JPWO2019157146A5 - - Google Patents
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- JPWO2019157146A5 JPWO2019157146A5 JP2020542626A JP2020542626A JPWO2019157146A5 JP WO2019157146 A5 JPWO2019157146 A5 JP WO2019157146A5 JP 2020542626 A JP2020542626 A JP 2020542626A JP 2020542626 A JP2020542626 A JP 2020542626A JP WO2019157146 A5 JPWO2019157146 A5 JP WO2019157146A5
- Authority
- JP
- Japan
- Prior art keywords
- liposome
- acid
- alpha
- glutamil
- composition according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 239000002502 liposome Substances 0.000 claims 34
- 239000000203 mixture Substances 0.000 claims 26
- 239000004052 folic acid antagonist Substances 0.000 claims 11
- 229920001223 polyethylene glycol Polymers 0.000 claims 11
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims 10
- 239000011724 folic acid Substances 0.000 claims 9
- 235000019152 folic acid Nutrition 0.000 claims 9
- 230000008685 targeting Effects 0.000 claims 9
- -1 (N- (3,4-dihydro-2-methyl-4-oxoquinazoline-6-yl-methyl) Amino) 2-thienyl Chemical group 0.000 claims 7
- 239000002202 Polyethylene glycol Substances 0.000 claims 7
- 239000002253 acid Substances 0.000 claims 7
- 230000003432 anti-folate effect Effects 0.000 claims 7
- 229940127074 antifolate Drugs 0.000 claims 7
- 238000000034 method Methods 0.000 claims 7
- 108010040003 polyglutamine Proteins 0.000 claims 7
- 229920000155 polyglutamine Polymers 0.000 claims 7
- 230000000340 anti-metabolite Effects 0.000 claims 6
- 229940100197 antimetabolite Drugs 0.000 claims 6
- 239000002256 antimetabolite Substances 0.000 claims 6
- 239000005557 antagonist Substances 0.000 claims 5
- 102000006815 folate receptor Human genes 0.000 claims 5
- 108020005243 folate receptor Proteins 0.000 claims 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 4
- 102000010449 Folate receptor beta Human genes 0.000 claims 4
- 108050001930 Folate receptor beta Proteins 0.000 claims 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims 4
- 239000000839 emulsion Substances 0.000 claims 4
- 229940014144 folate Drugs 0.000 claims 4
- 229920002498 Beta-glucan Polymers 0.000 claims 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims 3
- 239000000427 antigen Substances 0.000 claims 3
- 102000036639 antigens Human genes 0.000 claims 3
- 108091007433 antigens Proteins 0.000 claims 3
- 239000008121 dextrose Substances 0.000 claims 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 3
- 238000001125 extrusion Methods 0.000 claims 3
- 230000004060 metabolic process Effects 0.000 claims 3
- 229960003104 ornithine Drugs 0.000 claims 3
- 239000008194 pharmaceutical composition Substances 0.000 claims 3
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims 2
- MXBUWHDMZGKTHK-INIZCTEOSA-N (2s)-2-[[4-[[(2-amino-4-oxo-1h-quinazolin-6-yl)amino]methyl]benzoyl]amino]pentanedioic acid Chemical compound C=1C=C2NC(N)=NC(=O)C2=CC=1NCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 MXBUWHDMZGKTHK-INIZCTEOSA-N 0.000 claims 2
- MSTNYGQPCMXVAQ-RYUDHWBXSA-L (6S)-5,6,7,8-tetrahydrofolate(2-) Chemical compound C([C@H]1CNC=2N=C(NC(=O)C=2N1)N)NC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 MSTNYGQPCMXVAQ-RYUDHWBXSA-L 0.000 claims 2
- LVNGJLRDBYCPGB-LDLOPFEMSA-N (R)-1,2-distearoylphosphatidylethanolamine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-LDLOPFEMSA-N 0.000 claims 2
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 claims 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims 2
- 102000010451 Folate receptor alpha Human genes 0.000 claims 2
- 108050001931 Folate receptor alpha Proteins 0.000 claims 2
- 101001105486 Homo sapiens Proteasome subunit alpha type-7 Proteins 0.000 claims 2
