AU2013342015B2 - Bendamustine derivatives and methods of using same - Google Patents
Bendamustine derivatives and methods of using same Download PDFInfo
- Publication number
- AU2013342015B2 AU2013342015B2 AU2013342015A AU2013342015A AU2013342015B2 AU 2013342015 B2 AU2013342015 B2 AU 2013342015B2 AU 2013342015 A AU2013342015 A AU 2013342015A AU 2013342015 A AU2013342015 A AU 2013342015A AU 2013342015 B2 AU2013342015 B2 AU 2013342015B2
- Authority
- AU
- Australia
- Prior art keywords
- cancer
- bendamustine
- alkyl
- ester
- mmol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- 238000000034 method Methods 0.000 title claims description 54
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical class ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 title abstract description 120
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 82
- -1 bendamustine amides Chemical class 0.000 claims abstract description 67
- 201000011510 cancer Diseases 0.000 claims abstract description 25
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 23
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 23
- 239000002105 nanoparticle Substances 0.000 claims description 69
- 239000000203 mixture Substances 0.000 claims description 57
- 150000001875 compounds Chemical class 0.000 claims description 50
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 20
- 206010006187 Breast cancer Diseases 0.000 claims description 15
- 208000026310 Breast neoplasm Diseases 0.000 claims description 15
- 208000017604 Hodgkin disease Diseases 0.000 claims description 15
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 15
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 12
- 208000020816 lung neoplasm Diseases 0.000 claims description 12
- 208000034578 Multiple myelomas Diseases 0.000 claims description 11
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 10
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 9
- 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 description 9
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 9
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 9
- 229930195725 Mannitol Natural products 0.000 claims description 9
- 206010033128 Ovarian cancer Diseases 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 9
- 239000003085 diluting agent Substances 0.000 claims description 9
- 201000005202 lung cancer Diseases 0.000 claims description 9
- 239000000594 mannitol Substances 0.000 claims description 9
- 235000010355 mannitol Nutrition 0.000 claims description 9
- 206010009944 Colon cancer Diseases 0.000 claims description 8
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 8
- 206010039491 Sarcoma Diseases 0.000 claims description 8
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 8
- 239000002246 antineoplastic agent Substances 0.000 claims description 8
- 208000029742 colonic neoplasm Diseases 0.000 claims description 8
- 229940127089 cytotoxic agent Drugs 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 206010057644 Testis cancer Diseases 0.000 claims description 7
- 208000005017 glioblastoma Diseases 0.000 claims description 7
- 201000001441 melanoma Diseases 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 201000003120 testicular cancer Diseases 0.000 claims description 7
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 6
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 6
- 206010005003 Bladder cancer Diseases 0.000 claims description 6
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 6
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 6
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 6
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 6
- 229940100198 alkylating agent Drugs 0.000 claims description 6
- 239000002168 alkylating agent Substances 0.000 claims description 6
- 201000010881 cervical cancer Diseases 0.000 claims description 6
- 201000010536 head and neck cancer Diseases 0.000 claims description 6
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 6
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 6
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical group O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 claims description 5
- 206010060862 Prostate cancer Diseases 0.000 claims description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 5
