The s show
that the toxic effects of Lipotecan® on human oid and myeloid progenitors were
lower than that of free TLC388 HCl and Topotecan.
This data indicates that Lipotecan® composition of the present invention has
increased anti-cancer effect to various cancer cell lines, such as hepatoma, prostate
cancer and glioma cell lines, and lower toxicity on bone marrow cells such as
erythroid and myeloid CFCs.
When ranges are used herein for physical properties, such as molecular
weight, or chemical properties, such as al formulae, all ations, and
subcombinations of ranges specific embodiments therein are intended to be included.
Those skilled in the art will appreciate that numerous changes and
modifications can be made to the preferred embodiments of the invention and that
such changes and modifications can be made without departing from the spirit of the
invention. It is, therefore, ed that the appended claims cover all such
equivalent variations as fall within the true spirit and scope of the invention.
Claims (35)
1. A pharmaceutical composition, comprising: at least one hydrophobic camptothecin derivative or a pharmaceutically able salt of said derivative; and at least one polyethylene glycol (PEG) conjugated phospholipid; wherein the molar ratio of said PEG conjugated phospholipid to said hydrophobic camptothecin derivative or said pharmaceutically acceptable salt of said hydrophobic camptothecin tive is greater than about 0.45:1; wherein said hydrophobic camptothecin derivative comprises at least one compound of formula (I): or a pharmaceutically acceptable salt of said tive; wherein: W is alkyl-C(O) , or R1Y-L-C(O), provided that when W is alkyl-C(O) , at least one of R2, R3, R4, R5, or R6 is nitro; L is a bond or linear alkylene (1-8) group, optionally substituted with lower alkyl or substituted lower alkyl, wherein one or two methylene ( CH2 ) units of the linear alkylene group is optionally replaced with O, S or NH; Y is =NO , N(H)O , =N , NR , O, S, or a bond; R is H, alkyl, or optionally substituted alkyl; R1 is optionally substituted carbocyclic, heterocyclic, or fused 2-, 3- or 4-ring heterocyclic; R2 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RQY, RQY-L-C(O)O , cyano, nitro, amino, halogenated lower alkyl, nated lower , hydroxycarbonyl, formyl, lower alkoxycarbonyl, tri lower alkylsilyl, lower arbonyloxy, lower alkoxycarbonyloxy, sugar residue, phosphosugar e residue, O-quinone, substituted lower alkyl aminomethyl, lower alkylcarbonylamino, lower alkylcarbonyloxy methyl, optionally substituted lower alkylcarbonyloxy , substituted vinyl, 1-hydroxynitroethyl, alkoxycarbonylethyl, aminocarbonyl, alkylcarbonyl, benzoylmethyl, benzylcarbonyloxymethyl, lower minomethyl or lower alkoxymethyl; R3 is hydrogen, halo, lower alkyl, lower alkoxy, y, RQY-L-C(O)O , cyano, nitro, amino, nated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, CH2NR7R8 (where each of R7 and R8 is independently H, alkyl of 1-6 carbons, optionally substituted phenyl, hydroxy lower alkyl, amino lower alkyl, or mono- or dialkylamino lower alkyl, or R7 and R8 taken together with N represent a cyclic amino-), CH2R9 (where R9 is lower alkoxy, cyano, amino lower alkoxy, mono- or di-lower alkylamino lower alkoxy, lower alkylthio, amino lower alkylthio, or mono- or di-lower alkylamino lower alkylthio), NR10R11 (where each of R10 and R11 is independently hydrogen, lower alkyl, phenyl, hydroxy lower alkyl, or amino lower alkyl, or R10 and R11 taken together with --N-- represent a cyclic amino), ylsilyl, dialkylamino alkyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue, phosphosugar residue, one, substituted lower alkyl aminomethyl, or lower alkylcarbonylamino or R3 together with R4 is furan, dihydrofuran or 1,4-oxazineone; and R4 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RQY-L-C(O)O , cyano, nitro, amino, amino lower alkyl, nated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, carbamoyloxy, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue, phosphosugar residue residue, O-quinone, substituted lower alkyl aminomethyl, or lower alkylcarbonylamino, or R4 together with R3 is furan, dihydrofuran or 1,4-oxazineone, or R4 together with R5 is methylenedioxy; R5 