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 claims 2
- 229930195725 Mannitol Natural products 0.000 claims 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims 2
- 229960005556 ONX-0801 Drugs 0.000 claims 2
- 108010020346 Polyglutamic Acid Proteins 0.000 claims 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims 2
- 102100021201 Proteasome subunit alpha type-7 Human genes 0.000 claims 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims 2
- 102100023119 Sperm-egg fusion protein Juno Human genes 0.000 claims 2
- 101710093389 Sperm-egg fusion protein Juno Proteins 0.000 claims 2
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 claims 2
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims 2
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims 2
- 125000000129 anionic group Chemical group 0.000 claims 2
- 210000004899 c-terminal region Anatomy 0.000 claims 2
- 235000012000 cholesterol Nutrition 0.000 claims 2
- 201000010099 disease Diseases 0.000 claims 2
- 239000003937 drug carrier Substances 0.000 claims 2
- BPSMYQFMCXXNPC-MFCPCZTFSA-N eritoran Chemical class O[C@H]1[C@H](OCCCCCCCCCC)[C@@H](NC(=O)CC(=O)CCCCCCCCCCC)[C@@H](OP(O)(O)=O)O[C@@H]1CO[C@H]1[C@H](NC(=O)CCCCCCCCC\C=C/CCCCCC)[C@@H](OCC[C@@H](CCCCCCC)OC)[C@H](OP(O)(O)=O)[C@@H](COC)O1 BPSMYQFMCXXNPC-MFCPCZTFSA-N 0.000 claims 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 2
- 238000001704 evaporation Methods 0.000 claims 2
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 claims 2
- 229960002989 glutamic acid Drugs 0.000 claims 2
- 230000036571 hydration Effects 0.000 claims 2
- 238000006703 hydration reaction Methods 0.000 claims 2
- 229960001438 immunostimulant agent Drugs 0.000 claims 2
- 239000003022 immunostimulating agent Substances 0.000 claims 2
- 230000003308 immunostimulating effect Effects 0.000 claims 2
- 238000002347 injection Methods 0.000 claims 2
- 239000007924 injection Substances 0.000 claims 2
- 239000000594 mannitol Substances 0.000 claims 2
- 235000010355 mannitol Nutrition 0.000 claims 2
- 239000003550 marker Substances 0.000 claims 2
- 239000012528 membrane Substances 0.000 claims 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 230000007935 neutral effect Effects 0.000 claims 2
- WBXPDJSOTKVWSJ-ZDUSSCGKSA-N pemetrexed Chemical compound C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 WBXPDJSOTKVWSJ-ZDUSSCGKSA-N 0.000 claims 2
- 229920000729 poly(L-lysine) polymer Polymers 0.000 claims 2
- 229920002401 polyacrylamide Polymers 0.000 claims 2
- 238000007639 printing Methods 0.000 claims 2
- 239000000243 solution Substances 0.000 claims 2
- 239000010409 thin film Substances 0.000 claims 2
- AYDSBKMPDDZABS-AWEZNQCLSA-N (2s)-2-[[4-[[(2-amino-4-oxo-1h-pyrido[2,3-d]pyrimidin-6-yl)amino]methyl]benzoyl]amino]pentanedioic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=CC=1NCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 AYDSBKMPDDZABS-AWEZNQCLSA-N 0.000 claims 1
- OLNLRVHYZZQGBF-OCCSQVGLSA-N (2s)-2-[[4-[[[(6r)-2-amino-4-oxo-5,6,7,8-tetrahydro-1h-pyrido[2,3-d]pyrimidin-6-yl]amino]methyl]benzoyl]amino]pentanedioic acid Chemical compound N([C@@H]1CC=2C(=O)N=C(NC=2NC1)N)CC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OLNLRVHYZZQGBF-OCCSQVGLSA-N 0.000 claims 1
- FYGDTMLNYKFZSV-URKRLVJHSA-N (2s,3r,4s,5s,6r)-2-[(2r,4r,5r,6s)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(2r,4r,5r,6s)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1[C@@H](CO)O[C@@H](OC2[C@H](O[C@H](O)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O FYGDTMLNYKFZSV-URKRLVJHSA-N 0.000 claims 1
- CDZVJFRXJAUXPP-AREMUKBSSA-N 2-O-glutaroyl-1-O-palmitoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCC(O)=O)COP([O-])(=O)OCC[N+](C)(C)C CDZVJFRXJAUXPP-AREMUKBSSA-N 0.000 claims 1