- 102000008100 Human Serum Albumin Human genes 0.000 claims description 4
- 108091006905 Human Serum Albumin Proteins 0.000 claims description 4
- 229930006000 Sucrose Natural products 0.000 claims description 4
- 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 description 4
- 239000005720 sucrose Substances 0.000 claims description 4
- ZNZYKNKBJPZETN-WELNAUFTSA-N Dialdehyde 11678 Chemical compound N1C2=CC=CC=C2C2=C1[C@H](C[C@H](/C(=C/O)C(=O)OC)[C@@H](C=C)C=O)NCC2 ZNZYKNKBJPZETN-WELNAUFTSA-N 0.000 claims description 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 description 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 description 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 description 2
- 125000006539 C12 alkyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 2
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 2
- 229960002707 bendamustine Drugs 0.000 abstract description 164
- 238000011282 treatment Methods 0.000 abstract description 18
- 150000003839 salts Chemical group 0.000 abstract description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 128
- 239000007787 solid Substances 0.000 description 97
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 68
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 51
- 238000006243 chemical reaction Methods 0.000 description 49
- 150000002148 esters Chemical class 0.000 description 49
- 239000000243 solution Substances 0.000 description 49
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 45
- 239000000047 product Substances 0.000 description 42
- 238000004128 high performance liquid chromatography Methods 0.000 description 35
- 229910052757 nitrogen Inorganic materials 0.000 description 34
- 241000700159 Rattus Species 0.000 description 33
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 32
- 238000009472 formulation Methods 0.000 description 30
- 239000003921 oil Substances 0.000 description 30
- 235000019198 oils Nutrition 0.000 description 30
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 238000002360 preparation method Methods 0.000 description 27
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 26
- ZHSKUOZOLHMKEA-UHFFFAOYSA-N 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoic acid;hydron;chloride Chemical compound Cl.ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 ZHSKUOZOLHMKEA-UHFFFAOYSA-N 0.000 description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- 239000002245 particle Substances 0.000 description 24
- 238000003756 stirring Methods 0.000 description 23
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 22
- 229960001215 bendamustine hydrochloride Drugs 0.000 description 22
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 21
- 241000699670 Mus sp. Species 0.000 description 21
- 239000012071 phase Substances 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 19
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 18
- 238000001035 drying Methods 0.000 description 18
- 230000036470 plasma concentration Effects 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 17
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
- 229910052938 sodium sulfate Inorganic materials 0.000 description 16
- 235000011152 sodium sulphate Nutrition 0.000 description 16
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 15
- 210000002381 plasma Anatomy 0.000 description 15
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- 235000017557 sodium bicarbonate Nutrition 0.000 description 14
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 14
- 239000000725 suspension Substances 0.000 description 14
- 239000000839 emulsion Substances 0.000 description 13
- 238000010949 in-process test method Methods 0.000 description 13
- 239000000523 sample Substances 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 239000012267 brine Substances 0.000 description 11
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 10
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000011521 glass Substances 0.000 description 9
- 239000012535 impurity Substances 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 210000000056 organ Anatomy 0.000 description 9
