WO2024030825A1 - Crystalline salts of crystalline salts of (3s,5r,8r,9s,10s,13r,14s,17r)-14-hydroxy-10,13-dimethyl-17-(2- oxo-2h-pyran-5-yl)hexadecahydro-1h-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate - Google Patents
Crystalline salts of crystalline salts of (3s,5r,8r,9s,10s,13r,14s,17r)-14-hydroxy-10,13-dimethyl-17-(2- oxo-2h-pyran-5-yl)hexadecahydro-1h-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate Download PDFInfo
- Publication number
- WO2024030825A1 WO2024030825A1 PCT/US2023/071180 US2023071180W WO2024030825A1 WO 2024030825 A1 WO2024030825 A1 WO 2024030825A1 US 2023071180 W US2023071180 W US 2023071180W WO 2024030825 A1 WO2024030825 A1 WO 2024030825A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- crystalline form
- powder diffraction
- ray powder
- diffraction pattern
- thermogram
- Prior art date
Links
- JZQQZSSKRWJAAW-CZKHRBRPSA-N [(3s,5r,8r,9s,10s,13r,14s,17r)-14-hydroxy-10,13-dimethyl-17-(6-oxopyran-3-yl)-1,2,3,4,5,6,7,8,9,11,12,15,16,17-tetradecahydrocyclopenta[a]phenanthren-3-yl] piperazine-1-carboxylate Chemical class O([C@@H]1C[C@H]2CC[C@@H]3[C@@H]([C@]2(CC1)C)CC[C@]1([C@]3(O)CC[C@@H]1C1=COC(=O)C=C1)C)C(=O)N1CCNCC1 JZQQZSSKRWJAAW-CZKHRBRPSA-N 0.000 title claims description 28
- 150000003839 salts Chemical class 0.000 title description 45
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract description 44
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 318
- 238000000034 method Methods 0.000 claims description 114
- 238000001757 thermogravimetry curve Methods 0.000 claims description 104
- -1 (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17- (2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1- carboxylate phosphate Chemical compound 0.000 claims description 98
- 239000002904 solvent Substances 0.000 claims description 98
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 85
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 80
- 238000002411 thermogravimetry Methods 0.000 claims description 79
- 239000000203 mixture Substances 0.000 claims description 66
- 239000008194 pharmaceutical composition Substances 0.000 claims description 48
- 206010028980 Neoplasm Diseases 0.000 claims description 44
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 37
- 238000001179 sorption measurement Methods 0.000 claims description 35
- 238000001035 drying Methods 0.000 claims description 30
- 201000011510 cancer Diseases 0.000 claims description 25
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 24
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- 238000001816 cooling Methods 0.000 claims description 18
- 239000000725 suspension Substances 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 13
- 239000007788 liquid Substances 0.000 claims description 13
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 13
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 12
- 239000000843 powder Substances 0.000 claims description 10
- 239000002775 capsule Substances 0.000 claims description 9
- 241000124008 Mammalia Species 0.000 claims description 8
- 206010006187 Breast cancer Diseases 0.000 claims description 7
- 208000026310 Breast neoplasm Diseases 0.000 claims description 7
- 201000009030 Carcinoma Diseases 0.000 claims description 7
- 239000000443 aerosol Substances 0.000 claims description 7
- 208000035269 cancer or benign tumor Diseases 0.000 claims description 7
- 206010009944 Colon cancer Diseases 0.000 claims description 6
- 208000009798 Craniopharyngioma Diseases 0.000 claims description 6
- 208000017604 Hodgkin disease Diseases 0.000 claims description 6
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 6
- 208000009956 adenocarcinoma Diseases 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 6
- 208000032839 leukemia Diseases 0.000 claims description 6
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 6
- 239000000829 suppository Substances 0.000 claims description 6
- 239000011975 tartaric acid Substances 0.000 claims description 6
- 235000002906 tartaric acid Nutrition 0.000 claims description 6
- 201000001441 melanoma Diseases 0.000 claims description 5
- 208000000172 Medulloblastoma Diseases 0.000 claims description 4
- 206010027406 Mesothelioma Diseases 0.000 claims description 4
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 3
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 3
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 3
- 201000003076 Angiosarcoma Diseases 0.000 claims description 3
- 206010003571 Astrocytoma Diseases 0.000 claims description 3
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 3
- 206010004593 Bile duct cancer Diseases 0.000 claims description 3
- 206010005003 Bladder cancer Diseases 0.000 claims description 3
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 3
- 201000005262 Chondroma Diseases 0.000 claims description 3
- 208000005243 Chondrosarcoma Diseases 0.000 claims description 3
- 208000006332 Choriocarcinoma Diseases 0.000 claims description 3
- 201000009051 Embryonal Carcinoma Diseases 0.000 claims description 3
- 206010014967 Ependymoma Diseases 0.000 claims description 3
- 208000031637 Erythroblastic Acute Leukemia Diseases 0.000 claims description 3
- 208000036566 Erythroleukaemia Diseases 0.000 claims description 3
- 208000006168 Ewing Sarcoma Diseases 0.000 claims description 3
- 201000008808 Fibrosarcoma Diseases 0.000 claims description 3
- 208000032612 Glial tumor Diseases 0.000 claims description 3
- 206010018338 Glioma Diseases 0.000 claims description 3
- 208000001258 Hemangiosarcoma Diseases 0.000 claims description 3
- 208000018142 Leiomyosarcoma Diseases 0.000 claims description 3
- 206010024305 Leukaemia monocytic Diseases 0.000 claims description 3
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 3
- 206010025323 Lymphomas Diseases 0.000 claims description 3
- 208000007054 Medullary Carcinoma Diseases 0.000 claims description 3
- 208000003445 Mouth Neoplasms Diseases 0.000 claims description 3
- 208000034578 Multiple myelomas Diseases 0.000 claims description 3
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 3
- 206010029260 Neuroblastoma Diseases 0.000 claims description 3
- 201000010133 Oligodendroglioma Diseases 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 208000007641 Pinealoma Diseases 0.000 claims description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 3
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 3
- 201000000582 Retinoblastoma Diseases 0.000 claims description 3
- 201000010208 Seminoma Diseases 0.000 claims description 3
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 3
- 208000014070 Vestibular schwannoma Diseases 0.000 claims description 3
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 claims description 3
- 208000008383 Wilms tumor Diseases 0.000 claims description 3
- 208000004064 acoustic neuroma Diseases 0.000 claims description 3
- 208000017733 acquired polycythemia vera Diseases 0.000 claims description 3
- 208000021841 acute erythroid leukemia Diseases 0.000 claims description 3
- 201000007180 bile duct carcinoma Diseases 0.000 claims description 3
- 201000001531 bladder carcinoma Diseases 0.000 claims description 3
- 208000003362 bronchogenic carcinoma Diseases 0.000 claims description 3
- 201000010881 cervical cancer Diseases 0.000 claims description 3
- 230000001684 chronic effect Effects 0.000 claims description 3
- 208000024207 chronic leukemia Diseases 0.000 claims description 3
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 3
- 208000002445 cystadenocarcinoma Diseases 0.000 claims description 3
- 208000037828 epithelial carcinoma Diseases 0.000 claims description 3
- 208000025750 heavy chain disease Diseases 0.000 claims description 3
- 201000002222 hemangioblastoma Diseases 0.000 claims description 3
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 3
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 claims description 3
- 206010024627 liposarcoma Diseases 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 201000005296 lung carcinoma Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 208000037829 lymphangioendotheliosarcoma Diseases 0.000 claims description 3
- 208000012804 lymphangiosarcoma Diseases 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 claims description 3
- 206010027191 meningioma Diseases 0.000 claims description 3
- 201000006894 monocytic leukemia Diseases 0.000 claims description 3
- 208000001611 myxosarcoma Diseases 0.000 claims description 3
- 208000025189 neoplasm of testis Diseases 0.000 claims description 3
- 201000008968 osteosarcoma Diseases 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- 208000004019 papillary adenocarcinoma Diseases 0.000 claims description 3
- 201000010198 papillary carcinoma Diseases 0.000 claims description 3
- 239000006187 pill Substances 0.000 claims description 3
- 208000024724 pineal body neoplasm Diseases 0.000 claims description 3
- 201000004123 pineal gland cancer Diseases 0.000 claims description 3
- 208000037244 polycythemia vera Diseases 0.000 claims description 3
- 201000009410 rhabdomyosarcoma Diseases 0.000 claims description 3
- 201000008407 sebaceous adenocarcinoma Diseases 0.000 claims description 3
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 3
- 206010041823 squamous cell carcinoma Diseases 0.000 claims description 3
- 201000010965 sweat gland carcinoma Diseases 0.000 claims description 3
- 206010042863 synovial sarcoma Diseases 0.000 claims description 3
- 201000003120 testicular cancer Diseases 0.000 claims description 3
- 208000010570 urinary bladder carcinoma Diseases 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- 210000000270 basal cell Anatomy 0.000 claims 1
- 229940126062 Compound A Drugs 0.000 abstract description 201
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 abstract description 201
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 abstract description 35
- 229910019142 PO4 Inorganic materials 0.000 abstract description 31
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 abstract description 31
- 239000010452 phosphate Substances 0.000 abstract description 31
- 229940095064 tartrate Drugs 0.000 abstract description 29
- 150000001860 citric acid derivatives Chemical class 0.000 abstract description 5
- 239000000243 solution Substances 0.000 description 63
- 150000001875 compounds Chemical class 0.000 description 54
- 239000000126 substance Substances 0.000 description 51
- 235000002639 sodium chloride Nutrition 0.000 description 43
- 238000002425 crystallisation Methods 0.000 description 37
- 230000008025 crystallization Effects 0.000 description 37
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 31
- 238000011282 treatment Methods 0.000 description 22
- 239000003112 inhibitor Substances 0.000 description 21
- 239000002246 antineoplastic agent Substances 0.000 description 20
- 238000009472 formulation Methods 0.000 description 20
- 238000002360 preparation method Methods 0.000 description 20
- 229940127089 cytotoxic agent Drugs 0.000 description 17
- 230000000694 effects Effects 0.000 description 16
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 15
- 201000010099 disease Diseases 0.000 description 14
- 239000003814 drug Substances 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- 239000007795 chemical reaction product Substances 0.000 description 13
- 239000003795 chemical substances by application Substances 0.000 description 13
- 239000007924 injection Substances 0.000 description 13
- 238000002347 injection Methods 0.000 description 13
- 239000013078 crystal Substances 0.000 description 12
- 239000000651 prodrug Substances 0.000 description 11
- 229940002612 prodrug Drugs 0.000 description 11
- 238000013459 approach Methods 0.000 description 10
- 239000000969 carrier Substances 0.000 description 10
- 230000005855 radiation Effects 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000000872 buffer Substances 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 239000012453 solvate Substances 0.000 description 9
- 239000000499 gel Substances 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 239000003381 stabilizer Substances 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 230000008859 change Effects 0.000 description 7
- 150000005829 chemical entities Chemical class 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000000825 pharmaceutical preparation Substances 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 235000015165 citric acid Nutrition 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 235000011007 phosphoric acid Nutrition 0.000 description 6
- 229920000642 polymer Polymers 0.000 description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 6
- 239000003755 preservative agent Substances 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 229940124597 therapeutic agent Drugs 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000000839 emulsion Substances 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- 238000002955 isolation Methods 0.000 description 5
- 239000002502 liposome Substances 0.000 description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 5
- 238000001959 radiotherapy Methods 0.000 description 5
- 210000003491 skin Anatomy 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 108010010803 Gelatin Proteins 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 229940126534 drug product Drugs 0.000 description 4
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 239000003102 growth factor Substances 0.000 description 4
- 238000011065 in-situ storage Methods 0.000 description 4
- 229940043355 kinase inhibitor Drugs 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 4
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000013268 sustained release Methods 0.000 description 4
- 239000012730 sustained-release form Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 150000003892 tartrate salts Chemical class 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- 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 3
- 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 3
- 102000009465 Growth Factor Receptors Human genes 0.000 description 3
- 108010009202 Growth Factor Receptors Proteins 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 206010039491 Sarcoma Diseases 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229920002125 Sokalan® Polymers 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 3
- 230000001594 aberrant effect Effects 0.000 description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 235000010323 ascorbic acid Nutrition 0.000 description 3
- 239000011668 ascorbic acid Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 229960001433 erlotinib Drugs 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 3
- 150000004677 hydrates Chemical class 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 210000000214 mouth Anatomy 0.000 description 3
- 239000006186 oral dosage form Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000005022 packaging material Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 230000037317 transdermal delivery Effects 0.000 description 3
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 3
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 2
- XXJWYDDUDKYVKI-UHFFFAOYSA-N 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline Chemical compound COC1=CC2=C(OC=3C(=C4C=C(C)NC4=CC=3)F)N=CN=C2C=C1OCCCN1CCCC1 XXJWYDDUDKYVKI-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 2
- 206010004146 Basal cell carcinoma Diseases 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- QEEBRPGZBVVINN-UHFFFAOYSA-N Desacetyl-bufotalin Natural products CC12CCC(C3(CCC(O)CC3CC3)C)C3C1(O)CCC2C=1C=CC(=O)OC=1 QEEBRPGZBVVINN-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- WDJUZGPOPHTGOT-OAXVISGBSA-N Digitoxin Natural products O([C@H]1[C@@H](C)O[C@@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@@](C)([C@H](C6=CC(=O)OC6)CC5)CC4)CC3)CC2)C[C@H]1O)[C@H]1O[C@@H](C)[C@H](O[C@H]2O[C@@H](C)[C@@H](O)[C@@H](O)C2)[C@@H](O)C1 WDJUZGPOPHTGOT-OAXVISGBSA-N 0.000 description 2
- 241000792859 Enema Species 0.000 description 2
- 208000025127 Erdheim-Chester disease Diseases 0.000 description 2
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 2
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 2
- 201000005099 Langerhans cell histiocytosis Diseases 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 102000005393 Sodium-Potassium-Exchanging ATPase Human genes 0.000 description 2
- 108010006431 Sodium-Potassium-Exchanging ATPase Proteins 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- JIYCEZVOSQLKFA-HGLROYCYSA-N [(3s,5r,8r,9s,10s,13r,14s,17r)-14-hydroxy-10,13-dimethyl-17-(6-oxopyran-3-yl)-1,2,3,4,5,6,7,8,9,11,12,15,16,17-tetradecahydrocyclopenta[a]phenanthren-3-yl] (4-nitrophenyl) carbonate Chemical compound O([C@@H]1C[C@H]2CC[C@@H]3[C@@H]([C@]2(CC1)C)CC[C@]1([C@]3(O)CC[C@@H]1C1=COC(=O)C=C1)C)C(=O)OC1=CC=C([N+]([O-])=O)C=C1 JIYCEZVOSQLKFA-HGLROYCYSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 230000000692 anti-sense effect Effects 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 239000003886 aromatase inhibitor Substances 0.000 description 2
- 229940046844 aromatase inhibitors Drugs 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 229960000397 bevacizumab Drugs 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- QEEBRPGZBVVINN-BMPKRDENSA-N bufalin Chemical compound C=1([C@H]2CC[C@]3(O)[C@H]4[C@@H]([C@]5(CC[C@H](O)C[C@H]5CC4)C)CC[C@@]32C)C=CC(=O)OC=1 QEEBRPGZBVVINN-BMPKRDENSA-N 0.000 description 2
- OMZCMEYTWSXEPZ-UHFFFAOYSA-N canertinib Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCOCC3)=C(NC(=O)C=C)C=C12 OMZCMEYTWSXEPZ-UHFFFAOYSA-N 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 125000002843 carboxylic acid group Chemical group 0.000 description 2
- 230000003177 cardiotonic effect Effects 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 210000003679 cervix uteri Anatomy 0.000 description 2
- 238000002144 chemical decomposition reaction Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 239000002254 cytotoxic agent Substances 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 229960002086 dextran Drugs 0.000 description 2
- WDJUZGPOPHTGOT-XUDUSOBPSA-N digitoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)CC5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O WDJUZGPOPHTGOT-XUDUSOBPSA-N 0.000 description 2
- 229960000648 digitoxin Drugs 0.000 description 2
- OSVXSBDYLRYLIG-UHFFFAOYSA-N dioxidochlorine(.) Chemical compound O=Cl=O OSVXSBDYLRYLIG-UHFFFAOYSA-N 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000007920 enema Substances 0.000 description 2
- 229940079360 enema for constipation Drugs 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 229960000255 exemestane Drugs 0.000 description 2
- 239000010685 fatty oil Substances 0.000 description 2
- 229960002258 fulvestrant Drugs 0.000 description 2
- 229960002584 gefitinib Drugs 0.000 description 2
- 229960005277 gemcitabine Drugs 0.000 description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 2
- 238000001415 gene therapy Methods 0.000 description 2
- 238000010914 gene-directed enzyme pro-drug therapy Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 210000000244 kidney pelvis Anatomy 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000002736 nonionic surfactant Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 239000008177 pharmaceutical agent Substances 0.000 description 2
- 210000003800 pharynx Anatomy 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 238000012746 preparative thin layer chromatography Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- OUKYUETWWIPKQR-UHFFFAOYSA-N saracatinib Chemical compound C1CN(C)CCN1CCOC1=CC(OC2CCOCC2)=C(C(NC=2C(=CC=C3OCOC3=2)Cl)=NC=N2)C2=C1 OUKYUETWWIPKQR-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
- 239000000661 sodium alginate Substances 0.000 description 2
- 229940005550 sodium alginate Drugs 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000008247 solid mixture Substances 0.000 description 2
- 238000007711 solidification Methods 0.000 description 2
- 230000008023 solidification Effects 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 229960001796 sunitinib Drugs 0.000 description 2
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 201000002510 thyroid cancer Diseases 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- 229960000575 trastuzumab Drugs 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 238000009736 wetting Methods 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- WSWCOQWTEOXDQX-MQQKCMAXSA-M (E,E)-sorbate Chemical compound C\C=C\C=C\C([O-])=O WSWCOQWTEOXDQX-MQQKCMAXSA-M 0.000 description 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- ABEXEQSGABRUHS-UHFFFAOYSA-N 16-methylheptadecyl 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C ABEXEQSGABRUHS-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- XETLOFNELZCXMX-UHFFFAOYSA-N 2-(diethylamino)ethyl 2-(4-hexoxyphenyl)-2-hydroxy-2-phenylacetate;hydrochloride Chemical compound Cl.C1=CC(OCCCCCC)=CC=C1C(O)(C(=O)OCCN(CC)CC)C1=CC=CC=C1 XETLOFNELZCXMX-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- HNLXNOZHXNSSPN-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CC(C)(C)CC(C)(C)C1=CC=C(OCCOCCOCCOCCOCCOCCOCCO)C=C1 HNLXNOZHXNSSPN-UHFFFAOYSA-N 0.000 description 1
- IVHKZCSZELZKSJ-UHFFFAOYSA-N 2-hydroxyethyl sulfonate Chemical compound OCCOS(=O)=O IVHKZCSZELZKSJ-UHFFFAOYSA-N 0.000 description 1
- HZLCGUXUOFWCCN-UHFFFAOYSA-N 2-hydroxynonadecane-1,2,3-tricarboxylic acid Chemical compound CCCCCCCCCCCCCCCCC(C(O)=O)C(O)(C(O)=O)CC(O)=O HZLCGUXUOFWCCN-UHFFFAOYSA-N 0.000 description 1
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical group OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin 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-VTZDEGQISA-N 0.000 description 1
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 description 1
- HHFBDROWDBDFBR-UHFFFAOYSA-N 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1NC1=NC=C(CN=C(C=2C3=CC=C(Cl)C=2)C=2C(=CC=CC=2F)F)C3=N1 HHFBDROWDBDFBR-UHFFFAOYSA-N 0.000 description 1
- SGOOQMRIPALTEL-UHFFFAOYSA-N 4-hydroxy-N,1-dimethyl-2-oxo-N-phenyl-3-quinolinecarboxamide Chemical compound OC=1C2=CC=CC=C2N(C)C(=O)C=1C(=O)N(C)C1=CC=CC=C1 SGOOQMRIPALTEL-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- 108091006112 ATPases Proteins 0.000 description 1
- GBJVVSCPOBPEIT-UHFFFAOYSA-N AZT-1152 Chemical compound N=1C=NC2=CC(OCCCN(CC)CCOP(O)(O)=O)=CC=C2C=1NC(=NN1)C=C1CC(=O)NC1=CC=CC(F)=C1 GBJVVSCPOBPEIT-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 102000012936 Angiostatins Human genes 0.000 description 1
- 108010079709 Angiostatins Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 102000052609 BRCA2 Human genes 0.000 description 1
- 108700020462 BRCA2 Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 101150008921 Brca2 gene Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 241001415440 Bufo gargarizans Species 0.000 description 1
- 108010037003 Buserelin Proteins 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 239000004155 Chlorine dioxide Substances 0.000 description 1
- HVXBOLULGPECHP-WAYWQWQTSA-N Combretastatin A4 Chemical compound C1=C(O)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-WAYWQWQTSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 description 1
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 1
- 102100036239 Cyclin-dependent kinase 2 Human genes 0.000 description 1
- 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- 102000000311 Cytosine Deaminase Human genes 0.000 description 1
- 108010080611 Cytosine Deaminase Proteins 0.000 description 1
- 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 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 1
- 241001415432 Duttaphrynus melanostictus Species 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 229940118365 Endothelin receptor antagonist Drugs 0.000 description 1
- 102400001368 Epidermal growth factor Human genes 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 1
- 102100031706 Fibroblast growth factor 1 Human genes 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 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
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 102100024025 Heparanase Human genes 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 229920001499 Heparinoid Polymers 0.000 description 1
- 108090000100 Hepatocyte Growth Factor Proteins 0.000 description 1
- 102100021866 Hepatocyte growth factor Human genes 0.000 description 1
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- 102000014429 Insulin-like growth factor Human genes 0.000 description 1
- 102100037852 Insulin-like growth factor I Human genes 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102000004388 Interleukin-4 Human genes 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 241000764238 Isis Species 0.000 description 1
- 150000000996 L-ascorbic acids Chemical class 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 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 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 1
- 239000002145 L01XE14 - Bosutinib Substances 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- XNRVGTHNYCNCFF-UHFFFAOYSA-N Lapatinib ditosylate monohydrate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1.CC1=CC=C(S(O)(=O)=O)C=C1.O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 XNRVGTHNYCNCFF-UHFFFAOYSA-N 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229940124041 Luteinizing hormone releasing hormone (LHRH) antagonist Drugs 0.000 description 1
- 108700041567 MDR Genes Proteins 0.000 description 1
- 102100028198 Macrophage colony-stimulating factor 1 receptor Human genes 0.000 description 1
- 101710150918 Macrophage colony-stimulating factor 1 receptor Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 235000019759 Maize starch Nutrition 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 244000062730 Melissa officinalis Species 0.000 description 1
- 235000010654 Melissa officinalis Nutrition 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- FJHHZXWJVIEFGJ-UHFFFAOYSA-N N-(3-methoxy-5-methyl-2-pyrazinyl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]-3-pyridinesulfonamide Chemical compound COC1=NC(C)=CN=C1NS(=O)(=O)C1=CC=CN=C1C1=CC=C(C=2OC=NN=2)C=C1 FJHHZXWJVIEFGJ-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 102000004459 Nitroreductase Human genes 0.000 description 1
- JLPDBLFIVFSOCC-UHFFFAOYSA-N Oleandrin Natural products O1C(C)C(O)C(OC)CC1OC1CC(CCC2C3(CC(C(C3(C)CCC32)C=2COC(=O)C=2)OC(C)=O)O)C3(C)CC1 JLPDBLFIVFSOCC-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 1
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 1
- 108030005449 Polo kinases Proteins 0.000 description 1
- 229920000148 Polycarbophil calcium Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 102100024028 Progonadoliberin-1 Human genes 0.000 description 1
- 108091008611 Protein Kinase B Proteins 0.000 description 1
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 1
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 1
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 1
- 238000001069 Raman spectroscopy Methods 0.000 description 1
- HPHKTNXGYLOXMP-UHFFFAOYSA-N S(C)(=O)(=O)O.N1(CCNCC1)C(=O)O Chemical compound S(C)(=O)(=O)O.N1(CCNCC1)C(=O)O HPHKTNXGYLOXMP-UHFFFAOYSA-N 0.000 description 1
- 102000001332 SRC Human genes 0.000 description 1
- 108060006706 SRC Proteins 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 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 description 1
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- 229920002807 Thiomer Polymers 0.000 description 1
- 102000006601 Thymidine Kinase Human genes 0.000 description 1
- 108020004440 Thymidine kinase Proteins 0.000 description 1
- 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 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 102100022596 Tyrosine-protein kinase ABL1 Human genes 0.000 description 1
- 102000004504 Urokinase Plasminogen Activator Receptors Human genes 0.000 description 1
- 108010042352 Urokinase Plasminogen Activator Receptors Proteins 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 229940022663 acetate Drugs 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000005041 acyloxyalkyl group Chemical group 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229940040563 agaric acid Drugs 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000003432 anti-folate effect Effects 0.000 description 1
- 230000001740 anti-invasion Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000002137 anti-vascular effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940127074 antifolate Drugs 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000003080 antimitotic agent Substances 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 229940027983 antiseptic and disinfectant quaternary ammonium compound Drugs 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 description 1
- 229950010993 atrasentan Drugs 0.000 description 1
- MOTJMGVDPWRKOC-QPVYNBJUSA-N atrasentan Chemical compound C1([C@H]2[C@@H]([C@H](CN2CC(=O)N(CCCC)CCCC)C=2C=C3OCOC3=CC=2)C(O)=O)=CC=C(OC)C=C1 MOTJMGVDPWRKOC-QPVYNBJUSA-N 0.000 description 1
- 239000003719 aurora kinase inhibitor Substances 0.000 description 1
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 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
- 229960000997 bicalutamide Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- 235000010338 boric acid Nutrition 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- 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 1
- 229960003736 bosutinib Drugs 0.000 description 1
- UBPYILGKFZZVDX-UHFFFAOYSA-N bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- CUWODFFVMXJOKD-UVLQAERKSA-N buserelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 description 1
- 229960002719 buserelin Drugs 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- 229950002826 canertinib Drugs 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 229960004424 carbon dioxide Drugs 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229960002412 cediranib Drugs 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 229960001927 cetylpyridinium chloride Drugs 0.000 description 1
- NFCRBQADEGXVDL-UHFFFAOYSA-M cetylpyridinium chloride monohydrate Chemical compound O.[Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 NFCRBQADEGXVDL-UHFFFAOYSA-M 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- DGLFSNZWRYADFC-UHFFFAOYSA-N chembl2334586 Chemical compound C1CCC2=CN=C(N)N=C2C2=C1NC1=CC=C(C#CC(C)(O)C)C=C12 DGLFSNZWRYADFC-UHFFFAOYSA-N 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 235000019398 chlorine dioxide Nutrition 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940046044 combinations of antineoplastic agent Drugs 0.000 description 1
- 229960005537 combretastatin A-4 Drugs 0.000 description 1
- HVXBOLULGPECHP-UHFFFAOYSA-N combretastatin A4 Natural products C1=C(O)C(OC)=CC=C1C=CC1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-UHFFFAOYSA-N 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000002875 cyclin dependent kinase inhibitor Substances 0.000 description 1
- 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960000978 cyproterone acetate Drugs 0.000 description 1
- UWFYSQMTEOIJJG-FDTZYFLXSA-N cyproterone acetate Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 UWFYSQMTEOIJJG-FDTZYFLXSA-N 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin 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(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- CFCUWKMKBJTWLW-UHFFFAOYSA-N deoliosyl-3C-alpha-L-digitoxosyl-MTM Natural products CC=1C(O)=C2C(O)=C3C(=O)C(OC4OC(C)C(O)C(OC5OC(C)C(O)C(OC6OC(C)C(O)C(C)(O)C6)C5)C4)C(C(OC)C(=O)C(O)C(C)O)CC3=CC2=CC=1OC(OC(C)C1O)CC1OC1CC(O)C(O)C(C)O1 CFCUWKMKBJTWLW-UHFFFAOYSA-N 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229960000633 dextran sulfate Drugs 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 229940042935 dichlorodifluoromethane Drugs 0.000 description 1
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 description 1
- 229960005156 digoxin Drugs 0.000 description 1
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 229950004203 droloxifene Drugs 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000002308 endothelin receptor antagonist Substances 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 229940082789 erbitux Drugs 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 description 1
- 229960001596 famotidine Drugs 0.000 description 1
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 1
- 229960004039 finasteride Drugs 0.000 description 1
- 150000005699 fluoropyrimidines Chemical class 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 description 1
- 229960002913 goserelin Drugs 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 108010037536 heparanase Proteins 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 239000002554 heparinoid Substances 0.000 description 1
- 229940025770 heparinoids Drugs 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- DOUHZFSGSXMPIE-UHFFFAOYSA-N hydroxidooxidosulfur(.) Chemical compound [O]SO DOUHZFSGSXMPIE-UHFFFAOYSA-N 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 238000005417 image-selected in vivo spectroscopy Methods 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 238000012739 integrated shape imaging system Methods 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 229940028885 interleukin-4 Drugs 0.000 description 1
- 210000003228 intrahepatic bile duct Anatomy 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000004922 lacquer Substances 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960004891 lapatinib Drugs 0.000 description 1
- 210000000867 larynx Anatomy 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
- 229960004338 leuprorelin Drugs 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- DHMTURDWPRKSOA-RUZDIDTESA-N lonafarnib Chemical compound C1CN(C(=O)N)CCC1CC(=O)N1CCC([C@@H]2C3=C(Br)C=C(Cl)C=C3CCC3=CC(Br)=CN=C32)CC1 DHMTURDWPRKSOA-RUZDIDTESA-N 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229950008959 marimastat Drugs 0.000 description 1
- OCSMOTCMPXTDND-OUAUKWLOSA-N marimastat Chemical compound CNC(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC(C)C)[C@H](O)C(=O)NO OCSMOTCMPXTDND-OUAUKWLOSA-N 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960004296 megestrol acetate Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- 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 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 239000003475 metalloproteinase inhibitor Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- 108020001162 nitroreductase Proteins 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 229920004905 octoxynol-10 Polymers 0.000 description 1
- 229920004914 octoxynol-40 Polymers 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- JLPDBLFIVFSOCC-XYXFTTADSA-N oleandrin Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1C[C@@H](CC[C@H]2[C@]3(C[C@@H]([C@@H]([C@@]3(C)CC[C@H]32)C=2COC(=O)C=2)OC(C)=O)O)[C@]3(C)CC1 JLPDBLFIVFSOCC-XYXFTTADSA-N 0.000 description 1
- 229950010050 oleandrin Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 210000004798 organs belonging to the digestive system Anatomy 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 229960001972 panitumumab Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 description 1
- 229940043138 pentosan polysulfate Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000011129 pharmaceutical packaging material Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002935 phosphatidylinositol 3 kinase inhibitor Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229950005134 polycarbophil Drugs 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229920000151 polyglycol Polymers 0.000 description 1
- 239000010695 polyglycol Substances 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 229940095055 progestogen systemic hormonal contraceptives Drugs 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 1
- 230000029983 protein stabilization Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 230000000541 pulsatile effect Effects 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 description 1
- 229960000620 ranitidine Drugs 0.000 description 1
- 229940124617 receptor tyrosine kinase inhibitor Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 210000004994 reproductive system Anatomy 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 229960003522 roquinimex Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229950009919 saracatinib Drugs 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- KYITYFHKDODNCQ-UHFFFAOYSA-M sodium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [Na+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 KYITYFHKDODNCQ-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- IVDHYUQIDRJSTI-UHFFFAOYSA-N sorafenib tosylate Chemical compound [H+].CC1=CC=C(S([O-])(=O)=O)C=C1.C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 IVDHYUQIDRJSTI-UHFFFAOYSA-N 0.000 description 1
- 229940075554 sorbate Drugs 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 229960004906 thiomersal Drugs 0.000 description 1
- DHCDFWKWKRSZHF-UHFFFAOYSA-L thiosulfate(2-) Chemical compound [O-]S([S-])(=O)=O DHCDFWKWKRSZHF-UHFFFAOYSA-L 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- PLHJCIYEEKOWNM-HHHXNRCGSA-N tipifarnib Chemical compound CN1C=NC=C1[C@](N)(C=1C=C2C(C=3C=C(Cl)C=CC=3)=CC(=O)N(C)C2=CC=1)C1=CC=C(Cl)C=C1 PLHJCIYEEKOWNM-HHHXNRCGSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 210000002105 tongue Anatomy 0.000 description 1
- 239000012443 tonicity enhancing agent Substances 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 229960002647 warfarin sodium Drugs 0.000 description 1
- 229920003176 water-insoluble polymer Polymers 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- BACKGROUND OF THE INVENTION Cancer can be viewed as a breakdown in the communication between tumor cells and their environment, including their normal neighboring cells. Signals, both growth-stimulatory and growth-inhibitory, are routinely exchanged between cells within a tissue.
