IL98986A - Conjugates of anthracyclines, their preparation and pharmaceutical preparations containing them - Google Patents
Conjugates of anthracyclines, their preparation and pharmaceutical preparations containing themInfo
- Publication number
- IL98986A IL98986A IL9898691A IL9898691A IL98986A IL 98986 A IL98986 A IL 98986A IL 9898691 A IL9898691 A IL 9898691A IL 9898691 A IL9898691 A IL 9898691A IL 98986 A IL98986 A IL 98986A
- Authority
- IL
- Israel
- Prior art keywords
- formula
- compound
- derivative
- integer
- condensing
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 4
- 229940045799 anthracyclines and related substance Drugs 0.000 title description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- 125000006850 spacer group Chemical group 0.000 claims abstract description 5
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 3
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract 2
- 229910052736 halogen Inorganic materials 0.000 claims abstract 2
- 150000002367 halogens Chemical class 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 74
- 238000000034 method Methods 0.000 claims description 34
- 239000000126 substance Substances 0.000 claims description 22
- 239000000427 antigen Substances 0.000 claims description 20
- 102000036639 antigens Human genes 0.000 claims description 20
- 108091007433 antigens Proteins 0.000 claims description 20
- 206010028980 Neoplasm Diseases 0.000 claims description 18
- 230000027455 binding Effects 0.000 claims description 18
- -1 2-methoxy-4-morpholinyl group Chemical group 0.000 claims description 17
- 230000008569 process Effects 0.000 claims description 15
- 102000004169 proteins and genes Human genes 0.000 claims description 13
- 108090000623 proteins and genes Proteins 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 238000009833 condensation Methods 0.000 claims description 12
- 230000005494 condensation Effects 0.000 claims description 12
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 210000004881 tumor cell Anatomy 0.000 claims description 8
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 7
- 239000012634 fragment Substances 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 6
- 230000003213 activating effect Effects 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 4
- 230000003127 anti-melanomic effect Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000003102 growth factor Substances 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- IBVAQQYNSHJXBV-UHFFFAOYSA-N adipic acid dihydrazide Chemical class NNC(=O)CCCCC(=O)NN IBVAQQYNSHJXBV-UHFFFAOYSA-N 0.000 claims description 2
- 230000001093 anti-cancer Effects 0.000 claims description 2
- 201000008275 breast carcinoma Diseases 0.000 claims description 2
- HCOMFAYPHBFMKU-UHFFFAOYSA-N butanedihydrazide Chemical compound NNC(=O)CCC(=O)NN HCOMFAYPHBFMKU-UHFFFAOYSA-N 0.000 claims description 2
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 2
- 125000002346 iodo group Chemical group I* 0.000 claims description 2
- 239000003550 marker Substances 0.000 claims description 2
- 102000005962 receptors Human genes 0.000 claims description 2
- 108020003175 receptors Proteins 0.000 claims description 2
- 206010005003 Bladder cancer Diseases 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 201000001531 bladder carcinoma Diseases 0.000 claims 1
- 239000012581 transferrin Substances 0.000 claims 1
- 208000010570 urinary bladder carcinoma Diseases 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 13
- 229940079593 drug Drugs 0.000 abstract description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 40
