TWI537276B - ９ｅ－１５－（２－吡咯啶－１－基－乙氧基）－７，１２，２５－三－１９，２１，２４－三氮雜－四環〔１８．３．１．１（２，５）．１（１４，１８）〕二十六碳－１（２４），２，４，９，１４，１６，１８（２６），２０，２２－壬烯檸檬酸鹽 - Google Patents
９ｅ－１５－（２－吡咯啶－１－基－乙氧基）－７，１２，２５－三－１９，２１，２４－三氮雜－四環〔１８．３．１．１（２，５）．１（１４，１８）〕二十六碳－１（２４），２，４，９，１４，１６，１８（２６），２０，２２－壬烯檸檬酸鹽 Download PDFInfo
- Publication number
- TWI537276B TWI537276B TW099123331A TW99123331A TWI537276B TW I537276 B TWI537276 B TW I537276B TW 099123331 A TW099123331 A TW 099123331A TW 99123331 A TW99123331 A TW 99123331A TW I537276 B TWI537276 B TW I537276B
- Authority
- TW
- Taiwan
- Prior art keywords
- salt
- citrate
- scale
- batch
- diffraction pattern
- Prior art date
Links
- 150000001860 citric acid derivatives Chemical class 0.000 title description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 39
- 150000003839 salts Chemical class 0.000 claims description 26
- 238000002441 X-ray diffraction Methods 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 230000002062 proliferating effect Effects 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 3
- 238000000634 powder X-ray diffraction Methods 0.000 description 42
- 239000000523 sample Substances 0.000 description 31
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 25
- 239000002904 solvent Substances 0.000 description 25
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 239000013078 crystal Substances 0.000 description 14
- 238000004458 analytical method Methods 0.000 description 13
- 239000012458 free base Substances 0.000 description 13
- 238000000034 method Methods 0.000 description 13
- 238000010992 reflux Methods 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 11
- 239000013543 active substance Substances 0.000 description 11
- 229940125904 compound 1 Drugs 0.000 description 11
- 238000002411 thermogravimetry Methods 0.000 description 10
- 239000007787 solid Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- 238000004090 dissolution Methods 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 150000003840 hydrochlorides Chemical class 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000001179 sorption measurement Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 238000000113 differential scanning calorimetry Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 3
- 230000005855 radiation Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000004480 active ingredient Substances 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
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000036571 hydration Effects 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- 229910052738 indium Inorganic materials 0.000 description 2
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000010431 corundum Substances 0.000 description 1
- 229910052593 corundum Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000004442 gravimetric analysis Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 238000011170 pharmaceutical development Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000012106 screening analysis Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000004804 winding Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US22560909P | 2009-07-15 | 2009-07-15 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW201107336A TW201107336A (en) | 2011-03-01 |
| TWI537276B true TWI537276B (zh) | 2016-06-11 |
Family
ID=42790728
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW099123331A TWI537276B (zh) | 2009-07-15 | 2010-07-15 | ９ｅ－１５－（２－吡咯啶－１－基－乙氧基）－７，１２，２５－三－１９，２１，２４－三氮雜－四環〔１８．３．１．１（２，５）．１（１４，１８）〕二十六碳－１（２４），２，４，９，１４，１６，１８（２６），２０，２２－壬烯檸檬酸鹽 |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US9062074B2 (enExample) |
| EP (1) | EP2454266B1 (enExample) |
| JP (2) | JP6013911B2 (enExample) |
| CN (1) | CN102762577B (enExample) |
| AR (2) | AR077483A1 (enExample) |
| BR (1) | BR112012000750B1 (enExample) |