- Cardiotonic steroids like digoxin and digitoxin are a class of naturally derived compounds that bind to and inhibit Na + /K + -ATPase (sodium pump). Members of this family have been used for the treatment of heart failure and arrhythmia for many years. Recent findings have revealed that these compounds may be involved in the regulation of several important cellular processes.
- the disclosure provides a crystalline form of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate phosphate (Compound A phosphate), wherein the crystalline form is Crystalline Form I, further wherein Crystalline Form I is characterized by: (a) an X-ray powder diffraction pattern comprising peaks at 13.1 ⁇ 0.2° 2- ⁇ , 13.7 ⁇ 0.2° 2- ⁇ , and 15.6 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ ; WSGR
- Crystalline Form I is characterized by an X-ray powder diffraction pattern comprising peaks at 13.1 ⁇ 0.2° 2- ⁇ , 13.7 ⁇ 0.2° 2- ⁇ , and 15.6 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern further comprises at least one peak selected from 16.2 ⁇ 0.2° 2- ⁇ , 20.7 ⁇ 0.2° 2- ⁇ , and 19.4 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern further comprises at least one peak selected from 14.8 ⁇ 0.2° 2- ⁇ , 21.8 ⁇ 0.2° 2- ⁇ , and 17.0 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least five peaks selected from 13.1 ⁇ 0.2° 2- ⁇ , 13.7 ⁇ 0.2° 2- ⁇ , 15.6 ⁇ 0.2° 2- ⁇ , 16.2 ⁇ 0.2° 2- ⁇ , 20.7 ⁇ 0.2° 2- ⁇ , 19.4 ⁇ 0.2° 2- ⁇ , 14.8 ⁇ 0.2° 2- ⁇ , 21.8 ⁇ 0.2° 2- ⁇ , and 17.0 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises peaks at 13.1 ⁇ 0.2° 2- ⁇ , 13.7 ⁇ 0.2° 2- ⁇ , 15.6 ⁇ 0.2° 2- ⁇ , 16.2 ⁇ 0.2° 2- ⁇ , 20.7 ⁇ 0.2° 2- ⁇ , 19.4 ⁇ 0.2° 2- ⁇ , 14.8 ⁇ 0.2° 2- ⁇ , 21.8 ⁇ 0.2° 2- ⁇ , and 17.0 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- Crystalline Form I is characterized by an X-ray powder diffraction pattern substantially the same as shown in Figure 1.
- Crystalline Form I is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 280–295 °C. In some embodiments, Crystalline Form I is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 283 °C and a peak of about WSGR Docket No.43629-723.601 291 °C. In some embodiments, Crystalline Form I is characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 2.
- DSC differential scanning calorimetry
- Crystalline Form I is characterized by a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 3.
- TGA Thermogravimetric Analysis
- DFS dynamic vapor sorption
- the disclosure provides a crystalline form of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate mesylate (Compound A mesylate), wherein the crystalline form is Crystalline Form II, further wherein Crystalline Form II is characterized by: (a) an X-ray powder diffraction pattern comprising peaks at 13.8 ⁇ 0.2° 2- ⁇ , 20.4 ⁇ 0.2° 2- ⁇ , and 17.9 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ ; (b) an X-ray powder diffraction pattern substantially the same as shown in Figure 5; (c) a differential scanning calorimetry (DSC) thermogram comprising peaks at 13.8
- Crystalline Form II is characterized by an X-ray powder diffraction pattern comprising peaks at 13.8 ⁇ 0.2° 2- ⁇ , 20.4 ⁇ 0.2° 2- ⁇ , and 17.9 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern further comprises at least one peak selected from 19.4 ⁇ 0.2° 2- ⁇ , 15.1 ⁇ 0.2° 2- ⁇ , and 10.2 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern further comprises at least one peak selected from 27.3 ⁇ 0.2° 2- ⁇ , 12.6 ⁇ 0.2° 2- ⁇ , and 25.4 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of WSGR Docket No.43629-723.601 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least five peaks selected from 13.8 ⁇ 0.2° 2- ⁇ , 20.4 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 19.4 ⁇ 0.2° 2- ⁇ , 15.1 ⁇ 0.2° 2- ⁇ , 10.2 ⁇ 0.2° 2- ⁇ , 27.3 ⁇ 0.2° 2- ⁇ , 12.6 ⁇ 0.2° 2- ⁇ , and 25.4 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises peaks at 13.8 ⁇ 0.2° 2- ⁇ , 20.4 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 19.4 ⁇ 0.2° 2- ⁇ , 15.1 ⁇ 0.2° 2- ⁇ , 10.2 ⁇ 0.2° 2- ⁇ , 27.3 ⁇ 0.2° 2- ⁇ , 12.6 ⁇ 0.2° 2- ⁇ , and 25.4 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- Crystalline Form II is characterized by an X-ray powder diffraction pattern substantially the same as shown in Figure 5.
- Crystalline Form II is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 250–265 °C. In some embodiments, Crystalline Form II is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 255 °C and a peak of about 259 °C. In some embodiments, Crystalline Form II is characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 6. [13] In some embodiments, Crystalline Form II is characterized by a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 7.
- DSC differential scanning calorimetry
- Crystalline Form II is characterized by a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 8.
- the disclosure provides a crystalline form of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate tartrate (Compound A tartrate), wherein the crystalline form is Crystalline Form III, further wherein Crystalline Form III is characterized by: (a) an X-ray powder diffraction pattern comprising peaks at 10.1 ⁇ 0.2° 2- ⁇ , 13.5 ⁇ 0.2° 2- ⁇ , and 19.6 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ ; (b) an X-ray
- Crystalline Form III is characterized by an X-ray powder diffraction pattern comprising peaks at 10.1 ⁇ 0.2° 2- ⁇ , 13.5 ⁇ 0.2° 2- ⁇ , and 19.6 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern further comprises at least one peak selected from 20.3 ⁇ 0.2° 2- ⁇ , 15.6 ⁇ 0.2° 2- ⁇ , and 17.9 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern further comprises at least one peak selected from 22.8 ⁇ 0.2° 2- ⁇ , 17.3 ⁇ 0.2° 2- ⁇ , and 16.9 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least five peaks selected from 10.1 ⁇ 0.2° 2- ⁇ , 13.5 ⁇ 0.2° 2- ⁇ , 19.6 ⁇ 0.2° 2- ⁇ , 20.3 ⁇ 0.2° 2- ⁇ , 15.6 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 22.8 ⁇ 0.2° 2- ⁇ , 17.3 ⁇ 0.2° 2- ⁇ , and 16.9 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises peaks at 10.1 ⁇ 0.2° 2- ⁇ , 13.5 ⁇ 0.2° 2- ⁇ , 19.6 ⁇ 0.2° 2- ⁇ , 20.3 ⁇ 0.2° 2- ⁇ , 15.6 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 22.8 ⁇ 0.2° 2- ⁇ , 17.3 ⁇ 0.2° 2- ⁇ , and 16.9 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- Crystalline Form III is characterized by an X-ray powder diffraction pattern substantially the same as shown in Figure 9.
- Crystalline Form III is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 245–265 °C. In some embodiments, Crystalline Form III is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 250 °C and a peak of about 258 °C. In some embodiments, Crystalline Form III is characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 10. [18] In some embodiments, Crystalline Form III is characterized by a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 11.
- DSC differential scanning calorimetry
- Crystalline Form III is characterized by a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 12.
- the disclosure provides a crystalline form of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- WSGR Docket No.43629-723.601 yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate citrate (Compound A citrate), wherein the crystalline form is Crystalline IV, further wherein Crystalline Form IV is characterized by: (a) an X-ray powder diffraction pattern comprising peaks at 14.3 ⁇ 0.2° 2- ⁇ , 16.5 ⁇ 0.2° 2- ⁇ , and 17.0 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of
- Crystalline Form IV is characterized by an X-ray powder diffraction pattern comprising peaks at 14.3 ⁇ 0.2° 2- ⁇ , 16.5 ⁇ 0.2° 2- ⁇ , and 17.0 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern further comprises at least one peak selected from 15.8 ⁇ 0.2° 2- ⁇ , 15.1 ⁇ 0.2° 2- ⁇ , and 10.7 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern further comprises at least one peak selected from 17.9 ⁇ 0.2° 2- ⁇ , 20.9 ⁇ 0.2° 2- ⁇ , and 22.0 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least five peaks selected from 14.3 ⁇ 0.2° 2- ⁇ , 16.5 ⁇ 0.2° 2- ⁇ , 17.0 ⁇ 0.2° 2- ⁇ , 15.8 ⁇ 0.2° 2- ⁇ , 15.1 ⁇ 0.2° 2- ⁇ , 10.7 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 20.9 ⁇ 0.2° 2- ⁇ , and 22.0 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises peaks at 14.3 ⁇ 0.2° 2- ⁇ , 16.5 ⁇ 0.2° 2- ⁇ , 17.0 ⁇ 0.2° 2- ⁇ , 15.8 ⁇ 0.2° 2- ⁇ , 15.1 ⁇ 0.2° 2- ⁇ , 10.7 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 20.9 ⁇ 0.2° 2- ⁇ , and 22.0 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- Crystalline Form IV is characterized by an X-ray powder diffraction pattern substantially the same as shown in Figure 13.
- Crystalline Form IV is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 230–250 °C. In some embodiments, Crystalline Form IV is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 235 °C and a peak of about 242 °C. In some embodiments, Crystalline Form IV is characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 14. [23] In some embodiments, Crystalline Form IV is characterized by a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 15.
- DSC differential scanning calorimetry
- Crystalline Form IV is characterized by a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 16.
- the disclosure provides a pharmaceutical composition comprising a crystalline form of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate phosphate, (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate mesylate, (3S,5R,8R,9S,10S,13R,
- the pharmaceutical composition is formulated for administration to a mammal by oral administration.
- the pharmaceutical composition is in the form of a solid form pharmaceutical composition.
- the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a powder, a liquid, a suspension, a suppository, or an aerosol.
- the disclosure provides a packaged pharmaceutical composition comprising a pharmaceutical composition provided herein and instructions for using the composition to treat a subject suffering from cancer.
- the disclosure provides a method of treating a neoplasm in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the crystalline form of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate phosphate, (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- WSGR Docket No.43629-723.601 yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate mesylate, (3S,5R,8R,9S,
- the neoplasm is a cancer.
- the cancer is colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chondroma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, chori
- the cancer is colorectal cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is oral cancer. In some embodiments, the neoplasm is a benign tumor. In some embodiments, the tumor is craniopharyngioma.
- the disclosure provides a method of preparing Crystalline Form I of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate phosphate, wherein the method comprises: (a) contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate with phosphoric acid in a solvent to obtain a solution of the WSGR Docket No.43629-723.601 (3S,5R,8R,9S,10S,13R,
- the solvent in step (a) comprises ethyl acetate, DMF, ethanol, or isopropanol. In some embodiments, the solvent in step (a) comprises DMF. In some embodiments, step (a) is performed at a temperature of about 40–70 °C. In some embodiments, step (a) is performed at a temperature of about 50–60 °C. [30] In some embodiments, step (b) comprises cooling the solution obtained in step (a) to room temperature. In some embodiments, step (b) comprises cooling the solution obtained in step (a) to a temperature of about 20–25 °C. In some embodiments, the method further comprises filtering the crystallized solution obtained in step (b) to obtain Crystalline Form I.
- the method further comprises drying the obtained Crystalline Form I.
- the drying is performed under vacuum at a temperature of about 40–70 °C. In some embodiments, the drying is performed under vacuum at a temperature of about 50– 60 °C.
- the disclosure provides a method of preparing Crystalline Form II of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate mesylate, wherein the method comprises: (a) contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate with methanesulfonic acid in a solvent to obtain a solution of the (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10
- the solvent in step (a) comprises ethyl acetate, DMF, ethanol, or isopropanol. In some embodiments, the solvent in step (a) comprises DMF. In some WSGR Docket No.43629-723.601 embodiments, step (a) is performed at a temperature of about 40–70 °C. In some embodiments, step (a) is performed at a temperature of about 50–60 °C. [33] In some embodiments, step (b) comprises cooling the solution obtained in step (a) to room temperature. In some embodiments, step (b) comprises cooling the solution obtained in step (a) to a temperature of about 20–25 °C.
- the method further comprises filtering the crystallized solution obtained in step (b) to obtain Crystalline Form II. In some embodiments, the method further comprises drying the obtained Crystalline Form II. In some embodiments, the drying is performed under vacuum at a temperature of about 40–70 °C. In some embodiments, the drying is performed under vacuum at a temperature of about 50– 60 °C.
- the disclosure provides a method of preparing Crystalline Form III of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate tartrate, wherein the method comprises: (a) contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate with tartaric acid in a solvent to obtain a solution of the (3S,5R,8R,9S,10S,13R,14S,17R)- 14-hydroxy-10,13-di
- the solvent in step (a) comprises ethyl acetate, DMF, ethanol, or isopropanol. In some embodiments, the solvent in step (a) comprises DMF. In some embodiments, step (a) is performed at a temperature of about 40–70 °C. In some embodiments, step (a) is performed at a temperature of about 50–60 °C. [36] In some embodiments, step (b) comprises cooling the solution obtained in step (a) to room temperature. In some embodiments, step (b) comprises cooling the solution obtained in step (a) to a temperature of about 20–25 °C. In some embodiments, the method further comprises filtering the crystallized solution obtained in step (b) to obtain Crystalline Form III.
- the method further comprises drying the obtained Crystalline Form III. In some embodiments, the drying is performed under vacuum at a temperature of about 40–70 °C. In some embodiments, the drying is performed under vacuum at a temperature of about 50– 60 °C.
- the disclosure provides a method of preparing Crystalline Form IV of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate citrate, wherein the method comprises: (a) contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate with citric acid in a solvent to obtain a solution of the (3S,5R,8R,9S,10S,13R,14S
- the solvent in step (a) comprises ethyl acetate, DMF, ethanol, or isopropanol. In some embodiments, the solvent in step (a) comprises DMF. In some embodiments, step (a) is performed at a temperature of about 40–70 °C. In some embodiments, step (a) is performed at a temperature of about 50–60 °C. [39] In some embodiments, step (b) comprises cooling the solution obtained in step (a) to room temperature. In some embodiments, step (b) comprises cooling the solution obtained in step (a) to a temperature of about 20–25 °C. In some embodiments, the method further comprises filtering the crystallized solution obtained in step (b) to obtain Crystalline Form IV.
- the method further comprises drying the obtained Crystalline Form IV.
- the drying is performed under vacuum at a temperature of about 40–70 °C.
- the drying is performed under vacuum at a temperature of about 50– 60 °C.
- FIG. 1 shows the X-ray powder diffraction (XRPD) pattern for Crystalline Form I of Compound A phosphate.
- Figure 2 shows the differential scanning calorimetry (DSC) thermogram for Crystalline Form I of Compound A phosphate.
- Figure 3 shows the thermogravimetric analysis (TGA) pattern for Crystalline Form I of Compound A phosphate.
- Figure 4 shows the dynamic vapor sorption (DVS) pattern for Crystalline Form I of Compound A phosphate.
- Figure 5 shows the X-ray powder diffraction (XRPD) pattern for Crystalline Form II of Compound A mesylate.
- Figure 6 shows the differential scanning calorimetry (DSC) thermogram for Crystalline Form II of Compound A mesylate.
- Figure 7 shows the thermogravimetric analysis (TGA) pattern for Crystalline Form II of Compound A mesylate.
- Figure 8 shows the dynamic vapor sorption (DVS) pattern for Crystalline Form II of Compound A mesylate.
- Figure 9 shows the X-ray powder diffraction (XRPD) pattern for Crystalline Form III of Compound A tartrate.
- FIG. 10 shows the differential scanning calorimetry (DSC) thermogram for Crystalline Form III of Compound A tartrate.
- Figure 11 shows the thermogravimetric analysis (TGA) pattern for Crystalline Form III of Compound A tartrate.
- Figure 12 shows the dynamic vapor sorption (DVS) pattern for Crystalline Form III of Compound A tartrate.
- Figure 13 shows the X-ray powder diffraction (XRPD) pattern for Crystalline Form IV of Compound A citrate.
- Figure 14 shows the differential scanning calorimetry (DSC) thermogram for Crystalline Form IV of Compound A citrate.
- Figure 15 shows the thermogravimetric analysis (TGA) pattern for Crystalline Form IV of Compound A citrate.
- Figure 16 shows the dynamic vapor sorption (DVS) pattern for Crystalline Form IV of Compound A citrate.
- WSGR Docket No.43629-723.601 DETAILED DESCRIPTION OF THE INVENTION
- Polymorphic forms of a drug substance can have different physical properties, including melting point, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct effect on the ability to process or manufacture a drug substance and the drug product. Moreover, differences in these properties can and often lead to different pharmacokinetics profiles for different polymorphic forms of a drug.
- polymorphism is often an important factor under regulatory review of the ‘sameness’ of drug products from various manufacturers.
- polymorphism has been evaluated in many multi-million dollar and even multi-billion dollar drugs, such as warfarin sodium, famotidine, and ranitidine.
- Polymorphism can affect the quality, safety, and/or efficacy of a drug product.
- the present disclosure addresses this need and provides related advantages as well.
- Compound A refers to (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate, which has the chemical structure shown below: Compound A.
- Compound A has been prepared previously (see, WO 2011/085641, U.S. Patent No. 8,334,376, U.S. Patent No.8,993,550, U.S. Patent No.9,399,659, U.S. Patent No.9,814,735, U.S.
- Compound A is crystalline.
- the salt of Compound A is a phosphate salt, mesylate salt, tartrate salt, or citrate salt.
- the salt of Compound A is a phosphate salt.
- the salt of Compound A is a mesylate salt.
- the salt of Compound A is a tartrate salt. In some embodiments disclosed herein, the salt of Compound A is a citrate salt. [63] In some embodiments disclosed herein, the salt of Compound A is crystalline. In some embodiments disclosed herein, the salt of Compound A is a crystalline phosphate salt, crystalline mesylate salt, crystalline tartrate salt, or crystalline citrate salt. In some embodiments disclosed herein, the salt of Compound A is a crystalline phosphate salt. In some embodiments disclosed herein, the salt of Compound A is a crystalline mesylate salt.
- the salt of Compound A is a crystalline tartrate salt. In some embodiments disclosed herein, the salt of Compound A is a crystalline citrate salt.
- “crystalline form,” “polymorph,” “Form,” and “form” may be used interchangeably herein, and are meant to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to.
- Compounds of the present disclosure include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
- the crystalline form is a single solid-state form, e.g., crystalline Form I.
- Crystalline Forms of Compound A [65]
- the polymorphs made according to the methods of the invention may be characterized by any methodology according to the art.
- the polymorphs made according to the methods of the invention may be characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-stage microscopy, and/or spectroscopy (e.g., Raman, solid state nuclear magnetic resonance (ssNMR), and infrared (IR)).
- XRPD X-ray Powder Diffraction
- DSC differential scanning calorimetry
- TGA thermogravimetric analysis
- IR infrared
- crystallinity of a solid form is determined by X-Ray Powder Diffraction (XRPD).
- XRPD X-Ray Powder Diffraction
- Polymorphs according to the invention may be characterized by XRPD. The relative intensities of XRPD peaks can vary, depending upon the particle size, the sample preparation technique, the sample mounting procedure and the particular instrument employed.
- DSC Polymorphs according to the invention can also be identified by its characteristic DSC thermograms such as shown in Figures 2, 6, etc. For DSC, it is known that the WSGR Docket No.43629-723.601 temperatures observed will depend upon the rate of temperature change as well as sample preparation technique and the particular instrument employed. Thus, the values reported herein relating to DSC thermograms can vary, for example by plus or minus about 4 °C.
- TGA The polymorphic forms of the invention may also give rise to thermal behavior different from that of the amorphous material or another polymorphic form.
- Thermal behavior may be measured in the laboratory by thermogravimetric analysis (TGA) which may be used to distinguish some polymorphic forms from others.
- TGA thermogravimetric analysis
- the polymorph may be characterized by thermogravimetric analysis.
- the polymorph forms of Compound A are useful in the production of medicinal preparations and can be obtained by means of a crystallization process to produce crystalline and semi-crystalline forms or a solidification process to obtain the amorphous form.
- the crystallization is carried out by either generating the desired compound (for example Compound A) in a reaction mixture and isolating the desired polymorph from the reaction mixture, or by dissolving raw compound in a solvent, optionally with heat, followed by crystallizing/solidifying the product by cooling (including active cooling) and/or by the addition of an antisolvent for a period of time.
- the crystallization or solidification may be followed by drying carried out under controlled conditions until the desired water content is reached in the end polymorphic form.
- the various polymorph Forms disclosed herein e.g., Crystalline Form I, Crystalline Form II, Crystalline Form III, and Crystalline Form IV of Compound A
- the various polymorphs can be stored at room temperature for an extended period of time without significant chemical degradation or change in the crystalline form. In some examples, the various polymorphs can be stored at room temperature for a time period of at least about 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, 30 months, or 36 months. In some examples, the various polymorphs can be stored at room temperature for a time period of more than about 36 months.
- the various polymorphs can be stored at room temperature for a time period of 1–2 months, 1–3 months, 1–6 months, 1–9 months, 1–12 months, 1–18 months, 1–24 months, 1–30 months, 1–36 months, 2–3 months, 2–6 months, 2–9 months, 2–12 months, 2–18 months, 2–24 months, 2–30 months, 2–36 months, 3–6 months, 3–9 months, 3–12 months, 3–18 months, 3–24 months, 3–30 months, 3–36 months, 6–9 months, 6–12 months, 6–18 months, 6– 24 months, 6–30 months, 6–36 months, 9–12 months, 9–18 months, 9–24 months, 9–30 months, 9–36 months, 12–18 months, 12–24 months, 12–30 months, 12–36 months, 18–24 months, 18– 30 months, 18–36 months, 24–30 months, 24–36 months, or 30–36 months.
- the various polymorphs can be stored at room temperature for a time period of at least 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, 30 months, or 36 months.
- the various polymorph Forms disclosed herein e.g., Crystalline Form I, Crystalline Form II, Crystalline Form III, and Crystalline Form IV of Compound A
- RH relative humidity
- the various polymorph Forms disclosed herein can be stored at about 40 °C at about 75% RH for an extended period of time without significant chemical degradation or change in the crystalline form.
- the various polymorph Forms disclosed herein e.g., Crystalline Form I, Crystalline Form II, Crystalline Form III, and Crystalline Form IV of Compound A
- the various polymorph Forms disclosed herein can be stored at 40 °C and at about 75% RH for a time period of more than about 180 days.
- the various polymorph Forms disclosed herein can be stored at 40 °C and at about 75% RH for a time period of 10–14 days, 10–18 days, 10–22 days, 10–26 days, 10– 30 days, 10–40 days, 10–50 days, 10–60 days, 10–90 days, 10–120 days, 10–150 days, 10–180 days, 14–18 days, 14–22 days, 14–26 days, 14–30 days, 14–40 days, 14–50 days, 14–60 days, 14–90 days, 14–120 days, 14–150 days, 14–180 days, 18–22 days, 18–26 days, 18–30 days, 18– 40 days, 18–50 days, 18–60 days, 18–90 days, 18–120 days, 18–150 days, 18–180 days, 18–22 days, 18–26 days, 18–30 days, 18– 40 days, 18–50 days, 18–60 days, 18–90 days, 18–120 days, 18–150 days, 18–180 days, 22–26 days, 22–30 days
- the various polymorph Forms disclosed herein can be stored at 40 °C at about 75% RH for a time period of at least 10 days, 14 days, 18 days, 22 days, 26 days, 30 days, 40 days, 50 days, 60 days, 90 days, 120 days, 150 days, or 180 days.
- Crystalline Form I of Compound A Phosphate WSGR Docket No.43629-723.601 [72] Figure 1 shows the X-ray powder diffraction (XRPD) pattern for Crystalline Form I of Compound A phosphate.
- FIG. 1 shows the differential scanning calorimetry (DSC) thermogram for Crystalline Form I of Compound A phosphate.
- FIG 3 shows the thermogravimetric analysis (TGA) pattern for Crystalline Form I of Compound A phosphate.
- Figure 4 shows the dynamic vapor sorption (DVS) pattern for Crystalline Form I of Compound A phosphate.
- compositions comprising Crystalline Form I of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate phosphate.
- Crystalline Form I of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate phosphate is characterized as having: (a) an X-ray powder diffraction pattern comprising peaks at 13.1 ⁇ 0.2° 2- ⁇ , 13.7 ⁇ 0.2° 2- ⁇ , and 15.6 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ ; (b) an X-ray powder diffraction pattern substantially the same as shown in Figure 1; (c) a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 280–295 °C; (d) a differential scanning calorimetry (DSC)
- Crystalline Form I is characterized by an X-ray powder diffraction pattern substantially the same as shown in Figure 1.
- WSGR Docket No.43629-723.601 [78]
- Crystalline Form I is characterized by an X-ray powder diffraction pattern comprising peaks at 13.1 ⁇ 0.2° 2- ⁇ , 13.7 ⁇ 0.2° 2- ⁇ , and 15.6 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- Crystalline Form I is characterized by an X-ray powder diffraction pattern comprising peaks at 13.1 ⁇ 0.1° 2- ⁇ , 13.7 ⁇ 0.1° 2- ⁇ , and 15.6 ⁇ 0.1° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ . In some embodiments, Crystalline Form I is characterized by an X-ray powder diffraction pattern comprising peaks at about 13.1° 2- ⁇ , about 13.7° 2- ⁇ , and about 15.6° 2- ⁇ , as measured by X-ray powder diffraction using an X- ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern further comprises at least one peak selected from 16.2 ⁇ 0.2° 2- ⁇ , 20.7 ⁇ 0.2° 2- ⁇ , and 19.4 ⁇ 0.2° 2- ⁇ , as measured by X- ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X- ray powder diffraction pattern further comprises at least one peak selected from 16.2 ⁇ 0.1° 2- ⁇ , 20.7 ⁇ 0.1° 2- ⁇ , and 19.4 ⁇ 0.1° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern further comprises at least one peak selected from about 16.2° 2- ⁇ , about 20.7° 2- ⁇ , and about 19.4° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ . [80] In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 14.8 ⁇ 0.2° 2- ⁇ , 21.8 ⁇ 0.2° 2- ⁇ , and 17.0 ⁇ 0.2° 2- ⁇ , as measured by X- ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X- ray powder diffraction pattern further comprises at least one peak selected from 14.8 ⁇ 0.1° 2- ⁇ , 21.8 ⁇ 0.1° 2- ⁇ , and 17.0 ⁇ 0.1° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ . In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from about 14.8° 2- ⁇ , about 21.8° 2- ⁇ , and about 17.0° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least one peak selected from 13.1 ⁇ 0.2° 2- ⁇ , 13.7 ⁇ 0.2° 2- ⁇ , 15.6 ⁇ 0.2° 2- ⁇ , 16.2 ⁇ 0.2° 2- ⁇ , 20.7 ⁇ 0.2° 2- ⁇ , 19.4 ⁇ 0.2° 2- ⁇ , 14.8 ⁇ 0.2° 2- ⁇ , 21.8 ⁇ 0.2° 2- ⁇ , and 17.0 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least two peaks selected from 13.1 ⁇ 0.2° 2- ⁇ , 13.7 ⁇ 0.2° 2- ⁇ , 15.6 ⁇ 0.2° 2- ⁇ , 16.2 ⁇ 0.2° 2- ⁇ , 20.7 ⁇ 0.2° 2- ⁇ , 19.4 ⁇ 0.2° 2- ⁇ , 14.8 ⁇ 0.2° 2- ⁇ , 21.8 ⁇ 0.2° 2- ⁇ , and 17.0 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least three peaks selected from 13.1 ⁇ 0.2° 2- ⁇ , 13.7 ⁇ 0.2° 2- ⁇ , 15.6 ⁇ 0.2° 2- ⁇ , WSGR Docket No.43629-723.601 16.2 ⁇ 0.2° 2- ⁇ , 20.7 ⁇ 0.2° 2- ⁇ , 19.4 ⁇ 0.2° 2- ⁇ , 14.8 ⁇ 0.2° 2- ⁇ , 21.8 ⁇ 0.2° 2- ⁇ , and 17.0 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least four peaks selected from 13.1 ⁇ 0.2° 2- ⁇ , 13.7 ⁇ 0.2° 2- ⁇ , 15.6 ⁇ 0.2° 2- ⁇ , 16.2 ⁇ 0.2° 2- ⁇ , 20.7 ⁇ 0.2° 2- ⁇ , 19.4 ⁇ 0.2° 2- ⁇ , 14.8 ⁇ 0.2° 2- ⁇ , 21.8 ⁇ 0.2° 2- ⁇ , and 17.0 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least five peaks selected from 13.1 ⁇ 0.2° 2- ⁇ , 13.7 ⁇ 0.2° 2- ⁇ , 15.6 ⁇ 0.2° 2- ⁇ , 16.2 ⁇ 0.2° 2- ⁇ , 20.7 ⁇ 0.2° 2- ⁇ , 19.4 ⁇ 0.2° 2- ⁇ , 14.8 ⁇ 0.2° 2- ⁇ , 21.8 ⁇ 0.2° 2- ⁇ , and 17.0 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least six peaks selected from 13.1 ⁇ 0.2° 2- ⁇ , 13.7 ⁇ 0.2° 2- ⁇ , 15.6 ⁇ 0.2° 2- ⁇ , 16.2 ⁇ 0.2° 2- ⁇ , 20.7 ⁇ 0.2° 2- ⁇ , 19.4 ⁇ 0.2° 2- ⁇ , 14.8 ⁇ 0.2° 2- ⁇ , 21.8 ⁇ 0.2° 2- ⁇ , and 17.0 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least seven peaks selected from 13.1 ⁇ 0.2° 2- ⁇ , 13.7 ⁇ 0.2° 2- ⁇ , 15.6 ⁇ 0.2° 2- ⁇ , 16.2 ⁇ 0.2° 2- ⁇ , 20.7 ⁇ 0.2° 2- ⁇ , 19.4 ⁇ 0.2° 2- ⁇ , 14.8 ⁇ 0.2° 2- ⁇ , 21.8 ⁇ 0.2° 2- ⁇ , and 17.0 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least eight peaks selected from 13.1 ⁇ 0.2° 2- ⁇ , 13.7 ⁇ 0.2° 2- ⁇ , 15.6 ⁇ 0.2° 2- ⁇ , 16.2 ⁇ 0.2° 2- ⁇ , 20.7 ⁇ 0.2° 2- ⁇ , 19.4 ⁇ 0.2° 2- ⁇ , 14.8 ⁇ 0.2° 2- ⁇ , 21.8 ⁇ 0.2° 2- ⁇ , and 17.0 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises peaks at 13.1 ⁇ 0.2° 2- ⁇ , 13.7 ⁇ 0.2° 2- ⁇ , 15.6 ⁇ 0.2° 2- ⁇ , 16.2 ⁇ 0.2° 2- ⁇ , 20.7 ⁇ 0.2° 2- ⁇ , 19.4 ⁇ 0.2° 2- ⁇ , 14.8 ⁇ 0.2° 2- ⁇ , 21.8 ⁇ 0.2° 2- ⁇ , and 17.0 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises peaks at 13.1 ⁇ 0.1° 2- ⁇ , 13.7 ⁇ 0.1° 2- ⁇ , 15.6 ⁇ 0.1° 2- ⁇ , 16.2 ⁇ 0.1° 2- ⁇ , 20.7 ⁇ 0.1° 2- ⁇ , 19.4 ⁇ 0.1° 2- ⁇ , 14.8 ⁇ 0.1° 2- ⁇ , 21.8 ⁇ 0.1° 2- ⁇ , and 17.0 ⁇ 0.1° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises peaks at about 13.1° 2- ⁇ , about 13.7° 2- ⁇ , about 15.6° 2- ⁇ , about 16.2° 2- ⁇ , about 20.7° 2- ⁇ , about 19.4° 2- ⁇ , about 14.8° 2- ⁇ , about 21.8° 2- ⁇ , and about 17.0° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- Crystalline Form I is characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 2.
- Crystalline Form III is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 280–295 °C.
- WSGR Docket No.43629-723.601 Crystalline Form I is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 283 °C and a peak of about 291 °C.
- Crystalline Form I is characterized by an endotherm in the range of about 280–295 °C, for example at about 280–295 °C, 280–290 °C, 280–285 °C, 285–295 °C, 285–290 °C, or 290–295 °C in the DSC thermogram. In some examples, Crystalline Form I is characterized by an endotherm at about 291 °C in the DSC thermogram. [84] In some embodiments, Crystalline Form I is characterized by a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 3.
- TGA Thermogravimetric Analysis
- Crystalline Form I decomposes above a temperature of about 150 °C, about 200 °C, about 250 °C, about 300 °C, about 350 °C, about 400 °C, about 450 °C, about 500 °C, about 550 °C or above 600 °C. In some examples, Crystalline Form I decomposes above a temperature of about 250 °C. [85] In some embodiments, Crystalline Form I is characterized by a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 4. Crystalline Form II of Compound A Mesylate [86] Figure 5 shows the X-ray powder diffraction (XRPD) pattern for Crystalline Form II of Compound A mesylate.