- 239000002002 slurry Substances 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- 101150041968 CDC13 gene Proteins 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 150000001408 amides Chemical class 0.000 description 7
- 238000000604 cryogenic transmission electron microscopy Methods 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 239000002274 desiccant Substances 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000003828 vacuum filtration Methods 0.000 description 6
- 208000003174 Brain Neoplasms Diseases 0.000 description 5
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 5
- 238000013019 agitation Methods 0.000 description 5
- 239000007900 aqueous suspension Substances 0.000 description 5
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 5
- 238000000576 coating method Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 210000004072 lung Anatomy 0.000 description 5
- 108010082117 matrigel Proteins 0.000 description 5
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 238000005070 sampling Methods 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 239000011550 stock solution Substances 0.000 description 5
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 5
- 210000003462 vein Anatomy 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 239000007821 HATU Substances 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 4
- 206010041067 Small cell lung cancer Diseases 0.000 description 4
- 206010042971 T-cell lymphoma Diseases 0.000 description 4
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 210000000481 breast Anatomy 0.000 description 4
- 239000011248 coating agent Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 4
- 229910000397 disodium phosphate Inorganic materials 0.000 description 4
- 235000019800 disodium phosphate Nutrition 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 4
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 239000012669 liquid formulation Substances 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 4
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 4
- 238000011580 nude mouse model Methods 0.000 description 4
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 4
- 201000002528 pancreatic cancer Diseases 0.000 description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 229940099039 velcade Drugs 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- 208000003950 B-cell lymphoma Diseases 0.000 description 3
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 3
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- 206010029260 Neuroblastoma Diseases 0.000 description 3
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 238000011717 athymic nude mouse Methods 0.000 description 3
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 238000004364 calculation method Methods 0.000 description 3
- 235000011089 carbon dioxide Nutrition 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001493 electron microscopy Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 3
- 239000012798 spherical particle Substances 0.000 description 3
- 210000000952 spleen Anatomy 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 2
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- IPVYMXZYXFFDGW-UHFFFAOYSA-N 1-methylpiperidin-4-ol;hydrochloride Chemical compound Cl.CN1CCC(O)CC1 IPVYMXZYXFFDGW-UHFFFAOYSA-N 0.000 description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 2
- 239000012981 Hank's balanced salt solution Substances 0.000 description 2
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 238000011579 SCID mouse model Methods 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 2
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 2
- 150000008052 alkyl sulfonates Chemical class 0.000 description 2
- 229960000473 altretamine Drugs 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 2
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 2
- 229940106681 chloroacetic acid Drugs 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- 239000003431 cross linking reagent Substances 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 2
- GCFAUZGWPDYAJN-UHFFFAOYSA-N cyclohexyl 3-phenylprop-2-enoate Chemical compound C=1C=CC=CC=1C=CC(=O)OC1CCCCC1 GCFAUZGWPDYAJN-UHFFFAOYSA-N 0.000 description 2
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 2