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RQY-L-C(O)O , cyano, nitro, amino, trialkylsilyl, halogenated lower alkyl, nated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue, phosphosugar residue residue, O-quinone, substituted lower alkyl aminomethyl, or lower alkylcarbonylamino, or R5 together with R4 is methylenedioxy; R6 is hydrogen, halo, lower alkyl, lower alkoxy, y, RQY-L-C(O)O , cyano, nitro, amino, halogenated lower alkyl, halogenated lower , ycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue, phosphosugar residue residue, O-quinone, substituted lower alkyl aminomethyl, or lower alkylcarbonylamino; and RQ is optionally substituted carbocyclic, heterocyclic, or fused 2-, 3- or 4-ring heterocyclic; or wherein said hydrophobic thecin derivative comprises at least one nd of formula (II): (II) or a pharmaceutically acceptable salt of said derivative; wherein: X is a O, S, —NR—, or a bond; Y is ═NO—, —N(H)O—, ═N—, —NR—, O, S; or a covalent bond; T is independently CRR′; each of R and R′ is independently selected from en, C1-4 alkyl, and substituted C1-4 alkyl; n is an integer from 0 to 8; R1 is optionally substituted heterocyclic, aryl, or heteroaryl; provided that when X is a bond or CH2 and n is 1, 2, or 3, then Y, when bound to R1, is not oxygen; and provided that when X is a bond or CH2, n is 1, 2, or 3; and R1 is heterocyclic containing at least one nitrogen atom, then Y is not bound directly to said nitrogen atom; R2 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RQY-L-C(O)O—, cyano, nitro, amino, halogenated lower alkyl, halogenated lower , hydroxycarbonyl, , lower alkoxycarbonyl, tri lower ilyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar e, phosphosugar residue residue, O-quinone, substituted lower alkyl aminomethyl, lower alkylcarbonylamino, lower alkylcarbonyloxy methyl, optionally substituted lower arbonyloxy methyl, substituted vinyl, 1-hydroxynitroethyl, alkoxycarbonylethyl, aminocarbonyl, alkylcarbonyl, alkylcarbonyloxymethyl, benzoylmethyl, benzylcarbonyloxymethyl, lower alkyliminomethyl or lower alkoxymethyl; R3 is hydrogen, halo, lower alkyl, lower , hydroxy, RQY-L-C(O)O—, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, CH2NR7R8 (where each of R7 and R8 is independently H, alkyl of 1-6 carbons, optionally substituted phenyl, hydroxy lower alkyl, amino lower alkyl, or mono- or dialkylamino lower alkyl, or and R8 taken together with —N— represent a cyclic amino-), CH2R9 (where R9 is lower , CN, amino lower alkoxy, mono- or di-lower alkylamino lower alkoxy, lower alkylthio, amino lower alkylthio, or mono- or di-lower alkylamino lower alkylthio), NR10R11 (where each of R10 and R11 is independently hydrogen, lower alkyl, phenyl, y lower alkyl, or amino lower alkyl, or R10 and R11 taken together with —N— represent a cyclic amino), trialkylsilyl, dialkylamino alkyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue, phosphosugar residue residue, O-quinone, substituted lower alkyl aminomethyl, or lower arbonylamino or R3 together with R4 is furan, dihydrofuran or 1,4-oxazineone; R4 is en, halo, lower alkyl, lower alkoxy, hydroxy, RQY-L-C(O)O—, cyano, nitro, amino, amino lower alkyl, halogenated lower alkyl, halogenated lower alkoxy, ycarbonyl, formyl, lower alkoxycarbonyl, carbamoyloxy, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue, phosphosugar residue residue, O-quinone, substituted lower alkyl aminomethyl, or lower alkylcarbonylamino, or R4 together with R5 is methylenedioxy; R5 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RQY-L-C(O)O—, cyano, nitro, amino, halogenated lower alkyl, nated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue, phosphosugar residue residue, O-quinone, substituted lower alkyl ethyl, or lower alkylcarbonylamino; and R6 is hydrogen, halo, lower alkyl, lower alkoxy, y, C(O)O—, cyano, nitro, amino, trialkylsilyl, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue, phosphosugar residue, O-quinone, substituted lower alkyl aminomethyl, or lower alkylcarbonylamino; and RQ is an optionally substituted heterocyclic, aryl, or heteroaryl group, or R1Y together form a NRaRb group, where Ra, Rb, and the nitrogen to which they are attached form a cyclic amine or imide ring.