- XRPD X-ray powder diffraction
- FIG. 6 shows the differential scanning calorimetry (DSC) thermogram for Crystalline Form II of Compound A mesylate.
- FIG 7 shows the thermogravimetric analysis (TGA) pattern for Crystalline Form II of Compound A mesylate.
- Figure 8 shows the dynamic vapor sorption (DVS) pattern for Crystalline Form II of Compound A mesylate.
- compositions comprising Crystalline Form II of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate mesylate.
- Crystalline Form II of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate mesylate is characterized as having: WSGR Docket No.43629-723.601 (a) an X-ray powder diffraction pattern comprising peaks at 13.8 ⁇ 0.2° 2- ⁇ , 20.4 ⁇ 0.2° 2- ⁇ , and 17.9 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ ; (b) an X-ray powder diffraction pattern substantially the same as shown in Figure 5; (c) a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 250–265 °C;
- DSC
- Crystalline Form II is characterized by an X-ray powder diffraction pattern substantially the same as shown in Figure 5.
- Crystalline Form II is characterized by an X-ray powder diffraction pattern comprising peaks at 13.8 ⁇ 0.2° 2- ⁇ , 20.4 ⁇ 0.2° 2- ⁇ , and 17.9 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- Crystalline Form IV is characterized by an X-ray powder diffraction pattern comprising peaks at 13.8 ⁇ 0.1° 2- ⁇ , 20.4 ⁇ 0.1° 2- ⁇ , and 17.9 ⁇ 0.1° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ . In some embodiments, Crystalline Form IV is characterized by an X-ray powder diffraction pattern comprising peaks at about 13.8° 2- ⁇ , about 20.4° 2- ⁇ , and about 17.9° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern further comprises at least one peak selected from 19.4 ⁇ 0.2° 2- ⁇ , 15.1 ⁇ 0.2° 2- ⁇ , and 10.2 ⁇ 0.2° 2- ⁇ , as measured by X- ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X- ray powder diffraction pattern further comprises at least one peak selected from 19.4 ⁇ 0.1° 2- ⁇ , 15.1 ⁇ 0.1° 2- ⁇ , and 10.2 ⁇ 0.1° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern further comprises at least one peak selected from about 19.4° 2- ⁇ , about 15.1° 2- ⁇ , and about 10.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- WSGR Docket No.43629-723.601 [94]
- the X-ray powder diffraction pattern further comprises at least one peak selected from 27.3 ⁇ 0.2° 2- ⁇ , 12.6 ⁇ 0.2° 2- ⁇ , and 25.4 ⁇ 0.2° 2- ⁇ , as measured by X- ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X- ray powder diffraction pattern further comprises at least one peak selected from 27.3 ⁇ 0.1° 2- ⁇ , 12.6 ⁇ 0.1° 2- ⁇ , and 25.4 ⁇ 0.1° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ . In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from about 27.3° 2- ⁇ , about 12.6° 2- ⁇ , and about 25.4° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least one peak selected from 13.8 ⁇ 0.2° 2- ⁇ , 20.4 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 19.4 ⁇ 0.2° 2- ⁇ , 15.1 ⁇ 0.2° 2- ⁇ , 10.2 ⁇ 0.2° 2- ⁇ , 27.3 ⁇ 0.2° 2- ⁇ , 12.6 ⁇ 0.2° 2- ⁇ , and 25.4 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least two peaks selected from 13.8 ⁇ 0.2° 2- ⁇ , 20.4 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 19.4 ⁇ 0.2° 2- ⁇ , 15.1 ⁇ 0.2° 2- ⁇ , 10.2 ⁇ 0.2° 2- ⁇ , 27.3 ⁇ 0.2° 2- ⁇ , 12.6 ⁇ 0.2° 2- ⁇ , and 25.4 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least three peaks selected from 13.8 ⁇ 0.2° 2- ⁇ , 20.4 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 19.4 ⁇ 0.2° 2- ⁇ , 15.1 ⁇ 0.2° 2- ⁇ , 10.2 ⁇ 0.2° 2- ⁇ , 27.3 ⁇ 0.2° 2- ⁇ , 12.6 ⁇ 0.2° 2- ⁇ , and 25.4 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least four peaks selected from 13.8 ⁇ 0.2° 2- ⁇ , 20.4 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 19.4 ⁇ 0.2° 2- ⁇ , 15.1 ⁇ 0.2° 2- ⁇ , 10.2 ⁇ 0.2° 2- ⁇ , 27.3 ⁇ 0.2° 2- ⁇ , 12.6 ⁇ 0.2° 2- ⁇ , and 25.4 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least five peaks selected from 13.8 ⁇ 0.2° 2- ⁇ , 20.4 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 19.4 ⁇ 0.2° 2- ⁇ , 15.1 ⁇ 0.2° 2- ⁇ , 10.2 ⁇ 0.2° 2- ⁇ , 27.3 ⁇ 0.2° 2- ⁇ , 12.6 ⁇ 0.2° 2- ⁇ , and 25.4 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least six peaks selected from 13.8 ⁇ 0.2° 2- ⁇ , 20.4 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 19.4 ⁇ 0.2° 2- ⁇ , 15.1 ⁇ 0.2° 2- ⁇ , 10.2 ⁇ 0.2° 2- ⁇ , 27.3 ⁇ 0.2° 2- ⁇ , 12.6 ⁇ 0.2° 2- ⁇ , and 25.4 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least seven peaks selected from 13.8 ⁇ 0.2° 2- ⁇ , 20.4 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 19.4 ⁇ 0.2° 2- ⁇ , 15.1 ⁇ 0.2° 2- ⁇ , 10.2 ⁇ 0.2° 2- ⁇ , 27.3 ⁇ 0.2° 2- ⁇ , 12.6 ⁇ 0.2° 2- ⁇ , and 25.4 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least eight WSGR Docket No.43629-723.601 peaks selected from 13.8 ⁇ 0.2° 2- ⁇ , 20.4 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 19.4 ⁇ 0.2° 2- ⁇ , 15.1 ⁇ 0.2° 2- ⁇ , 10.2 ⁇ 0.2° 2- ⁇ , 27.3 ⁇ 0.2° 2- ⁇ , 12.6 ⁇ 0.2° 2- ⁇ , and 25.4 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises peaks at 13.8 ⁇ 0.2° 2- ⁇ , 20.4 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 19.4 ⁇ 0.2° 2- ⁇ , 15.1 ⁇ 0.2° 2- ⁇ , 10.2 ⁇ 0.2° 2- ⁇ , 27.3 ⁇ 0.2° 2- ⁇ , 12.6 ⁇ 0.2° 2- ⁇ , and 25.4 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises peaks at 13.8 ⁇ 0.1° 2- ⁇ , 20.4 ⁇ 0.1° 2- ⁇ , 17.9 ⁇ 0.1° 2- ⁇ , 19.4 ⁇ 0.1° 2- ⁇ , 15.1 ⁇ 0.1° 2- ⁇ , 10.2 ⁇ 0.1° 2- ⁇ , 27.3 ⁇ 0.1° 2- ⁇ , 12.6 ⁇ 0.1° 2- ⁇ , and 25.4 ⁇ 0.1° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises peaks at about 13.8° 2- ⁇ , about 20.4° 2- ⁇ , about 17.9° 2- ⁇ , about 19.4° 2- ⁇ , about 15.1° 2- ⁇ , about 10.2° 2- ⁇ , about 27.3° 2- ⁇ , about 12.6° 2- ⁇ , and about 25.4° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- Crystalline Form II is characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 6.
- Crystalline Form II is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 250–265 °C. In some embodiments, Crystalline Form II is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 255 °C and a peak of about 259 °C.
- DSC differential scanning calorimetry
- Crystalline Form II is characterized by an endotherm in the range of about 250–265 °C, for example at about 250–265 °C, 250–260 °C, 250–255 °C, 255–265 °C, 255–260 °C, or 260–265 °C in the DSC thermogram. In some examples, Crystalline Form II is characterized by an endotherm at about 259 °C in the DSC thermogram. [98] In some embodiments, Crystalline Form II is characterized by a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 7.
- TGA Thermogravimetric Analysis
- Crystalline Form II decomposes above a temperature of about 150 °C, about 200 °C, about 250 °C, about 300 °C, about 350 °C, about 400 °C, about 450 °C, about 500 °C, about 550 °C or above 600 °C. In some examples, Crystalline Form II decomposes above a temperature of about 250 °C. [99] In some embodiments, Crystalline Form II is characterized by a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 8. Crystalline Form III of Compound A Tartrate [100] Figure 9 shows the X-ray powder diffraction (XRPD) pattern for Crystalline Form III of Compound A tartrate.
- XRPD X-ray powder diffraction
- Figure 10 shows the differential scanning calorimetry (DSC) thermogram for Crystalline Form III of Compound A tartrate.
- DSC differential scanning calorimetry
- Figure 11 shows the thermogravimetric analysis (TGA) pattern for Crystalline Form III of Compound A tartrate.
- Figure 12 shows the dynamic vapor sorption (DVS) pattern for Crystalline Form III of Compound A tartrate.
- compositions comprising Crystalline Form III of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate tartrate.
- Crystalline Form III of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate tartrate is characterized as having: (a) an X-ray powder diffraction pattern comprising peaks at 10.1 ⁇ 0.2° 2- ⁇ , 13.5 ⁇ 0.2° 2- ⁇ , and 19.6 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ ; (b) an X-ray powder diffraction pattern substantially the same as shown in Figure 9; (c) a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 245–265 °C; (d) a differential scanning calorimetry (DSC) thermogram comprising an endother
- Crystalline Form III is characterized by an X-ray powder diffraction pattern substantially the same as shown in Figure 19. [106] In some embodiments, Crystalline Form III is characterized by an X-ray powder diffraction pattern comprising peaks at 10.1 ⁇ 0.2° 2- ⁇ , 13.5 ⁇ 0.2° 2- ⁇ , and 19.6 ⁇ 0.2° 2- ⁇ , as WSGR Docket No.43629-723.601 measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- Crystalline Form III is characterized by an X-ray powder diffraction pattern comprising peaks at 10.1 ⁇ 0.1° 2- ⁇ , 13.5 ⁇ 0.1° 2- ⁇ , and 19.6 ⁇ 0.1° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ . In some embodiments, Crystalline Form III is characterized by an X-ray powder diffraction pattern comprising peaks at about 10.1° 2- ⁇ , about 13.5° 2- ⁇ , and about 19.6° 2- ⁇ , as measured by X-ray powder diffraction using an X- ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern further comprises at least one peak selected from 20.3 ⁇ 0.2° 2- ⁇ , 15.6 ⁇ 0.2° 2- ⁇ , and 17.9 ⁇ 0.2° 2- ⁇ , as measured by X- ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ . In some embodiments, the X- ray powder diffraction pattern further comprises at least one peak selected from 20.3 ⁇ 0.1° 2- ⁇ , 15.6 ⁇ 0.1° 2- ⁇ , and 17.9 ⁇ 0.1° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern further comprises at least one peak selected from about 20.3° 2- ⁇ , about 15.6° 2- ⁇ , and about 17.9° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern further comprises at least one peak selected from 22.8 ⁇ 0.2° 2- ⁇ , 17.3 ⁇ 0.2° 2- ⁇ , and 16.9 ⁇ 0.2° 2- ⁇ , as measured by X- ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X- ray powder diffraction pattern further comprises at least one peak selected from 22.8 ⁇ 0.1° 2- ⁇ , 17.3 ⁇ 0.1° 2- ⁇ , and 16.9 ⁇ 0.1° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ . In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from about 22.8° 2- ⁇ , about 17.3° 2- ⁇ , and about 16.9° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least one peak selected from 10.1 ⁇ 0.2° 2- ⁇ , 13.5 ⁇ 0.2° 2- ⁇ , 19.6 ⁇ 0.2° 2- ⁇ , 20.3 ⁇ 0.2° 2- ⁇ , 15.6 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 22.8 ⁇ 0.2° 2- ⁇ , 17.3 ⁇ 0.2° 2- ⁇ , and 16.9 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least two peaks selected from 10.1 ⁇ 0.2° 2- ⁇ , 13.5 ⁇ 0.2° 2- ⁇ , 19.6 ⁇ 0.2° 2- ⁇ , 20.3 ⁇ 0.2° 2- ⁇ , 15.6 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 22.8 ⁇ 0.2° 2- ⁇ , 17.3 ⁇ 0.2° 2- ⁇ , and 16.9 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least three peaks selected from 10.1 ⁇ 0.2° 2- ⁇ , 13.5 ⁇ 0.2° 2- ⁇ , 19.6 ⁇ 0.2° 2- ⁇ , 20.3 ⁇ 0.2° 2- ⁇ , 15.6 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 22.8 ⁇ 0.2° 2- ⁇ , 17.3 ⁇ 0.2° 2- ⁇ , and 16.9 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least four peaks selected from 10.1 ⁇ 0.2° 2- ⁇ , 13.5 ⁇ 0.2° 2- ⁇ , 19.6 ⁇ 0.2° 2- ⁇ , 20.3 ⁇ 0.2° 2- ⁇ , 15.6 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 22.8 ⁇ 0.2° 2- ⁇ , 17.3 ⁇ 0.2° 2- ⁇ , and 16.9 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least five peaks selected from 10.1 ⁇ 0.2° 2- ⁇ , 13.5 ⁇ 0.2° 2- ⁇ , 19.6 ⁇ 0.2° 2- ⁇ , 20.3 ⁇ 0.2° 2- ⁇ , 15.6 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 22.8 ⁇ 0.2° 2- ⁇ , 17.3 ⁇ 0.2° 2- ⁇ , and 16.9 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least six peaks selected from 10.1 ⁇ 0.2° 2- ⁇ , 13.5 ⁇ 0.2° 2- ⁇ , 19.6 ⁇ 0.2° 2- ⁇ , 20.3 ⁇ 0.2° 2- ⁇ , 15.6 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 22.8 ⁇ 0.2° 2- ⁇ , 17.3 ⁇ 0.2° 2- ⁇ , and 16.9 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least seven peaks selected from 10.1 ⁇ 0.2° 2- ⁇ , 13.5 ⁇ 0.2° 2- ⁇ , 19.6 ⁇ 0.2° 2- ⁇ , 20.3 ⁇ 0.2° 2- ⁇ , 15.6 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 22.8 ⁇ 0.2° 2- ⁇ , 17.3 ⁇ 0.2° 2- ⁇ , and 16.9 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least eight peaks selected from 10.1 ⁇ 0.2° 2- ⁇ , 13.5 ⁇ 0.2° 2- ⁇ , 19.6 ⁇ 0.2° 2- ⁇ , 20.3 ⁇ 0.2° 2- ⁇ , 15.6 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 22.8 ⁇ 0.2° 2- ⁇ , 17.3 ⁇ 0.2° 2- ⁇ , and 16.9 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises peaks at 10.1 ⁇ 0.2° 2- ⁇ , 13.5 ⁇ 0.2° 2- ⁇ , 19.6 ⁇ 0.2° 2- ⁇ , 20.3 ⁇ 0.2° 2- ⁇ , 15.6 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 22.8 ⁇ 0.2° 2- ⁇ , 17.3 ⁇ 0.2° 2- ⁇ , and 16.9 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises peaks at 10.1 ⁇ 0.1° 2- ⁇ , 13.5 ⁇ 0.1° 2- ⁇ , 19.6 ⁇ 0.1° 2- ⁇ , 20.3 ⁇ 0.1° 2- ⁇ , 15.6 ⁇ 0.1° 2- ⁇ , 17.9 ⁇ 0.1° 2- ⁇ , 22.8 ⁇ 0.1° 2- ⁇ , 17.3 ⁇ 0.1° 2- ⁇ , and 16.9 ⁇ 0.1° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises peaks at about 10.1° 2- ⁇ , about 13.5° 2- ⁇ , about 19.6° 2- ⁇ , about 20.3° 2- ⁇ , about 15.6° 2- ⁇ , about 17.9° 2- ⁇ , about 22.8° 2- ⁇ , about 17.3° 2- ⁇ , and about 16.9° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- Crystalline Form III is characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 10.
- Crystalline Form III is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 245–265 °C. In some embodiments, Crystalline Form III is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 250 °C and a peak of about 258 °C.
- DSC differential scanning calorimetry
- Crystalline Form III is characterized by an endotherm in the range of about 245–265 °C, for example at about 245–265 °C, 245–260 °C, 245–255 °C, 245– 250 °C, 250–265 °C, 250–260 °C, 250–255 °C, 255–265 °C, 255–260 °C, or 260–265 °C in the DSC thermogram.
- Crystalline Form III is characterized by an endotherm at about 258 °C in the DSC thermogram.
- Crystalline Form III is characterized by a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 11. In various embodiments, Crystalline Form III decomposes above a temperature of about 150 °C, about 200 °C, about 250 °C, about 300 °C, about 350 °C, about 400 °C, about 450 °C, about 500 °C, about 550 °C or above 600 °C. In some examples, Crystalline Form III decomposes above a temperature of about 300 °C. [113] In some embodiments, Crystalline Form III is characterized by a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 12.
- DFS dynamic vapor sorption
- FIG. 13 shows the X-ray powder diffraction (XRPD) pattern for Crystalline Form IV of Compound A citrate.
- Figure 14 shows the differential scanning calorimetry (DSC) thermogram for Crystalline Form IV of Compound A citrate.
- Figure 15 shows the thermogravimetric analysis (TGA) pattern for Crystalline Form IV of Compound A citrate.
- Figure 16 shows the dynamic vapor sorption (DVS) pattern for Crystalline Form IV of Compound A citrate.
- compositions comprising Crystalline Form IV of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate citrate.
- Crystalline Form IV of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate citrate is characterized as having: (a) an X-ray powder diffraction pattern comprising peaks at 14.3 ⁇ 0.2° 2- ⁇ , 16.5 ⁇ 0.2° 2- ⁇ , and 17.0 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ ; WSGR Docket No.43629-723.601 (b) an X-ray powder diffraction pattern substantially the same as shown in Figure 13; (c) a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 230–250 °C; (d)
- DSC differential
- Crystalline Form IV is characterized by an X-ray powder diffraction pattern substantially the same as shown in Figure 13. [120] In some embodiments, Crystalline Form IV is characterized by an X-ray powder diffraction pattern comprising peaks at 14.3 ⁇ 0.2° 2- ⁇ , 16.5 ⁇ 0.2° 2- ⁇ , and 17.0 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- Crystalline Form IV is characterized by an X-ray powder diffraction pattern comprising peaks at 14.3 ⁇ 0.1° 2- ⁇ , 16.5 ⁇ 0.1° 2- ⁇ , and 17.0 ⁇ 0.1° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ . In some embodiments, Crystalline Form IV is characterized by an X-ray powder diffraction pattern comprising peaks at about 14.3° 2- ⁇ , about 16.5° 2- ⁇ , and about 17.0° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern further comprises at least one peak selected from 15.8 ⁇ 0.2° 2- ⁇ , 15.1 ⁇ 0.2° 2- ⁇ , and 10.7 ⁇ 0.2° 2- ⁇ , as measured by X- ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X- ray powder diffraction pattern further comprises at least one peak selected from 15.8 ⁇ 0.1° 2- ⁇ , 15.1 ⁇ 0.1° 2- ⁇ , and 10.7 ⁇ 0.1° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern further comprises at least one peak selected from about 15.8° 2- ⁇ , about 15.1° 2- ⁇ , and about 10.7° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern further comprises at least one peak selected from 17.9 ⁇ 0.2° 2- ⁇ , 20.9 ⁇ 0.2° 2- ⁇ , and 22.0 ⁇ 0.2° 2- ⁇ , as measured by X- ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X- WSGR Docket No.43629-723.601 ray powder diffraction pattern further comprises at least one peak selected from 17.9 ⁇ 0.1° 2- ⁇ , 20.9 ⁇ 0.1° 2- ⁇ , and 22.0 ⁇ 0.1° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern further comprises at least one peak selected from about 17.9° 2- ⁇ , about 20.9° 2- ⁇ , and about 22.0° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least one peak selected from 14.3 ⁇ 0.2° 2- ⁇ , 16.5 ⁇ 0.2° 2- ⁇ , 17.0 ⁇ 0.2° 2- ⁇ , 15.8 ⁇ 0.2° 2- ⁇ , 15.1 ⁇ 0.2° 2- ⁇ , 10.7 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 20.9 ⁇ 0.2° 2- ⁇ , and 22.0 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least two peaks selected from 14.3 ⁇ 0.2° 2- ⁇ , 16.5 ⁇ 0.2° 2- ⁇ , 17.0 ⁇ 0.2° 2- ⁇ , 15.8 ⁇ 0.2° 2- ⁇ , 15.1 ⁇ 0.2° 2- ⁇ , 10.7 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 20.9 ⁇ 0.2° 2- ⁇ , and 22.0 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least three peaks selected from 14.3 ⁇ 0.2° 2- ⁇ , 16.5 ⁇ 0.2° 2- ⁇ , 17.0 ⁇ 0.2° 2- ⁇ , 15.8 ⁇ 0.2° 2- ⁇ , 15.1 ⁇ 0.2° 2- ⁇ , 10.7 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 20.9 ⁇ 0.2° 2- ⁇ , and 22.0 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least four peaks selected from 14.3 ⁇ 0.2° 2- ⁇ , 16.5 ⁇ 0.2° 2- ⁇ , 17.0 ⁇ 0.2° 2- ⁇ , 15.8 ⁇ 0.2° 2- ⁇ , 15.1 ⁇ 0.2° 2- ⁇ , 10.7 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 20.9 ⁇ 0.2° 2- ⁇ , and 22.0 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least five peaks selected from 14.3 ⁇ 0.2° 2- ⁇ , 16.5 ⁇ 0.2° 2- ⁇ , 17.0 ⁇ 0.2° 2- ⁇ , 15.8 ⁇ 0.2° 2- ⁇ , 15.1 ⁇ 0.2° 2- ⁇ , 10.7 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 20.9 ⁇ 0.2° 2- ⁇ , and 22.0 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least six peaks selected from 14.3 ⁇ 0.2° 2- ⁇ , 16.5 ⁇ 0.2° 2- ⁇ , 17.0 ⁇ 0.2° 2- ⁇ , 15.8 ⁇ 0.2° 2- ⁇ , 15.1 ⁇ 0.2° 2- ⁇ , 10.7 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 20.9 ⁇ 0.2° 2- ⁇ , and 22.0 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least seven peaks selected from 14.3 ⁇ 0.2° 2- ⁇ , 16.5 ⁇ 0.2° 2- ⁇ , 17.0 ⁇ 0.2° 2- ⁇ , 15.8 ⁇ 0.2° 2- ⁇ , 15.1 ⁇ 0.2° 2- ⁇ , 10.7 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 20.9 ⁇ 0.2° 2- ⁇ , and 22.0 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises at least eight peaks selected from 14.3 ⁇ 0.2° 2- ⁇ , 16.5 ⁇ 0.2° 2- ⁇ , 17.0 ⁇ 0.2° 2- ⁇ , 15.8 ⁇ 0.2° 2- ⁇ , 15.1 ⁇ 0.2° 2- ⁇ , 10.7 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 20.9 ⁇ 0.2° 2- ⁇ , and 22.0 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray WSGR Docket No.43629-723.601 powder diffraction pattern comprises peaks at 14.3 ⁇ 0.2° 2- ⁇ , 16.5 ⁇ 0.2° 2- ⁇ , 17.0 ⁇ 0.2° 2- ⁇ , 15.8 ⁇ 0.2° 2- ⁇ , 15.1 ⁇ 0.2° 2- ⁇ , 10.7 ⁇ 0.2° 2- ⁇ , 17.9 ⁇ 0.2° 2- ⁇ , 20.9 ⁇ 0.2° 2- ⁇ , and 22.0 ⁇ 0.2° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises peaks at 14.3 ⁇ 0.1° 2- ⁇ , 16.5 ⁇ 0.1° 2- ⁇ , 17.0 ⁇ 0.1° 2- ⁇ , 15.8 ⁇ 0.1° 2- ⁇ , 15.1 ⁇ 0.1° 2- ⁇ , 10.7 ⁇ 0.1° 2- ⁇ , 17.9 ⁇ 0.1° 2- ⁇ , 20.9 ⁇ 0.1° 2- ⁇ , and 22.0 ⁇ 0.1° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- the X-ray powder diffraction pattern comprises peaks at about 14.3° 2- ⁇ , about 16.5° 2- ⁇ , about 17.0° 2- ⁇ , about 15.8° 2- ⁇ , about 15.1° 2- ⁇ , about 10.7° 2- ⁇ , about 17.9° 2- ⁇ , about 20.9° 2- ⁇ , and about 22.0° 2- ⁇ , as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 ⁇ .
- Crystalline Form IV is characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 14.
- Crystalline Form IV is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 230–250 °C. In some embodiments, Crystalline Form IV is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 235 °C and a peak of about 242 °C.
- DSC differential scanning calorimetry
- Crystalline Form IV is characterized by an endotherm in the range of about 230–250 °C, for example at about 230–250 °C, 230–245 °C, 230–240 °C, 230– 235 °C, 235–250 °C, 235–245 °C, 235–240 °C, 240–250 °C, 240–245 °C, or 245–250 °C in the DSC thermogram.
- Crystalline Form IV is characterized by an endotherm at about 242 °C in the DSC thermogram.
- Crystalline Form IV is characterized by a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 15. In various embodiments, Crystalline Form IV decomposes above a temperature of about 150 °C, about 200 °C, about 250 °C, about 300 °C, about 350 °C, about 400 °C, about 450 °C, about 500 °C, about 550 °C or above 600 °C. In some examples, Crystalline Form IV decomposes above a temperature of about 250 °C. [127] In some embodiments, Crystalline Form IV is characterized by a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 16.
- DFS dynamic vapor sorption
- the invention provides methods of making one or more polymorphs of Compound A: Compound A.
- Compound A is prepared according to the examples herein.
- the polymorphs according to the invention are not limited by the starting materials used to produce Compound A.
- the invention is directed to methods of making polymorphs of Compound A, or a pharmaceutically acceptable salt and/or solvate thereof, either by isolation of the desired polymorph as the first solid form after synthesis of Compound A, or alternatively, by isolation of the desired polymorph as a transition from a prior solid form of Compound A.
- Polymorphs of Compound A can be selected from Crystalline Form I, Crystalline Form II, Crystalline Form III, Crystalline Form IV, and mixtures thereof.
- Isolation and purification of the chemical entities and intermediates described herein can be performed, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples below. However, other equivalent separation or isolation procedures can also be used.
- Compound A Prior to crystallization, Compound A may be isolated in about 50% chemical purity, 55% chemical purity, 60% chemical purity, 65% chemical purity, 70% chemical purity, 75% chemical purity, 80% chemical purity, 90% chemical purity, 91% chemical purity, 92% purity, 93% chemical purity, 94% chemical purity, 95% chemical purity, 96% chemical purity, 97% WSGR Docket No.43629-723.601 chemical purity, 98% chemical purity, 99% chemical purity, about 98% chemical purity, or about 100% chemical purity.
- the crystalline forms disclosed herein are obtained by crystallizing Compound A with a chemical purity of less than about 98%, less than about 97%, less than about 96%, less than about 95%, less than about 94%, less than about 93%, less than about 92%, less than about 91%, less than about 90%, less than about 89%, less than about 88%, less than about 87%, less than about 86%, less than about 85%, less than about 84%, less than about 83%, less than about 82%, less than about 81%, less than about 80%, less than about 78%, less than about 76%, less than about 74%, less than about 72%, or less than about 70%.
- the crystalline forms are obtained by crystallizing Compound A with a chemical purity in the range of about 70% to about 99%, 80% to about 96%, about 85% to about 96%, about 90% to about 96%, about 80% to 98%, about 85% to about 98%, about 90% to about 98%, about 92% to about 98%, about 94% to 98%, or about 96% to about 98%.
- isolating the desired polymorph of Compound A involves crystallization of crude reaction product from a mono-solvent system.
- isolating the desired polymorph of Compound A involves crystallization of crude product from a binary, tertiary, or greater solvent system, collectively understood as a multi-solvent system.
- the crystallization is carried out by generating the desired Compound A in a reaction mixture and isolating the desired polymorph from the reaction mixture.
- the reaction mixture is formed by adding phosphoric acid to a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate to form dissolved (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate phosphate (Compound A phosphate).
- the reaction mixture is formed by adding methanesulfonic acid to a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate to form dissolved (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate mesylate (Compound A mesylate).
- the reaction mixture is formed by adding tartaric acid to a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate to form dissolved (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- WSGR Docket No.43629-723.601 yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate tartrate (Compound A tartrate).
- the reaction mixture is formed by adding citric acid to a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate to form dissolved (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate citrate (Compound A citrate).
- the reaction mixture is formed by dissolving Compound A phosphate, Compound A mesylate, Compound A tartrate, or Compound A citrate into a solvent.
- Preparation of Crystalline Form I [137]
- the desired polymorph is Crystalline Form I of Compound A phosphate, and the isolating step involves crystallization of crude reaction product from a mono- solvent system.
- the desired polymorph is Crystalline Form I of Compound A phosphate, and the isolating step involves crystallization of crude reaction product from a binary, tertiary, or greater solvent system, collectively understood as a multi-solvent system.
- the crude reaction product is formed by contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate with phosphoric acid to form dissolved (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo- 2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate phosphate (Compound A phosphate).
- the desired polymorph is Crystalline Form I of Compound A phosphate
- isolating Compound A phosphate involves crystallization from a mono- or multi- solvent system, where the crystallization involves forming Compound A phosphate in situ by contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate with phosphoric acid at a temperature above ambient temperature.
- the reaction in the mono- or multi-solvent system is performed at a temperature of about 10–60 °C, 10–55 °C, 10–50 °C, 10–45 °C, 10–40 °C, 10–35 °C, 10–30 °C, 10–25 °C, 10–20 °C, 10–15 °C, 15–60 °C, 15–55 °C, 15–50 °C, 15–45 °C, 15–40 °C, 15–35 °C, 15–30 °C, 15–25 °C, 15–20 °C, 20–60 °C, 20–55 °C, 20–50 °C, 20–45 °C, 20–40 °C, 20–35 °C, 20–30 °C, 20–25 °C, 25–60 °C, 25–55 °C, 25–50 °C, 25–45 °C, 25–40 °C, 25–35 °C,
- the solvent comprises ethyl acetate, DMF, ethanol, or isopropanol. In some examples, the solvent comprises DMF. In some embodiments, the solvent comprises DMF, and the reaction is performed at a temperature of about 50–60 °C. Any suitable amount of solvent can be used. In some embodiments, the amount of solvent (e.g., DMF) used is from about 10–50 mL per gram of Compound A phosphate. For example, in some embodiments, the amount of solvent used is 20 mL per gram of Compound A phosphate.
- the solvent comprises DMF
- the reaction is performed at a temperature of about 50–60 °C
- the amount of solvent is about 20 mL/g of Compound A phosphate.
- the crystallization further involves filtering the solution containing the obtained crystals of Compound A phosphate.
- the crystallization optionally involves washing the obtained crystals by a solvent, for example by the recrystallization solvent one or more times.
- the crystallization optionally involves drying the obtained crystals, for example under vacuum at a temperature of about 50– 60 °C.
- the chemical purity of the Crystalline Form I is greater than 60%, 70%, 80%, 90%, 95%, or 99%.
- the chemical purity of the Crystalline Form I is greater than about 90%. In some embodiments, the chemical purity of the Crystalline Form I is greater than about 95%. In some embodiments, the chemical purity of the Crystalline Form I greater than about 99%.
- the chemical purity of Crystalline Form I may be measured by any available analytical technique, for example by HPLC analysis.
- Preparation of Crystalline Form II [142] In some embodiments, the desired polymorph is Crystalline Form II of Compound A mesylate, and the isolating step involves crystallization of crude reaction product from a mono- solvent system.
- the desired polymorph is Crystalline Form II of Compound A mesylate
- the isolating step involves crystallization of crude reaction product from a binary, tertiary, or greater solvent system, collectively understood as a multi-solvent system.
- the crude reaction product is formed by contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate with methanesulfonic acid to form dissolved (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate mesylate (Compound A mesylate).
- the desired polymorph is Crystalline Form II of Compound A mesylate, and isolating Compound A phosphate involves crystallization from a mono- or multi- WSGR Docket No.43629-723.601 solvent system, where the crystallization involves forming Compound A mesylate in situ by contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate with methanesulfonic acid at a temperature above ambient temperature.