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 31
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- 229960004679 doxorubicin Drugs 0.000 description 19
- 239000000203 mixture Substances 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 239000000969 carrier Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 229920001577 copolymer Polymers 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical group [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 239000012867 bioactive agent Substances 0.000 description 7
- 201000011510 cancer Diseases 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 6
- 235000012239 silicon dioxide Nutrition 0.000 description 6
- 239000000872 buffer Substances 0.000 description 5
- 238000002523 gelfiltration Methods 0.000 description 5
- OKPYIWASQZGASP-UHFFFAOYSA-N n-(2-hydroxypropyl)-2-methylprop-2-enamide Chemical compound CC(O)CNC(=O)C(C)=C OKPYIWASQZGASP-UHFFFAOYSA-N 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 230000000975 bioactive effect Effects 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 231100000433 cytotoxic Toxicity 0.000 description 4
- 230000001472 cytotoxic effect Effects 0.000 description 4
- 229960002918 doxorubicin hydrochloride Drugs 0.000 description 4
- 208000032839 leukemia Diseases 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- VHSHLMUCYSAUQU-UHFFFAOYSA-N 2-hydroxypropyl methacrylate Chemical compound CC(O)COC(=O)C(C)=C VHSHLMUCYSAUQU-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 229920002643 polyglutamic acid Polymers 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 238000010526 radical polymerization reaction Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- FRACPXUHUTXLCX-BELIEFIBSA-N tert-butyl N-{1-[(1S)-1-{[(1R,2S)-1-(benzylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-2-cyclopropylethyl]-2-oxopyridin-3-yl}carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CN(C1=O)[C@@H](CC2CC2)C(=O)N[C@@H](C[C@@H]3CCNC3=O)[C@H](C(=O)NCC4=CC=CC=C4)O FRACPXUHUTXLCX-BELIEFIBSA-N 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- QMXCRMQIVATQMR-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 3-pyridin-2-ylsulfanylpropanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCSC1=CC=CC=N1 QMXCRMQIVATQMR-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 108010007013 Melanocyte-Stimulating Hormones Proteins 0.000 description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 2
- 229920005654 Sephadex Polymers 0.000 description 2
- 239000012507 Sephadex™ Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- 239000008351 acetate buffer Substances 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 125000003172 aldehyde group Chemical group 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 238000011088 calibration curve Methods 0.000 description 2
- 150000001720 carbohydrates Chemical group 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000001641 gel filtration chromatography Methods 0.000 description 2
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- 201000001441 melanoma Diseases 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
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- 238000007254 oxidation reaction Methods 0.000 description 2
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- 239000001632 sodium acetate Substances 0.000 description 2