| CA (1) | CA2768210C (enExample) |
| DK (1) | DK2454266T3 (enExample) |
| ES (1) | ES2429525T3 (enExample) |
| HR (1) | HRP20130941T1 (enExample) |
| MX (1) | MX2012000680A (enExample) |
| PL (1) | PL2454266T3 (enExample) |
| PT (1) | PT2454266E (enExample) |
| RU (1) | RU2543721C2 (enExample) |
| SI (1) | SI2454266T1 (enExample) |
| SM (1) | SMT201300112B (enExample) |
| TW (1) | TWI537276B (enExample) |
| WO (1) | WO2011008172A1 (enExample) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2966753A1 (en) | 2014-11-17 | 2016-05-26 | Arno Therapeutics, Inc. | Onapristone extended-release compositions and methods |
| AU2016326657B2 (en) | 2015-09-25 | 2019-10-24 | Context Biopharma, Inc. | Methods of making onapristone intermediates |
| CA3008422A1 (en) | 2015-12-15 | 2017-06-22 | Context Biopharma Inc. | Amorphous onapristone compositions and methods of making the same |
| US20180148471A1 (en) | 2016-11-30 | 2018-05-31 | Arno Therapeutics, Inc. | Methods for onapristone synthesis dehydration and deprotection |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MY110603A (en) * | 1993-05-27 | 1998-08-29 | Novartis Ag | Tetrahydropyran derivatives |
| US7151096B2 (en) * | 2003-03-05 | 2006-12-19 | Irm Llc | Cyclic compounds and compositions as protein kinase inhibitors |
| CN101365703B (zh) * | 2005-11-16 | 2013-11-06 | S*Bio私人有限公司 | 杂烷基连接的嘧啶衍生物 |
-
2010
- 2010-07-14 EP EP10737645.1A patent/EP2454266B1/en active Active
- 2010-07-14 SI SI201030347T patent/SI2454266T1/sl unknown
- 2010-07-14 RU RU2012105044/04A patent/RU2543721C2/ru active
- 2010-07-14 PT PT107376451T patent/PT2454266E/pt unknown
- 2010-07-14 HR HRP20130941AT patent/HRP20130941T1/hr unknown
- 2010-07-14 BR BR112012000750-5A patent/BR112012000750B1/pt active IP Right Grant
- 2010-07-14 US US13/384,139 patent/US9062074B2/en active Active
- 2010-07-14 CN CN201080032627.5A patent/CN102762577B/zh active Active
- 2010-07-14 MX MX2012000680A patent/MX2012000680A/es active IP Right Grant
- 2010-07-14 PL PL10737645T patent/PL2454266T3/pl unknown
- 2010-07-14 ES ES10737645T patent/ES2429525T3/es active Active
- 2010-07-14 CA CA2768210A patent/CA2768210C/en active Active
- 2010-07-14 DK DK10737645.1T patent/DK2454266T3/da active
- 2010-07-14 JP JP2012520571A patent/JP6013911B2/ja active Active
- 2010-07-14 WO PCT/SG2010/000265 patent/WO2011008172A1/en not_active Ceased
- 2010-07-15 AR ARP100102594A patent/AR077483A1/es not_active Application Discontinuation
- 2010-07-15 TW TW099123331A patent/TWI537276B/zh active
-
2013
- 2013-10-04 SM SM201300112T patent/SMT201300112B/xx unknown
-
2015
- 2015-05-07 JP JP2015094972A patent/JP2015164941A/ja active Pending
-
2019
- 2019-08-05 AR ARP190102219A patent/AR114987A2/es unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CN102762577A (zh) | 2012-10-31 |
| AR114987A2 (es) | 2020-11-11 |
| EP2454266A1 (en) | 2012-05-23 |
| JP2012533539A (ja) | 2012-12-27 |
| WO2011008172A1 (en) | 2011-01-20 |
| CA2768210C (en) | 2017-08-15 |
| ES2429525T3 (es) | 2013-11-15 |
| PL2454266T3 (pl) | 2014-01-31 |
| AR077483A1 (es) | 2011-08-31 |
| HRP20130941T1 (hr) | 2013-11-08 |
| MX2012000680A (es) | 2012-02-28 |
| BR112012000750A8 (pt) | 2018-02-06 |
| EP2454266B1 (en) | 2013-07-10 |
| CA2768210A1 (en) | 2011-01-20 |
| SI2454266T1 (sl) | 2013-10-30 |
| BR112012000750B1 (pt) | 2021-05-25 |
| BR112012000750A2 (pt) | 2016-08-09 |
| SMT201300112B (it) | 2013-11-08 |
| JP2015164941A (ja) | 2015-09-17 |
| US9062074B2 (en) | 2015-06-23 |
| RU2012105044A (ru) | 2013-08-20 |
| HK1178159A1 (en) | 2013-09-06 |
| DK2454266T3 (da) | 2013-09-08 |
| TW201107336A (en) | 2011-03-01 |
| US20120196876A1 (en) | 2012-08-02 |
| RU2543721C2 (ru) | 2015-03-10 |
| JP6013911B2 (ja) | 2016-10-25 |
| CN102762577B (zh) | 2015-01-07 |
| PT2454266E (pt) | 2013-10-10 |
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