- the reaction in the mono- or multi-solvent system is performed at a temperature of about 10–60 °C, 10–55 °C, 10–50 °C, 10–45 °C, 10–40 °C, 10–35 °C, 10–30 °C, 10–25 °C, 10–20 °C, 10–15 °C, 15–60 °C, 15–55 °C, 15–50 °C, 15–45 °C, 15–40 °C, 15–35 °C, 15–30 °C, 15–25 °C, 15–20 °C, 20–60 °C, 20–55 °C, 20–50 °C, 20–45 °C, 20–40 °C, 20–35 °C, 20–30 °C, 20–25 °C, 25–60 °C, 25–55 °C, 25–50 °C, 25–45 °C, 25–40 °C, 25–35 °C,
- the solvent comprises ethyl acetate, DMF, ethanol, or isopropanol. In some examples, the solvent comprises DMF. In some embodiments, the solvent comprises DMF, and the reaction is performed at a temperature of about 50–60 °C. Any suitable amount of solvent can be used. In some embodiments, the amount of solvent (e.g., DMF) used is from about 10–50 mL per gram of Compound A mesylate. For example, in some embodiments, the amount of solvent used is 20 mL per gram of Compound A mesylate.
- the solvent comprises DMF
- the reaction is performed at a temperature of about 50–60 °C
- the amount of solvent is about 20 mL/g of Compound A mesylate.
- the crystallization further involves filtering the solution containing the obtained crystals of Compound A mesylate.
- the crystallization optionally involves washing the obtained crystals by a solvent, for example by the recrystallization solvent one or more times.
- the crystallization optionally involves drying the obtained crystals, for example under vacuum at a temperature of about 50– 60 °C.
- the chemical purity of the Crystalline Form II is greater than 60%, 70%, 80%, 90%, 95%, or 99%.
- the chemical purity of the Crystalline Form II is greater than about 90%. In some embodiments, the chemical purity of the Crystalline Form II is greater than about 95%. In some embodiments, the chemical purity of the Crystalline Form II greater than about 99%.
- the chemical purity of Crystalline Form II may be measured by any available analytical technique, for example by HPLC analysis.
- WSGR Docket No.43629-723.601 Preparation of Crystalline Form III [147]
- the desired polymorph is Crystalline Form III of Compound A tartrate, and the isolating step involves crystallization of crude reaction product from a mono- solvent system.
- the desired polymorph is Crystalline Form III of Compound A tartrate
- the isolating step involves crystallization of crude reaction product from a binary, tertiary, or greater solvent system, collectively understood as a multi-solvent system.
- the crude reaction product is formed by contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate with tartaric acid to form dissolved (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate tartrate (Compound A tartrate).
- the desired polymorph is Crystalline Form III of Compound A tartrate
- isolating Compound A tartrate involves crystallization from a mono- or multi- solvent system, where the crystallization involves forming Compound A tartrate in situ by contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate with tartaric acid at a temperature above ambient temperature.
- the reaction in the mono- or multi-solvent system is performed at a temperature of about 10–60 °C, 10–55 °C, 10–50 °C, 10– 45 °C, 10–40 °C, 10–35 °C, 10–30 °C, 10–25 °C, 10–20 °C, 10–15 °C, 15–60 °C, 15–55 °C, 15–50 °C, 15–45 °C, 15–40 °C, 15–35 °C, 15–30 °C, 15–25 °C, 15–20 °C, 20–60 °C, 20–55 °C, 20–50 °C, 20–45 °C, 20–40 °C, 20–35 °C, 20–30 °C, 20–25 °C, 25–60 °C, 25–55 °C, 25–50 °C, 25–45 °C, 25–40 °C, 25–35 °C,
- the solvent comprises ethyl acetate, DMF, ethanol, or isopropanol. In some examples, the solvent comprises DMF. In some embodiments, the solvent comprises DMF, and the reaction is performed at a temperature of about 50–60 °C. Any suitable amount of solvent can be used. In some embodiments, the amount of solvent (e.g., DMF) used is from about 10–50 mL per gram of Compound A tartrate. For example, in some embodiments, the amount of solvent used is 20 mL per gram of Compound A tartrate.
- the solvent comprises DMF
- the reaction is performed at a temperature of about 50–60 °C
- the amount of solvent is about 20 mL/g of Compound A tartrate.
- the crystallization further involves filtering the solution containing the obtained crystals of Compound A tartrate.
- the crystallization optionally involves washing the obtained crystals by a solvent, for example by the recrystallization solvent one or more times.
- the crystallization optionally involves drying the obtained crystals, for example under vacuum at a temperature of about 50– 60 °C.
- the chemical purity of the Crystalline Form III is greater than 60%, 70%, 80%, 90%, 95%, or 99%. In some embodiments, the chemical purity of the Crystalline Form III is greater than about 90%. In some embodiments, the chemical purity of the Crystalline Form III is greater than about 95%. In some embodiments, the chemical purity of the Crystalline Form III greater than about 99%.
- the chemical purity of Crystalline Form III may be measured by any available analytical technique, for example by HPLC analysis.
- Preparation of Crystalline Form IV [152] In some embodiments, the desired polymorph is Crystalline Form IV of Compound A citrate, and the isolating step involves crystallization of crude reaction product from a mono- solvent system.
- the desired polymorph is Crystalline Form IV of Compound A citrate
- the isolating step involves crystallization of crude reaction product from a binary, tertiary, or greater solvent system, collectively understood as a multi-solvent system.
- the crude reaction product is formed by contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate with citric acid to form dissolved (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate citrate (Compound A citrate).
- the desired polymorph is Crystalline Form IV of Compound A citrate
- isolating Compound A citrate involves crystallization from a mono- or multi-solvent system, where the crystallization involves forming Compound A citrate in situ by contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate with citric acid at a temperature above ambient temperature.
- the reaction in the mono- or multi-solvent system is performed at a temperature of about 10–60 °C, 10–55 °C, 10–50 °C, 10– 45 °C, 10–40 °C, 10–35 °C, 10–30 °C, 10–25 °C, 10–20 °C, 10–15 °C, 15–60 °C, 15–55 °C, 15–50 °C, 15–45 °C, 15–40 °C, 15–35 °C, 15–30 °C, 15–25 °C, 15–20 °C, 20–60 °C, 20–55 °C, 20–50 °C, 20–45 °C, 20–40 °C, 20–35 °C, 20–30 °C, 20–25 °C, 25–60 °C, 25–55 °C, 25–50 °C, WSGR Docket No.43629-723.601 25–45 °C
- the solvent comprises ethyl acetate, DMF, ethanol, or isopropanol. In some examples, the solvent comprises DMF. In some embodiments, the solvent comprises DMF, and the reaction is performed at a temperature of about 50–60 °C. Any suitable amount of solvent can be used. In some embodiments, the amount of solvent (e.g., DMF) used is from about 10–50 mL per gram of Compound A citrate. For example, in some embodiments, the amount of solvent used is 20 mL per gram of Compound A citrate.
- the solvent comprises DMF
- the reaction is performed at a temperature of about 50–60 °C
- the amount of solvent is about 20 mL/g of Compound A citrate.
- the crystallization further involves filtering the solution containing the obtained crystals of Compound A citrate.
- the crystallization optionally involves washing the obtained crystals by a solvent, for example by the recrystallization solvent one or more times.
- the crystallization optionally involves drying the obtained crystals, for example under vacuum at a temperature of about 50– 60 °C.
- the chemical purity of the Crystalline Form IV is greater than 60%, 70%, 80%, 90%, 95%, or 99%.
- the chemical purity of the Crystalline Form IV is greater than about 90%. In some embodiments, the chemical purity of the Crystalline Form IV is greater than about 95%. In some embodiments, the chemical purity of the Crystalline Form IV greater than about 99%.
- the chemical purity of Crystalline Form IV may be measured by any available analytical technique, for example by HPLC analysis. III. Additional Definitions [157]
- active agent is used to indicate a chemical entity which has biological activity. In certain embodiments, an “active agent” is a compound having pharmaceutical utility. For example, an active agent may be an anti-cancer therapeutic.
- modulation refers to a change in activity as a direct or indirect response to the presence of a chemical entity as described herein, relative to the activity of in the absence of the chemical entity.
- the change may be an increase in activity or a decrease in activity and may be due to the direct interaction of the compound with the target or due to the interaction of the compound with one or more other factors that in turn affect the target’s activity.
- the presence of the chemical entity may, for example, increase or decrease WSGR Docket No.43629-723.601 the target activity by directly binding to the target, by causing (directly or indirectly) another factor to increase or decrease the target activity, or by (directly or indirectly) increasing or decreasing the amount of target present in the cell or organism.
- “therapeutically effective amount” of a chemical entity described herein refers to an amount effective, when administered to a human or non-human subject, to provide a therapeutic benefit such as amelioration of symptoms, slowing of disease progression, or prevention of disease.
- “Treating” or “treatment” encompasses administration of Compound A, or a pharmaceutically acceptable salt thereof, to a mammalian subject, particularly a human subject, in need of such an administration and includes (i) arresting the development of clinical symptoms of the disease, such as cancer, (ii) bringing about a regression in the clinical symptoms of the disease, such as cancer, and/or (iii) prophylactic treatment for preventing the onset of the disease, such as cancer.
- a “pharmaceutically acceptable” component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
- “Pharmaceutically acceptable salts” include, but are not limited to salts with inorganic acids, such as hydrochlorate, carbonate, phosphate, hydrogenphosphate, diphosphate, hydrobromate, sulfate, sulfinate, nitrate, and like salts; as well as salts with an organic acid, such as malate, malonate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, gluconate, methanesulfonate, Tris (hydroxymethyl-aminomethane), p-toluenesulfonate, priopionate, 2- hydroxyethylsulfonate, benzoate, salicylate, stearate, oxalate, pamoate, and alkanoate such as acetate, HOOC-(CH 2 ) n -COOH where n is 0–4, and like salts.
- inorganic acids such as hydrochlorate, carbonate,
- salts include sulfate, methasulfonate, bromide, trifluoroacetate, picrate, sorbate, benzilate, salicilate, nitrate, phthalate or morpholine.
- Pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium, and ammonium.
- an addition salt particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
- WSGR Docket No.43629-723.601 refers to a mammal that has been or will be the object of treatment, observation, or experiment. The methods described herein can be useful in both human therapy and veterinary applications. In some embodiments, the subject is a human.
- the term “mammal” is intended to have its standard meaning, and encompasses humans, dogs, cats, sheep, and cows, for example.
- “Prodrugs” described herein include any compound that becomes Compound A when administered to a subject, e.g., upon metabolic processing of the prodrug.
- prodrugs include derivatives of functional groups, such as a carboxylic acid group, in Compound A.
- exemplary prodrugs of a carboxylic acid group include, but are not limited to, carboxylic acid esters such as alkyl esters, hydroxyalkyl esters, arylalkyl esters, and aryloxyalkyl esters.
- Other exemplary prodrugs include lower alkyl esters such as ethyl ester, acyloxyalkyl esters such as pivaloyloxymethyl (POM), glycosides, and ascorbic acid derivatives.
- Other exemplary prodrugs include amides of carboxylic acids.
- prodrugs are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14 C.
- the compound is deuterated at least one position. Such deuterated forms can be made by the procedure described in U.S.
- Patent Nos.5,846,514 and 6,334,997 As described in U.S. Patent Nos.5,846,514 and 6,334,997, deuteration can improve the efficacy and increase the duration of action of drugs.
- Deuterium substituted compounds can be synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601–21; and Evans, E. Anthony.
- a “solvate” is formed by the interaction of a solvent and a compound.
- the term “compound” is intended to include solvates of compounds.
- “pharmaceutically acceptable salts” includes solvates of pharmaceutically acceptable salts. Suitable solvates are WSGR Docket No.43629-723.601 pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemi- hydrates. Also included are solvates formed with the one or more crystallization solvents.
- compositions recited herein include pharmaceutically acceptable salts, chelates, non-covalent complexes, prodrugs, and mixtures thereof.
- a “chelate” is formed by the coordination of a compound to a metal ion at two (or more) points.
- the term “compound” is intended to include chelates of compounds.
- pharmaceutically acceptable salts includes chelates of pharmaceutically acceptable salts.
- a “non-covalent complex” is formed by the interaction of a compound and another molecule wherein a covalent bond is not formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding).
- non-covalent complexes are included in the term “compound”.
- pharmaceutically acceptable salts include “non-covalent complexes” of pharmaceutically acceptable salts.
- ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and sub combinations of ranges and specific embodiments therein are intended to be included.
- the term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary from, for example, between 1% and 15% of the stated number or numerical range. In some instances of numerical ranges, “about” means ⁇ 10%.
- cancer refers to all types of cancer or neoplasm or malignant tumors found in mammals, including carcinomas and sarcomas. Examples of cancer are cancer of the brain, breast, cervix, colon, head & neck, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus and Medulloblastoma. IV.
- the polymorphs described herein may be used in treating a variety of neoplasms, including malignant and benign tumors, as well as cancers. Cancers that can be prevented and/or treated by the polymorphs, compositions, and methods described herein include, but are not WSGR Docket No.43629-723.601 limited to, human sarcomas and carcinomas, e.g., carcinomas, e.g., colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, thyroid cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chondroma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdom
- Benign tumors that can be prevented and/or treated by the polymorphs, compositions, and methods described herein include, but are not limited to, craniopharyngioma.
- the polymorphs described herein are used for the treatment of cancers of the i. digestive system including, without limitation, the esophagus, stomach, small intestine, colon (including colorectal), liver & intrahepatic bile duct, gallbladder & other biliary, pancreas, and other digestive organs; ii. respiratory system, including without limitation, larynx, lung & bronchus, and other respiratory organs; iii. skin; iv. thyroid; v. breast; vi.
- the polymorphs described herein are used for the treatment of colon cancer, liver cancer, lung cancer, melanoma, thyroid cancer, breast cancer, ovarian cancer, and oral cancer.
- the polymorphs described herein may also be used in conjunction with other well- known therapeutic agents that are selected for their particular usefulness against the condition that is being treated.
- polymorphs described herein may be useful in combination with at least one additional anti-cancer and/or cytotoxic agents. Further, the polymorphs described herein may also be useful in combination with other inhibitors of parts of the signaling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation.
- Such known anti-cancer and/or cytotoxic agents that may be used in combination with the polymorphs described herein include: (i) other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide, and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumor antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin C,
- inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stem et al.
- growth factor antibodies and growth factor receptor antibodies for example the anti-erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stem et al.
- inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4- fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N- (3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6- acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitor
- the at least one polymorph of Compound A is administered in combination with one or more agents chosen from pacliataxel, bortezomib, dacarbazine, gemcitabine, trastuzumab, bevacizumab, capecitabine, docetaxel, erlotinib, aromatase inhibitors, such as AROMASINTM (exemestane), and estrogen receptor inhibitors, such as FASLODEXTM (fulvestrant).
- the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual subject, as well as the severity of the subject’s symptoms.
- a suitable amount of at least one polymorph of Compound A is administered to a mammal undergoing treatment for cancer, for example, breast cancer.
- Administration typically occurs in an amount of between about 0.01 mg/kg of body weight to about 100 mg/kg of body weight per day (administered in single or divided doses), such as at least about 0.1 mg/kg of body weight per day.
- a particular therapeutic dosage can include, e.g., from about 0.01 mg to about 1000 mg of the polymorph of Compound A, such as including, e.g., from about 1 mg to about 1000 mg.
- the quantity of the at least one polymorph of Compound A WSGR Docket No.43629-723.601 in a unit dose of preparation may be varied or adjusted from about 0.1 mg to 1000 mg, such as from about 1 mg to 300 mg, for example 10 mg to 200 mg, according to the particular application.
- the amount administered will vary depending on the particular IC 50 value of the at least one polymorph of Compound A used and the judgment of the attending clinician taking into consideration factors such as health, weight, and age.
- the at least one polymorph of Compound A described herein is not the sole active ingredient, it may be possible to administer lesser amounts of the at least one polymorph of Compound A and still have therapeutic or prophylactic effect.
- the pharmaceutical preparation is in unit dosage form.
- the preparation is subdivided into unit doses containing appropriate quantities of the polymorph of Compound A, e.g., an effective amount to achieve the desired purpose.
- the actual dosage employed may be varied depending upon the requirements of the subject and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the at least one polymorph of Compound A. Thereafter, the dosage is increased by small amounts until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
- the amount and frequency of administration of the at least one polymorph of Compound A, and if applicable other chemotherapeutic agents and/or radiation therapy will be regulated according to the judgment of the attending clinician (physician) considering such factors as age, condition, and size of the subject as well as severity of the disease being treated.
- the chemotherapeutic agent and/or radiation therapy can be administered according to therapeutic protocols well known in the art. It will be apparent to those skilled in the art that the administration of the chemotherapeutic agent and/or radiation therapy can be varied depending on the disease being treated and the known effects of the chemotherapeutic agent and/or radiation therapy on that disease.
- the therapeutic protocols can be varied in view of the observed effects of the administered therapeutic agents (i.e., antineoplastic agent or radiation) on the subject, and in view of the observed responses of the disease to the administered therapeutic agents.
- the at least one polymorph of Compound A need not be administered in the same pharmaceutical composition as a chemotherapeutic agent, and may, because of different physical and chemical characteristics, be administered by a different route.
- the polymorphs/compositions may be administered orally to generate and maintain good blood levels thereof, while the chemotherapeutic agent may be administered intravenously.
- the determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition, is well within the knowledge of the skilled clinician.
- the initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.
- the particular choice of polymorph (and where appropriate, chemotherapeutic agent and/or radiation) will depend upon the diagnosis of the attending physicians and their judgment of the condition of the subject and the appropriate treatment protocol.
- the one or more polymorphs of Compound A may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the nature of the proliferative disease, the condition of the subject, and the actual choice of chemotherapeutic agent and/or radiation to be administered in conjunction (i.e., within a single treatment protocol) with the one or more polymorphs/composition.
- the one or more polymorphs/composition and the chemotherapeutic agent and/or radiation need not be administered simultaneously or essentially simultaneously, and the initial order of administration of the one or more polymorphs/composition, and the chemotherapeutic agent and/or radiation, may not be important.
- the at least one polymorph of Compound A may be administered first followed by the administration of the chemotherapeutic agent and/or radiation; or the chemotherapeutic agent and/or radiation may be administered first followed by the administration of the at least one polymorph of Compound A. This alternate administration may be repeated during a single treatment protocol.
- the determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the subject.
- the chemotherapeutic agent and/or radiation may be administered first, and then the treatment continued with the administration of the at least one polymorph of Compound A followed, where determined advantageous, by the administration of the chemotherapeutic agent and/or radiation, and so on until the treatment protocol is complete.
- the practicing physician can modify each protocol for the administration of a polymorph of Compound A/composition for treatment according to the individual subject ‘s needs, as the treatment proceeds.
- WSGR Docket No.43629-723.601 [194] The attending clinician, in judging whether treatment is effective at the dosage administered, will consider the general well-being of the subject as well as more definite signs such as relief of disease-related symptoms, inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis. Size of the tumor can be measured by standard methods such as radiological studies, e.g., CAT or MRI scan, and successive measurements can be used to judge whether or not growth of the tumor has been retarded or even reversed. Relief of disease- related symptoms such as pain, and improvement in overall condition can also be used to help judge effectiveness of treatment. V.
- compositions and Formulations [195] The disclosure provides compositions, including pharmaceutical compositions, comprising one or more crystalline forms of the present invention.
- the ratio of desired crystalline form such as Crystalline Form 1 to all other crystalline forms in a composition is greater than about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or more w/w.
- the ratio of Crystalline Form II to all other polymorphs is greater than about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or more w/w.
- the ratio of Crystalline Form III to all other polymorphs is greater than about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or more w/w.
- the ratio of Crystalline Form IV to all other polymorphs is greater than about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or more w/w.
- the one or more polymorphs of Compound A are formulated into pharmaceutical compositions.
- pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds/polymorphs into preparations which can be used pharmaceutically.
- compositions comprising one or more polymorphs of Compound A and a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s).
- the one or more polymorphs of Compound A are administered as pharmaceutical compositions in which the one or more polymorphs, are mixed with other active ingredients, as in combination therapy.
- the pharmaceutical compositions include one or more polymorphs of Compound A.
- a pharmaceutical composition refers to a mixture of one or more polymorphs of Compound A with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
- the pharmaceutical composition facilitates administration of the polymorphs to an organism.
- therapeutically effective amounts of one or more polymorphs of Compound A are administered in a pharmaceutical composition to a mammal having a disease or condition to be treated.
- the mammal is a human.
- therapeutically effective amounts vary depending on the severity of the disease, the age and relative health of the subject and other factors.
- one or more polymorphs of Compound A described herein are used singly or in combination with one or more therapeutic agents as components of mixtures.
- one or more polymorphs of Compound A are formulated in an aqueous solution.
- the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank’s solution, Ringer’s solution, or physiological saline buffer.
- one or more polymorphs of Compound A are formulated for transmucosal administration.
- transmucosal formulations include penetrants that are appropriate to the barrier to be permeated.
- appropriate formulations include aqueous or nonaqueous solutions.
- such solutions include physiologically compatible buffers and/or excipients.
- the polymorphs described herein are formulated for oral administration.
- the polymorphs of Compound A are formulated by combining the polymorphs with, e.g., pharmaceutically acceptable carriers or excipients.
- the polymorphs described herein are formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, and the like.
- oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, and the like.
- WSGR Docket No.43629-723.601 [202]
- pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the polymorphs described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
- Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
- disintegrating agents are optionally added.
- Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
- dosage forms such as dragee cores and tablets, are provided with one or more suitable coating.
- concentrated sugar solutions are used for coating the dosage form.
- the sugar solutions optionally contain additional components, such as by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
- Dyestuffs and/or pigments are also optionally added to the coatings for identification purposes.
- therapeutically effective amounts of at least one of the polymorphs described herein is formulated into other oral dosage forms.
- Oral dosage forms include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
- push-fit capsules contain the active ingredients in admixture with one or more filler. Fillers include, by way of example only, lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
- soft capsules contain one or more active compound that is dissolved or suspended in a suitable liquid.
- suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol.
- stabilizers are optionally added.
- therapeutically effective amounts of at least one of the polymorphs described herein are formulated for buccal or sublingual administration.
- Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels.
- the polymorphs described herein are formulated for parental injection, including formulations suitable for bolus injection or WSGR Docket No.43629-723.601 continuous infusion.
- formulations for injection are presented in unit dosage form (e.g., in ampoules) or in multi-dose containers. Preservatives are, optionally, added to the injection formulations.
- the pharmaceutical composition of a polymorph of Compound A is formulated in a form suitable for parenteral injection as sterile suspension, solution, or emulsion in oily or aqueous vehicles.
- Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing, and/or dispersing agents.
- pharmaceutical formulations for parenteral administration include aqueous solutions of the active polymorphs in water-soluble form.
- suspensions of the active polymorphs are prepared as appropriate oily injection suspensions.
- Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
- aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
- the suspension contains suitable stabilizers or agents which increase the solubility of the polymorphs to allow for the preparation of highly concentrated solutions.
- the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen- free water, before use.
- the one or more polymorphs of Compound A are administered topically.
- the one or more polymorphs described herein are formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments.
- Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers, and preservatives.
- the one or more polymorphs of Compound A are formulated for transdermal administration.
- transdermal formulations employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive.
- patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
- the transdermal delivery of the one or more polymorphs of Compound A is accomplished by means of iontophoretic patches and the like.
- transdermal patches provide controlled delivery of the one or more polymorphs of Compound A.
- the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel.
- absorption enhancers are used to increase absorption.
- Absorption enhancers or carriers include absorbable pharmaceutically acceptable solvents that assist passage through the skin.
- transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
- the one or more polymorphs of Compound A are formulated for administration by inhalation.
- compositions of the polymorphs of Compound A are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas).
- a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
- the dosage unit of a pressurized aerosol is determined by providing a valve to deliver a metered amount.
- capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator are formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
- a powder mix of the compound such as lactose or starch.
- the one or more polymorphs of Compound A are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like.
- a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.
- pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active polymorphs into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are optionally used as suitable.
- compositions comprising the one or more polymorphs of Compound A are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
- WSGR Docket No.43629-723.601 Pharmaceutical compositions include at least one pharmaceutically acceptable carrier, diluent, or excipient and at least one polymorph of Compound A described herein as an active ingredient. The active ingredient is in free-acid or free-base form, or in a pharmaceutically acceptable salt form. All tautomers of the compounds described herein are included within the scope of the compounds presented herein.
- compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and/or other therapeutically valuable substances.
- Methods for the preparation of compositions, comprising the one or more polymorphs of Compound A described herein include formulating the polymorphs with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid.
- Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories.
- Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein.
- Semi-solid compositions include, but are not limited to, gels, suspensions, and creams.
- the form of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions.
- compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.
- a pharmaceutical composition comprising at least one polymorph of Compound A illustratively takes the form of a liquid where the agents are present in solution, in suspension or both. Typically, when the composition is administered as a solution or suspension a first portion of the agent is present in solution and a second portion of the agent is present in particulate form, in suspension in a liquid matrix.
- a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous.
- useful aqueous suspensions contain one or more polymers as suspending agents.
- Useful polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers.
- Certain pharmaceutical compositions described herein comprise WSGR Docket No.43629-723.601 a mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.
- Useful pharmaceutical compositions also, optionally, include solubilizing agents to aid in the solubility of a polymorph of Compound A.
- solubilizing agent generally includes agents that result in formation of a micellar solution or a true solution of the agent.
- Certain acceptable nonionic surfactants for example polysorbate 80, are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.
- useful pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric, and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride.
- acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.
- useful compositions also, optionally, include one or more salts in an amount required to bring osmolality of the composition into an acceptable range.
- Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.
- Other useful pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity.
- Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.
- Still other useful compositions include one or more surfactants to enhance physical stability or for other purposes.
- Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides, and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.
- compositions include one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.
- Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.
- WSGR Docket No.43629-723.601 [221] In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition. [222] In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also employed.
- the polymorphs described herein are delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
- sustained-release materials are useful herein.
- sustained-release capsules release the polymorphs for a few weeks up to over 100 days.
- additional strategies for protein stabilization are employed.
- the formulations described herein comprise one or more antioxidants, metal chelating agents, thiol containing compounds and/or other general stabilizing agents.
- stabilizing agents include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v.
- Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.
- parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
- a polymorph of Compound A is administered in a local rather than systemic manner, for example, via injection of the polymorph directly into an organ, often in a depot preparation or sustained release formulation.
- long-acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
- the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody.
- kits and articles of manufacture are also provided.
- kits comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein.
- Suitable containers include, for example, bottles, vials, syringes, and test tubes.
- the containers are formed from a variety of materials such as glass or plastic.
- the articles of manufacture provided herein contain packaging materials.
- Packaging materials for use in packaging pharmaceutical products include those found in, e.g., U.S. Pat. Nos.5,323,907, 5,052,558 and 5,033,252.
- Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
- the container(s) includes one or more polymorphs described herein, optionally in a composition or in combination with another agent as disclosed herein.
- the container(s) optionally have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
- kits optionally comprising a compound with an identifying description or label or instructions relating to its use in the methods described herein.
- a kit typically includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a compound described herein.
- materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use.
- a set of instructions will also typically be included.
- a label is optionally on or associated with the container.
- a label is on a container when letters, numbers or other characters forming the label are attached, molded, or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert.
- a label is WSGR Docket No.43629-723.601 used to indicate that the contents are to be used for a specific therapeutic application.
- the label indicates directions for use of the contents, such as in the methods described herein.
- the pharmaceutical composition is presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein.
- the pack for example contains metal or plastic foil, such as a blister pack.
- the pack or dispenser device is accompanied by instructions for administration.
- the pack or dispenser is accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
- Such notice for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
- compositions containing a polymorph of Compound A formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
- references to particular buffers, media, reagents, cells, culture conditions and the like are not intended to be limiting, but are to be read so as to include all related materials that one of ordinary skill in the art would recognize as being of interest or value in the particular context in which that discussion is presented. For example, it is often possible to substitute one buffer system or culture medium for another and still achieve similar, if not identical, results.
- the polymorphs described herein can be synthesized utilizing techniques well known in the art from commercially available starting materials and reagents. For example, the polymorphs described herein can be prepared as illustrated below with reference to the examples and reaction schemes.
- Bufalin can be obtained from the skin glands of Bufo gargarizans or B. melanostictus toads and is commercially available, e.g., from Sigma-Aldrich Corp. (St. Louis, MO).
- WSGR Docket No.43629-723.601 reagents are commercially available, e.g., from Sigma-Aldrich Corp., or can be readily prepared by those skilled in the art using commonly employed synthetic methodology.
- the polymorphs described herein may be prepared in substantially pure form, typically by standard chromatographic methods, prior to formulation in a pharmaceutically acceptable form.
- Step 2 To a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl- 17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 4-nitrophenyl carbonate (29 mg, 0.054 mmol) in CH 2 Cl 2 was added piperazine (46.4 mg, 0.54 mmol).
- Citric acid (0.5 M, 0.5 mL) was added dropwise to the solution with stirring at 50 ⁇ 60 °C. The solution was cooled to room temperature slowly. The precipitate was filtered, and dried under vacuum at 50 ⁇ 60 °C to afford Crystalline Form IV of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate citrate.
- Example 6
- the TGA pattern obtained for Crystalline Form II of Compound A mesylate is shown in Figure 7.
- the TGA pattern obtained for Crystalline Form III of Compound A tartrate is shown in Figure 11.
- the TGA pattern obtained for Crystalline Form IV of Compound A citrate is shown in Figure 15.
- the TGA patterns obtained for Crystalline Forms of Compound A are summarized in Table 5: Table 5.
- Example 8. Differential Scanning Calorimetry (DSC) [248] Differential scanning calorimetry analysis was carried out on a PerkinElmer Diamond. Samples were heated in non-hermetic aluminum pans from ambient to 350 °C at 20 °C/min. The DSC thermogram obtained for Crystalline Form I of Compound A phosphate is summarized in Figure 2.
- the DSC thermogram obtained for Crystalline Form II of Compound A mesylate is summarized in Figure 6.
- the DSC thermogram obtained for Crystalline Form III of Compound A tartrate is summarized in Figure 10.
- the DSC thermogram obtained for Crystalline Form IV of Compound A citrate is summarized in Figure 14. [249]
- the DSC thermograms obtained for Crystalline Forms of Compound A are summarized in Table 6: Table 6. WSGR Docket No.43629-723.601 Example 9.
- Dynamic Vapor Sorption [250] The moisture sorption profile was generated at 25 °C using a DVS intrinsic SMS with the following conditions: sample size approximately 5 to 10 mg, drying 25 °C for 60 minutes, adsorption range 0% to 95% RH, desorption range 95% to 0% RH, and step interval 5%. The equilibrium criterion was ⁇ 0.01% weight change in 5 minutes for a maximum of 120 minutes.
- the DVS isoterm obtained for Crystalline Form I of Compound A phosphate is summarized in Figure 4.
- the DVS isoterm obtained for Crystalline Form II of Compound A mesylate is summarized in Figure 8.
- the DVS isoterm obtained for Crystalline Form III of Compound A tartrate is summarized in Figure 12.
Abstract
The present invention relates to crystalline forms of the phosphate, mesylate, tartrate and citrate salts of compound A.