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- FLCQLSRLQIPNLM-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 2-acetylsulfanylacetate Chemical compound CC(=O)SCC(=O)ON1C(=O)CCC1=O FLCQLSRLQIPNLM-UHFFFAOYSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- GJRWQNMXJZVBCD-UHFFFAOYSA-N (4-nitrophenyl) 2-(2-methylprop-2-enoylamino)hexanoate Chemical compound CCCCC(NC(=O)C(C)=C)C(=O)OC1=CC=C([N+]([O-])=O)C=C1 GJRWQNMXJZVBCD-UHFFFAOYSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- HXKKHQJGJAFBHI-UHFFFAOYSA-N 1-aminopropan-2-ol Chemical compound CC(O)CN HXKKHQJGJAFBHI-UHFFFAOYSA-N 0.000 description 1
- BOURDYMMTZXVRY-UHFFFAOYSA-N 2-(2-methylprop-2-enoylamino)acetic acid Chemical compound CC(=C)C(=O)NCC(O)=O BOURDYMMTZXVRY-UHFFFAOYSA-N 0.000 description 1
- WFIYPADYPQQLNN-UHFFFAOYSA-N 2-[2-(4-bromopyrazol-1-yl)ethyl]isoindole-1,3-dione Chemical compound C1=C(Br)C=NN1CCN1C(=O)C2=CC=CC=C2C1=O WFIYPADYPQQLNN-UHFFFAOYSA-N 0.000 description 1
- OXMPTOUMIXXMNT-ROUUACIJSA-N 2-[[(2s)-4-methyl-2-[[(2s)-2-[[2-(2-methylprop-2-enoylamino)acetyl]amino]-3-phenylpropanoyl]amino]pentanoyl]amino]acetic acid Chemical compound OC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)CNC(=O)C(C)=C)CC1=CC=CC=C1 OXMPTOUMIXXMNT-ROUUACIJSA-N 0.000 description 1
- REYLLNRLWCBKCM-UHFFFAOYSA-N 2-acetamido-4-sulfanylbutanoic acid Chemical compound CC(=O)NC(C(O)=O)CCS REYLLNRLWCBKCM-UHFFFAOYSA-N 0.000 description 1
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- LIMFPAAAIVQRRD-BCGVJQADSA-N N-[2-[(3S,4R)-3-fluoro-4-methoxypiperidin-1-yl]pyrimidin-4-yl]-8-[(2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl]-5-propan-2-ylisoquinolin-3-amine Chemical compound F[C@H]1CN(CC[C@H]1OC)C1=NC=CC(=N1)NC=1N=CC2=C(C=CC(=C2C=1)C(C)C)N1[C@@H]([C@H](C1)CS(=O)(=O)C)C LIMFPAAAIVQRRD-BCGVJQADSA-N 0.000 description 1
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- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
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- A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
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- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB909017024A GB9017024D0 (en) | 1990-08-03 | 1990-08-03 | New linker for bioactive agents |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL98986A0 IL98986A0 (en) | 1992-07-15 |
| IL98986A true IL98986A (en) | 1995-12-08 |
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| IL9898691A IL98986A (en) | 1990-08-03 | 1991-07-29 | Conjugates of anthracyclines, their preparation and pharmaceutical preparations containing them |
| IL11310195A IL113101A0 (en) | 1990-08-03 | 1995-03-23 | Anthracycline derivatives and their preparation |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
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| IL11310195A IL113101A0 (en) | 1990-08-03 | 1995-03-23 | Anthracycline derivatives and their preparation |
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| EP (1) | EP0495053B1 (pt) |
| JP (1) | JP3169222B2 (pt) |
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| CN (1) | CN1058598A (pt) |
| AT (1) | ATE135919T1 (pt) |
| AU (1) | AU650900B2 (pt) |
| CA (1) | CA2067184C (pt) |
| CS (1) | CS241491A3 (pt) |
| DE (1) | DE69118350T2 (pt) |
| DK (1) | DK0495053T3 (pt) |
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| FI (1) | FI100697B (pt) |
| GB (1) | GB9017024D0 (pt) |
| GR (1) | GR3019449T3 (pt) |
| HU (1) | HUT61898A (pt) |
| IE (1) | IE76467B1 (pt) |
| IL (2) | IL98986A (pt) |
| MY (1) | MY106526A (pt) |
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| RU (1) | RU2116087C1 (pt) |
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| YU (1) | YU48441B (pt) |
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| US5439936A (en) * | 1989-10-03 | 1995-08-08 | The Regents Of The University Of California | Method of treating certain tumors using illudin analogs |