- XSWSEQPWKOWORN-UHFFFAOYSA-N dodecan-2-ol Chemical compound CCCCCCCCCCC(C)O XSWSEQPWKOWORN-UHFFFAOYSA-N 0.000 description 2
- RJNURICEBYUKHL-UHFFFAOYSA-N dodecyl 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoate Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(=O)OCCCCCCCCCCCC)=NC2=C1 RJNURICEBYUKHL-UHFFFAOYSA-N 0.000 description 2
- 238000002296 dynamic light scattering Methods 0.000 description 2
- 238000005538 encapsulation Methods 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 201000005787 hematologic cancer Diseases 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 2
- 229960001924 melphalan Drugs 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 201000005962 mycosis fungoides Diseases 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- REIUXOLGHVXAEO-UHFFFAOYSA-N pentadecan-1-ol Chemical compound CCCCCCCCCCCCCCCO REIUXOLGHVXAEO-UHFFFAOYSA-N 0.000 description 2
- 238000005191 phase separation Methods 0.000 description 2
- 229920000747 poly(lactic acid) Polymers 0.000 description 2
- 239000004626 polylactic acid Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- 208000000587 small cell lung carcinoma Diseases 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000005846 sugar alcohols Polymers 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229940066958 treanda Drugs 0.000 description 2
- 229940086542 triethylamine Drugs 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- OLZMGZSRWXDGRO-UHFFFAOYSA-N 4-(5-amino-1-methylbenzimidazol-2-yl)butanoic acid Chemical compound NC1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 OLZMGZSRWXDGRO-UHFFFAOYSA-N 0.000 description 1
- BEUPWNATQIQNCO-UHFFFAOYSA-N 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]-n-octadecylbutanamide Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(=O)NCCCCCCCCCCCCCCCCCC)=NC2=C1 BEUPWNATQIQNCO-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical class C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 206010006143 Brain stem glioma Diseases 0.000 description 1
- 208000011691 Burkitt lymphomas Diseases 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- NYNKCGWJPNZJMI-UHFFFAOYSA-N Clebopride malate Chemical compound [O-]C(=O)C(O)CC(O)=O.COC1=CC(N)=C(Cl)C=C1C(=O)NC1CC[NH+](CC=2C=CC=CC=2)CC1 NYNKCGWJPNZJMI-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 102100021906 Cyclin-O Human genes 0.000 description 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 description 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 description 1
- MHZGKXUYDGKKIU-UHFFFAOYSA-N Decylamine Chemical compound CCCCCCCCCCN MHZGKXUYDGKKIU-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 208000032320 Germ cell tumor of testis Diseases 0.000 description 1
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 1
- 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 description 1
- 101000897441 Homo sapiens Cyclin-O Proteins 0.000 description 1
- 206010023774 Large cell lung cancer Diseases 0.000 description 1
- 208000037196 Medullary thyroid carcinoma Diseases 0.000 description 1
- 206010027480 Metastatic malignant melanoma Diseases 0.000 description 1
- UUIQMZJEGPQKFD-UHFFFAOYSA-N Methyl butyrate Chemical compound CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- REYJJPSVUYRZGE-UHFFFAOYSA-N Octadecylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 208000007452 Plasmacytoma Diseases 0.000 description 1
- 229920005372 Plexiglas® Polymers 0.000 description 1
- 239000012979 RPMI medium Substances 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 208000031673 T-Cell Cutaneous Lymphoma Diseases 0.000 description 1
- PLZVEHJLHYMBBY-UHFFFAOYSA-N Tetradecylamine Chemical compound CCCCCCCCCCCCCCN PLZVEHJLHYMBBY-UHFFFAOYSA-N 0.000 description 1
- 208000005485 Thrombocytosis Diseases 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 1
- JUGFAYYRTWNSEE-MCDZGGTQSA-N [(2r,3s,4r,5r)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphono hydrogen phosphate;pyridine-3-carboxamide Chemical compound NC(=O)C1=CC=CN=C1.C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O JUGFAYYRTWNSEE-MCDZGGTQSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 230000004931 aggregating effect Effects 0.000 description 1
- 229940098174 alkeran Drugs 0.000 description 1