Description
WSGR Docket No.43629-723.601 CERTAIN CHEMICAL ENTITIES, COMPOSITIONS, AND METHODS CROSS-REFERENCE TO RELATED APPLICATIONS [01] This application claims benefit of U.S. Provisional Patent Application No.63/370,006, filed on August 1, 2022, which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION [02] Described herein are crystalline forms of salts of Na+/K+-ATPase (sodium pump) inhibitors, methods of making such crystalline forms, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulation of Na+/K+- ATPase activity. BACKGROUND OF THE INVENTION [03] Cancer can be viewed as a breakdown in the communication between tumor cells and their environment, including their normal neighboring cells. Signals, both growth-stimulatory and growth-inhibitory, are routinely exchanged between cells within a tissue. Normally, cells do not divide in the absence of stimulatory signals, and likewise, will cease dividing in the presence of inhibitory signals. In a cancerous, or neoplastic state, a cell acquires the ability to “override” these signals and to proliferate under conditions in which normal cells would not grow. [04] Cardiotonic steroids like digoxin and digitoxin are a class of naturally derived compounds that bind to and inhibit Na+/K+-ATPase (sodium pump). Members of this family have been used for the treatment of heart failure and arrhythmia for many years. Recent findings have revealed that these compounds may be involved in the regulation of several important cellular processes. Several cardiotonic steroids such as digitoxin and oleandrin have shown inhibitory effect on the growth of human tumor cells. SUMMARY OF THE INVENTION [05] In one aspect, the disclosure provides a crystalline form of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate phosphate (Compound A phosphate), wherein the crystalline form is Crystalline Form I, further wherein Crystalline Form I is characterized by: (a) an X-ray powder diffraction pattern comprising peaks at 13.1 ± 0.2° 2-θ, 13.7 ± 0.2° 2-θ, and 15.6 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å;
WSGR Docket No.43629-723.601 (b) an X-ray powder diffraction pattern substantially the same as shown in Figure 1; (c) a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 280–295 °C; (d) a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 283 °C and a peak of about 291 °C; (e) a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 2; (f) a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 3; (g) a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 4; or (h) combinations thereof. [06] In some embodiments, Crystalline Form I is characterized by an X-ray powder diffraction pattern comprising peaks at 13.1 ± 0.2° 2-θ, 13.7 ± 0.2° 2-θ, and 15.6 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 16.2 ± 0.2° 2-θ, 20.7 ± 0.2° 2-θ, and 19.4 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 14.8 ± 0.2° 2-θ, 21.8 ± 0.2° 2-θ, and 17.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least five peaks selected from 13.1 ± 0.2° 2-θ, 13.7 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ, 16.2 ± 0.2° 2-θ, 20.7 ± 0.2° 2-θ, 19.4 ± 0.2° 2-θ, 14.8 ± 0.2° 2-θ, 21.8 ± 0.2° 2-θ, and 17.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at 13.1 ± 0.2° 2-θ, 13.7 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ, 16.2 ± 0.2° 2-θ, 20.7 ± 0.2° 2-θ, 19.4 ± 0.2° 2-θ, 14.8 ± 0.2° 2-θ, 21.8 ± 0.2° 2-θ, and 17.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, Crystalline Form I is characterized by an X-ray powder diffraction pattern substantially the same as shown in Figure 1. [07] In some embodiments, Crystalline Form I is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 280–295 °C. In some embodiments, Crystalline Form I is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 283 °C and a peak of about
WSGR Docket No.43629-723.601 291 °C. In some embodiments, Crystalline Form I is characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 2. [08] In some embodiments, Crystalline Form I is characterized by a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 3. [09] In some embodiments, Crystalline Form I is characterized by a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 4. [10] In another aspect, the disclosure provides a crystalline form of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate mesylate (Compound A mesylate), wherein the crystalline form is Crystalline Form II, further wherein Crystalline Form II is characterized by: (a) an X-ray powder diffraction pattern comprising peaks at 13.8 ± 0.2° 2-θ, 20.4 ± 0.2° 2-θ, and 17.9 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å; (b) an X-ray powder diffraction pattern substantially the same as shown in Figure 5; (c) a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 250–265 °C; (d) a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 255 °C and a peak of about 259 °C; (e) a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 6; (f) a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 7; (g) a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 8; or (h) combinations thereof. [11] In some embodiments, Crystalline Form II is characterized by an X-ray powder diffraction pattern comprising peaks at 13.8 ± 0.2° 2-θ, 20.4 ± 0.2° 2-θ, and 17.9 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 19.4 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, and 10.2 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 27.3 ± 0.2° 2-θ, 12.6 ± 0.2° 2-θ, and 25.4 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of
WSGR Docket No.43629-723.601 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least five peaks selected from 13.8 ± 0.2° 2-θ, 20.4 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 19.4 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, 10.2 ± 0.2° 2-θ, 27.3 ± 0.2° 2-θ, 12.6 ± 0.2° 2-θ, and 25.4 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at 13.8 ± 0.2° 2-θ, 20.4 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 19.4 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, 10.2 ± 0.2° 2-θ, 27.3 ± 0.2° 2-θ, 12.6 ± 0.2° 2-θ, and 25.4 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, Crystalline Form II is characterized by an X-ray powder diffraction pattern substantially the same as shown in Figure 5. [12] In some embodiments, Crystalline Form II is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 250–265 °C. In some embodiments, Crystalline Form II is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 255 °C and a peak of about 259 °C. In some embodiments, Crystalline Form II is characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 6. [13] In some embodiments, Crystalline Form II is characterized by a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 7. [14] In some embodiments, Crystalline Form II is characterized by a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 8. [15] In still another aspect, the disclosure provides a crystalline form of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate tartrate (Compound A tartrate), wherein the crystalline form is Crystalline Form III, further wherein Crystalline Form III is characterized by: (a) an X-ray powder diffraction pattern comprising peaks at 10.1 ± 0.2° 2-θ, 13.5 ± 0.2° 2-θ, and 19.6 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å; (b) an X-ray powder diffraction pattern substantially the same as shown in Figure 9; (c) a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 245–265 °C; (d) a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 250 °C and a peak of about 258 °C; (e) a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 10;
WSGR Docket No.43629-723.601 (f) a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 11; (g) a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 12; or (h) combinations thereof. [16] In some embodiments, Crystalline Form III is characterized by an X-ray powder diffraction pattern comprising peaks at 10.1 ± 0.2° 2-θ, 13.5 ± 0.2° 2-θ, and 19.6 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 20.3 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ, and 17.9 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 22.8 ± 0.2° 2-θ, 17.3 ± 0.2° 2-θ, and 16.9 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least five peaks selected from 10.1 ± 0.2° 2-θ, 13.5 ± 0.2° 2-θ, 19.6 ± 0.2° 2-θ, 20.3 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 22.8 ± 0.2° 2-θ, 17.3 ± 0.2° 2-θ, and 16.9 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at 10.1 ± 0.2° 2-θ, 13.5 ± 0.2° 2-θ, 19.6 ± 0.2° 2-θ, 20.3 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 22.8 ± 0.2° 2-θ, 17.3 ± 0.2° 2-θ, and 16.9 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, Crystalline Form III is characterized by an X-ray powder diffraction pattern substantially the same as shown in Figure 9. [17] In some embodiments, Crystalline Form III is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 245–265 °C. In some embodiments, Crystalline Form III is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 250 °C and a peak of about 258 °C. In some embodiments, Crystalline Form III is characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 10. [18] In some embodiments, Crystalline Form III is characterized by a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 11. [19] In some embodiments, Crystalline Form III is characterized by a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 12. [20] In yet another aspect, the disclosure provides a crystalline form of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-
WSGR Docket No.43629-723.601 yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate citrate (Compound A citrate), wherein the crystalline form is Crystalline IV, further wherein Crystalline Form IV is characterized by: (a) an X-ray powder diffraction pattern comprising peaks at 14.3 ± 0.2° 2-θ, 16.5 ± 0.2° 2-θ, and 17.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å; (b) an X-ray powder diffraction pattern substantially the same as shown in Figure 13; (c) a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 230–250 °C; (d) a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 235 °C and a peak of about 242 °C; (e) a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 14; (f) a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 15; (g) a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 16; or (h) combinations thereof. [21] In some embodiments, Crystalline Form IV is characterized by an X-ray powder diffraction pattern comprising peaks at 14.3 ± 0.2° 2-θ, 16.5 ± 0.2° 2-θ, and 17.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 15.8 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, and 10.7 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 17.9 ± 0.2° 2-θ, 20.9 ± 0.2° 2-θ, and 22.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least five peaks selected from 14.3 ± 0.2° 2-θ, 16.5 ± 0.2° 2-θ, 17.0 ± 0.2° 2-θ, 15.8 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, 10.7 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 20.9 ± 0.2° 2-θ, and 22.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at 14.3 ± 0.2° 2-θ, 16.5 ± 0.2° 2-θ, 17.0 ± 0.2° 2-θ, 15.8 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, 10.7 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 20.9 ± 0.2° 2-θ, and 22.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some
WSGR Docket No.43629-723.601 embodiments, Crystalline Form IV is characterized by an X-ray powder diffraction pattern substantially the same as shown in Figure 13. [22] In some embodiments, Crystalline Form IV is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 230–250 °C. In some embodiments, Crystalline Form IV is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 235 °C and a peak of about 242 °C. In some embodiments, Crystalline Form IV is characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 14. [23] In some embodiments, Crystalline Form IV is characterized by a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 15. [24] In some embodiments, Crystalline Form IV is characterized by a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 16. [25] In another aspect, the disclosure provides a pharmaceutical composition comprising a crystalline form of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate phosphate, (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate mesylate, (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate tartrate, or (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate citrate, and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by oral administration. In some embodiments, the pharmaceutical composition is in the form of a solid form pharmaceutical composition. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a powder, a liquid, a suspension, a suppository, or an aerosol. [26] In another aspect, the disclosure provides a packaged pharmaceutical composition comprising a pharmaceutical composition provided herein and instructions for using the composition to treat a subject suffering from cancer. [27] In another aspect, the disclosure provides a method of treating a neoplasm in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the crystalline form of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate phosphate, (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-
WSGR Docket No.43629-723.601 yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate mesylate, (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate tartrate, or (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate citrate provided herein, or one or more of the pharmaceutical compositions provided herein. In some embodiments, the neoplasm is a cancer. In some embodiments, the cancer is colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chondroma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms’ tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemias, e.g., acute lymphocytic leukemia and acute myelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic, monocytic and erythroleukemia); chronic leukemia (chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia); and polycythemia vera, lymphoma (Hodgkin’s disease and non- Hodgkin’s disease), multiple myeloma, Waldenström’s macroglobulinemia, and heavy chain disease. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is oral cancer. In some embodiments, the neoplasm is a benign tumor. In some embodiments, the tumor is craniopharyngioma. [28] In another aspect, the disclosure provides a method of preparing Crystalline Form I of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate phosphate, wherein the method comprises: (a) contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate with phosphoric acid in a solvent to obtain a solution of the
WSGR Docket No.43629-723.601 (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate phosphate; and (b) crystallizing the solution obtained in step (a) to obtain Crystalline Form I of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate phosphate. [29] In some embodiments, the solvent in step (a) comprises ethyl acetate, DMF, ethanol, or isopropanol. In some embodiments, the solvent in step (a) comprises DMF. In some embodiments, step (a) is performed at a temperature of about 40–70 °C. In some embodiments, step (a) is performed at a temperature of about 50–60 °C. [30] In some embodiments, step (b) comprises cooling the solution obtained in step (a) to room temperature. In some embodiments, step (b) comprises cooling the solution obtained in step (a) to a temperature of about 20–25 °C. In some embodiments, the method further comprises filtering the crystallized solution obtained in step (b) to obtain Crystalline Form I. In some embodiments, the method further comprises drying the obtained Crystalline Form I. In some embodiments, the drying is performed under vacuum at a temperature of about 40–70 °C. In some embodiments, the drying is performed under vacuum at a temperature of about 50– 60 °C. [31] In another aspect, the disclosure provides a method of preparing Crystalline Form II of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate mesylate, wherein the method comprises: (a) contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate with methanesulfonic acid in a solvent to obtain a solution of the (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate mesylate; and (b) crystallizing the solution obtained in step (a) to obtain Crystalline Form II of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate mesylate. [32] In some embodiments, the solvent in step (a) comprises ethyl acetate, DMF, ethanol, or isopropanol. In some embodiments, the solvent in step (a) comprises DMF. In some
WSGR Docket No.43629-723.601 embodiments, step (a) is performed at a temperature of about 40–70 °C. In some embodiments, step (a) is performed at a temperature of about 50–60 °C. [33] In some embodiments, step (b) comprises cooling the solution obtained in step (a) to room temperature. In some embodiments, step (b) comprises cooling the solution obtained in step (a) to a temperature of about 20–25 °C. In some embodiments, the method further comprises filtering the crystallized solution obtained in step (b) to obtain Crystalline Form II. In some embodiments, the method further comprises drying the obtained Crystalline Form II. In some embodiments, the drying is performed under vacuum at a temperature of about 40–70 °C. In some embodiments, the drying is performed under vacuum at a temperature of about 50– 60 °C. [34] In another aspect, the disclosure provides a method of preparing Crystalline Form III of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate tartrate, wherein the method comprises: (a) contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate with tartaric acid in a solvent to obtain a solution of the (3S,5R,8R,9S,10S,13R,14S,17R)- 14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate tartrate; and (b) crystallizing the solution obtained in step (a) to obtain Crystalline Form III of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate tartrate. [35] In some embodiments, the solvent in step (a) comprises ethyl acetate, DMF, ethanol, or isopropanol. In some embodiments, the solvent in step (a) comprises DMF. In some embodiments, step (a) is performed at a temperature of about 40–70 °C. In some embodiments, step (a) is performed at a temperature of about 50–60 °C. [36] In some embodiments, step (b) comprises cooling the solution obtained in step (a) to room temperature. In some embodiments, step (b) comprises cooling the solution obtained in step (a) to a temperature of about 20–25 °C. In some embodiments, the method further comprises filtering the crystallized solution obtained in step (b) to obtain Crystalline Form III. In some embodiments, the method further comprises drying the obtained Crystalline Form III. In some embodiments, the drying is performed under vacuum at a temperature of about 40–70 °C. In some embodiments, the drying is performed under vacuum at a temperature of about 50– 60 °C.
WSGR Docket No.43629-723.601 [37] In another aspect, the disclosure provides a method of preparing Crystalline Form IV of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate citrate, wherein the method comprises: (a) contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate with citric acid in a solvent to obtain a solution of the (3S,5R,8R,9S,10S,13R,14S,17R)- 14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate citrate; and (b) crystallizing the solution obtained in step (a) to obtain Crystalline Form IV of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate citrate. [38] In some embodiments, the solvent in step (a) comprises ethyl acetate, DMF, ethanol, or isopropanol. In some embodiments, the solvent in step (a) comprises DMF. In some embodiments, step (a) is performed at a temperature of about 40–70 °C. In some embodiments, step (a) is performed at a temperature of about 50–60 °C. [39] In some embodiments, step (b) comprises cooling the solution obtained in step (a) to room temperature. In some embodiments, step (b) comprises cooling the solution obtained in step (a) to a temperature of about 20–25 °C. In some embodiments, the method further comprises filtering the crystallized solution obtained in step (b) to obtain Crystalline Form IV. In some embodiments, the method further comprises drying the obtained Crystalline Form IV. In some embodiments, the drying is performed under vacuum at a temperature of about 40–70 °C. In some embodiments, the drying is performed under vacuum at a temperature of about 50– 60 °C. INCORPORATION BY REFERENCE [40] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entireties to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DESCRIPTION OF THE DRAWINGS [41] The novel features of the invention are set forth with particularity in the appended claims. An understanding of the features and advantages of the present invention may be obtained by reference to the following detailed description that sets forth illustrative
WSGR Docket No.43629-723.601 embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: [42] Figure 1 shows the X-ray powder diffraction (XRPD) pattern for Crystalline Form I of Compound A phosphate. [43] Figure 2 shows the differential scanning calorimetry (DSC) thermogram for Crystalline Form I of Compound A phosphate. [44] Figure 3 shows the thermogravimetric analysis (TGA) pattern for Crystalline Form I of Compound A phosphate. [45] Figure 4 shows the dynamic vapor sorption (DVS) pattern for Crystalline Form I of Compound A phosphate. [46] Figure 5 shows the X-ray powder diffraction (XRPD) pattern for Crystalline Form II of Compound A mesylate. [47] Figure 6 shows the differential scanning calorimetry (DSC) thermogram for Crystalline Form II of Compound A mesylate. [48] Figure 7 shows the thermogravimetric analysis (TGA) pattern for Crystalline Form II of Compound A mesylate. [49] Figure 8 shows the dynamic vapor sorption (DVS) pattern for Crystalline Form II of Compound A mesylate. [50] Figure 9 shows the X-ray powder diffraction (XRPD) pattern for Crystalline Form III of Compound A tartrate. [51] Figure 10 shows the differential scanning calorimetry (DSC) thermogram for Crystalline Form III of Compound A tartrate. [52] Figure 11 shows the thermogravimetric analysis (TGA) pattern for Crystalline Form III of Compound A tartrate. [53] Figure 12 shows the dynamic vapor sorption (DVS) pattern for Crystalline Form III of Compound A tartrate. [54] Figure 13 shows the X-ray powder diffraction (XRPD) pattern for Crystalline Form IV of Compound A citrate. [55] Figure 14 shows the differential scanning calorimetry (DSC) thermogram for Crystalline Form IV of Compound A citrate. [56] Figure 15 shows the thermogravimetric analysis (TGA) pattern for Crystalline Form IV of Compound A citrate. [57] Figure 16 shows the dynamic vapor sorption (DVS) pattern for Crystalline Form IV of Compound A citrate.
WSGR Docket No.43629-723.601 DETAILED DESCRIPTION OF THE INVENTION [58] While small molecule inhibitors are often initially evaluated for their activity when dissolved in solution, solid state characteristics such as polymorphism are also important. Polymorphic forms of a drug substance can have different physical properties, including melting point, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct effect on the ability to process or manufacture a drug substance and the drug product. Moreover, differences in these properties can and often lead to different pharmacokinetics profiles for different polymorphic forms of a drug. Therefore, polymorphism is often an important factor under regulatory review of the ‘sameness’ of drug products from various manufacturers. For example, polymorphism has been evaluated in many multi-million dollar and even multi-billion dollar drugs, such as warfarin sodium, famotidine, and ranitidine. Polymorphism can affect the quality, safety, and/or efficacy of a drug product. Thus, there still remains a need for polymorphs of drug products. The present disclosure addresses this need and provides related advantages as well. Compound A [59] As used herein, Compound A refers to (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate, which has the chemical structure shown below:
Compound A. [60] Compound A has been prepared previously (see, WO 2011/085641, U.S. Patent No. 8,334,376, U.S. Patent No.8,993,550, U.S. Patent No.9,399,659, U.S. Patent No.9,814,735, U.S. Patent No.10,179,141, U.S. Patent No.10,471,078, and U.S. Patent Application No. 16/584,263). [61] In some embodiments disclosed herein, Compound A is crystalline. [62] In some embodiments disclosed herein, is a salt of Compound A. In some embodiments disclosed herein, the salt of Compound A is a phosphate salt, mesylate salt, tartrate salt, or citrate salt. In some embodiments disclosed herein, the salt of Compound A is a phosphate salt. In some embodiments disclosed herein, the salt of Compound A is a mesylate salt. In some
WSGR Docket No.43629-723.601 embodiments disclosed herein, the salt of Compound A is a tartrate salt. In some embodiments disclosed herein, the salt of Compound A is a citrate salt. [63] In some embodiments disclosed herein, the salt of Compound A is crystalline. In some embodiments disclosed herein, the salt of Compound A is a crystalline phosphate salt, crystalline mesylate salt, crystalline tartrate salt, or crystalline citrate salt. In some embodiments disclosed herein, the salt of Compound A is a crystalline phosphate salt. In some embodiments disclosed herein, the salt of Compound A is a crystalline mesylate salt. In some embodiments disclosed herein, the salt of Compound A is a crystalline tartrate salt. In some embodiments disclosed herein, the salt of Compound A is a crystalline citrate salt. [64] As used herein, “crystalline form,” “polymorph,” “Form,” and “form” may be used interchangeably herein, and are meant to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to. Compounds of the present disclosure include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof. In some embodiments, the crystalline form is a single solid-state form, e.g., crystalline Form I. I. Crystalline Forms of Compound A [65] The polymorphs made according to the methods of the invention may be characterized by any methodology according to the art. For example, the polymorphs made according to the methods of the invention may be characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-stage microscopy, and/or spectroscopy (e.g., Raman, solid state nuclear magnetic resonance (ssNMR), and infrared (IR)). In some embodiments, crystallinity of a solid form is determined by X-Ray Powder Diffraction (XRPD). [66] XRPD: Polymorphs according to the invention may be characterized by XRPD. The relative intensities of XRPD peaks can vary, depending upon the particle size, the sample preparation technique, the sample mounting procedure and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-θ values. Therefore, the XRPD peak assignments can vary, for example by plus or minus about 0.2 degrees. [67] DSC: Polymorphs according to the invention can also be identified by its characteristic DSC thermograms such as shown in Figures 2, 6, etc. For DSC, it is known that the
WSGR Docket No.43629-723.601 temperatures observed will depend upon the rate of temperature change as well as sample preparation technique and the particular instrument employed. Thus, the values reported herein relating to DSC thermograms can vary, for example by plus or minus about 4 °C. [68] TGA: The polymorphic forms of the invention may also give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior may be measured in the laboratory by thermogravimetric analysis (TGA) which may be used to distinguish some polymorphic forms from others. In one aspect, the polymorph may be characterized by thermogravimetric analysis. [69] The polymorph forms of Compound A are useful in the production of medicinal preparations and can be obtained by means of a crystallization process to produce crystalline and semi-crystalline forms or a solidification process to obtain the amorphous form. In various embodiments, the crystallization is carried out by either generating the desired compound (for example Compound A) in a reaction mixture and isolating the desired polymorph from the reaction mixture, or by dissolving raw compound in a solvent, optionally with heat, followed by crystallizing/solidifying the product by cooling (including active cooling) and/or by the addition of an antisolvent for a period of time. The crystallization or solidification may be followed by drying carried out under controlled conditions until the desired water content is reached in the end polymorphic form. [70] In various embodiments, the various polymorph Forms disclosed herein (e.g., Crystalline Form I, Crystalline Form II, Crystalline Form III, and Crystalline Form IV of Compound A) are stable at room temperature. In some examples, the various polymorphs can be stored at room temperature for an extended period of time without significant chemical degradation or change in the crystalline form. In some examples, the various polymorphs can be stored at room temperature for a time period of at least about 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, 30 months, or 36 months. In some examples, the various polymorphs can be stored at room temperature for a time period of more than about 36 months. In some examples, the various polymorphs can be stored at room temperature for a time period of 1–2 months, 1–3 months, 1–6 months, 1–9 months, 1–12 months, 1–18 months, 1–24 months, 1–30 months, 1–36 months, 2–3 months, 2–6 months, 2–9 months, 2–12 months, 2–18 months, 2–24 months, 2–30 months, 2–36 months, 3–6 months, 3–9 months, 3–12 months, 3–18 months, 3–24 months, 3–30 months, 3–36 months, 6–9 months, 6–12 months, 6–18 months, 6– 24 months, 6–30 months, 6–36 months, 9–12 months, 9–18 months, 9–24 months, 9–30 months, 9–36 months, 12–18 months, 12–24 months, 12–30 months, 12–36 months, 18–24 months, 18– 30 months, 18–36 months, 24–30 months, 24–36 months, or 30–36 months. In some examples,
WSGR Docket No.43629-723.601 the various polymorphs can be stored at room temperature for a time period of at least 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, 30 months, or 36 months. [71] In various embodiments, the various polymorph Forms disclosed herein (e.g., Crystalline Form I, Crystalline Form II, Crystalline Form III, and Crystalline Form IV of Compound A) are stable at temperatures above the room temperature and/or at high relative humidity (RH). In some examples, the various polymorph Forms disclosed herein (e.g., Crystalline Form I, Crystalline Form II, Crystalline Form III, and Crystalline Form IV of Compound A) can be stored at about 40 °C at about 75% RH for an extended period of time without significant chemical degradation or change in the crystalline form. In some examples, the various polymorph Forms disclosed herein (e.g., Crystalline Form I, Crystalline Form II, Crystalline Form III, and Crystalline Form IV of Compound A) can be stored at 40 °C and at about 75% RH for a time period of at least about 10 days, 30 days, 60 days, 90 days, 120 days, 150 days, or 180 days. In some examples, the various polymorph Forms disclosed herein (e.g., Crystalline Form I, Crystalline Form II, Crystalline Form III, and Crystalline Form IV of Compound A) can be stored at 40 °C and at about 75% RH for a time period of more than about 180 days. In some examples, the various polymorph Forms disclosed herein (e.g., Crystalline Form I, Crystalline Form II, Crystalline Form III, and Crystalline Form IV of Compound A) can be stored at 40 °C and at about 75% RH for a time period of 10–14 days, 10–18 days, 10–22 days, 10–26 days, 10– 30 days, 10–40 days, 10–50 days, 10–60 days, 10–90 days, 10–120 days, 10–150 days, 10–180 days, 14–18 days, 14–22 days, 14–26 days, 14–30 days, 14–40 days, 14–50 days, 14–60 days, 14–90 days, 14–120 days, 14–150 days, 14–180 days, 18–22 days, 18–26 days, 18–30 days, 18– 40 days, 18–50 days, 18–60 days, 18–90 days, 18–120 days, 18–150 days, 18–180 days, 22–26 days, 22–30 days, 22–40 days, 22–50 days, 22–60 days, 22–90 days, 22–120 days, 22–150 days, 22–180 days, 26–30 days, 26–40 days, 26–50 days, 26– 60 days, 26–90 days, 26–120 days, 26– 150 days, 26–180 days, 30–40 days, 30–50 days, 30–60 days, 30–90 days, 30–120 days, 30–150 days, 30–180 days, 40–50 days, 40–60 days, 40–90 days, 40–120 days, 40–150 days, 40–180 days, 50–60 days, 50–90 days, 50–120 days, 50–150 days, 50–180 days, 60–90 days, 60–120 days, 60–150 days, 60–180 days, 90–120 days, 90–150 days, or 90–180 days. In some examples, the various polymorph Forms disclosed herein (e.g., Crystalline Form I, Crystalline Form II, Crystalline Form III, and Crystalline Form IV of Compound A) can be stored at 40 °C at about 75% RH for a time period of at least 10 days, 14 days, 18 days, 22 days, 26 days, 30 days, 40 days, 50 days, 60 days, 90 days, 120 days, 150 days, or 180 days. Crystalline Form I of Compound A Phosphate
WSGR Docket No.43629-723.601 [72] Figure 1 shows the X-ray powder diffraction (XRPD) pattern for Crystalline Form I of Compound A phosphate. [73] Figure 2 shows the differential scanning calorimetry (DSC) thermogram for Crystalline Form I of Compound A phosphate. [74] Figure 3 shows the thermogravimetric analysis (TGA) pattern for Crystalline Form I of Compound A phosphate. [75] Figure 4 shows the dynamic vapor sorption (DVS) pattern for Crystalline Form I of Compound A phosphate. [76] In one aspect, provided herein is Crystalline Form I of (3S,5R,8R,9S,10S,13R,14S,17R)- 14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate phosphate. Some embodiments provide a composition comprising Crystalline Form I of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate phosphate. In some embodiments, Crystalline Form I of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate phosphate is characterized as having: (a) an X-ray powder diffraction pattern comprising peaks at 13.1 ± 0.2° 2-θ, 13.7 ± 0.2° 2-θ, and 15.6 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å; (b) an X-ray powder diffraction pattern substantially the same as shown in Figure 1; (c) a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 280–295 °C; (d) a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 283 °C and a peak of about 291 °C; (e) a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 2; (f) a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 3; (g) a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 4; or (h) combinations thereof. [77] In some embodiments, Crystalline Form I is characterized by an X-ray powder diffraction pattern substantially the same as shown in Figure 1.
WSGR Docket No.43629-723.601 [78] In some embodiments, Crystalline Form I is characterized by an X-ray powder diffraction pattern comprising peaks at 13.1 ± 0.2° 2-θ, 13.7 ± 0.2° 2-θ, and 15.6 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, Crystalline Form I is characterized by an X-ray powder diffraction pattern comprising peaks at 13.1 ± 0.1° 2-θ, 13.7 ± 0.1° 2-θ, and 15.6 ± 0.1° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, Crystalline Form I is characterized by an X-ray powder diffraction pattern comprising peaks at about 13.1° 2-θ, about 13.7° 2-θ, and about 15.6° 2-θ, as measured by X-ray powder diffraction using an X- ray wavelength of 1.54056 Å. [79] In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 16.2 ± 0.2° 2-θ, 20.7 ± 0.2° 2-θ, and 19.4 ± 0.2° 2-θ, as measured by X- ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X- ray powder diffraction pattern further comprises at least one peak selected from 16.2 ± 0.1° 2-θ, 20.7 ± 0.1° 2-θ, and 19.4 ± 0.1° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from about 16.2° 2-θ, about 20.7° 2-θ, and about 19.4° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. [80] In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 14.8 ± 0.2° 2-θ, 21.8 ± 0.2° 2-θ, and 17.0 ± 0.2° 2-θ, as measured by X- ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X- ray powder diffraction pattern further comprises at least one peak selected from 14.8 ± 0.1° 2-θ, 21.8 ± 0.1° 2-θ, and 17.0 ± 0.1° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from about 14.8° 2-θ, about 21.8° 2-θ, and about 17.0° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. [81] In some embodiments, the X-ray powder diffraction pattern comprises at least one peak selected from 13.1 ± 0.2° 2-θ, 13.7 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ, 16.2 ± 0.2° 2-θ, 20.7 ± 0.2° 2-θ, 19.4 ± 0.2° 2-θ, 14.8 ± 0.2° 2-θ, 21.8 ± 0.2° 2-θ, and 17.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least two peaks selected from 13.1 ± 0.2° 2-θ, 13.7 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ, 16.2 ± 0.2° 2-θ, 20.7 ± 0.2° 2-θ, 19.4 ± 0.2° 2-θ, 14.8 ± 0.2° 2-θ, 21.8 ± 0.2° 2-θ, and 17.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least three peaks selected from 13.1 ± 0.2° 2-θ, 13.7 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ,
WSGR Docket No.43629-723.601 16.2 ± 0.2° 2-θ, 20.7 ± 0.2° 2-θ, 19.4 ± 0.2° 2-θ, 14.8 ± 0.2° 2-θ, 21.8 ± 0.2° 2-θ, and 17.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least four peaks selected from 13.1 ± 0.2° 2-θ, 13.7 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ, 16.2 ± 0.2° 2-θ, 20.7 ± 0.2° 2-θ, 19.4 ± 0.2° 2- θ, 14.8 ± 0.2° 2-θ, 21.8 ± 0.2° 2-θ, and 17.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least five peaks selected from 13.1 ± 0.2° 2-θ, 13.7 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ, 16.2 ± 0.2° 2-θ, 20.7 ± 0.2° 2-θ, 19.4 ± 0.2° 2-θ, 14.8 ± 0.2° 2-θ, 21.8 ± 0.2° 2-θ, and 17.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least six peaks selected from 13.1 ± 0.2° 2-θ, 13.7 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ, 16.2 ± 0.2° 2-θ, 20.7 ± 0.2° 2-θ, 19.4 ± 0.2° 2-θ, 14.8 ± 0.2° 2-θ, 21.8 ± 0.2° 2-θ, and 17.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least seven peaks selected from 13.1 ± 0.2° 2-θ, 13.7 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ, 16.2 ± 0.2° 2-θ, 20.7 ± 0.2° 2-θ, 19.4 ± 0.2° 2-θ, 14.8 ± 0.2° 2-θ, 21.8 ± 0.2° 2- θ, and 17.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least eight peaks selected from 13.1 ± 0.2° 2-θ, 13.7 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ, 16.2 ± 0.2° 2-θ, 20.7 ± 0.2° 2-θ, 19.4 ± 0.2° 2-θ, 14.8 ± 0.2° 2-θ, 21.8 ± 0.2° 2-θ, and 17.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at 13.1 ± 0.2° 2-θ, 13.7 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ, 16.2 ± 0.2° 2-θ, 20.7 ± 0.2° 2-θ, 19.4 ± 0.2° 2-θ, 14.8 ± 0.2° 2-θ, 21.8 ± 0.2° 2-θ, and 17.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at 13.1 ± 0.1° 2-θ, 13.7 ± 0.1° 2-θ, 15.6 ± 0.1° 2-θ, 16.2 ± 0.1° 2-θ, 20.7 ± 0.1° 2-θ, 19.4 ± 0.1° 2-θ, 14.8 ± 0.1° 2-θ, 21.8 ± 0.1° 2-θ, and 17.0 ± 0.1° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at about 13.1° 2-θ, about 13.7° 2-θ, about 15.6° 2-θ, about 16.2° 2-θ, about 20.7° 2-θ, about 19.4° 2-θ, about 14.8° 2-θ, about 21.8° 2-θ, and about 17.0° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. [82] In some embodiments, Crystalline Form I is characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 2. In some embodiments, Crystalline Form III is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 280–295 °C. In some embodiments,
WSGR Docket No.43629-723.601 Crystalline Form I is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 283 °C and a peak of about 291 °C. [83] In some embodiments, Crystalline Form I is characterized by an endotherm in the range of about 280–295 °C, for example at about 280–295 °C, 280–290 °C, 280–285 °C, 285–295 °C, 285–290 °C, or 290–295 °C in the DSC thermogram. In some examples, Crystalline Form I is characterized by an endotherm at about 291 °C in the DSC thermogram. [84] In some embodiments, Crystalline Form I is characterized by a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 3. In various embodiments, Crystalline Form I decomposes above a temperature of about 150 °C, about 200 °C, about 250 °C, about 300 °C, about 350 °C, about 400 °C, about 450 °C, about 500 °C, about 550 °C or above 600 °C. In some examples, Crystalline Form I decomposes above a temperature of about 250 °C. [85] In some embodiments, Crystalline Form I is characterized by a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 4. Crystalline Form II of Compound A Mesylate [86] Figure 5 shows the X-ray powder diffraction (XRPD) pattern for Crystalline Form II of Compound A mesylate. [87] Figure 6 shows the differential scanning calorimetry (DSC) thermogram for Crystalline Form II of Compound A mesylate. [88] Figure 7 shows the thermogravimetric analysis (TGA) pattern for Crystalline Form II of Compound A mesylate. [89] Figure 8 shows the dynamic vapor sorption (DVS) pattern for Crystalline Form II of Compound A mesylate. [90] In one aspect, provided herein is Crystalline Form II of (3S,5R,8R,9S,10S,13R,14S,17R)- 14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate mesylate. Some embodiments provide a composition comprising Crystalline Form II of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate mesylate. In some embodiments, Crystalline Form II of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate mesylate is characterized as having:
WSGR Docket No.43629-723.601 (a) an X-ray powder diffraction pattern comprising peaks at 13.8 ± 0.2° 2-θ, 20.4 ± 0.2° 2-θ, and 17.9 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å; (b) an X-ray powder diffraction pattern substantially the same as shown in Figure 5; (c) a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 250–265 °C; (d) a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 255 °C and a peak of about 259 °C; (e) a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 6; (f) a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 7; (g) a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 8; or (h) combinations thereof. [91] In some embodiments, Crystalline Form II is characterized by an X-ray powder diffraction pattern substantially the same as shown in Figure 5. [92] In some embodiments, Crystalline Form II is characterized by an X-ray powder diffraction pattern comprising peaks at 13.8 ± 0.2° 2-θ, 20.4 ± 0.2° 2-θ, and 17.9 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, Crystalline Form IV is characterized by an X-ray powder diffraction pattern comprising peaks at 13.8 ± 0.1° 2-θ, 20.4 ± 0.1° 2-θ, and 17.9 ± 0.1° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, Crystalline Form IV is characterized by an X-ray powder diffraction pattern comprising peaks at about 13.8° 2-θ, about 20.4° 2-θ, and about 17.9° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. [93] In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 19.4 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, and 10.2 ± 0.2° 2-θ, as measured by X- ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X- ray powder diffraction pattern further comprises at least one peak selected from 19.4 ± 0.1° 2-θ, 15.1 ± 0.1° 2-θ, and 10.2 ± 0.1° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from about 19.4° 2-θ, about 15.1° 2-θ, and about 10.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å.