- FSIRXIHZBIXHKT-UHFFFAOYSA-N 2-[[4-[1-(2,4-diaminopteridin-6-yl)butan-2-yl]benzoyl]amino]pentanedioic acid Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CC(CC)C1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 FSIRXIHZBIXHKT-UHFFFAOYSA-N 0.000 claims 1
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 claims 1
- 229940105150 5-methyltetrahydrofolic acid Drugs 0.000 claims 1
- BCCZFOXKKDTUTF-UHFFFAOYSA-N 5h-cyclopenta[g]quinazoline Chemical compound C1=NC=C2CC3=CC=CC3=CC2=N1 BCCZFOXKKDTUTF-UHFFFAOYSA-N 0.000 claims 1
- 208000023275 Autoimmune disease Diseases 0.000 claims 1
- NVHRBQOZEMFKLD-CUYJMHBOSA-N BGC 945 Chemical compound C#CCN([C@@H]1C=2C=C3C(=O)N=C(NC3=CC=2CC1)CO)C1=CC=C(C(=O)N[C@@H](CCC(=O)N[C@H](CCC(O)=O)C(O)=O)C(O)=O)C=C1 NVHRBQOZEMFKLD-CUYJMHBOSA-N 0.000 claims 1
- 208000035473 Communicable disease Diseases 0.000 claims 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims 1
- 108010016626 Dipeptides Proteins 0.000 claims 1
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 claims 1
- 150000008575 L-amino acids Chemical class 0.000 claims 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 claims 1
- 239000004372 Polyvinyl alcohol Substances 0.000 claims 1
- 108010003723 Single-Domain Antibodies Proteins 0.000 claims 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims 1
- 229930006000 Sucrose Natural products 0.000 claims 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims 1
- 238000013019 agitation Methods 0.000 claims 1
- 229960003896 aminopterin Drugs 0.000 claims 1
- 238000004458 analytical method Methods 0.000 claims 1
- 229920006187 aquazol Polymers 0.000 claims 1
- 239000012861 aquazol Substances 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims 1
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 claims 1
- 239000001639 calcium acetate Substances 0.000 claims 1
- 229960005147 calcium acetate Drugs 0.000 claims 1
- 235000011092 calcium acetate Nutrition 0.000 claims 1
- 201000011510 cancer Diseases 0.000 claims 1
- 190000008236 carboplatin Chemical compound 0.000 claims 1
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- 125000002091 cationic group Chemical group 0.000 claims 1
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- 230000008020 evaporation Effects 0.000 claims 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical group O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 claims 1
- 229960000304 folic acid Drugs 0.000 claims 1
- 150000002224 folic acids Chemical class 0.000 claims 1
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 claims 1
- 239000011672 folinic acid Substances 0.000 claims 1
- 239000012634 fragment Substances 0.000 claims 1
- 229920000370 gamma-poly(glutamate) polymer Polymers 0.000 claims 1
- 235000011187 glycerol Nutrition 0.000 claims 1
- 210000000987 immune system Anatomy 0.000 claims 1
- 208000015181 infectious disease Diseases 0.000 claims 1
- 230000004968 inflammatory condition Effects 0.000 claims 1
- 239000007951 isotonicity adjuster Substances 0.000 claims 1
- 229960001691 leucovorin Drugs 0.000 claims 1
- ZNOVTXRBGFNYRX-ABLWVSNPSA-N levomefolic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 ZNOVTXRBGFNYRX-ABLWVSNPSA-N 0.000 claims 1
- 239000003446 ligand Substances 0.000 claims 1
- 150000002632 lipids Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- FQPSGWSUVKBHSU-UHFFFAOYSA-N methacrylamide Chemical compound CC(=C)C(N)=O FQPSGWSUVKBHSU-UHFFFAOYSA-N 0.000 claims 1
- 229960000485 methotrexate Drugs 0.000 claims 1
- 108010071584 oxidized low density lipoprotein Proteins 0.000 claims 1
- 229960002621 pembrolizumab Drugs 0.000 claims 1