- PAZJSJFMUHDSTF-UHFFFAOYSA-N alprenolol Chemical compound CC(C)NCC(O)COC1=CC=CC=C1CC=C PAZJSJFMUHDSTF-UHFFFAOYSA-N 0.000 description 1
- 229960002213 alprenolol Drugs 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 206010002224 anaplastic astrocytoma Diseases 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 239000002585 base Substances 0.000 description 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 description 1
- 229940108502 bicnu Drugs 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- JSMRMEYFZHIPJV-UHFFFAOYSA-N bicyclo[2.1.1]hexane Chemical compound C1C2CC1CC2 JSMRMEYFZHIPJV-UHFFFAOYSA-N 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- 201000007405 brain stem astrocytic neoplasm Diseases 0.000 description 1
- 201000000387 brain stem ependymoma Diseases 0.000 description 1
- 201000003339 brain stem medulloblastoma Diseases 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 229940112133 busulfex Drugs 0.000 description 1
- FJNIPBOAGFXTAL-UHFFFAOYSA-N butyl 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoate Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(=O)OCCCC)=NC2=C1 FJNIPBOAGFXTAL-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- CLKKMQJJZOTKAH-UHFFFAOYSA-N cyclohexyl 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoate Chemical compound N=1C2=CC(N(CCCl)CCCl)=CC=C2N(C)C=1CCCC(=O)OC1CCCCC1 CLKKMQJJZOTKAH-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- SZMNDOUFZGODBR-UHFFFAOYSA-N decan-5-ol Chemical compound CCCCCC(O)CCCC SZMNDOUFZGODBR-UHFFFAOYSA-N 0.000 description 1
- HVGMEWHTDIWRLM-UHFFFAOYSA-N decan-5-yl 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoate Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(=O)OC(CCCC)CCCCC)=NC2=C1 HVGMEWHTDIWRLM-UHFFFAOYSA-N 0.000 description 1
- NHNGOYCDKVLEDS-UHFFFAOYSA-N decyl 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoate Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(=O)OCCCCCCCCCC)=NC2=C1 NHNGOYCDKVLEDS-UHFFFAOYSA-N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000011026 diafiltration Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 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 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- OJVHCKQEILBNQW-UHFFFAOYSA-N docosyl 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoate Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(=O)OCCCCCCCCCCCCCCCCCCCCCC)=NC2=C1 OJVHCKQEILBNQW-UHFFFAOYSA-N 0.000 description 1
- WNTPWLOBUTZCDW-UHFFFAOYSA-N dodecan-2-yl 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoate Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(=O)OC(C)CCCCCCCCCC)=NC2=C1 WNTPWLOBUTZCDW-UHFFFAOYSA-N 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 230000002357 endometrial effect Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 230000009969 flowable effect Effects 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- PRXFULGLLHPRIQ-UHFFFAOYSA-N hexadecyl 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoate Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(=O)OCCCCCCCCCCCCCCCC)=NC2=C1 PRXFULGLLHPRIQ-UHFFFAOYSA-N 0.000 description 1
- 229940003183 hexalen Drugs 0.000 description 1
- IOYNZSRLWWQJFV-UHFFFAOYSA-N hexyl 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoate Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(=O)OCCCCCC)=NC2=C1 IOYNZSRLWWQJFV-UHFFFAOYSA-N 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229940090411 ifex Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 210000002414 leg Anatomy 0.000 description 1
- 229940063725 leukeran Drugs 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 201000009546 lung large cell carcinoma Diseases 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- 208000025036 lymphosarcoma Diseases 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 208000021039 metastatic melanoma Diseases 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- IYUKFAFDFHZKPI-DFWYDOINSA-N methyl (2s)-2-aminopropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@H](C)N IYUKFAFDFHZKPI-DFWYDOINSA-N 0.000 description 1
- MGOHUKBFSWEKRL-UHFFFAOYSA-N methyl 4-(5-amino-1-methylbenzimidazol-2-yl)butanoate Chemical compound NC1=CC=C2N(C)C(CCCC(=O)OC)=NC2=C1 MGOHUKBFSWEKRL-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 229940087004 mustargen Drugs 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 229940090009 myleran Drugs 0.000 description 1