| GB9017024D0 (en) * | 1990-08-03 | 1990-09-19 | Erba Carlo Spa | New linker for bioactive agents |
| DE4236237A1 (de) * | 1992-10-27 | 1994-04-28 | Behringwerke Ag | Prodrugs, ihre Herstellung und Verwendung als Arzneimittel |
| GB9309663D0 (en) * | 1993-05-11 | 1993-06-23 | Erba Carlo Spa | Biologically active compounds |
| GB9416007D0 (en) * | 1994-08-08 | 1994-09-28 | Erba Carlo Spa | Anthracyclinone derivatives |
| US5783178A (en) * | 1994-11-18 | 1998-07-21 | Supratek Pharma. Inc. | Polymer linked biological agents |
| US6030941A (en) * | 1996-05-01 | 2000-02-29 | Avi Biopharma, Inc. | Polymer composition for delivering substances in living organisms |
| EP0966303A2 (en) * | 1996-05-01 | 1999-12-29 | Antivirals Inc. | Polypeptide conjugates for transporting substances across cell membranes |
| US5932553A (en) | 1996-07-18 | 1999-08-03 | The Regents Of The University Of California | Illudin analogs useful as antitumor agents |
| US5723632A (en) * | 1996-08-08 | 1998-03-03 | Mgi Pharma, Inc. | Total synthesis of antitumor acylfulvenes |
| DE19636889A1 (de) | 1996-09-11 | 1998-03-12 | Felix Dr Kratz | Antineoplastisch wirkende Transferrin- und Albuminkonjugate zytostatischer Verbindungen aus der Gruppe der Anthrazykline, Alkylantien, Antimetabolite und Cisplatin-Analoga und diese enthaltende Arzneimittel |
| US5965118A (en) * | 1997-04-18 | 1999-10-12 | Access Pharmaceuticals, Inc. | Polymer-platinum compounds |
| AU7124598A (en) * | 1997-04-18 | 1998-11-13 | Access Pharmaceuticals, Inc. | Polymer-platinum compounds |
| ES2210761T3 (es) * | 1997-05-21 | 2004-07-01 | The Board Of Trustees Of The Leland Stanford Junior University | Composicion y procedimiento para mejorar el transporte a traves de las membranas biologicas. |
| US6531230B1 (en) * | 1998-01-13 | 2003-03-11 | 3M Innovative Properties Company | Color shifting film |
| US7141603B2 (en) * | 1999-02-19 | 2006-11-28 | The Regents Of The University California | Antitumor agents |
| US6025328A (en) | 1998-02-20 | 2000-02-15 | The Regents Of The University Of California | Antitumor agents |
| ATE268905T1 (de) * | 1998-07-30 | 2004-06-15 | Oakville Trading Hong Kong Ltd | Verfahren zur herstellung von wasserlöslichen vernetzten conjugate |
| US6706892B1 (en) * | 1999-09-07 | 2004-03-16 | Conjuchem, Inc. | Pulmonary delivery for bioconjugation |
| WO2001024763A2 (en) | 1999-10-01 | 2001-04-12 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
| EP1333811A4 (en) * | 2000-10-16 | 2004-03-03 | Neopharm Inc | LIPOSOMAL PREPARATION BASED ON MITOXANTRONE |
| EP1383492A4 (en) * | 2001-03-23 | 2008-12-24 | Napro Biotherapeutics Inc | MOLECULAR CONJUGATES FOR USE IN CANCER THERAPY |
| EP1401875A4 (en) * | 2001-05-04 | 2005-01-26 | Univ Utah Res Found | HYALURONIC ACID-CONTAINING BIOKON JUGATES: TARGETED DELIVERY OF ANTIBODIES TO CANCER CELLS |
| CN101671335A (zh) | 2001-05-31 | 2010-03-17 | 梅达莱克斯公司 | 细胞毒素、其有用的前体药物、连接基团和稳定剂 |
| CA2483696A1 (en) * | 2002-05-06 | 2003-11-20 | University Of Utah Research Foundation | Preblocking with non-ha gags increases effectiveness of ha conjugated anticancer agents |
| US7691962B2 (en) * | 2004-05-19 | 2010-04-06 | Medarex, Inc. | Chemical linkers and conjugates thereof |
| NZ550934A (en) * | 2004-05-19 | 2010-05-28 | Medarex Inc | Chemical linkers and conjugates thereof |
| US20060105941A1 (en) * | 2004-11-12 | 2006-05-18 | Allergan, Inc. | Mixed antibiotic codrugs |
| US7714016B2 (en) * | 2005-04-08 | 2010-05-11 | Medarex, Inc. | Cytotoxic compounds and conjugates with cleavable substrates |
| JP4989648B2 (ja) * | 2005-08-03 | 2012-08-01 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 抗癌剤として有用なイルジン類似体 |