WSGR Docket No.43629-723.601 [94] In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 27.3 ± 0.2° 2-θ, 12.6 ± 0.2° 2-θ, and 25.4 ± 0.2° 2-θ, as measured by X- ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X- ray powder diffraction pattern further comprises at least one peak selected from 27.3 ± 0.1° 2-θ, 12.6 ± 0.1° 2-θ, and 25.4 ± 0.1° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from about 27.3° 2-θ, about 12.6° 2-θ, and about 25.4° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. [95] In some embodiments, the X-ray powder diffraction pattern comprises at least one peak selected from 13.8 ± 0.2° 2-θ, 20.4 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 19.4 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, 10.2 ± 0.2° 2-θ, 27.3 ± 0.2° 2-θ, 12.6 ± 0.2° 2-θ, and 25.4 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least two peaks selected from 13.8 ± 0.2° 2-θ, 20.4 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 19.4 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, 10.2 ± 0.2° 2-θ, 27.3 ± 0.2° 2-θ, 12.6 ± 0.2° 2-θ, and 25.4 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least three peaks selected from 13.8 ± 0.2° 2-θ, 20.4 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 19.4 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, 10.2 ± 0.2° 2-θ, 27.3 ± 0.2° 2-θ, 12.6 ± 0.2° 2-θ, and 25.4 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least four peaks selected from 13.8 ± 0.2° 2-θ, 20.4 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 19.4 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, 10.2 ± 0.2° 2- θ, 27.3 ± 0.2° 2-θ, 12.6 ± 0.2° 2-θ, and 25.4 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least five peaks selected from 13.8 ± 0.2° 2-θ, 20.4 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 19.4 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, 10.2 ± 0.2° 2-θ, 27.3 ± 0.2° 2-θ, 12.6± 0.2° 2-θ, and 25.4 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least six peaks selected from 13.8 ± 0.2° 2-θ, 20.4 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 19.4 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, 10.2 ± 0.2° 2-θ, 27.3 ± 0.2° 2-θ, 12.6 ± 0.2° 2-θ, and 25.4 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least seven peaks selected from 13.8 ± 0.2° 2-θ, 20.4 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 19.4 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, 10.2 ± 0.2° 2-θ, 27.3 ± 0.2° 2-θ, 12.6 ± 0.2° 2- θ, and 25.4 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least eight
WSGR Docket No.43629-723.601 peaks selected from 13.8 ± 0.2° 2-θ, 20.4 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 19.4 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, 10.2 ± 0.2° 2-θ, 27.3 ± 0.2° 2-θ, 12.6 ± 0.2° 2-θ, and 25.4 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at 13.8 ± 0.2° 2-θ, 20.4 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 19.4 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, 10.2 ± 0.2° 2-θ, 27.3 ± 0.2° 2-θ, 12.6 ± 0.2° 2-θ, and 25.4 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at 13.8 ± 0.1° 2-θ, 20.4 ± 0.1° 2-θ, 17.9 ± 0.1° 2-θ, 19.4 ± 0.1° 2-θ, 15.1 ± 0.1° 2-θ, 10.2 ± 0.1° 2-θ, 27.3 ± 0.1° 2-θ, 12.6 ± 0.1° 2-θ, and 25.4 ± 0.1° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at about 13.8° 2-θ, about 20.4° 2-θ, about 17.9° 2-θ, about 19.4° 2-θ, about 15.1° 2-θ, about 10.2° 2-θ, about 27.3° 2-θ, about 12.6° 2-θ, and about 25.4° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. [96] In some embodiments, Crystalline Form II is characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 6. In some embodiments, Crystalline Form II is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 250–265 °C. In some embodiments, Crystalline Form II is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 255 °C and a peak of about 259 °C. [97] In some embodiments, Crystalline Form II is characterized by an endotherm in the range of about 250–265 °C, for example at about 250–265 °C, 250–260 °C, 250–255 °C, 255–265 °C, 255–260 °C, or 260–265 °C in the DSC thermogram. In some examples, Crystalline Form II is characterized by an endotherm at about 259 °C in the DSC thermogram. [98] In some embodiments, Crystalline Form II is characterized by a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 7. In various embodiments, Crystalline Form II decomposes above a temperature of about 150 °C, about 200 °C, about 250 °C, about 300 °C, about 350 °C, about 400 °C, about 450 °C, about 500 °C, about 550 °C or above 600 °C. In some examples, Crystalline Form II decomposes above a temperature of about 250 °C. [99] In some embodiments, Crystalline Form II is characterized by a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 8. Crystalline Form III of Compound A Tartrate [100] Figure 9 shows the X-ray powder diffraction (XRPD) pattern for Crystalline Form III of Compound A tartrate.
WSGR Docket No.43629-723.601 [101] Figure 10 shows the differential scanning calorimetry (DSC) thermogram for Crystalline Form III of Compound A tartrate. [102] Figure 11 shows the thermogravimetric analysis (TGA) pattern for Crystalline Form III of Compound A tartrate. [103] Figure 12 shows the dynamic vapor sorption (DVS) pattern for Crystalline Form III of Compound A tartrate. [104] In one aspect, provided herein is Crystalline Form III of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate tartrate. Some embodiments provide a composition comprising Crystalline Form III of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate tartrate. In some embodiments, Crystalline Form III of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate tartrate is characterized as having: (a) an X-ray powder diffraction pattern comprising peaks at 10.1 ± 0.2° 2-θ, 13.5 ± 0.2° 2-θ, and 19.6 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å; (b) an X-ray powder diffraction pattern substantially the same as shown in Figure 9; (c) a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 245–265 °C; (d) a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 250 °C and a peak of about 258 °C; (e) a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 10; (f) a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 11; (g) a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 12; or (h) combinations thereof. [105] In some embodiments, Crystalline Form III is characterized by an X-ray powder diffraction pattern substantially the same as shown in Figure 19. [106] In some embodiments, Crystalline Form III is characterized by an X-ray powder diffraction pattern comprising peaks at 10.1 ± 0.2° 2-θ, 13.5 ± 0.2° 2-θ, and 19.6 ± 0.2° 2-θ, as
WSGR Docket No.43629-723.601 measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, Crystalline Form III is characterized by an X-ray powder diffraction pattern comprising peaks at 10.1 ± 0.1° 2-θ, 13.5 ± 0.1° 2-θ, and 19.6 ± 0.1° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, Crystalline Form III is characterized by an X-ray powder diffraction pattern comprising peaks at about 10.1° 2-θ, about 13.5° 2-θ, and about 19.6° 2-θ, as measured by X-ray powder diffraction using an X- ray wavelength of 1.54056 Å. [107] In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 20.3 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ, and 17.9 ± 0.2° 2-θ, as measured by X- ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X- ray powder diffraction pattern further comprises at least one peak selected from 20.3 ± 0.1° 2-θ, 15.6 ± 0.1° 2-θ, and 17.9 ± 0.1° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from about 20.3° 2-θ, about 15.6° 2-θ, and about 17.9° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. [108] In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 22.8 ± 0.2° 2-θ, 17.3 ± 0.2° 2-θ, and 16.9 ± 0.2° 2-θ, as measured by X- ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X- ray powder diffraction pattern further comprises at least one peak selected from 22.8 ± 0.1° 2-θ, 17.3 ± 0.1° 2-θ, and 16.9 ± 0.1° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from about 22.8° 2-θ, about 17.3° 2-θ, and about 16.9° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. [109] In some embodiments, the X-ray powder diffraction pattern comprises at least one peak selected from 10.1 ± 0.2° 2-θ, 13.5 ± 0.2° 2-θ, 19.6 ± 0.2° 2-θ, 20.3 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 22.8 ± 0.2° 2-θ, 17.3 ± 0.2° 2-θ, and 16.9 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least two peaks selected from 10.1 ± 0.2° 2-θ, 13.5 ± 0.2° 2-θ, 19.6 ± 0.2° 2-θ, 20.3 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 22.8 ± 0.2° 2-θ, 17.3 ± 0.2° 2-θ, and 16.9 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least three peaks selected from 10.1 ± 0.2° 2-θ, 13.5 ± 0.2° 2-θ, 19.6 ± 0.2° 2-θ, 20.3 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 22.8 ± 0.2° 2-θ, 17.3 ± 0.2° 2-θ, and 16.9 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some
WSGR Docket No.43629-723.601 embodiments, the X-ray powder diffraction pattern comprises at least four peaks selected from 10.1 ± 0.2° 2-θ, 13.5 ± 0.2° 2-θ, 19.6 ± 0.2° 2-θ, 20.3 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ, 17.9 ± 0.2° 2- θ, 22.8 ± 0.2° 2-θ, 17.3 ± 0.2° 2-θ, and 16.9 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least five peaks selected from 10.1 ± 0.2° 2-θ, 13.5 ± 0.2° 2-θ, 19.6 ± 0.2° 2-θ, 20.3 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 22.8 ± 0.2° 2-θ, 17.3 ± 0.2° 2-θ, and 16.9 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least six peaks selected from 10.1 ± 0.2° 2-θ, 13.5 ± 0.2° 2-θ, 19.6 ± 0.2° 2-θ, 20.3 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 22.8 ± 0.2° 2-θ, 17.3 ± 0.2° 2-θ, and 16.9 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least seven peaks selected from 10.1 ± 0.2° 2-θ, 13.5 ± 0.2° 2-θ, 19.6 ± 0.2° 2-θ, 20.3 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 22.8 ± 0.2° 2-θ, 17.3 ± 0.2° 2- θ, and 16.9 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least eight peaks selected from 10.1 ± 0.2° 2-θ, 13.5 ± 0.2° 2-θ, 19.6 ± 0.2° 2-θ, 20.3 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 22.8 ± 0.2° 2-θ, 17.3 ± 0.2° 2-θ, and 16.9 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at 10.1 ± 0.2° 2-θ, 13.5 ± 0.2° 2-θ, 19.6 ± 0.2° 2-θ, 20.3 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 22.8 ± 0.2° 2-θ, 17.3 ± 0.2° 2-θ, and 16.9 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at 10.1 ± 0.1° 2-θ, 13.5 ± 0.1° 2-θ, 19.6 ± 0.1° 2-θ, 20.3 ± 0.1° 2-θ, 15.6 ± 0.1° 2-θ, 17.9 ± 0.1° 2-θ, 22.8 ± 0.1° 2-θ, 17.3 ± 0.1° 2-θ, and 16.9 ± 0.1° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at about 10.1° 2-θ, about 13.5° 2-θ, about 19.6° 2-θ, about 20.3° 2-θ, about 15.6° 2-θ, about 17.9° 2-θ, about 22.8° 2-θ, about 17.3° 2-θ, and about 16.9° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. [110] In some embodiments, Crystalline Form III is characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 10. In some embodiments, Crystalline Form III is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 245–265 °C. In some embodiments, Crystalline Form III is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 250 °C and a peak of about 258 °C.
WSGR Docket No.43629-723.601 [111] In some embodiments, Crystalline Form III is characterized by an endotherm in the range of about 245–265 °C, for example at about 245–265 °C, 245–260 °C, 245–255 °C, 245– 250 °C, 250–265 °C, 250–260 °C, 250–255 °C, 255–265 °C, 255–260 °C, or 260–265 °C in the DSC thermogram. In some examples, Crystalline Form III is characterized by an endotherm at about 258 °C in the DSC thermogram. [112] In some embodiments, Crystalline Form III is characterized by a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 11. In various embodiments, Crystalline Form III decomposes above a temperature of about 150 °C, about 200 °C, about 250 °C, about 300 °C, about 350 °C, about 400 °C, about 450 °C, about 500 °C, about 550 °C or above 600 °C. In some examples, Crystalline Form III decomposes above a temperature of about 300 °C. [113] In some embodiments, Crystalline Form III is characterized by a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 12. Crystalline Form IV of Compound A Citrate [114] Figure 13 shows the X-ray powder diffraction (XRPD) pattern for Crystalline Form IV of Compound A citrate. [115] Figure 14 shows the differential scanning calorimetry (DSC) thermogram for Crystalline Form IV of Compound A citrate. [116] Figure 15 shows the thermogravimetric analysis (TGA) pattern for Crystalline Form IV of Compound A citrate. [117] Figure 16 shows the dynamic vapor sorption (DVS) pattern for Crystalline Form IV of Compound A citrate. [118] In one aspect, provided herein is Crystalline Form IV of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate citrate. Some embodiments provide a composition comprising Crystalline Form IV of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate citrate. In some embodiments, Crystalline Form IV of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate citrate is characterized as having: (a) an X-ray powder diffraction pattern comprising peaks at 14.3 ± 0.2° 2-θ, 16.5 ± 0.2° 2-θ, and 17.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å;
WSGR Docket No.43629-723.601 (b) an X-ray powder diffraction pattern substantially the same as shown in Figure 13; (c) a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 230–250 °C; (d) a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 235 °C and a peak of about 242 °C; (e) a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 14; (f) a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 15; (g) a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 16; or (h) combinations thereof. [119] In some embodiments, Crystalline Form IV is characterized by an X-ray powder diffraction pattern substantially the same as shown in Figure 13. [120] In some embodiments, Crystalline Form IV is characterized by an X-ray powder diffraction pattern comprising peaks at 14.3 ± 0.2° 2-θ, 16.5 ± 0.2° 2-θ, and 17.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, Crystalline Form IV is characterized by an X-ray powder diffraction pattern comprising peaks at 14.3 ± 0.1° 2-θ, 16.5 ± 0.1° 2-θ, and 17.0 ± 0.1° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, Crystalline Form IV is characterized by an X-ray powder diffraction pattern comprising peaks at about 14.3° 2-θ, about 16.5° 2-θ, and about 17.0° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. [121] In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 15.8 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, and 10.7 ± 0.2° 2-θ, as measured by X- ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X- ray powder diffraction pattern further comprises at least one peak selected from 15.8 ± 0.1° 2-θ, 15.1 ± 0.1° 2-θ, and 10.7 ± 0.1° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from about 15.8° 2-θ, about 15.1° 2-θ, and about 10.7° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. [122] In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 17.9 ± 0.2° 2-θ, 20.9 ± 0.2° 2-θ, and 22.0 ± 0.2° 2-θ, as measured by X- ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-
WSGR Docket No.43629-723.601 ray powder diffraction pattern further comprises at least one peak selected from 17.9 ± 0.1° 2-θ, 20.9 ± 0.1° 2-θ, and 22.0 ± 0.1° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from about 17.9° 2-θ, about 20.9° 2-θ, and about 22.0° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. [123] In some embodiments, the X-ray powder diffraction pattern comprises at least one peak selected from 14.3 ± 0.2° 2-θ, 16.5 ± 0.2° 2-θ, 17.0 ± 0.2° 2-θ, 15.8 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, 10.7 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 20.9 ± 0.2° 2-θ, and 22.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least two peaks selected from 14.3 ± 0.2° 2-θ, 16.5 ± 0.2° 2-θ, 17.0 ± 0.2° 2-θ, 15.8 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, 10.7 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 20.9 ± 0.2° 2-θ, and 22.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least three peaks selected from 14.3 ± 0.2° 2-θ, 16.5 ± 0.2° 2-θ, 17.0 ± 0.2° 2-θ, 15.8 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, 10.7 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 20.9 ± 0.2° 2-θ, and 22.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least four peaks selected from 14.3 ± 0.2° 2-θ, 16.5 ± 0.2° 2-θ, 17.0 ± 0.2° 2-θ, 15.8 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, 10.7 ± 0.2° 2- θ, 17.9 ± 0.2° 2-θ, 20.9 ± 0.2° 2-θ, and 22.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least five peaks selected from 14.3 ± 0.2° 2-θ, 16.5 ± 0.2° 2-θ, 17.0 ± 0.2° 2-θ, 15.8 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, 10.7 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 20.9 ± 0.2° 2-θ, and 22.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least six peaks selected from 14.3 ± 0.2° 2-θ, 16.5 ± 0.2° 2-θ, 17.0 ± 0.2° 2-θ, 15.8 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, 10.7 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 20.9 ± 0.2° 2-θ, and 22.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least seven peaks selected from 14.3 ± 0.2° 2-θ, 16.5 ± 0.2° 2-θ, 17.0 ± 0.2° 2-θ, 15.8 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, 10.7 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 20.9 ± 0.2° 2- θ, and 22.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least eight peaks selected from 14.3 ± 0.2° 2-θ, 16.5 ± 0.2° 2-θ, 17.0 ± 0.2° 2-θ, 15.8 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, 10.7 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 20.9 ± 0.2° 2-θ, and 22.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray
WSGR Docket No.43629-723.601 powder diffraction pattern comprises peaks at 14.3 ± 0.2° 2-θ, 16.5 ± 0.2° 2-θ, 17.0 ± 0.2° 2-θ, 15.8 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, 10.7 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 20.9 ± 0.2° 2-θ, and 22.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at 14.3 ± 0.1° 2-θ, 16.5 ± 0.1° 2-θ, 17.0 ± 0.1° 2-θ, 15.8 ± 0.1° 2-θ, 15.1 ± 0.1° 2-θ, 10.7 ± 0.1° 2-θ, 17.9 ± 0.1° 2-θ, 20.9 ± 0.1° 2-θ, and 22.0 ± 0.1° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at about 14.3° 2-θ, about 16.5° 2-θ, about 17.0° 2-θ, about 15.8° 2-θ, about 15.1° 2-θ, about 10.7° 2-θ, about 17.9° 2-θ, about 20.9° 2-θ, and about 22.0° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. [124] In some embodiments, Crystalline Form IV is characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 14. In some embodiments, Crystalline Form IV is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 230–250 °C. In some embodiments, Crystalline Form IV is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 235 °C and a peak of about 242 °C. [125] In some embodiments, Crystalline Form IV is characterized by an endotherm in the range of about 230–250 °C, for example at about 230–250 °C, 230–245 °C, 230–240 °C, 230– 235 °C, 235–250 °C, 235–245 °C, 235–240 °C, 240–250 °C, 240–245 °C, or 245–250 °C in the DSC thermogram. In some examples, Crystalline Form IV is characterized by an endotherm at about 242 °C in the DSC thermogram. [126] In some embodiments, Crystalline Form IV is characterized by a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 15. In various embodiments, Crystalline Form IV decomposes above a temperature of about 150 °C, about 200 °C, about 250 °C, about 300 °C, about 350 °C, about 400 °C, about 450 °C, about 500 °C, about 550 °C or above 600 °C. In some examples, Crystalline Form IV decomposes above a temperature of about 250 °C. [127] In some embodiments, Crystalline Form IV is characterized by a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 16.
WSGR Docket No.43629-723.601 II. Methods of Making Compound A and Polymorphic Forms Thereof [128] In one aspect, the invention provides methods of making one or more polymorphs of Compound A:
Compound A. [129] In some embodiments, Compound A is prepared according to the examples herein. [130] The polymorphs according to the invention are not limited by the starting materials used to produce Compound A. [131] In one aspect, the invention is directed to methods of making polymorphs of Compound A, or a pharmaceutically acceptable salt and/or solvate thereof, either by isolation of the desired polymorph as the first solid form after synthesis of Compound A, or alternatively, by isolation of the desired polymorph as a transition from a prior solid form of Compound A. Transitions from one form to another are within the scope of the invention because they can be an alternative manufacturing method for obtaining the form desired for the production of the medicinal preparations. [132] Polymorphs of Compound A, according to the methods of the invention can be selected from Crystalline Form I, Crystalline Form II, Crystalline Form III, Crystalline Form IV, and mixtures thereof. [133] Isolation and purification of the chemical entities and intermediates described herein can be performed, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples below. However, other equivalent separation or isolation procedures can also be used. Prior to crystallization, Compound A may be isolated in about 50% chemical purity, 55% chemical purity, 60% chemical purity, 65% chemical purity, 70% chemical purity, 75% chemical purity, 80% chemical purity, 90% chemical purity, 91% chemical purity, 92% purity, 93% chemical purity, 94% chemical purity, 95% chemical purity, 96% chemical purity, 97%
WSGR Docket No.43629-723.601 chemical purity, 98% chemical purity, 99% chemical purity, about 98% chemical purity, or about 100% chemical purity. [134] In some embodiments, the crystalline forms disclosed herein are obtained by crystallizing Compound A with a chemical purity of less than about 98%, less than about 97%, less than about 96%, less than about 95%, less than about 94%, less than about 93%, less than about 92%, less than about 91%, less than about 90%, less than about 89%, less than about 88%, less than about 87%, less than about 86%, less than about 85%, less than about 84%, less than about 83%, less than about 82%, less than about 81%, less than about 80%, less than about 78%, less than about 76%, less than about 74%, less than about 72%, or less than about 70%. In some embodiments, the crystalline forms are obtained by crystallizing Compound A with a chemical purity in the range of about 70% to about 99%, 80% to about 96%, about 85% to about 96%, about 90% to about 96%, about 80% to 98%, about 85% to about 98%, about 90% to about 98%, about 92% to about 98%, about 94% to 98%, or about 96% to about 98%. [135] In some embodiments, isolating the desired polymorph of Compound A involves crystallization of crude reaction product from a mono-solvent system. In various embodiments, isolating the desired polymorph of Compound A involves crystallization of crude product from a binary, tertiary, or greater solvent system, collectively understood as a multi-solvent system. [136] In some embodiments, the crystallization is carried out by generating the desired Compound A in a reaction mixture and isolating the desired polymorph from the reaction mixture. In some embodiments, the reaction mixture is formed by adding phosphoric acid to a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate to form dissolved (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate phosphate (Compound A phosphate). In some embodiments, the reaction mixture is formed by adding methanesulfonic acid to a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate to form dissolved (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate mesylate (Compound A mesylate). In some embodiments, the reaction mixture is formed by adding tartaric acid to a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate to form dissolved (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-
WSGR Docket No.43629-723.601 yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate tartrate (Compound A tartrate). In some embodiments, the reaction mixture is formed by adding citric acid to a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate to form dissolved (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate citrate (Compound A citrate). In other embodiments, the reaction mixture is formed by dissolving Compound A phosphate, Compound A mesylate, Compound A tartrate, or Compound A citrate into a solvent. Preparation of Crystalline Form I [137] In some embodiments, the desired polymorph is Crystalline Form I of Compound A phosphate, and the isolating step involves crystallization of crude reaction product from a mono- solvent system. In some embodiments, the desired polymorph is Crystalline Form I of Compound A phosphate, and the isolating step involves crystallization of crude reaction product from a binary, tertiary, or greater solvent system, collectively understood as a multi-solvent system. In some embodiments, the crude reaction product is formed by contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate with phosphoric acid to form dissolved (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo- 2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate phosphate (Compound A phosphate). [138] In some embodiments, the desired polymorph is Crystalline Form I of Compound A phosphate, and isolating Compound A phosphate involves crystallization from a mono- or multi- solvent system, where the crystallization involves forming Compound A phosphate in situ by contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate with phosphoric acid at a temperature above ambient temperature. In some examples, the reaction in the mono- or multi-solvent system is performed at a temperature of about 10–60 °C, 10–55 °C, 10–50 °C, 10–45 °C, 10–40 °C, 10–35 °C, 10–30 °C, 10–25 °C, 10–20 °C, 10–15 °C, 15–60 °C, 15–55 °C, 15–50 °C, 15–45 °C, 15–40 °C, 15–35 °C, 15–30 °C, 15–25 °C, 15–20 °C, 20–60 °C, 20–55 °C, 20–50 °C, 20–45 °C, 20–40 °C, 20–35 °C, 20–30 °C, 20–25 °C, 25–60 °C, 25–55 °C, 25–50 °C, 25–45 °C, 25–40 °C, 25–35 °C, 25–30 °C, 30–60 °C, 30–55 °C, 30–50 °C, 30–45 °C, 30–40 °C, 30–35 °C, 35–60 °C, 35–55 °C, 35–50 °C, 35–45 °C, 35–40 °C, 40–60 °C, 40–55 °C, 40–50 °C, 40–45 °C, 45–60 °C, 45–55 °C, 45–50 °C, 50–60 °C, 50–55 °C, or 55–60 °C.
WSGR Docket No.43629-723.601 [139] In some examples, the solvent comprises ethyl acetate, DMF, ethanol, or isopropanol. In some examples, the solvent comprises DMF. In some embodiments, the solvent comprises DMF, and the reaction is performed at a temperature of about 50–60 °C. Any suitable amount of solvent can be used. In some embodiments, the amount of solvent (e.g., DMF) used is from about 10–50 mL per gram of Compound A phosphate. For example, in some embodiments, the amount of solvent used is 20 mL per gram of Compound A phosphate. In some examples, the solvent comprises DMF, the reaction is performed at a temperature of about 50–60 °C, and the amount of solvent is about 20 mL/g of Compound A phosphate. [140] In various embodiments, the crystallization further involves filtering the solution containing the obtained crystals of Compound A phosphate. In some embodiments, the crystallization optionally involves washing the obtained crystals by a solvent, for example by the recrystallization solvent one or more times. In some embodiments, the crystallization optionally involves drying the obtained crystals, for example under vacuum at a temperature of about 50– 60 °C. [141] In some embodiments, the chemical purity of the Crystalline Form I is greater than 60%, 70%, 80%, 90%, 95%, or 99%. In some embodiments, the chemical purity of the Crystalline Form I is greater than about 90%. In some embodiments, the chemical purity of the Crystalline Form I is greater than about 95%. In some embodiments, the chemical purity of the Crystalline Form I greater than about 99%. The chemical purity of Crystalline Form I may be measured by any available analytical technique, for example by HPLC analysis. Preparation of Crystalline Form II [142] In some embodiments, the desired polymorph is Crystalline Form II of Compound A mesylate, and the isolating step involves crystallization of crude reaction product from a mono- solvent system. In some embodiments, the desired polymorph is Crystalline Form II of Compound A mesylate, and the isolating step involves crystallization of crude reaction product from a binary, tertiary, or greater solvent system, collectively understood as a multi-solvent system. In some embodiments, the crude reaction product is formed by contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate with methanesulfonic acid to form dissolved (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate mesylate (Compound A mesylate). [143] In some embodiments, the desired polymorph is Crystalline Form II of Compound A mesylate, and isolating Compound A phosphate involves crystallization from a mono- or multi-
WSGR Docket No.43629-723.601 solvent system, where the crystallization involves forming Compound A mesylate in situ by contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate with methanesulfonic acid at a temperature above ambient temperature. In some examples, the reaction in the mono- or multi-solvent system is performed at a temperature of about 10–60 °C, 10–55 °C, 10–50 °C, 10–45 °C, 10–40 °C, 10–35 °C, 10–30 °C, 10–25 °C, 10–20 °C, 10–15 °C, 15–60 °C, 15–55 °C, 15–50 °C, 15–45 °C, 15–40 °C, 15–35 °C, 15–30 °C, 15–25 °C, 15–20 °C, 20–60 °C, 20–55 °C, 20–50 °C, 20–45 °C, 20–40 °C, 20–35 °C, 20–30 °C, 20–25 °C, 25–60 °C, 25–55 °C, 25–50 °C, 25–45 °C, 25–40 °C, 25–35 °C, 25–30 °C, 30–60 °C, 30–55 °C, 30–50 °C, 30–45 °C, 30–40 °C, 30–35 °C, 35–60 °C, 35–55 °C, 35–50 °C, 35–45 °C, 35–40 °C, 40–60 °C, 40–55 °C, 40–50 °C, 40–45 °C, 45–60 °C, 45–55 °C, 45–50 °C, 50–60 °C, 50–55 °C, or 55– 60 °C. [144] In some examples, the solvent comprises ethyl acetate, DMF, ethanol, or isopropanol. In some examples, the solvent comprises DMF. In some embodiments, the solvent comprises DMF, and the reaction is performed at a temperature of about 50–60 °C. Any suitable amount of solvent can be used. In some embodiments, the amount of solvent (e.g., DMF) used is from about 10–50 mL per gram of Compound A mesylate. For example, in some embodiments, the amount of solvent used is 20 mL per gram of Compound A mesylate. In some examples, the solvent comprises DMF, the reaction is performed at a temperature of about 50–60 °C, and the amount of solvent is about 20 mL/g of Compound A mesylate. [145] In various embodiments, the crystallization further involves filtering the solution containing the obtained crystals of Compound A mesylate. In some embodiments, the crystallization optionally involves washing the obtained crystals by a solvent, for example by the recrystallization solvent one or more times. In some embodiments, the crystallization optionally involves drying the obtained crystals, for example under vacuum at a temperature of about 50– 60 °C. [146] In some embodiments, the chemical purity of the Crystalline Form II is greater than 60%, 70%, 80%, 90%, 95%, or 99%. In some embodiments, the chemical purity of the Crystalline Form II is greater than about 90%. In some embodiments, the chemical purity of the Crystalline Form II is greater than about 95%. In some embodiments, the chemical purity of the Crystalline Form II greater than about 99%. The chemical purity of Crystalline Form II may be measured by any available analytical technique, for example by HPLC analysis.
WSGR Docket No.43629-723.601 Preparation of Crystalline Form III [147] In some embodiments, the desired polymorph is Crystalline Form III of Compound A tartrate, and the isolating step involves crystallization of crude reaction product from a mono- solvent system. In some embodiments, the desired polymorph is Crystalline Form III of Compound A tartrate, and the isolating step involves crystallization of crude reaction product from a binary, tertiary, or greater solvent system, collectively understood as a multi-solvent system. In some embodiments, the crude reaction product is formed by contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate with tartaric acid to form dissolved (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate tartrate (Compound A tartrate). [148] In some embodiments, the desired polymorph is Crystalline Form III of Compound A tartrate, and isolating Compound A tartrate involves crystallization from a mono- or multi- solvent system, where the crystallization involves forming Compound A tartrate in situ by contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate with tartaric acid at a temperature above ambient temperature. In some examples, the reaction in the mono- or multi-solvent system is performed at a temperature of about 10–60 °C, 10–55 °C, 10–50 °C, 10– 45 °C, 10–40 °C, 10–35 °C, 10–30 °C, 10–25 °C, 10–20 °C, 10–15 °C, 15–60 °C, 15–55 °C, 15–50 °C, 15–45 °C, 15–40 °C, 15–35 °C, 15–30 °C, 15–25 °C, 15–20 °C, 20–60 °C, 20–55 °C, 20–50 °C, 20–45 °C, 20–40 °C, 20–35 °C, 20–30 °C, 20–25 °C, 25–60 °C, 25–55 °C, 25–50 °C, 25–45 °C, 25–40 °C, 25–35 °C, 25–30 °C, 30–60 °C, 30–55 °C, 30–50 °C, 30–45 °C, 30–40 °C, 30–35 °C, 35–60 °C, 35–55 °C, 35–50 °C, 35–45 °C, 35–40 °C, 40–60 °C, 40–55 °C, 40–50 °C, 40–45 °C, 45–60 °C, 45–55 °C, 45–50 °C, 50–60 °C, 50–55 °C, or 55–60 °C. [149] In some examples, the solvent comprises ethyl acetate, DMF, ethanol, or isopropanol. In some examples, the solvent comprises DMF. In some embodiments, the solvent comprises DMF, and the reaction is performed at a temperature of about 50–60 °C. Any suitable amount of solvent can be used. In some embodiments, the amount of solvent (e.g., DMF) used is from about 10–50 mL per gram of Compound A tartrate. For example, in some embodiments, the amount of solvent used is 20 mL per gram of Compound A tartrate. In some examples, the solvent comprises DMF, the reaction is performed at a temperature of about 50–60 °C, and the amount of solvent is about 20 mL/g of Compound A tartrate.