- OKDQKPLMQBXTNH-UHFFFAOYSA-N n,n-dimethyl-2h-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000007908 nanoemulsion Substances 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 238000009116 palliative therapy Methods 0.000 description 1
- 201000002530 pancreatic endocrine carcinoma Diseases 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000006920 protein precipitation Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000012066 reaction slurry Substances 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 231100000444 skin lesion Toxicity 0.000 description 1
- 206010040882 skin lesion Diseases 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 229940061353 temodar Drugs 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000002381 testicular Effects 0.000 description 1
- 208000002918 testicular germ cell tumor Diseases 0.000 description 1
- HAGRUQNJAITVKY-UHFFFAOYSA-N tetradecyl 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoate Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(=O)OCCCCCCCCCCCCCC)=NC2=C1 HAGRUQNJAITVKY-UHFFFAOYSA-N 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 208000013818 thyroid gland medullary carcinoma Diseases 0.000 description 1
- PBJUNZJWGZTSKL-MRXNPFEDSA-N tiagabine Chemical compound C1=CSC(C(=CCCN2C[C@@H](CCC2)C(O)=O)C2=C(C=CS2)C)=C1C PBJUNZJWGZTSKL-MRXNPFEDSA-N 0.000 description 1
- 229960001918 tiagabine Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 150000004654 triazenes Chemical class 0.000 description 1
- 150000003918 triazines Chemical class 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 239000013026 undiluted sample Substances 0.000 description 1
- 238000004017 vitrification Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940053890 zanosar Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Inorganic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Saccharide Compounds (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261725213P | 2012-11-12 | 2012-11-12 | |
| US61/725,213 | 2012-11-12 | ||
| US201361776951P | 2013-03-12 | 2013-03-12 | |
| US61/776,951 | 2013-03-12 | ||
| PCT/US2013/069550 WO2014075035A1 (en) | 2012-11-12 | 2013-11-12 | Bendamustine derivatives and methods of using same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2013342015A1 AU2013342015A1 (en) | 2015-05-28 |
| AU2013342015B2 true AU2013342015B2 (en) | 2016-11-24 |
Family
ID=49667594
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2013342015A Ceased AU2013342015B2 (en) | 2012-11-12 | 2013-11-12 | Bendamustine derivatives and methods of using same |
Country Status (17)
| Country | Link |
|---|---|
| US (7) | US9452988B2 (enExample) |
| EP (1) | EP2917183A1 (enExample) |
| JP (1) | JP6262246B2 (enExample) |
| KR (1) | KR20150086308A (enExample) |
| AR (1) | AR093457A1 (enExample) |
| AU (1) | AU2013342015B2 (enExample) |
| BR (1) | BR112015010501A2 (enExample) |
| CA (1) | CA2890462A1 (enExample) |
| CL (1) | CL2015001246A1 (enExample) |
| EA (1) | EA029706B1 (enExample) |
| HK (2) | HK1215701A1 (enExample) |
| IL (1) | IL238662A (enExample) |
| MX (1) | MX2015005805A (enExample) |
| PH (1) | PH12015501024A1 (enExample) |
| SG (1) | SG11201503560TA (enExample) |
| TW (1) | TWI598341B (enExample) |
| WO (1) | WO2014075035A1 (enExample) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105693720B (zh) | 2010-05-20 | 2019-01-18 | 阵列生物制药公司 | 作为trk激酶抑制剂的大环化合物 |
| MX2015005805A (es) * | 2012-11-12 | 2016-04-15 | Ignyta Inc | Derivados de bendamustina y métodos para utilizarlos. |
| CA2904143A1 (en) * | 2013-03-12 | 2014-10-09 | Cephalon, Inc. | Nanoparticulate and macroparticulate formulations |
| EP3322706B1 (en) | 2015-07-16 | 2020-11-11 | Array Biopharma, Inc. | Substituted pyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors |
| WO2018013783A1 (en) * | 2016-07-13 | 2018-01-18 | Cephalon, Inc. | Pharmaceutical prodrugs and methods of their preparation and use |
| TWI704148B (zh) | 2016-10-10 | 2020-09-11 | 美商亞雷生物製藥股份有限公司 | 作為ret激酶抑制劑之經取代吡唑并[1,5-a]吡啶化合物 |
| JOP20190077A1 (ar) | 2016-10-10 | 2019-04-09 | Array Biopharma Inc | مركبات بيرازولو [1، 5-a]بيريدين بها استبدال كمثبطات كيناز ret |