2. The pharmaceutical composition of claim 1, further comprising at least one pH adjusting agent.
3. The pharmaceutical composition of claim 2, wherein the pH adjusting agent is tartaric acid.
4. The pharmaceutical composition of claim 2, wherein the pH adjusting agent is citric acid.
5. The pharmaceutical composition of claim 2, further comprising at least one pharmaceutically acceptable excipient or r.
6. The pharmaceutical composition of claim 1, wherein said hydrophobic camptothecin derivative is a compound selected from the group consisting of: HCl; TLC1988HCl; and mixtures thereof.
7. The pharmaceutical composition of claim 1, n the molar ratio of said PEG conjugated phospholipid to said hydrophobic camptothecin tive or said pharmaceutically acceptable salt of said hydrophobic camptothecin derivative is about 0.60:1 to about 1.00:1.
8. The pharmaceutical ition of claim 1, wherein the molar ratio of said PEG conjugated phospholipid to said hydrophobic thecin derivative or said pharmaceutically acceptable salt of said hydrophobic camptothecin derivative is about 0.70:1 to about 0.90:1.
9. The pharmaceutical composition of claim 1, wherein said pharmaceutical composition has a pH less than about 4.
10. The ceutical composition of claim 1, wherein the PEG conjugated phospholipid comprises a PEG moiety having a molecular weight from about 1,000 to about 20,000 s conjugated to a phospholipid moiety.
11. The pharmaceutical composition claim 1, wherein the PEG conjugated phospholipid is a PEG-DSPE conjugate.
12. The pharmaceutical composition of claim 11, wherein the PEG-DSPE conjugate is a methoxyl PEG-DSPE conjugate.
13. The pharmaceutical composition of claim 1, wherein the hobic camptothecin derivative or the pharmaceutically acceptable salt of said hobic camptothecin derivative and PEG ated phospholipid form micelles with a size less than about 40 nm.
14. A plurality of micelles, wherein each of said micelles comprises a pharmaceutical composition of claim 1.
15. A plurality of micelles of claim 14, r comprising at least one pH adjusting agent.
16. A plurality of micelles of claim 15, wherein the pH adjusting agent is tartaric acid.
17. A plurality of micelles of claim 15, wherein the pH adjusting agent is citric acid.
18. A plurality of micelles of claim 14, further comprising at least one pharmaceutically acceptable excipient or carrier.
19. A plurality of micelles of claim 14, wherein said hydrophobic camptothecin derivative is selected from the group consisting of: TLC388HCl; TLC1988HCl; and mixtures f.
20. A plurality of micelles of claim 14, wherein the molar ratio of said PEG conjugated phospholipid to said hydrdophobic camptothecin derivative or said ceutically acceptable salt of said hydrophobic camptothecin derivative is about 0.60:1 to about 1.00:1.
21. A plurality of micelles of claim 14, wherein the molar ratio of said PEG conjugated phospholipid to said hobic camptothecin derivative or said ceutically acceptable salt of said hobic camptothecin derivative is about 0.70:1 to about 0.90:1.
22. A plurality of micelles of claim 14, wherein said pharmaceutical composition has a pH less than about 4.
23. A plurality of micelles of claim 14, wherein the PEG conjugated phospholipid ses a PEG moiety having a molecular weight from about 1,000 to about 20,000 daltons conjugated to a phospholipid moiety
24. A plurality of micelles of claim 14, n the PEG conjugated phospholipid is PEG-DSPE conjugate.
25. A plurality of micelles of claim 24, wherein the PEG-DSPE conjugate is a methoxyl PEG-DSPE conjugate.
26. A plurality of micelles of claim 14, wherein the micelles have a size less than about 40 nm.
27. A pharmaceutical composition, comprising: at least one compound selected from the group consisting of TLC388HCl or a pharmaceutically acceptable salt of TLC388 HCl; methoxyl PEG-DSPE conjugate; and citric acid; wherein the molar ratio of said methoxyl PEG ated olipid to said TLC388HCl or a pharmaceutically acceptable salt of TLC388 HCl is greater than about 0.45: 1 to about 0.9:1.