| US20080279868A1 (en) * | 2005-09-26 | 2008-11-13 | Medarex, Inc. | Antibody-Drug Conjugates and Methods of Use |
| CN101365679B (zh) | 2005-10-26 | 2012-11-14 | 梅达莱克斯公司 | 制备cc-1065类似物的方法和化合物 |
| WO2007059404A2 (en) | 2005-11-10 | 2007-05-24 | Medarex, Inc. | Duocarmycin derivatives as novel cytotoxic compounds and conjugates |
| TWI412367B (zh) | 2006-12-28 | 2013-10-21 | Medarex Llc | 化學鏈接劑與可裂解基質以及其之綴合物 |
| CL2008000510A1 (es) * | 2007-02-21 | 2008-08-22 | Medarex Inc | Compuestos conjugados farmaco-ligandos, que se unen a citotoxinas potentes; composicion farmaceutica; y uso para retardar o detener el crecimiento de un tumor en un mamifero. |
| WO2009099741A1 (en) | 2008-02-01 | 2009-08-13 | Genentech, Inc. | Nemorubicin metabolite and analog reagents, antibody-drug conjugates and methods |
| EP2303332B1 (en) | 2008-07-15 | 2014-12-31 | Genentech, Inc. | Anthracycline conjugates, process for their preparation and their use as antitumor compounds |
| ES2533710T3 (es) | 2010-12-02 | 2015-04-14 | Nerviano Medical Sciences S.R.L. | Proceso para la preparación de derivados de morfolinil antraciclina |
| WO2014067960A2 (en) | 2012-10-30 | 2014-05-08 | Nerviano Medical Sciences S.R.L. | Functionalized 9-bromo-camptothecin derivatives |
| AU2012395148B2 (en) | 2012-11-24 | 2016-10-27 | Hangzhou Dac Biotech Co., Ltd. | Hydrophilic linkers and their uses for conjugation of drugs to cell binding molecules |
| EP2968440B1 (en) | 2013-03-15 | 2019-06-05 | Zymeworks Inc. | Cytotoxic and anti-mitotic compounds, and methods of using the same |
| ES2916722T3 (es) | 2013-12-27 | 2022-07-05 | Zymeworks Inc | Sistemas de enlace que contienen sulfonamida para conjugados de fármacos |
| EP3122757B1 (en) | 2014-02-28 | 2023-09-06 | Hangzhou Dac Biotech Co., Ltd | Charged linkers and their uses for conjugation |
| CA2960899C (en) | 2014-09-17 | 2021-08-17 | Zymeworks Inc. | Cytotoxic and anti-mitotic compounds, and methods of using the same |
| CA2991973C (en) | 2015-07-12 | 2021-12-07 | Suzhou M-Conj Biotech Co., Ltd. | Bridge linkers for conjugation of a cell-binding molecule |
| US9839687B2 (en) | 2015-07-15 | 2017-12-12 | Suzhou M-Conj Biotech Co., Ltd. | Acetylenedicarboxyl linkers and their uses in specific conjugation of a cell-binding molecule |
| CR20180484A (es) | 2016-04-15 | 2019-03-05 | Macrogenics Inc | Moléculas de unón b7-h3 novedosas, conjugados anticuerpos-fármaco de los mismos y métodos de uso de los mismos |
| KR20220147720A (ko) | 2016-11-14 | 2022-11-03 | 항저우 디에이씨 바이오테크 씨오, 엘티디 | 결합 링커, 그러한 결합 링커를 함유하는 세포 결합 분자-약물 결합체, 링커를 갖는 그러한 결합체의 제조 및 사용 |
| US10386338B2 (en) | 2017-10-30 | 2019-08-20 | Cynthia Rena Wright | DNA/RNA PEMS microcantilever probe for detection of viral infection and detection of genetic variants |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2098219A (en) * | 1981-05-08 | 1982-11-17 | Erba Farmitalia | Daunorubicin-protein conjugates |
| JPS63241541A (ja) * | 1987-03-30 | 1988-10-06 | Konica Corp | 感光性組成物および感光性平版印刷版 |
| FI102355B1 (fi) * | 1988-02-11 | 1998-11-30 | Bristol Myers Squibb Co | Menetelmä yhdistävän välikappaleen omaavien antrasykliini-immunokonjugaattien valmistamiseksi |
| US5066490A (en) * | 1988-06-01 | 1991-11-19 | The United States Of America As Represented By The Secretary Of The Department Of Health & Human Services | Protein crosslinking reagents cleavable within acidified intracellular vesicles |
| GB9017024D0 (en) * | 1990-08-03 | 1990-09-19 | Erba Carlo Spa | New linker for bioactive agents |
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1990
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