| CN110267960B (zh) | 2017-01-18 | 2022-04-26 | 阿雷生物药品公司 | 作为RET激酶抑制剂的取代的吡唑并[1,5-a]吡嗪化合物 |
| WO2018136663A1 (en) | 2017-01-18 | 2018-07-26 | Array Biopharma, Inc. | Ret inhibitors |
| JOP20190213A1 (ar) | 2017-03-16 | 2019-09-16 | Array Biopharma Inc | مركبات حلقية ضخمة كمثبطات لكيناز ros1 |
| TWI791053B (zh) | 2017-10-10 | 2023-02-01 | 美商亞雷生物製藥股份有限公司 | 6-(2-羥基-2-甲基丙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮雜雙環[3.1.1]庚-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈之結晶形式及其醫藥組合物 |
| TWI812649B (zh) | 2017-10-10 | 2023-08-21 | 美商絡速藥業公司 | 6-(2-羥基-2-甲基丙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮雜雙環[3.1.1]庚-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈之調配物 |
| TW201938169A (zh) | 2018-01-18 | 2019-10-01 | 美商亞雷生物製藥股份有限公司 | 作為RET激酶抑制劑之經取代吡唑并[3,4-d]嘧啶化合物 |
| WO2019143994A1 (en) | 2018-01-18 | 2019-07-25 | Array Biopharma Inc. | Substituted pyrazolyl[4,3-c]pyridinecompounds as ret kinase inhibitors |
| CN111971286B (zh) | 2018-01-18 | 2023-04-14 | 阿雷生物药品公司 | 作为RET激酶抑制剂的取代的吡咯并[2,3-d]嘧啶化合物 |
| KR102653681B1 (ko) | 2018-07-31 | 2024-04-03 | 록쏘 온콜로지, 인코포레이티드 | (s)-5-아미노-3-(4-((5-플루오로-2-메톡시벤즈아미도)메틸)페닐)-1-(1,1,1-트리플루오로프로판-2-일)-1h-피라졸-4-카르복스아미드의분무-건조된 분산물 및 제제 |
| ES2922314T3 (es) | 2018-09-10 | 2022-09-13 | Array Biopharma Inc | Compuestos heterocíclicos condensados como inhibidores de cinasa RET |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010063493A1 (en) * | 2008-12-03 | 2010-06-10 | Astellas Deutschland Gmbh | Oral dosage forms of bendamustine |
Family Cites Families (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5681964A (en) * | 1990-10-23 | 1997-10-28 | University Of Kentucky Research Foundation | Permeable, non-irritating prodrugs of nonsteroidal and steroidal agents |
| US5834025A (en) | 1995-09-29 | 1998-11-10 | Nanosystems L.L.C. | Reduction of intravenously administered nanoparticulate-formulation-induced adverse physiological reactions |
| US7089218B1 (en) | 2004-01-06 | 2006-08-08 | Neuric Technologies, Llc | Method for inclusion of psychological temperament in an electronic emulation of the human brain |
| US8853260B2 (en) | 1997-06-27 | 2014-10-07 | Abraxis Bioscience, Llc | Formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof |
| WO2002043663A2 (en) | 2000-12-01 | 2002-06-06 | Enzon, Inc. | Tetrapartate prodrugs |
| WO2003086369A2 (en) * | 2002-04-05 | 2003-10-23 | Valorisation-Recherche, Societe En Commandite | Stealthy polymeric biodegradable nanospheres and uses thereof |
| EP2359859A1 (en) | 2002-12-09 | 2011-08-24 | Abraxis BioScience, LLC | Compositions comprising albumin nanoparticles and methods of delivery of pharmacological agents |
| US8436190B2 (en) | 2005-01-14 | 2013-05-07 | Cephalon, Inc. | Bendamustine pharmaceutical compositions |
| CA2598239C (en) | 2005-02-18 | 2019-10-29 | Abraxis Bioscience, Inc. | Nanoparticulate formulations of taxanes and carrier proteins for use in combination chemotherapy |
| DE102005062440B4 (de) * | 2005-12-27 | 2011-02-24 | Lts Lohmann Therapie-Systeme Ag | Proteinbasiertes Trägersystem zur Resistenzüberwindung von Tumorzellen |
| EP2222278B1 (en) | 2007-11-28 | 2015-04-08 | Celator Pharmaceuticals, Inc. | Improved taxane delivery system |
| AR072777A1 (es) | 2008-03-26 | 2010-09-22 | Cephalon Inc | Formas solidas de clorhidrato de bendamustina |
| JP5670335B2 (ja) * | 2008-09-25 | 2015-02-18 | セファロン、インク. | ベンダムスチン液体製剤 |
| WO2010037142A1 (en) * | 2008-09-29 | 2010-04-01 | The Corporation Of Mercer University | Nanospheres encapsulating bioactive material and method for formulation of nanospheres |
| JP5773874B2 (ja) * | 2008-10-08 | 2015-09-02 | セファロン、インク. | ベンダムスチンの調製方法 |
| BR112012030654B1 (pt) | 2010-06-02 | 2021-11-09 | Astellas Deutschland Gmbh | Composição farmacêutica para administração oral compreendendo bendamustina ou um sal farmaceuticamente aceitável da mesma, como um ingrediente ativo, e um excipiente farmaceuticamente aceitável |
| TWI455722B (zh) | 2010-06-04 | 2014-10-11 | Pfizer Vaccines Llc | 用於預防或治療菸鹼成癮之共軛體 |
| CN101966158A (zh) | 2010-09-28 | 2011-02-09 | 上海丽思化工科技有限公司 | 一种注射用盐酸苯达莫司汀冻干粉针剂及其制备方法 |
| EP2635558A4 (en) | 2010-11-01 | 2014-08-06 | Shilpa Medicare Ltd | PROCESS FOR PREPARING BENDAMUSTINE HYDROCHLORIDE MONOHYDRATE |
| DE102010055499A1 (de) | 2010-12-22 | 2011-06-16 | W.C. Heraeus Gmbh | Prozess zur Herstellung von Bendamustinalkylester, Bendarmustin sowie Derivaten davon |