28. Use of a pharmaceutical composition comprising: at least one hydrophobic camptothecin derivative or a pharmaceutically acceptable salt of said derivative; and at least one polyethylene glycol (PEG) conjugated phospholipid; in the manufacture of a medicament for inhibiting growth of cancer cells, n the molar ratio of said PEG conjugated phospholipid to said hydrophobic camptothecin derivative or said pharmaceutically acceptable salt of said hobic thecin derivative is greater than about 0.45:1, wherein said hobic camptothecin derivative comprises at least one compound of formula (I): or a pharmaceutically acceptable salt of said derivative; wherein: W is alkyl-C(O) , or R1Y-L-C(O), provided that when W is alkyl-C(O) , at least one of R2, R3, R4, R5, or R6 is nitro; L is a bond or linear alkylene (1-8) group, optionally substituted with lower alkyl or substituted lower alkyl, wherein one or two methylene ( CH2 ) units of the linear alkylene group is optionally replaced with O, S or NH; Y is =NO , N(H)O , =N , NR , O, S, or a bond; R is H, alkyl, or optionally substituted alkyl; R1 is optionally substituted carbocyclic, heterocyclic, or fused 2-, 3- or 4-ring heterocyclic; R2 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RQY, RQY-L-C(O)O , cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower carbonyl, tri lower alkylsilyl, lower arbonyloxy, lower alkoxycarbonyloxy, sugar residue, osugar residue residue, O-quinone, substituted lower alkyl aminomethyl, lower arbonylamino, lower alkylcarbonyloxy , optionally substituted lower alkylcarbonyloxy methyl, substituted vinyl, 1-hydroxynitroethyl, alkoxycarbonylethyl, aminocarbonyl, alkylcarbonyl, benzoylmethyl, benzylcarbonyloxymethyl, lower minomethyl or lower alkoxymethyl; R3 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RQY-L-C(O)O , cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, CH2NR7R8 (where each of R7 and R8 is independently H, alkyl of 1-6 carbons, optionally substituted , hydroxy lower alkyl, amino lower alkyl, or mono- or lamino lower alkyl, or R7 and R8 taken together with N represent a cyclic amino-), CH2R9 (where R9 is lower alkoxy, cyano, amino lower alkoxy, mono- or di-lower alkylamino lower alkoxy, lower alkylthio, amino lower alkylthio, or mono- or di-lower alkylamino lower alkylthio), NR10R11 (where each of R10 and R11 is independently hydrogen, lower alkyl, phenyl, hydroxy lower alkyl, or amino lower alkyl, or R10 and R11 taken together with --N-- represent a cyclic amino), trialkylsilyl, dialkylamino alkyl, lower arbonyloxy, lower alkoxycarbonyloxy, sugar residue, phosphosugar residue, O-quinone, substituted lower alkyl aminomethyl, or lower alkylcarbonylamino or R3 together with R4 is furan, ofuran or 1,4-oxazineone; and R4 is hydrogen, halo, lower alkyl, lower , hydroxy, RQY-L-C(O)O , cyano, nitro, amino, amino lower alkyl, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower carbonyl, carbamoyloxy, lower alkylcarbonyloxy, lower carbonyloxy, sugar residue, phosphosugar residue residue, O-quinone, substituted lower alkyl aminomethyl, or lower alkylcarbonylamino, or R4 together with R3 is furan, dihydrofuran or 1,4-oxazineone, or R4 together with R5 is methylenedioxy; R5 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RQY-L-C(O)O , cyano, nitro, amino, trialkylsilyl, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar e, phosphosugar residue residue, O-quinone, substituted lower alkyl ethyl, or lower alkylcarbonylamino, or R5 together with R4 is methylenedioxy; R6 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RQY-L-C(O)O , cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue, phosphosugar residue residue, O-quinone, substituted lower alkyl aminomethyl, or lower alkylcarbonylamino; and RQ is optionally substituted yclic, heterocyclic, or fused 2-, 3- or 4-ring heterocyclic; or wherein said hydrophobic camptothecin derivative comprises at least one compound of formula (II): (II) or a pharmaceutically acceptable salt of said derivative; wherein: X is a O, S, —NR—, or a bond; Y is ═NO—, —, ═N—, —NR—, O, S; or a covalent bond; T is independently CRR′; each of R and R′ is independently ed from en, C1-4 alkyl, and substituted C1-4 alkyl; n is an integer from 0 to 8; R1 is optionally substituted heterocyclic, aryl, or heteroaryl; provided that when X is a bond or CH2 and n is 1, 2, or 3, then Y, when