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- 125000001095 phosphatidyl group Chemical group 0.000 claims 1
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- 229920000773 poly(2-methyl-2-oxazoline) polymer Polymers 0.000 claims 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 claims 1
- 229920002643 polyglutamic acid Polymers 0.000 claims 1
- 229920000223 polyglycerol Polymers 0.000 claims 1
- 229920000642 polymer Polymers 0.000 claims 1
- 229920001451 polypropylene glycol Polymers 0.000 claims 1
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- 239000001103 potassium chloride Substances 0.000 claims 1
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- 229960000214 pralatrexate Drugs 0.000 claims 1
- OGSBUKJUDHAQEA-WMCAAGNKSA-N pralatrexate Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CC(CC#C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OGSBUKJUDHAQEA-WMCAAGNKSA-N 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims 1
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- 239000001632 sodium acetate Substances 0.000 claims 1
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- 239000011780 sodium chloride Substances 0.000 claims 1
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- 239000003381 stabilizer Substances 0.000 claims 1
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Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2024075984A JP7679114B2 (ja) | 2018-02-07 | 2024-05-08 | アルファポリグルタミン酸化葉酸代謝拮抗薬およびその使用 |
| JP2025072834A JP2025107218A (ja) | 2018-02-07 | 2025-04-25 | アルファポリグルタミン酸化葉酸代謝拮抗薬およびその使用 |
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| US201862627741P | 2018-02-07 | 2018-02-07 | |
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| US201862630744P | 2018-02-14 | 2018-02-14 | |
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| US201862630634P | 2018-02-14 | 2018-02-14 | |
| US201862630728P | 2018-02-14 | 2018-02-14 | |
| US201862630820P | 2018-02-14 | 2018-02-14 | |
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| US201862662374P | 2018-04-25 | 2018-04-25 | |
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| US201862702561P | 2018-07-24 | 2018-07-24 | |
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| US201862764955P | 2018-08-17 | 2018-08-17 | |
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| US12239734B2 (en) | 2018-02-07 | 2025-03-04 | L.E.A.F. Holdings Group Llc | Gamma polyglutamated raltitrexed and uses thereof |
| CA3090500A1 (en) * | 2018-02-07 | 2019-08-15 | L.E.A.F. Holdings Group Llc | Alpha polyglutamated antifolates and uses thereof |
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| CN111954531A (zh) | 2018-02-07 | 2020-11-17 | L.E.A.F.控股集团公司 | α聚谷氨酸化培美曲塞及其用途 |
| EP3749321A4 (en) | 2018-02-07 | 2022-03-09 | L.E.A.F Holdings Group LLC | Gamma polyglutamated antifolates and uses thereof |
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| EP3752156A4 (en) | 2018-02-14 | 2021-10-27 | L.E.A.F Holdings Group LLC | GAMMA-POLYGLUTAMIZED PRALATREXATE AND USES THEREOF |
| EP3752157A4 (en) | 2018-02-14 | 2022-07-06 | L.E.A.F Holdings Group LLC | GAMMA-POLYGLUTAMATED LOMETREXOLE AND USES THEREOF |
| WO2019160732A1 (en) | 2018-02-14 | 2019-08-22 | L.E.A.F. Holdings Group Llc | Gamma polyglutamated aminopterin and uses thereof |
| CN111936145A (zh) | 2018-02-14 | 2020-11-13 | L.E.A.F.控股集团公司 | γ聚谷氨酸化氨甲蝶呤及其用途 |
| US12048766B2 (en) | 2018-02-14 | 2024-07-30 | L.E.A.F. Holdings Group Llc | Gamma polyglutamated tetrahydrofolates and uses thereof |
| CA3149914A1 (en) | 2019-08-06 | 2021-02-11 | L.E.A.F. Holdings Group Llc | Processes of preparing polyglutamated antifolates and uses of their compositions |
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