WSGR Docket No.43629-723.601 [150] In various embodiments, the crystallization further involves filtering the solution containing the obtained crystals of Compound A tartrate. In some embodiments, the crystallization optionally involves washing the obtained crystals by a solvent, for example by the recrystallization solvent one or more times. In some embodiments, the crystallization optionally involves drying the obtained crystals, for example under vacuum at a temperature of about 50– 60 °C. [151] In some embodiments, the chemical purity of the Crystalline Form III is greater than 60%, 70%, 80%, 90%, 95%, or 99%. In some embodiments, the chemical purity of the Crystalline Form III is greater than about 90%. In some embodiments, the chemical purity of the Crystalline Form III is greater than about 95%. In some embodiments, the chemical purity of the Crystalline Form III greater than about 99%. The chemical purity of Crystalline Form III may be measured by any available analytical technique, for example by HPLC analysis. Preparation of Crystalline Form IV [152] In some embodiments, the desired polymorph is Crystalline Form IV of Compound A citrate, and the isolating step involves crystallization of crude reaction product from a mono- solvent system. In some embodiments, the desired polymorph is Crystalline Form IV of Compound A citrate, and the isolating step involves crystallization of crude reaction product from a binary, tertiary, or greater solvent system, collectively understood as a multi-solvent system. In some embodiments, the crude reaction product is formed by contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate with citric acid to form dissolved (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate citrate (Compound A citrate). [153] In some embodiments, the desired polymorph is Crystalline Form IV of Compound A citrate, and isolating Compound A citrate involves crystallization from a mono- or multi-solvent system, where the crystallization involves forming Compound A citrate in situ by contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate with citric acid at a temperature above ambient temperature. In some examples, the reaction in the mono- or multi-solvent system is performed at a temperature of about 10–60 °C, 10–55 °C, 10–50 °C, 10– 45 °C, 10–40 °C, 10–35 °C, 10–30 °C, 10–25 °C, 10–20 °C, 10–15 °C, 15–60 °C, 15–55 °C, 15–50 °C, 15–45 °C, 15–40 °C, 15–35 °C, 15–30 °C, 15–25 °C, 15–20 °C, 20–60 °C, 20–55 °C, 20–50 °C, 20–45 °C, 20–40 °C, 20–35 °C, 20–30 °C, 20–25 °C, 25–60 °C, 25–55 °C, 25–50 °C,
WSGR Docket No.43629-723.601 25–45 °C, 25–40 °C, 25–35 °C, 25–30 °C, 30–60 °C, 30–55 °C, 30–50 °C, 30–45 °C, 30–40 °C, 30–35 °C, 35–60 °C, 35–55 °C, 35–50 °C, 35–45 °C, 35–40 °C, 40–60 °C, 40–55 °C, 40–50 °C, 40–45 °C, 45–60 °C, 45–55 °C, 45–50 °C, 50–60 °C, 50–55 °C, or 55–60 °C. [154] In some examples, the solvent comprises ethyl acetate, DMF, ethanol, or isopropanol. In some examples, the solvent comprises DMF. In some embodiments, the solvent comprises DMF, and the reaction is performed at a temperature of about 50–60 °C. Any suitable amount of solvent can be used. In some embodiments, the amount of solvent (e.g., DMF) used is from about 10–50 mL per gram of Compound A citrate. For example, in some embodiments, the amount of solvent used is 20 mL per gram of Compound A citrate. In some examples, the solvent comprises DMF, the reaction is performed at a temperature of about 50–60 °C, and the amount of solvent is about 20 mL/g of Compound A citrate. [155] In various embodiments, the crystallization further involves filtering the solution containing the obtained crystals of Compound A citrate. In some embodiments, the crystallization optionally involves washing the obtained crystals by a solvent, for example by the recrystallization solvent one or more times. In some embodiments, the crystallization optionally involves drying the obtained crystals, for example under vacuum at a temperature of about 50– 60 °C. [156] In some embodiments, the chemical purity of the Crystalline Form IV is greater than 60%, 70%, 80%, 90%, 95%, or 99%. In some embodiments, the chemical purity of the Crystalline Form IV is greater than about 90%. In some embodiments, the chemical purity of the Crystalline Form IV is greater than about 95%. In some embodiments, the chemical purity of the Crystalline Form IV greater than about 99%. The chemical purity of Crystalline Form IV may be measured by any available analytical technique, for example by HPLC analysis. III. Additional Definitions [157] As used herein, “active agent” is used to indicate a chemical entity which has biological activity. In certain embodiments, an “active agent” is a compound having pharmaceutical utility. For example, an active agent may be an anti-cancer therapeutic. [158] As used herein, “modulation” refers to a change in activity as a direct or indirect response to the presence of a chemical entity as described herein, relative to the activity of in the absence of the chemical entity. The change may be an increase in activity or a decrease in activity and may be due to the direct interaction of the compound with the target or due to the interaction of the compound with one or more other factors that in turn affect the target’s activity. For example, the presence of the chemical entity may, for example, increase or decrease
WSGR Docket No.43629-723.601 the target activity by directly binding to the target, by causing (directly or indirectly) another factor to increase or decrease the target activity, or by (directly or indirectly) increasing or decreasing the amount of target present in the cell or organism. [159] As used herein, “therapeutically effective amount” of a chemical entity described herein refers to an amount effective, when administered to a human or non-human subject, to provide a therapeutic benefit such as amelioration of symptoms, slowing of disease progression, or prevention of disease. [160] “Treating” or “treatment” encompasses administration of Compound A, or a pharmaceutically acceptable salt thereof, to a mammalian subject, particularly a human subject, in need of such an administration and includes (i) arresting the development of clinical symptoms of the disease, such as cancer, (ii) bringing about a regression in the clinical symptoms of the disease, such as cancer, and/or (iii) prophylactic treatment for preventing the onset of the disease, such as cancer. [161] As used herein, a “pharmaceutically acceptable” component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio. [162] “Pharmaceutically acceptable salts” include, but are not limited to salts with inorganic acids, such as hydrochlorate, carbonate, phosphate, hydrogenphosphate, diphosphate, hydrobromate, sulfate, sulfinate, nitrate, and like salts; as well as salts with an organic acid, such as malate, malonate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, gluconate, methanesulfonate, Tris (hydroxymethyl-aminomethane), p-toluenesulfonate, priopionate, 2- hydroxyethylsulfonate, benzoate, salicylate, stearate, oxalate, pamoate, and alkanoate such as acetate, HOOC-(CH2)n-COOH where n is 0–4, and like salts. Other salts include sulfate, methasulfonate, bromide, trifluoroacetate, picrate, sorbate, benzilate, salicilate, nitrate, phthalate or morpholine. Pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium, and ammonium. [163] In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare non-toxic pharmaceutically acceptable addition salts.
WSGR Docket No.43629-723.601 [164] As used herein, “subject” refers to a mammal that has been or will be the object of treatment, observation, or experiment. The methods described herein can be useful in both human therapy and veterinary applications. In some embodiments, the subject is a human. [165] The term “mammal” is intended to have its standard meaning, and encompasses humans, dogs, cats, sheep, and cows, for example. [166] “Prodrugs” described herein include any compound that becomes Compound A when administered to a subject, e.g., upon metabolic processing of the prodrug. Similarly, “pharmaceutically acceptable salts” includes “prodrugs” of pharmaceutically acceptable salts. Examples of prodrugs include derivatives of functional groups, such as a carboxylic acid group, in Compound A. Exemplary prodrugs of a carboxylic acid group include, but are not limited to, carboxylic acid esters such as alkyl esters, hydroxyalkyl esters, arylalkyl esters, and aryloxyalkyl esters. Other exemplary prodrugs include lower alkyl esters such as ethyl ester, acyloxyalkyl esters such as pivaloyloxymethyl (POM), glycosides, and ascorbic acid derivatives. Other exemplary prodrugs include amides of carboxylic acids. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series, in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985. [167] The compounds disclosed herein can be used in different enriched isotopic forms, e.g., enriched in the content of 2H, 3H, 11C, 13C and/or 14C. In one particular embodiment, the compound is deuterated at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos.5,846,514 and 6,334,997. As described in U.S. Patent Nos.5,846,514 and 6,334,997, deuteration can improve the efficacy and increase the duration of action of drugs. [168] Deuterium substituted compounds can be synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601–21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1–2), 9–32. [169] A “solvate” is formed by the interaction of a solvent and a compound. The term “compound” is intended to include solvates of compounds. Similarly, “pharmaceutically acceptable salts” includes solvates of pharmaceutically acceptable salts. Suitable solvates are
WSGR Docket No.43629-723.601 pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemi- hydrates. Also included are solvates formed with the one or more crystallization solvents. [170] Pharmaceutically acceptable forms of the compounds recited herein include pharmaceutically acceptable salts, chelates, non-covalent complexes, prodrugs, and mixtures thereof. [171] A “chelate” is formed by the coordination of a compound to a metal ion at two (or more) points. The term “compound” is intended to include chelates of compounds. Similarly, “pharmaceutically acceptable salts” includes chelates of pharmaceutically acceptable salts. [172] A “non-covalent complex” is formed by the interaction of a compound and another molecule wherein a covalent bond is not formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding). Such non-covalent complexes are included in the term “compound”. Similarly, pharmaceutically acceptable salts include “non-covalent complexes” of pharmaceutically acceptable salts. [173] When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and sub combinations of ranges and specific embodiments therein are intended to be included. [174] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary from, for example, between 1% and 15% of the stated number or numerical range. In some instances of numerical ranges, “about” means ± 10%. [175] As used herein, “significant” refers to any detectable change that is statistically significant in a standard parametric test of statistical significance such as Student’s T-test, where p < 0.05. [176] As used herein, “cancer” refers to all types of cancer or neoplasm or malignant tumors found in mammals, including carcinomas and sarcomas. Examples of cancer are cancer of the brain, breast, cervix, colon, head & neck, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus and Medulloblastoma. IV. Methods of Use [177] The polymorphs described herein may be used in treating a variety of neoplasms, including malignant and benign tumors, as well as cancers. Cancers that can be prevented and/or treated by the polymorphs, compositions, and methods described herein include, but are not
WSGR Docket No.43629-723.601 limited to, human sarcomas and carcinomas, e.g., carcinomas, e.g., colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, thyroid cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chondroma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms’ tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), leukemias, e.g., acute lymphocytic leukemia and acute myelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic, monocytic and erythroleukemia); chronic leukemia (chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia); and polycythemia vera, lymphoma (Hodgkin’s disease and non-Hodgkin’s disease), multiple myeloma, Waldenström’s macroglobulinemia, and heavy chain disease. Benign tumors that can be prevented and/or treated by the polymorphs, compositions, and methods described herein include, but are not limited to, craniopharyngioma. [178] In some embodiments, the polymorphs described herein are used for the treatment of cancers of the i. digestive system including, without limitation, the esophagus, stomach, small intestine, colon (including colorectal), liver & intrahepatic bile duct, gallbladder & other biliary, pancreas, and other digestive organs; ii. respiratory system, including without limitation, larynx, lung & bronchus, and other respiratory organs; iii. skin; iv. thyroid; v. breast; vi. genital system, including without limitation, uterine cervix, ovary, and prostate; vii. urinary system, including without limitation, urinary bladder and kidney and renal pelvis; and
WSGR Docket No.43629-723.601 viii. oral cavity & pharynx, including without limitation, tongue, mouth, pharynx, and other oral cavity. [179] In some embodiments, the polymorphs described herein are used for the treatment of colon cancer, liver cancer, lung cancer, melanoma, thyroid cancer, breast cancer, ovarian cancer, and oral cancer. [180] The polymorphs described herein may also be used in conjunction with other well- known therapeutic agents that are selected for their particular usefulness against the condition that is being treated. For example, the polymorphs described herein may be useful in combination with at least one additional anti-cancer and/or cytotoxic agents. Further, the polymorphs described herein may also be useful in combination with other inhibitors of parts of the signaling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. [181] Such known anti-cancer and/or cytotoxic agents that may be used in combination with the polymorphs described herein include: (i) other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide, and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumor antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin C, dactinomycin, and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine, and vinorelbine and taxoids like taxol and taxotere, and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan, and camptothecin); (ii) cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin, and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole, and exemestane) and inhibitors of 5a-reductase such as finasteride; (iii) anti-invasion agents [for example c-Src kinase family inhibitors like 4-(6-chloro- 2,3methylenedioxyanilino)-7-[2-(4-methylpiperazin-l-yl)ethoxy]-5-tetrahydropyran- 4yloxyquinazoline (AZD0530; International Patent Application WO 01/94341), N-(2-chloro-6-
WSGR Docket No.43629-723.601 methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-l-yl]-2-methylpyrimidin-4ylamino}thiazole- 5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 66586661) and bosutinib (SKl-606), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase]; (iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stem et al. Critical reviews in oncology/haematology, 2005, Vol.54, pp 11–29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4- fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N- (3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6- acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family such as imatinib and/or nilotinib (AMN107); inhibitors of serine/threonine kinases (for example Ras/Raf signaling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006), tipifarnib (R115777) and lonafarnib (SCH66336)), inhibitors of cell signaling through MEK and/or AKT kinases, c-kit inhibitors, ABL kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin like growth factor) kinase inhibitors; aurora kinase inhibitors (for example AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors; (v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1- yl)propoxy)quinazoline (AZD2171; Example 240 within WO 00/47212), compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354, and compounds that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 function, and angiostatin);
WSGR Docket No.43629-723.601 (vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434, and WO 02/08213; (vii) an endothelin receptor antagonist, for example zibotentan (ZD4054) or atrasentan; (viii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense; (ix) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro- drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase subject tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and (x) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of subject’s tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell energy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines and approaches using anti-idiotypic antibodies. [182] In certain embodiments, the at least one polymorph of Compound A is administered in combination with one or more agents chosen from pacliataxel, bortezomib, dacarbazine, gemcitabine, trastuzumab, bevacizumab, capecitabine, docetaxel, erlotinib, aromatase inhibitors, such as AROMASIN™ (exemestane), and estrogen receptor inhibitors, such as FASLODEX™ (fulvestrant). [183] When a polymorph of Compound A is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual subject, as well as the severity of the subject’s symptoms. [184] In one exemplary application, a suitable amount of at least one polymorph of Compound A is administered to a mammal undergoing treatment for cancer, for example, breast cancer. Administration typically occurs in an amount of between about 0.01 mg/kg of body weight to about 100 mg/kg of body weight per day (administered in single or divided doses), such as at least about 0.1 mg/kg of body weight per day. A particular therapeutic dosage can include, e.g., from about 0.01 mg to about 1000 mg of the polymorph of Compound A, such as including, e.g., from about 1 mg to about 1000 mg. The quantity of the at least one polymorph of Compound A
WSGR Docket No.43629-723.601 in a unit dose of preparation may be varied or adjusted from about 0.1 mg to 1000 mg, such as from about 1 mg to 300 mg, for example 10 mg to 200 mg, according to the particular application. The amount administered will vary depending on the particular IC50 value of the at least one polymorph of Compound A used and the judgment of the attending clinician taking into consideration factors such as health, weight, and age. In combinational applications in which the at least one polymorph of Compound A described herein is not the sole active ingredient, it may be possible to administer lesser amounts of the at least one polymorph of Compound A and still have therapeutic or prophylactic effect. [185] In some embodiments, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the polymorph of Compound A, e.g., an effective amount to achieve the desired purpose. [186] The actual dosage employed may be varied depending upon the requirements of the subject and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the at least one polymorph of Compound A. Thereafter, the dosage is increased by small amounts until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired. [187] The amount and frequency of administration of the at least one polymorph of Compound A, and if applicable other chemotherapeutic agents and/or radiation therapy, will be regulated according to the judgment of the attending clinician (physician) considering such factors as age, condition, and size of the subject as well as severity of the disease being treated. [188] The chemotherapeutic agent and/or radiation therapy can be administered according to therapeutic protocols well known in the art. It will be apparent to those skilled in the art that the administration of the chemotherapeutic agent and/or radiation therapy can be varied depending on the disease being treated and the known effects of the chemotherapeutic agent and/or radiation therapy on that disease. Also, in accordance with the knowledge of the skilled clinician, the therapeutic protocols (e.g., dosage amounts and times of administration) can be varied in view of the observed effects of the administered therapeutic agents (i.e., antineoplastic agent or radiation) on the subject, and in view of the observed responses of the disease to the administered therapeutic agents. [189] Also, in general, the at least one polymorph of Compound A need not be administered in the same pharmaceutical composition as a chemotherapeutic agent, and may, because of different physical and chemical characteristics, be administered by a different route. For
WSGR Docket No.43629-723.601 example, the polymorphs/compositions may be administered orally to generate and maintain good blood levels thereof, while the chemotherapeutic agent may be administered intravenously. The determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition, is well within the knowledge of the skilled clinician. The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician. [190] The particular choice of polymorph (and where appropriate, chemotherapeutic agent and/or radiation) will depend upon the diagnosis of the attending physicians and their judgment of the condition of the subject and the appropriate treatment protocol. [191] The one or more polymorphs of Compound A (and where appropriate chemotherapeutic agent and/or radiation) may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the nature of the proliferative disease, the condition of the subject, and the actual choice of chemotherapeutic agent and/or radiation to be administered in conjunction (i.e., within a single treatment protocol) with the one or more polymorphs/composition. [192] In combinational applications and uses, the one or more polymorphs/composition and the chemotherapeutic agent and/or radiation need not be administered simultaneously or essentially simultaneously, and the initial order of administration of the one or more polymorphs/composition, and the chemotherapeutic agent and/or radiation, may not be important. Thus, the at least one polymorph of Compound A may be administered first followed by the administration of the chemotherapeutic agent and/or radiation; or the chemotherapeutic agent and/or radiation may be administered first followed by the administration of the at least one polymorph of Compound A. This alternate administration may be repeated during a single treatment protocol. The determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the subject. For example, the chemotherapeutic agent and/or radiation may be administered first, and then the treatment continued with the administration of the at least one polymorph of Compound A followed, where determined advantageous, by the administration of the chemotherapeutic agent and/or radiation, and so on until the treatment protocol is complete. [193] Thus, in accordance with experience and knowledge, the practicing physician can modify each protocol for the administration of a polymorph of Compound A/composition for treatment according to the individual subject ‘s needs, as the treatment proceeds.
WSGR Docket No.43629-723.601 [194] The attending clinician, in judging whether treatment is effective at the dosage administered, will consider the general well-being of the subject as well as more definite signs such as relief of disease-related symptoms, inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis. Size of the tumor can be measured by standard methods such as radiological studies, e.g., CAT or MRI scan, and successive measurements can be used to judge whether or not growth of the tumor has been retarded or even reversed. Relief of disease- related symptoms such as pain, and improvement in overall condition can also be used to help judge effectiveness of treatment. V. Compositions and Formulations [195] The disclosure provides compositions, including pharmaceutical compositions, comprising one or more crystalline forms of the present invention. [196] In various embodiments, the ratio of desired crystalline form such as Crystalline Form 1 to all other crystalline forms in a composition is greater than about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or more w/w. In other embodiments, the ratio of Crystalline Form II to all other polymorphs is greater than about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or more w/w. In other embodiments, the ratio of Crystalline Form III to all other polymorphs is greater than about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or more w/w. In other embodiments, the ratio of Crystalline Form IV to all other polymorphs is greater than about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or more w/w. [197] In some embodiments, the one or more polymorphs of Compound A are formulated into pharmaceutical compositions. In specific embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds/polymorphs into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are used as suitable to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).
WSGR Docket No.43629-723.601 [198] Provided herein are pharmaceutical compositions comprising one or more polymorphs of Compound A and a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s). In certain embodiments, the one or more polymorphs of Compound A are administered as pharmaceutical compositions in which the one or more polymorphs, are mixed with other active ingredients, as in combination therapy. Encompassed herein are all combinations of actives set forth in the combination therapies section below and throughout this disclosure. In specific embodiments, the pharmaceutical compositions include one or more polymorphs of Compound A. [199] A pharmaceutical composition, as used herein, refers to a mixture of one or more polymorphs of Compound A with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of the polymorphs to an organism. In some embodiments, in practicing the methods of treatment or use provided herein, therapeutically effective amounts of one or more polymorphs of Compound A are administered in a pharmaceutical composition to a mammal having a disease or condition to be treated. In specific embodiments, the mammal is a human. In certain embodiments, therapeutically effective amounts vary depending on the severity of the disease, the age and relative health of the subject and other factors. The one or more polymorphs of Compound A described herein are used singly or in combination with one or more therapeutic agents as components of mixtures. [200] In one embodiment, one or more polymorphs of Compound A are formulated in an aqueous solution. In specific embodiments, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank’s solution, Ringer’s solution, or physiological saline buffer. In other embodiments, one or more polymorphs of Compound A are formulated for transmucosal administration. In specific embodiments, transmucosal formulations include penetrants that are appropriate to the barrier to be permeated. In still other embodiments wherein the one or more polymorphs described herein are formulated for other parenteral injections, appropriate formulations include aqueous or nonaqueous solutions. In specific embodiments, such solutions include physiologically compatible buffers and/or excipients. [201] In another embodiment, the polymorphs described herein are formulated for oral administration. The polymorphs of Compound A are formulated by combining the polymorphs with, e.g., pharmaceutically acceptable carriers or excipients. In various embodiments, the polymorphs described herein are formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, and the like.
WSGR Docket No.43629-723.601 [202] In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the polymorphs described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrating agents are optionally added. Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. [203] In one embodiment, dosage forms, such as dragee cores and tablets, are provided with one or more suitable coating. In specific embodiments, concentrated sugar solutions are used for coating the dosage form. The sugar solutions, optionally contain additional components, such as by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs and/or pigments are also optionally added to the coatings for identification purposes. Additionally, the dyestuffs and/or pigments are optionally utilized to characterize different combinations of active compound doses. [204] In certain embodiments, therapeutically effective amounts of at least one of the polymorphs described herein is formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In specific embodiments, push-fit capsules contain the active ingredients in admixture with one or more filler. Fillers include, by way of example only, lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In other embodiments, soft capsules, contain one or more active compound that is dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added. [205] In other embodiments, therapeutically effective amounts of at least one of the polymorphs described herein are formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels. In still other embodiments, the polymorphs described herein are formulated for parental injection, including formulations suitable for bolus injection or
WSGR Docket No.43629-723.601 continuous infusion. In specific embodiments, formulations for injection are presented in unit dosage form (e.g., in ampoules) or in multi-dose containers. Preservatives are, optionally, added to the injection formulations. In still other embodiments, the pharmaceutical composition of a polymorph of Compound A is formulated in a form suitable for parenteral injection as sterile suspension, solution, or emulsion in oily or aqueous vehicles. Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing, and/or dispersing agents. In specific embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active polymorphs in water-soluble form. In additional embodiments, suspensions of the active polymorphs are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents which increase the solubility of the polymorphs to allow for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen- free water, before use. [206] In still other embodiments, the one or more polymorphs of Compound A are administered topically. The one or more polymorphs described herein are formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments. Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers, and preservatives. [207] In yet other embodiments, the one or more polymorphs of Compound A are formulated for transdermal administration. In specific embodiments, transdermal formulations employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive. In various embodiments, such patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. In additional embodiments, the transdermal delivery of the one or more polymorphs of Compound A is accomplished by means of iontophoretic patches and the like. In certain embodiments, transdermal patches provide controlled delivery of the one or more polymorphs of Compound A. In specific embodiments, the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. In alternative embodiments, absorption enhancers are used to increase absorption.
WSGR Docket No.43629-723.601 Absorption enhancers or carriers include absorbable pharmaceutically acceptable solvents that assist passage through the skin. For example, in one embodiment, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin. [208] In other embodiments, the one or more polymorphs of Compound A are formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists, or powders. Pharmaceutical compositions of the polymorphs of Compound A are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In specific embodiments, the dosage unit of a pressurized aerosol is determined by providing a valve to deliver a metered amount. In certain embodiments, capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator are formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. [209] In still other embodiments, the one or more polymorphs of Compound A are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted. [210] In certain embodiments, pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active polymorphs into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are optionally used as suitable. Pharmaceutical compositions comprising the one or more polymorphs of Compound A are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
WSGR Docket No.43629-723.601 [211] Pharmaceutical compositions include at least one pharmaceutically acceptable carrier, diluent, or excipient and at least one polymorph of Compound A described herein as an active ingredient. The active ingredient is in free-acid or free-base form, or in a pharmaceutically acceptable salt form. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Additionally, the compounds described herein encompass unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. In addition, the pharmaceutical compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and/or other therapeutically valuable substances. [212] Methods for the preparation of compositions, comprising the one or more polymorphs of Compound A described herein include formulating the polymorphs with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The form of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth. [213] In some embodiments, a pharmaceutical composition comprising at least one polymorph of Compound A illustratively takes the form of a liquid where the agents are present in solution, in suspension or both. Typically, when the composition is administered as a solution or suspension a first portion of the agent is present in solution and a second portion of the agent is present in particulate form, in suspension in a liquid matrix. In some embodiments, a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous. [214] In certain embodiments, useful aqueous suspensions contain one or more polymers as suspending agents. Useful polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein comprise
WSGR Docket No.43629-723.601 a mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran. [215] Useful pharmaceutical compositions also, optionally, include solubilizing agents to aid in the solubility of a polymorph of Compound A. The term “solubilizing agent” generally includes agents that result in formation of a micellar solution or a true solution of the agent. Certain acceptable nonionic surfactants, for example polysorbate 80, are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers. [216] Furthermore, useful pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric, and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range. [217] Additionally, useful compositions also, optionally, include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate. [218] Other useful pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride. [219] Still other useful compositions include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides, and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40. [220] Still other useful compositions include one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.
WSGR Docket No.43629-723.601 [221] In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition. [222] In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also employed. In additional embodiments, the polymorphs described herein are delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the polymorphs for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization are employed. [223] In certain embodiments, the formulations described herein comprise one or more antioxidants, metal chelating agents, thiol containing compounds and/or other general stabilizing agents. Examples of such stabilizing agents, include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof. VI. Routes of Administration [224] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections. [225] In certain embodiments, a polymorph of Compound A is administered in a local rather than systemic manner, for example, via injection of the polymorph directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long-acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody.
WSGR Docket No.43629-723.601 In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, a polymorph of Compound A is provided in the form of a rapid release formulation, in the form of an extended-release formulation, or in the form of an intermediate release formulation. In yet other embodiments, a polymorph of Compound A is administered topically. VII. Kits/Articles of Manufacture [226] For use in the therapeutic applications described herein, kits and articles of manufacture are also provided. In some embodiments, such kits comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers are formed from a variety of materials such as glass or plastic. [227] The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products include those found in, e.g., U.S. Pat. Nos.5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. For example, the container(s) includes one or more polymorphs described herein, optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprising a compound with an identifying description or label or instructions relating to its use in the methods described herein. [228] For example, a kit typically includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a compound described herein. Non- limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. A label is optionally on or associated with the container. For example, a label is on a container when letters, numbers or other characters forming the label are attached, molded, or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In addition, a label is
WSGR Docket No.43629-723.601 used to indicate that the contents are to be used for a specific therapeutic application. In addition, the label indicates directions for use of the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical composition is presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack for example contains metal or plastic foil, such as a blister pack. Or the pack or dispenser device is accompanied by instructions for administration. Or the pack or dispenser is accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In some embodiments, compositions containing a polymorph of Compound A formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. EXAMPLES [229] The following examples serve to more fully describe the manner of using the invention. These examples are presented for illustrative purposes and should not serve to limit the true scope of the invention. [230] In carrying out the procedures of the methods described herein, it is of course to be understood that references to particular buffers, media, reagents, cells, culture conditions and the like are not intended to be limiting, but are to be read so as to include all related materials that one of ordinary skill in the art would recognize as being of interest or value in the particular context in which that discussion is presented. For example, it is often possible to substitute one buffer system or culture medium for another and still achieve similar, if not identical, results. Those of skill in the art will have sufficient knowledge of such systems and methodologies so as to be able, without undue experimentation, to make such substitutions as will optimally serve their purposes in using the methods and procedures disclosed herein. [231] The polymorphs described herein can be synthesized utilizing techniques well known in the art from commercially available starting materials and reagents. For example, the polymorphs described herein can be prepared as illustrated below with reference to the examples and reaction schemes. [232] Bufalin can be obtained from the skin glands of Bufo gargarizans or B. melanostictus toads and is commercially available, e.g., from Sigma-Aldrich Corp. (St. Louis, MO). Other
WSGR Docket No.43629-723.601 reagents are commercially available, e.g., from Sigma-Aldrich Corp., or can be readily prepared by those skilled in the art using commonly employed synthetic methodology. [233] The polymorphs described herein may be prepared in substantially pure form, typically by standard chromatographic methods, prior to formulation in a pharmaceutically acceptable form. [234] The following abbreviations and terms have the indicated meanings throughout: AcOH = acetic acid Boc = tert-butoxycarbonyl c- = cyclo DCC = dicyclohexylcarbodiimide DCM = dichloromethane DIPEA = N,N-diisopropylethylamine DMAP = 4-dimethylaminopyridine EDC = 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide eq = equivalent(s) Et = ethyl EtOAc or EA = ethyl acetate EtOH = ethanol g = gram h or hr = hour HBTU = O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate HOBt = hydroxybenzotriazole HPLC = high pressure liquid chromatography i- = iso kg or Kg = kilogram L or l = liter LC/MS = LCMS = liquid chromatography-mass spectrometry LRMS = low resolution mass spectrometry m/z = mass-to-charge ratio Me = methyl MeOH = methanol mg = milligram min = minute
WSGR Docket No.43629-723.601 mL = milliliter mmol = millimole n- = normal NaOAc = sodium acetate PE = petroleum ether Ph = phenyl Prep = preparative quant. = quantitative RP-HPLC = reverse phase-high pressure liquid chromatography rt or RT = room temperature s- = sec- = secondary t- = tert- = tertiary THF = tetrahydrofuran TLC = thin layer chromatography UV = ultraviolet Example 1: Preparation of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17- (2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1- carboxylate (Compound A)
[235] Step 1: To a solution of bufalin (60 mg, 0.15 mmol) and DMAP (16.8 mg, 0.15 mmol) in CH2Cl2 (10 mL) was added DIPEA (77.5 mg, 0.6 mmol) and 4-nitrophenyl carbonochloridate (60.6 mg, 0.3 mmol). The mixture was stirred at 37 °C for 16 h and then purified via preparative TLC (PE/EA=1:1) to afford (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2- oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 4-nitrophenyl carbonate as a white solid (72 mg, 87.1%). [236] Step 2: To a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl- 17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 4-nitrophenyl carbonate (29 mg, 0.054 mmol) in CH2Cl2 was added piperazine (46.4 mg, 0.54 mmol). The resultant mixture was stirred at rt for 16 h and then purified via preparative TLC to afford
WSGR Docket No.43629-723.601 (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate (18.6 mg, 69.2%) as a white solid. LRMS (M+H+) m/z 499.5.1H NMR (CD3OD, 400 MHz) δ 7.90 (dd, J = 9.6, 2.4 Hz, 1H), 7.33 (m, 1H), 6.18 (d, J = 9.6 Hz, 1H), 4.89 (m, 1H), 3.41 (m, 4H), 2.77-2.80 (m, 4H), 2.44-2.48 (m, 1H), 1.08-2.15 (m, 21H), 0.88 (s, 3H), 0.62 (s, 3H). Example 2. Preparation of Crystalline Form I of (3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate phosphate (Compound A phosphate) [237] A solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo- 2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate (100 mg, 0.20 mmol) in N,N-dimethylformamide (2 mL) was stirred at 50~60 ℃. Phosphoric acid (1 M, 0.2 mL) was added dropwise to the solution with stirring at 50~60 ℃. The solution was cooled to room temperature slowly. The precipitate was filtered, and dried under vacuum at 50~60 ℃ to afford Crystalline Form I of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate phosphate. Example 3. Preparation of Crystalline Form II of (3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate mesylate (Compound A mesylate) [238] A solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo- 2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate (100 mg, 0.20 mmol) in N,N-dimethylformamide (2 mL) was stirred at 50~60 ℃. Methanesulfonic acid (1 M, 0.2 mL) was added dropwise to the solution with stirring at 50~60 ℃. The solution was cooled to room temperature slowly. The precipitate was filtered, and dried under vacuum at 50~60 ℃ to afford Crystalline Form II of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate mesylate.
WSGR Docket No.43629-723.601 Example 4. Preparation of Crystalline Form III of (3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate tartrate (Compound A tartrate) [239] A solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo- 2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate (100 mg, 0.20 mmol) in N,N-dimethylformamide (2 mL) was stirred at 50~60 ℃ to be clear. Tartaric acid (0.5 M, 0.2 mL) was added dropwise to the solution with stirring at 50~60 ℃. The solution was cooled to room temperature slowly. The precipitate was filtered, and dried under vacuum at 50~60 ℃ to afford Crystalline Form III of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate tartrate. Example 5. Preparation of Crystalline Form IV of (3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate citrate (Compound A citrate) [240] A solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo- 2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate (100 mg, 0.20 mmol) in N,N-dimethylformamide (2 mL) was stirred at 50~60 ℃ to be clear. Citric acid (0.5 M, 0.5 mL) was added dropwise to the solution with stirring at 50~60 ℃. The solution was cooled to room temperature slowly. The precipitate was filtered, and dried under vacuum at 50~60 ℃ to afford Crystalline Form IV of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate citrate. Example 6. X-Ray Powder Diffraction (XRPD) [241] X-ray powder diffraction (XRPD) patterns were obtained on a Shimadzu XRD-6000. A CuK source (=1.54056 angstrom) operating minimally at 40 kV and 30 mA scans each sample between 5 and 50 degrees 2-theta. The scanning rate is 5 degrees 2-theta per minute. [242] The XRPD pattern obtained for Crystalline Form I of Compound A phosphate is summarized in Table 1 and Figure 1. Table 1.
WSGR Docket No.43629-723.601
[243] The XRPD pattern obtained for Crystalline Form II of Compound A mesylate is summarized in Table 2 and Figure 5. Table 2.
[244] The XRPD pattern obtained for Crystalline Form III of Compound A tartrate is summarized in Table 3 and Figure 9. Table 3.
WSGR Docket No.43629-721.101
[245] The XRPD pattern obtained for Crystalline Form IV of Compound A citrate is summarized in Table 4 and Figure 13. Table 4.
WSGR Docket No.43629-723.601 Example 7. Thermogravimetric Analysis (TGA) [246] Thermogravimetric analysis was carried out on a PerkinElmer Pyris 1 TGA. Samples were heated in platinum pans from ambient to 350 °C at 20 °C/min. The TGA pattern obtained for Crystalline Form I of Compound A phosphate is shown in Figure 3. The TGA pattern obtained for Crystalline Form II of Compound A mesylate is shown in Figure 7. The TGA pattern obtained for Crystalline Form III of Compound A tartrate is shown in Figure 11. The TGA pattern obtained for Crystalline Form IV of Compound A citrate is shown in Figure 15. [247] The TGA patterns obtained for Crystalline Forms of Compound A are summarized in Table 5: Table 5.
Example 8. Differential Scanning Calorimetry (DSC) [248] Differential scanning calorimetry analysis was carried out on a PerkinElmer Diamond. Samples were heated in non-hermetic aluminum pans from ambient to 350 °C at 20 °C/min. The DSC thermogram obtained for Crystalline Form I of Compound A phosphate is summarized in Figure 2. The DSC thermogram obtained for Crystalline Form II of Compound A mesylate is summarized in Figure 6. The DSC thermogram obtained for Crystalline Form III of Compound A tartrate is summarized in Figure 10. The DSC thermogram obtained for Crystalline Form IV of Compound A citrate is summarized in Figure 14. [249] The DSC thermograms obtained for Crystalline Forms of Compound A are summarized in Table 6: Table 6.
WSGR Docket No.43629-723.601
Example 9. Dynamic Vapor Sorption (DVS) [250] The moisture sorption profile was generated at 25 °C using a DVS intrinsic SMS with the following conditions: sample size approximately 5 to 10 mg, drying 25 °C for 60 minutes, adsorption range 0% to 95% RH, desorption range 95% to 0% RH, and step interval 5%. The equilibrium criterion was <0.01% weight change in 5 minutes for a maximum of 120 minutes. The DVS isoterm obtained for Crystalline Form I of Compound A phosphate is summarized in Figure 4. The DVS isoterm obtained for Crystalline Form II of Compound A mesylate is summarized in Figure 8. The DVS isoterm obtained for Crystalline Form III of Compound A tartrate is summarized in Figure 12. The DVS isoterm obtained for Crystalline Form IV of Compound A citrate is summarized in Figure 16. [251] While some embodiments have been shown and described, various modifications and substitutions may be made thereto without departing from the spirit and scope of the invention. For example, for claim construction purposes, it is not intended that the claims set forth hereinafter be construed in any way narrower than the literal language thereof, and it is thus not intended that exemplary embodiments from the specification be read into the claims. Accordingly, it is to be understood that the present invention has been described by way of illustration and not limitations on the scope of the claims.
Claims
WSGR Docket No.43629-723.601 CLAIMS WHAT IS CLAIMED IS: 1. A crystalline form of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17- (2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1- carboxylate phosphate, wherein the crystalline form is Crystalline Form I, further wherein Crystalline Form I is characterized by: (a) an X-ray powder diffraction pattern comprising peaks at 13.1 ± 0.2° 2-θ, 13.7 ± 0.2° 2-θ, and 15.6 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å; (b) an X-ray powder diffraction pattern substantially the same as shown in Figure 1; (c) a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 280–295 °C; (d) a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 283 °C and a peak of about 291 °C; (e) a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 2; (f) a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 3; (g) a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 4; or (h) combinations thereof. 2. The crystalline form of claim 1, wherein Crystalline Form I is characterized by an X-ray powder diffraction pattern comprising peaks at 13.1 ± 0.2° 2-θ, 13.7 ± 0.2° 2-θ, and 15.6 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. 3. The crystalline form of either claim 1 or claim 2, wherein the X-ray powder diffraction pattern further comprises at least one peak selected from 16.2 ± 0.2° 2-θ, 20.7 ± 0.2° 2-θ, and 19.4 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. 4. The crystalline form according to any one of claims 1–3, wherein the X-ray powder diffraction pattern further comprises at least one peak selected from 14.8 ± 0.2° 2-θ, 21.8 ± 0.2° 2-θ, and 17.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å.
WSGR Docket No.43629-723.601 5. The crystalline form according to any one of claims 1–4, wherein the X-ray powder diffraction pattern comprises at least five peaks selected from 13.1 ± 0.2° 2-θ, 13.7 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ, 16.2 ± 0.2° 2-θ, 20.7 ± 0.2° 2-θ, 19.4 ± 0.2° 2-θ, 14.8 ± 0.2° 2-θ, 21.8 ± 0.2° 2-θ, and 17.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. 6. The crystalline form according to any one of claims 1–5, wherein the X-ray powder diffraction pattern comprises peaks at 13.1 ± 0.2° 2-θ, 13.7 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ, 16.2 ± 0.2° 2-θ, 20.7 ± 0.2° 2-θ, 19.4 ± 0.2° 2-θ, 14.8 ± 0.2° 2-θ, 21.8 ± 0.2° 2-θ, and 17.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. 7. The crystalline form according to any one of claims 1–6, wherein Crystalline Form I is characterized by an X-ray powder diffraction pattern substantially the same as shown in Figure 1. 8. The crystalline form according to any one of claims 1–7, wherein Crystalline Form I is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 280–295 °C. 9. The crystalline form according to any one of claims 1–8, wherein Crystalline Form I is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 283 °C and a peak of about 291 °C. 10. The crystalline form according to any one of claims 1–9, wherein Crystalline Form I is characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 2. 11. The crystalline form according to any one of claims 1–10, wherein Crystalline Form I is characterized by a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 3. 12. The crystalline form according to any one of claims 1–11, wherein Crystalline Form I is characterized by a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 4. 13. A crystalline form (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2- oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1- carboxylate mesylate, wherein the crystalline form is Crystalline Form II, further wherein Crystalline Form II is characterized by:
WSGR Docket No.43629-723.601 (a) an X-ray powder diffraction pattern comprising peaks at 13.8 ± 0.2° 2-θ, 20.4 ± 0.2° 2-θ, and 17.9 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å; (b) an X-ray powder diffraction pattern substantially the same as shown in Figure 5; (c) a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 250–265 °C; (d) a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 255 °C and a peak of about 259 °C; (e) a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 6; (f) a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 7; (g) a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 8; or (h) combinations thereof. 14. The crystalline form of claim 13, wherein Crystalline Form II is characterized by an X- ray powder diffraction pattern comprising peaks at 13.8 ± 0.2° 2-θ, 20.4 ± 0.2° 2-θ, and 17.9 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. 15. The crystalline form of either claim 13 or claim 14, wherein the X-ray powder diffraction pattern further comprises at least one peak selected from 19.4 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, and 10.2 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. 16. The crystalline form according to any one of claims 13–15, wherein the X-ray powder diffraction pattern further comprises at least one peak selected from 27.3 ± 0.2° 2-θ, 12.6 ± 0.2° 2-θ, and 25.4 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. 17. The crystalline form according to any one of claims 13–16, wherein the X-ray powder diffraction pattern comprises at least five peaks selected from 13.8 ± 0.2° 2-θ, 20.4 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 19.4 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, 10.2 ± 0.2° 2-θ, 27.3 ± 0.2° 2-θ, 12.6 ± 0.2° 2-θ, and 25.4 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å.
WSGR Docket No.43629-723.601 18. The crystalline form according to any one of claims 13–17, wherein the X-ray powder diffraction pattern comprises peaks at 13.8 ± 0.2° 2-θ, 20.4 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 19.4 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, 10.2 ± 0.2° 2-θ, 27.3 ± 0.2° 2-θ, 12.6 ± 0.2° 2-θ, and 25.4 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. 19. The crystalline form according to any one of claims 13–18, wherein Crystalline Form II is characterized by an X-ray powder diffraction pattern substantially the same as shown in Figure 5. 20. The crystalline form according to any one of claims 13–19, wherein Crystalline Form II is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 250–265 °C. 21. The crystalline form according to any one of claims 13–20, wherein Crystalline Form II is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 255 °C and a peak of about 259 °C. 22. The crystalline form according to any one of claims 13–21, wherein Crystalline Form II is characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 6. 23. The crystalline form according to any one of claims 13–22, wherein Crystalline Form II is characterized by a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 7. 24. The crystalline form according to any one of claims 13–23, wherein Crystalline Form II is characterized by a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 8. 25. A crystalline form of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17- (2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1- carboxylate tartrate, wherein the crystalline form is Crystalline Form III, further wherein Crystalline Form III is characterized by: (a) an X-ray powder diffraction pattern comprising peaks at 10.1 ± 0.2° 2-θ, 13.5 ± 0.2° 2-θ, and 19.6 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å; (b) an X-ray powder diffraction pattern substantially the same as shown in Figure 9; (c) a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 245–265 °C;
WSGR Docket No.43629-723.601 (d) a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 250 °C and a peak of about 258 °C; (e) a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 10; (f) a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 11; (g) a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 12; or (h) combinations thereof. 26. The crystalline form of claim 25, wherein Crystalline Form III is characterized by an X- ray powder diffraction pattern comprising peaks at 10.1 ± 0.2° 2-θ, 13.5 ± 0.2° 2-θ, and 19.6 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. 27. The crystalline form of either claim 25 or claim 26, wherein the X-ray powder diffraction pattern further comprises at least one peak selected from 20.3 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ, and 17.9 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. 28. The crystalline form according to any one of claims 25–27, wherein the X-ray powder diffraction pattern further comprises at least one peak selected from 22.8 ± 0.2° 2-θ, 17.3 ± 0.2° 2-θ, and 16.9 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. 29. The crystalline form according to any one of claims 25–28, wherein the X-ray powder diffraction pattern comprises at least five peaks selected from 10.1 ± 0.2° 2-θ, 13.5 ± 0.2° 2-θ, 19.6 ± 0.2° 2-θ, 20.3 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 22.8 ± 0.2° 2-θ, 17.3 ± 0.2° 2-θ, and 16.9 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. 30. The crystalline form according to any one of claims 25–29, wherein the X-ray powder diffraction pattern comprises peaks at 10.1 ± 0.2° 2-θ, 13.5 ± 0.2° 2-θ, 19.6 ± 0.2° 2-θ, 20.3 ± 0.2° 2-θ, 15.6 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 22.8 ± 0.2° 2-θ, 17.3 ± 0.2° 2-θ, and 16.9 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å.
WSGR Docket No.43629-723.601 31. The crystalline form according to any one of claims 25–30, wherein Crystalline Form III is characterized by an X-ray powder diffraction pattern substantially the same as shown in Figure 9. 32. The crystalline form according to any one of claims 25–31, wherein Crystalline Form III is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 245–265 °C. 33. The crystalline form according to any one of claims 25–32, wherein Crystalline Form III is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 250 °C and a peak of about 258 °C. 34. The crystalline form according to any one of claims 25–33, wherein Crystalline Form III is characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 10. 35. The crystalline form according to any one of claims 25–34, wherein Crystalline Form III is characterized by a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 11. 36. The crystalline form according to any one of claims 25–35, wherein Crystalline Form III is characterized by a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 12. 37. A crystalline form of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17- (2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1- carboxylate citrate, wherein Crystalline Form IV is characterized by: (a) an X-ray powder diffraction pattern comprising peaks at 14.3 ± 0.2° 2-θ, 16.5 ± 0.2° 2-θ, and 17.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å; (b) an X-ray powder diffraction pattern substantially the same as shown in Figure 13; (c) a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 230–250 °C; (d) a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 235 °C and a peak of about 242 °C; (e) a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 14; (f) a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 15;
WSGR Docket No.43629-723.601 (g) a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 16; or (h) combinations thereof. 38. The crystalline form of claim 37, wherein Crystalline Form IV is characterized by an X- ray powder diffraction pattern comprising peaks at 14.3 ± 0.2° 2-θ, 16.5 ± 0.2° 2-θ, and 17.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. 39. The crystalline form of either claim 37 or claim 38, wherein the X-ray powder diffraction pattern further comprises at least one peak selected from 15.8 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, and 10.7 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. 40. The crystalline form according to any one of claims 37–39, wherein the X-ray powder diffraction pattern further comprises at least one peak selected from 17.9 ± 0.2° 2-θ, 20.9 ± 0.2° 2-θ, and 22.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. 41. The crystalline form according to any one of claims 37–40, wherein the X-ray powder diffraction pattern comprises at least five peaks selected from 14.3 ± 0.2° 2-θ, 16.5 ± 0.2° 2-θ, 17.0 ± 0.2° 2-θ, 15.8 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, 10.7 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 20.9 ± 0.2° 2-θ, and 22.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. 42. The crystalline form according to any one of claims 37–41, wherein the X-ray powder diffraction pattern comprises peaks at 14.3 ± 0.2° 2-θ, 16.5 ± 0.2° 2-θ, 17.0 ± 0.2° 2-θ, 15.8 ± 0.2° 2-θ, 15.1 ± 0.2° 2-θ, 10.7 ± 0.2° 2-θ, 17.9 ± 0.2° 2-θ, 20.9 ± 0.2° 2-θ, and 22.0 ± 0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54056 Å. 43. The crystalline form according to any one of claims 37–42, wherein Crystalline Form IV is characterized by an X-ray powder diffraction pattern substantially the same as shown in Figure 13. 44. The crystalline form according to any one of claims 37–43, wherein Crystalline Form IV is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 230–250 °C.
WSGR Docket No.43629-723.601 45. The crystalline form according to any one of claims 37–44, wherein Crystalline Form IV is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 235 °C and a peak of about 242 °C. 46. The crystalline form according to any one of claims 37–45, wherein Crystalline Form IV is characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as shown in Figure 14. 47. The crystalline form according to any one of claims 37–46, wherein Crystalline Form IV is characterized by a Thermogravimetric Analysis (TGA) thermogram substantially the same as shown in Figure 15. 48. The crystalline form according to any one of claims 37–47, wherein Crystalline Form IV is characterized by a dynamic vapor sorption (DVS) pattern substantially the same as shown in Figure 16. 49. A pharmaceutical composition comprising the crystalline form according to any one of claims 1–48, and at least one pharmaceutically acceptable excipient. 50. The pharmaceutical composition of claim 49, wherein the pharmaceutical composition is formulated for administration to a mammal by oral administration. 51. The pharmaceutical composition of either claim 49 or claim 50, wherein the pharmaceutical composition is in the form of a solid form pharmaceutical composition. 52. The pharmaceutical composition of claim 49, wherein the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a powder, a liquid, a suspension, a suppository, or an aerosol. 53. A packaged pharmaceutical composition comprising a pharmaceutical composition of any one of claims 49–52 and instructions for using the composition to treat a subject suffering from cancer. 54. A method of treating a neoplasm in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the crystalline form according to any one of claims 1–48, or the pharmaceutical composition according to any one of claims 49–52. 55. The method of claim 54, wherein the neoplasm is a cancer. 56. The method of claim 55, wherein the cancer is colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chondroma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell
WSGR Docket No.43629-723.601 carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms’ tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemias, e.g., acute lymphocytic leukemia and acute myelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic, monocytic and erythroleukemia); chronic leukemia (chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia); and polycythemia vera, lymphoma (Hodgkin’s disease and non-Hodgkin’s disease), multiple myeloma, Waldenström’s macroglobulinemia, and heavy chain disease. 57. The method of claim 55 or claim 56, wherein the cancer is colorectal cancer. 58. The method of claim 55 or claim 56, wherein the cancer is liver cancer. 59. The method of claim 55 or claim 56, wherein the cancer is lung cancer. 60. The method of claim 55 or claim 56, wherein the cancer is breast cancer. 61. The method of claim 55 or claim 56, wherein the cancer is oral cancer. 62. The method of claim 54, wherein the neoplasm is a benign tumor. 63. The method of claim 62, wherein the tumor is craniopharyngioma. 64. A method of preparing Crystalline Form I of (3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate phosphate, wherein the method comprises: (a) contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2- oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate with phosphoric acid in a solvent to obtain a solution of the (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1- carboxylate phosphate; and (b) crystallizing the solution obtained in step (a) to obtain Crystalline Form I of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1- carboxylate phosphate.
WSGR Docket No.43629-723.601 65. The method of claim 64, wherein the solvent in step (a) comprises ethyl acetate, DMF, ethanol, or isopropanol. 66. The method of either claim 64 or claim 65, wherein the solvent in step (a) comprises DMF. 67. The method according to any one of claims 64–66, wherein step (a) is performed at a temperature of about 40–70 °C. 68. The method according to any one of claims 64–67, wherein step (a) is performed at a temperature of about 50–60 °C. 69. The method according to any one of claims 64–68, wherein step (b) comprises cooling the solution obtained in step (a) to room temperature. 70. The method according to any one of claims 64–69, wherein step (b) comprises cooling the solution obtained in step (a) to a temperature of about 20–25 °C. 71. The method according to any one of claims 64–70, further comprising filtering the crystallized solution obtained in step (b) to obtain Crystalline Form I. 72. The method according to any one of claims 64–71, further comprising drying the obtained Crystalline Form I. 73. The method of claim 72, wherein the drying is performed under vacuum at a temperature of about 40–70 °C. 74. The method of either claim 72 or claim 73, wherein the drying is performed under vacuum at a temperature of about 50–60 °C. 75. A method of preparing Crystalline Form II of (3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate mesylate, wherein the method comprises: (a) contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2- oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate with methanesulfonic acid in a solvent to obtain a solution of the (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17- (2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate mesylate; and (b) crystallizing the solution obtained in step (a) to obtain Crystalline Form II of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1- carboxylate mesylate.
WSGR Docket No.43629-723.601 76. The method of claim 75, wherein the solvent in step (a) comprises ethyl acetate, DMF, ethanol, or isopropanol. 77. The method of either claim 75 or claim 76, wherein the solvent in step (a) comprises DMF. 78. The method according to any one of claims 75–77, wherein step (a) is performed at a temperature of about 40–70 °C. 79. The method according to any one of claims 75–78, wherein step (a) is performed at a temperature of about 50–60 °C. 80. The method according to any one of claims 75–79, wherein step (b) comprises cooling the solution obtained in step (a) to room temperature. 81. The method according to any one of claims 75–80, wherein step (b) comprises cooling the solution obtained in step (a) to a temperature of about 20–25 °C. 82. The method according to any one of claims 75–81, further comprising filtering the crystallized solution obtained in step (b) to obtain Crystalline Form II. 83. The method according to any one of claims 75–82, further comprising drying the obtained Crystalline Form IV. 84. The method of claim 83, wherein the drying is performed under vacuum at a temperature of about 40–70 °C. 85. The method of either claim 83 or claim 84, wherein the drying is performed under vacuum at a temperature of about 50–60 °C. 86. A method of preparing Crystalline Form III of (3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate tartrate, wherein the method comprises: (a) contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2- oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate with tartaric acid in a solvent to obtain a solution of the (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1- carboxylate tartrate; and (b) crystallizing the solution obtained in step (a) to obtain Crystalline Form III of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1- carboxylate tartrate.
WSGR Docket No.43629-723.601 87. The method of claim 86, wherein the solvent in step (a) comprises ethyl acetate, DMF, ethanol, or isopropanol. 88. The method of either claim 86 or claim 87, wherein the solvent in step (a) comprises DMF. 89. The method according to any one of claims 86–88, wherein step (a) is performed at a temperature of about 40–70 °C. 90. The method according to any one of claims 86–89, wherein step (a) is performed at a temperature of about 50–60 °C. 91. The method according to any one of claims 86–90, wherein step (b) comprises cooling the solution obtained in step (a) to room temperature. 92. The method according to any one of claims 86–91, wherein step (b) comprises cooling the solution obtained in step (a) to a temperature of about 20–25 °C. 93. The method according to any one of claims 86–92, further comprising filtering the crystallized solution obtained in step (b) to obtain Crystalline Form III. 94. The method according to any one of claims 86–93, further comprising drying the obtained Crystalline Form III. 95. The method of claim 94, wherein the drying is performed under vacuum at a temperature of about 40–70 °C. 96. The method of either claim 94 or claim 95, wherein the drying is performed under vacuum at a temperature of about 50–60 °C. 97. A method of preparing Crystalline Form IV of (3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate citrate, wherein the method comprises: (a) contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2- oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate with citric acid in a solvent to obtain a solution of the (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1- carboxylate citrate; and (b) crystallizing the solution obtained in step (a) to obtain Crystalline Form IV of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1- carboxylate citrate.
WSGR Docket No.43629-723.601 98. The method of claim 97, wherein the solvent in step (a) comprises ethyl acetate, DMF, ethanol, or isopropanol. 99. The method of either claim 97 or claim 98, wherein the solvent in step (a) comprises DMF. 100. The method according to any one of claims 97–99, wherein step (a) is performed at a temperature of about 40–70 °C. 101. The method according to any one of claims 97–100, wherein step (a) is performed at a temperature of about 50–60 °C. 102. The method according to any one of claims 97–101, wherein step (b) comprises cooling the solution obtained in step (a) to room temperature. 103. The method according to any one of claims 97–102, wherein step (b) comprises cooling the solution obtained in step (a) to a temperature of about 20–25 °C. 104. The method according to any one of claims 97–103, further comprising filtering the crystallized solution obtained in step (b) to obtain Crystalline Form IV. 105. The method according to any one of claims 97–104, further comprising drying the obtained Crystalline Form IV. 106. The method of claim 105, wherein the drying is performed under vacuum at a temperature of about 40–70 °C. 107. The method of either claim 105 or claim 106, wherein the drying is performed under vacuum at a temperature of about 50–60 °C.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202263370006P | 2022-08-01 | 2022-08-01 | |
US63/370,006 | 2022-08-01 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2024030825A1 true WO2024030825A1 (en) | 2024-02-08 |
Family
ID=87797739
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2023/071180 WO2024030825A1 (en) | 2022-08-01 | 2023-07-28 | Crystalline salts of crystalline salts of (3s,5r,8r,9s,10s,13r,14s,17r)-14-hydroxy-10,13-dimethyl-17-(2- oxo-2h-pyran-5-yl)hexadecahydro-1h-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2024030825A1 (en) |
Citations (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5033252A (en) | 1987-12-23 | 1991-07-23 | Entravision, Inc. | Method of packaging and sterilizing a pharmaceutical product |
US5052558A (en) | 1987-12-23 | 1991-10-01 | Entravision, Inc. | Packaged pharmaceutical product |
US5323907A (en) | 1992-06-23 | 1994-06-28 | Multi-Comp, Inc. | Child resistant package assembly for dispensing pharmaceutical medications |
WO1997022596A1 (en) | 1995-12-18 | 1997-06-26 | Zeneca Limited | Quinazoline derivatives |
WO1997030035A1 (en) | 1996-02-13 | 1997-08-21 | Zeneca Limited | Quinazoline derivatives as vegf inhibitors |
WO1997032856A1 (en) | 1996-03-05 | 1997-09-12 | Zeneca Limited | 4-anilinoquinazoline derivatives |
WO1998013354A1 (en) | 1996-09-25 | 1998-04-02 | Zeneca Limited | Quinazoline derivatives and pharmaceutical compositions containing them |
US5846514A (en) | 1994-03-25 | 1998-12-08 | Isotechnika, Inc. | Enhancement of the efficacy of nifedipine by deuteration |
WO1999002166A1 (en) | 1997-07-08 | 1999-01-21 | Angiogene Pharmaceuticals Ltd. | Use of colchinol derivatives as vascular damaging agents |
WO2000040529A1 (en) | 1999-01-07 | 2000-07-13 | Angiogene Pharmaceuticals Ltd. | Colchinol derivatives as vascular damaging agents |
WO2000041669A2 (en) | 1999-01-15 | 2000-07-20 | Angiogene Pharmaceuticals Ltd. | Benzimidazole vascular damaging agents |
WO2000047212A1 (en) | 1999-02-10 | 2000-08-17 | Astrazeneca Ab | Quinazoline derivatives as angiogenesis inhibitors |
WO2001092224A1 (en) | 2000-05-31 | 2001-12-06 | Astrazeneca Ab | Indole derivatives with vascular damaging activity |
WO2001094341A1 (en) | 2000-06-06 | 2001-12-13 | Astrazeneca Ab | Quinazoline derivatives for the treatment of tumours |
US6334997B1 (en) | 1994-03-25 | 2002-01-01 | Isotechnika, Inc. | Method of using deuterated calcium channel blockers |
WO2002004434A1 (en) | 2000-07-07 | 2002-01-17 | Angiogene Pharmaceuticals Limited | Colchinol derivatives as vascular damaging agents |
WO2002008213A1 (en) | 2000-07-07 | 2002-01-31 | Angiogene Pharmaceuticals Limited | Colchinol derivatives as angiogenesis inhibitors |
WO2011085641A1 (en) | 2010-01-15 | 2011-07-21 | Suzhou Neupharma Co., Ltd. | Certain chemical entities, compositions, and methods |
WO2019118907A1 (en) * | 2017-12-15 | 2019-06-20 | Neupharma, Inc. | Methods of treating cancer |
WO2022169705A1 (en) * | 2021-02-02 | 2022-08-11 | Neupharma, Inc | Certain chemical entities, compositions, and methods |
-
2023
- 2023-07-28 WO PCT/US2023/071180 patent/WO2024030825A1/en unknown
Patent Citations (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5033252A (en) | 1987-12-23 | 1991-07-23 | Entravision, Inc. | Method of packaging and sterilizing a pharmaceutical product |
US5052558A (en) | 1987-12-23 | 1991-10-01 | Entravision, Inc. | Packaged pharmaceutical product |
US5323907A (en) | 1992-06-23 | 1994-06-28 | Multi-Comp, Inc. | Child resistant package assembly for dispensing pharmaceutical medications |
US6334997B1 (en) | 1994-03-25 | 2002-01-01 | Isotechnika, Inc. | Method of using deuterated calcium channel blockers |
US5846514A (en) | 1994-03-25 | 1998-12-08 | Isotechnika, Inc. | Enhancement of the efficacy of nifedipine by deuteration |
WO1997022596A1 (en) | 1995-12-18 | 1997-06-26 | Zeneca Limited | Quinazoline derivatives |
WO1997030035A1 (en) | 1996-02-13 | 1997-08-21 | Zeneca Limited | Quinazoline derivatives as vegf inhibitors |
WO1997032856A1 (en) | 1996-03-05 | 1997-09-12 | Zeneca Limited | 4-anilinoquinazoline derivatives |
WO1998013354A1 (en) | 1996-09-25 | 1998-04-02 | Zeneca Limited | Quinazoline derivatives and pharmaceutical compositions containing them |
WO1999002166A1 (en) | 1997-07-08 | 1999-01-21 | Angiogene Pharmaceuticals Ltd. | Use of colchinol derivatives as vascular damaging agents |
WO2000040529A1 (en) | 1999-01-07 | 2000-07-13 | Angiogene Pharmaceuticals Ltd. | Colchinol derivatives as vascular damaging agents |
WO2000041669A2 (en) | 1999-01-15 | 2000-07-20 | Angiogene Pharmaceuticals Ltd. | Benzimidazole vascular damaging agents |
WO2000047212A1 (en) | 1999-02-10 | 2000-08-17 | Astrazeneca Ab | Quinazoline derivatives as angiogenesis inhibitors |
WO2001092224A1 (en) | 2000-05-31 | 2001-12-06 | Astrazeneca Ab | Indole derivatives with vascular damaging activity |
WO2001094341A1 (en) | 2000-06-06 | 2001-12-13 | Astrazeneca Ab | Quinazoline derivatives for the treatment of tumours |
WO2002004434A1 (en) | 2000-07-07 | 2002-01-17 | Angiogene Pharmaceuticals Limited | Colchinol derivatives as vascular damaging agents |
WO2002008213A1 (en) | 2000-07-07 | 2002-01-31 | Angiogene Pharmaceuticals Limited | Colchinol derivatives as angiogenesis inhibitors |
WO2011085641A1 (en) | 2010-01-15 | 2011-07-21 | Suzhou Neupharma Co., Ltd. | Certain chemical entities, compositions, and methods |
US8334376B2 (en) | 2010-01-15 | 2012-12-18 | Xiangping Qian | Certain chemical entities, compositions, and methods |
US8993550B2 (en) | 2010-01-15 | 2015-03-31 | Suzhou Neupharma Co., Ltd. | Certain chemical entities, compositions, and methods |
US9399659B2 (en) | 2010-01-15 | 2016-07-26 | Suzhou Neupharma Co., Ltd | Certain chemical entities, compositions, and methods |
US9814735B2 (en) | 2010-01-15 | 2017-11-14 | Suzhou Neupharma Co., Ltd | Certain chemical entities, compositions, and methods |
US10179141B2 (en) | 2010-01-15 | 2019-01-15 | Suzhou Neupharma Co., Ltd. | Certain chemical entities, compositions, and methods |
US10471078B2 (en) | 2010-01-15 | 2019-11-12 | Suzhou Neupharma Co., Ltd. | Certain chemical entities, compositions, and methods |
WO2019118907A1 (en) * | 2017-12-15 | 2019-06-20 | Neupharma, Inc. | Methods of treating cancer |
WO2022169705A1 (en) * | 2021-02-02 | 2022-08-11 | Neupharma, Inc | Certain chemical entities, compositions, and methods |
Non-Patent Citations (11)
Title |
---|
"Design of Prodrugs", 1985, ELSEVIER |
"Pharmaceutical Dosage Forms and Drug Delivery Systems", 1999, LIPPINCOTT WILLIAMS & WILKINS |
"Pharmaceutical Dosage Forms", 1980, MARCEL DECKER |
"Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development", CURR., PHARM. DES., vol. 6, no. 10, 2000, pages 110 |
"Remington: The Science and Practice of Pharmacy", 1995, MACK PUBLISHING COMPANY |
EVANSE. ANTHONY: "Synthesis of radiolabeled compounds", J. RADIOANAL. CHEM., vol. 64, 1981, pages 9 - 32 |
GEORGE W.; VARMARAJENDER S: "The Synthesis of Radiolabeled Compounds via Organometallic Intermediates", TETRAHEDRON, vol. 45, no. 21, 1989, pages 6601 - 21 |
HOOVER, JOHN E.: "Remington's Pharmaceutical Sciences", 1975, MACK PUBLISHING CO. |
J. MED. CHEM., vol. 47, 2004 |
STEM ET AL., CRITICAL REVIEWS IN ONCOLOGY/HAEMATOLOGY, vol. 54, 2005, pages 11 - 29 |
T. HIGUCHIV. STELLA: "Bioreversible Carriers in Drug Design", vol. 14, 1987, PERGAMON PRESS, article "Pro-drugs as Novel Delivery Systems" |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10471078B2 (en) | Certain chemical entities, compositions, and methods | |
US10766920B2 (en) | Certain chemical entities, compositions, and methods | |
US9340570B2 (en) | Certain chemical entities, compositions, and methods | |
US20160303066A1 (en) | Certain chemical entities, compositions, and methods | |
US20240092825A1 (en) | Certain chemical entities, compositions, and methods | |
WO2024030825A1 (en) | Crystalline salts of crystalline salts of (3s,5r,8r,9s,10s,13r,14s,17r)-14-hydroxy-10,13-dimethyl-17-(2- oxo-2h-pyran-5-yl)hexadecahydro-1h-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate | |
US20240116880A1 (en) | Certain chemical entities, compositions, and methods | |
US20150284349A1 (en) | Epidithiodiketopiperazine compounds, compositions, and methods |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 23758793 Country of ref document: EP Kind code of ref document: A1 |