bound to R1, is not oxygen; and provided that when X is a bond or CH2, n is 1, 2, or 3; and R1 is heterocyclic containing at least one nitrogen atom, then Y is not bound directly to said nitrogen atom; R2 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RQY-L-C(O)O—, cyano, nitro, amino, halogenated lower alkyl, halogenated lower , hydroxycarbonyl, formyl, lower alkoxycarbonyl, tri lower alkylsilyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue, osugar residue residue, O-quinone, substituted lower alkyl aminomethyl, lower alkylcarbonylamino, lower arbonyloxy methyl, optionally substituted lower alkylcarbonyloxy methyl, substituted vinyl, 1-hydroxynitroethyl, alkoxycarbonylethyl, aminocarbonyl, alkylcarbonyl, alkylcarbonyloxymethyl, benzoylmethyl, benzylcarbonyloxymethyl, lower alkyliminomethyl or lower methyl; R3 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RQY-L-C(O)O—, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, , lower alkoxycarbonyl, R8 (where each of R7 and R8 is independently H, alkyl of 1-6 carbons, optionally substituted phenyl, hydroxy lower alkyl, amino lower alkyl, or mono- or dialkylamino lower alkyl, or and R8 taken together with —N— represent a cyclic amino-), CH2R9 (where R9 is lower alkoxy, CN, amino lower alkoxy, mono- or di-lower alkylamino lower alkoxy, lower alkylthio, amino lower alkylthio, or mono- or di-lower alkylamino lower alkylthio), NR10R11 (where each of R10 and R11 is independently hydrogen, lower alkyl, , hydroxy lower alkyl, or amino lower alkyl, or R10 and R11 taken together with —N— represent a cyclic amino), trialkylsilyl, dialkylamino alkyl, lower alkylcarbonyloxy, lower carbonyloxy, sugar residue, phosphosugar residue residue, O-quinone, substituted lower alkyl aminomethyl, or lower arbonylamino or R3 er with R4 is furan, dihydrofuran or 1,4-oxazineone; R4 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RQY-L-C(O)O—, cyano, nitro, amino, amino lower alkyl, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, oyloxy, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue, phosphosugar residue e, O-quinone, substituted lower alkyl aminomethyl, or lower arbonylamino, or R4 together with R5 is methylenedioxy; R5 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RQY-L-C(O)O—, cyano, nitro, amino, halogenated lower alkyl, nated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue, phosphosugar residue residue, O-quinone, substituted lower alkyl aminomethyl, or lower alkylcarbonylamino; and R6 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RQY-L-C(O)O—, cyano, nitro, amino, trialkylsilyl, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar residue, phosphosugar residue, O-quinone, substituted lower alkyl aminomethyl, or lower arbonylamino; and RQ is an optionally substituted heterocyclic, aryl, or heteroaryl group, or R1Y together form a NRaRb group, where Ra, Rb, and the nitrogen to which they are ed form a cyclic amine or imide ring.
29. The use of claim 28, wherein the medicament further includes one or more anti-cancer agents.
30. The use of claim 29, wherein said anti-cancer agent is to be administered in combination with ng radiation.
31. The use of claim 29, wherein said anti-cancer agent is conventional hemotherapy including cycline antibiotic, DNA synthesis inhibitor, alkylating agent, antifolate agent or metabolic inhibitor.
32. The use of claim 29, wherein said anti-cancer agent is targeted cancer therapy.
33. A pharmaceutical composition as claimed in any one of claims 1 to 13, or 27, substantially as herein described with reference to any embodiment thereof.
34. A plurality of micelles as claimed in any one of claims 14 to 26, ntially as herein described with reference to any embodiment thereof.
35. A use as claimed in any one of claims 28 to 32, ntially as herein described with reference to any embodiment thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161555084P | 2011-11-03 | 2011-11-03 | |
US61/555,084 | 2011-11-03 | ||
PCT/US2012/063447 WO2013067449A1 (en) | 2011-11-03 | 2012-11-02 | Pharmaceutical compositions of hydrophobic camptothecin derivatives |
Publications (2)
Publication Number | Publication Date |
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NZ620933A NZ620933A (en) | 2016-05-27 |
NZ620933B2 true NZ620933B2 (en) | 2016-08-30 |
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