| PT2707030T (pt) | 2011-05-09 | 2020-05-22 | Mayo Found Medical Education & Res | Tratamentos de cancro |
| US9308276B2 (en) | 2011-05-17 | 2016-04-12 | University Of South Alabama | Combination therapy for treatment of cancer |
| ES2613838T3 (es) | 2011-09-26 | 2017-05-26 | Fresenius Kabi Oncology Ltd | Un procedimiento mejorado para la preparación de hidrocloruro de bendamustina |
| PT2656843E (pt) | 2012-04-26 | 2015-04-14 | Helmut Schickaneder | Ésteres de bendamustina e compostos relacionados e a sua utilização médica |
| US10526290B2 (en) | 2012-06-19 | 2020-01-07 | Synbias Pharma Ag | Bendamustine derivatives and related compounds, and medical use thereof in cancer therapy |
| JP2015525799A (ja) | 2012-08-10 | 2015-09-07 | ユニバーシティ・オブ・ノース・テキサス・ヘルス・サイエンス・センターUniversity of North Texas Health Science Center | ターゲティングポリアミノ酸および脂肪酸のコンジュゲートを含む薬物送達ビークル |
| MX2015005805A (es) * | 2012-11-12 | 2016-04-15 | Ignyta Inc | Derivados de bendamustina y métodos para utilizarlos. |
-
2013
- 2013-11-12 MX MX2015005805A patent/MX2015005805A/es unknown
- 2013-11-12 KR KR1020157015682A patent/KR20150086308A/ko not_active Withdrawn
- 2013-11-12 SG SG11201503560TA patent/SG11201503560TA/en unknown
- 2013-11-12 US US14/442,088 patent/US9452988B2/en not_active Expired - Fee Related
- 2013-11-12 EA EA201590925A patent/EA029706B1/ru not_active IP Right Cessation
- 2013-11-12 WO PCT/US2013/069550 patent/WO2014075035A1/en not_active Ceased
- 2013-11-12 HK HK16100090.1A patent/HK1215701A1/zh unknown
- 2013-11-12 EP EP13795940.9A patent/EP2917183A1/en not_active Withdrawn
- 2013-11-12 BR BR112015010501A patent/BR112015010501A2/pt not_active IP Right Cessation
- 2013-11-12 JP JP2015541995A patent/JP6262246B2/ja not_active Expired - Fee Related
- 2013-11-12 CA CA2890462A patent/CA2890462A1/en not_active Abandoned
- 2013-11-12 TW TW102140964A patent/TWI598341B/zh not_active IP Right Cessation
- 2013-11-12 AU AU2013342015A patent/AU2013342015B2/en not_active Ceased
- 2013-11-12 AR ARP130104160A patent/AR093457A1/es unknown
- 2013-11-12 HK HK16100891.2A patent/HK1212977A1/zh unknown
-
2015
- 2015-04-29 US US14/699,965 patent/US9150517B2/en not_active Expired - Fee Related
- 2015-05-06 IL IL238662A patent/IL238662A/en not_active IP Right Cessation
- 2015-05-07 PH PH12015501024A patent/PH12015501024A1/en unknown
- 2015-05-08 CL CL2015001246A patent/CL2015001246A1/es unknown
- 2015-05-13 US US14/711,747 patent/US9149464B2/en not_active Expired - Fee Related
- 2015-09-28 US US14/868,278 patent/US20160016912A1/en not_active Abandoned
-
2016
- 2016-06-16 US US15/184,968 patent/US9630926B2/en not_active Expired - Fee Related
-
2017
- 2017-03-10 US US15/456,439 patent/US9913827B2/en not_active Expired - Fee Related
-
2018
- 2018-01-24 US US15/879,130 patent/US20180147186A1/en not_active Abandoned
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010063493A1 (en) * | 2008-12-03 | 2010-06-10 | Astellas Deutschland Gmbh | Oral dosage forms of bendamustine |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2013342015B2 (en) | Bendamustine derivatives and methods of using same | |
| JP6740391B2 (ja) | 安定なミセルのためのブロックコポリマー | |
| KR101697363B1 (ko) | 소수성 제제를 캡슐화하기 위해 사용되는 혼합 입체화학을 가지는 혼성 블록 공중합체 미셀 | |
| CN103044437B (zh) | 用于治疗肿瘤的两亲性缀合物纳米颗粒及制备方法、应用 | |
| JP2012526049A (ja) | 腫瘍治療のためのsn−38を含有するポリマーミセル | |
| EP3844208A1 (en) | Cyanine-based telodendrimers and uses for treating cancer | |
| US8629186B2 (en) | Polymer micelles containing anthracyclines for the treatment of cancer | |
| CN105051016B (zh) | 苯达莫司汀衍生物及其使用方法 | |
| Song et al. | Celastrol Loaded PEGylated Nanographene Oxide for Highly Efficient Synergistic Chemo/Photothermal Therapy | |
| Xu et al. | Cascade-responsive nanoplatform for synergistic cancer therapy via ROS amplification and hypoxia targeting | |
| Ali et al. | Solubility and Dissolution Rate Enhancement of Bilastine by Solid Dispersion Technique | |
| Zhang et al. | Transferrin-mediated fuller‐enes nanoparticles as Fe2+-dependent drug vehicles for synergistic anti-tumor efficacy |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FGA | Letters patent sealed or granted (standard patent) | ||
| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |