JP2014534189A - ホスファプラチン系抗腫瘍剤の大規模調製のための効率的プロセス - Google Patents
ホスファプラチン系抗腫瘍剤の大規模調製のための効率的プロセス Download PDFInfo
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- JP2014534189A JP2014534189A JP2014534791A JP2014534791A JP2014534189A JP 2014534189 A JP2014534189 A JP 2014534189A JP 2014534791 A JP2014534791 A JP 2014534791A JP 2014534791 A JP2014534791 A JP 2014534791A JP 2014534189 A JP2014534189 A JP 2014534189A
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- 238000000034 method Methods 0.000 title claims abstract description 62
- 239000002246 antineoplastic agent Substances 0.000 title description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims abstract description 70
- 229910052697 platinum Inorganic materials 0.000 claims abstract description 34
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims abstract description 32
- 235000011180 diphosphates Nutrition 0.000 claims abstract description 28
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 24
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 21
- 238000003756 stirring Methods 0.000 claims abstract description 6
- 239000011541 reaction mixture Substances 0.000 claims description 32
- 239000003446 ligand Substances 0.000 claims description 28
- 150000001412 amines Chemical class 0.000 claims description 12
- 239000000539 dimer Substances 0.000 claims description 6
- 230000003287 optical effect Effects 0.000 claims description 4
- 230000001376 precipitating effect Effects 0.000 claims 4
- 239000006227 byproduct Substances 0.000 claims 2
- 230000035484 reaction time Effects 0.000 abstract description 12
- 239000007858 starting material Substances 0.000 abstract description 6
- 239000000463 material Substances 0.000 abstract description 4
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 238000004064 recycling Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 27
- 229940048084 pyrophosphate Drugs 0.000 description 22
- 150000001875 compounds Chemical class 0.000 description 16
- 239000000243 solution Substances 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 239000012452 mother liquor Substances 0.000 description 6
- 238000001394 phosphorus-31 nuclear magnetic resonance spectrum Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 230000008901 benefit Effects 0.000 description 5
- 239000012467 final product Substances 0.000 description 5
- NDBYXKQCPYUOMI-UHFFFAOYSA-N platinum(4+) Chemical class [Pt+4] NDBYXKQCPYUOMI-UHFFFAOYSA-N 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 206010033128 Ovarian cancer Diseases 0.000 description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000010192 crystallographic characterization Methods 0.000 description 4
- 238000004949 mass spectrometry Methods 0.000 description 4
- KOFSPIJRNIFNBK-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2].[Pt+2] KOFSPIJRNIFNBK-UHFFFAOYSA-N 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- SSJXIUAHEKJCMH-PHDIDXHHSA-N (1r,2r)-cyclohexane-1,2-diamine Chemical compound N[C@@H]1CCCC[C@H]1N SSJXIUAHEKJCMH-PHDIDXHHSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 229910017604 nitric acid Inorganic materials 0.000 description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 150000003057 platinum Chemical class 0.000 description 2
- 150000003058 platinum compounds Chemical class 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- VZWGHDYJGOMEKT-UHFFFAOYSA-J sodium pyrophosphate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O VZWGHDYJGOMEKT-UHFFFAOYSA-J 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003828 vacuum filtration Methods 0.000 description 2
- 238000004679 31P NMR spectroscopy Methods 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 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 1
- 241000699660 Mus musculus Species 0.000 description 1
- 238000012565 NMR experiment Methods 0.000 description 1
- 229920000388 Polyphosphate Chemical class 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000011365 complex material Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process 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
- 230000007935 neutral effect Effects 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 239000001205 polyphosphate Chemical class 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 235000019818 tetrasodium diphosphate Nutrition 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical class OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F19/00—Metal compounds according to more than one of main groups C07F1/00 - C07F17/00
- C07F19/005—Metal compounds according to more than one of main groups C07F1/00 - C07F17/00 without metal-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
Description
[0001] この出願は2012年10月5日に出願された米国特許出願第13/922,917号および2011年10月5日に出願された米国仮出願第61/543,540号に対する優先権を主張し、その両方を参照によりそのまま本明細書に援用する。
[0002] 該当なし
[0003] 本発明は、大規模産業生産に適用できるホスファプラチン(phosphaplatin)系抗腫瘍剤の生産のための効率的な合成および反応管理プロセスに関する。
[00026] 本明細書で記述される発明は大量のホスファプラチン化合物を作製するための新規プロセスに具体的に焦点を合わせているが、当業者は、この開示の利益により、そのようなアプローチの他の系への拡張を認識するであろう。当業者は、上記で記述された態様に対して、その幅広い発明概念から逸脱することなく変更を行うことができることを認識するであろう。従って、本明細書で開示される発明は開示された特定の態様に限定されず、添付された特許請求の範囲により定義される通りの本発明の精神および範囲内の修正を含むことが意図されていることは理解されている。
Claims (20)
- ホスファプラチン類を合成するためのプロセスであって、以下の工程:
おおよそ6〜8.5のpHを有する反応混合物中でピロホスフェート配位子を濃縮し;そして
白金錯体を該反応混合物に添加する;
を含む、前記プロセス。 - 反応混合物をおおよそ20℃〜60℃の温度で維持する、請求項1に記載のプロセス。
- 反応混合物をおおよそ20℃〜50℃の温度で維持する、請求項1に記載のプロセス。
- 反応混合物がHnNa4−nP2O7を含む、請求項1に記載のプロセス。
- ホスファプラチン類が一般式(I)を有するホスファプラチン類の1つまたはあらゆる組み合わせであり、ここでR1およびR2はアミン配位子であり、かつR3およびR4はアミンまたは他の単座配位子のどちらかである、請求項1に記載のプロセス。
- ホスファプラチン類がシス−、トランス−、ラセミおよび高光学純度の形態を含む、請求項5に記載のプロセス。
- さらに白金錯体を濃縮ピロホスフェート溶液に該白金錯体の全部が反応混合物中に溶解することを確実にする速度でゆっくりと添加することを含む、請求項1に記載のプロセス。
- さらに白金錯体の添加後に反応混合物を約6〜15時間攪拌することを含む、請求項7に記載のプロセス。
- さらに反応混合物のpHをおおよそ2まで下げ、温度をおおよそ0〜5℃まで下げることによりホスファプラチン類を沈殿させることを含む、請求項8に記載のプロセス。
- さらに温度をおおよそ40℃に上げることにより二量体およびオリゴマー副産物を沈殿させることを含む、請求項9に記載のプロセス。
- さらに未反応のピロホスフェート配位子および白金錯体をその後のホスファプラチン類の合成において用いることを含む、請求項1に記載のプロセス。
- 反応混合物をおおよそ20℃〜50℃の温度で維持する、請求項12に記載のプロセス。
- 反応混合物がHnNa4−nP2O7を含む、請求項12に記載のプロセス。
- ホスファプラチン類がシス−、トランス−、ラセミおよび高光学純度の形態を含む、請求項12に記載のプロセス。
- さらに反応混合物を白金錯体の添加後に約6〜15時間攪拌することを含む、請求項12に記載のプロセス。
- さらに反応混合物のpHをおおよそ2まで下げ、温度をおおよそ0〜5℃まで下げることによりホスファプラチン類を沈殿させることを含む、請求項16に記載のプロセス。
- さらに温度をおおよそ40℃に上げることにより二量体およびオリゴマー副産物を沈殿させることを含む、請求項17に記載のプロセス。
- さらに未反応のピロホスフェート配位子および白金錯体をその後のホスファプラチン類の合成において用いることを含む、請求項12に記載のプロセス。
- ホスファプラチン類を合成するためのプロセスであって、以下の工程:
HnNa4−nP2O7を含む反応混合物中でピロホスフェート配位子を濃縮し;そして
白金錯体を該反応混合物に添加する;
を含む、前記プロセス。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161543540P | 2011-10-05 | 2011-10-05 | |
US61/543,540 | 2011-10-05 | ||
PCT/US2012/059016 WO2013052839A1 (en) | 2011-10-05 | 2012-10-05 | Efficient processes for large scale preparation of phosphaplatins antitumor agents |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2014534189A true JP2014534189A (ja) | 2014-12-18 |
JP6027619B2 JP6027619B2 (ja) | 2016-11-16 |
Family
ID=48655214
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2014534791A Expired - Fee Related JP6027619B2 (ja) | 2011-10-05 | 2012-10-05 | ホスファプラチン系抗腫瘍剤の大規模調製のための効率的プロセス |
Country Status (5)
Country | Link |
---|---|
US (1) | US9012669B2 (ja) |
EP (1) | EP2763537B1 (ja) |
JP (1) | JP6027619B2 (ja) |
HK (1) | HK1199795A1 (ja) |
MX (1) | MX357865B (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2019510831A (ja) * | 2016-04-06 | 2019-04-18 | フォスプラティン・セラピューティクス・エルエルシー | ホスファプラチン液体製剤 |
JP2020504140A (ja) * | 2017-01-06 | 2020-02-06 | フォスプラティン・セラピューティクス・エルエルシー | 骨がんまたは血液がんの治療のための治療薬としてのホスファプラチン化合物 |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101052513B1 (ko) * | 2009-03-27 | 2011-07-29 | 삼성중공업 주식회사 | 다단 압축기용 냉각사이클 장치 |
SG185722A1 (en) | 2010-06-04 | 2013-01-30 | Univ Ohio | Phosphaplatins and their use for treatment of cancers |
IN2014KN02722A (ja) * | 2012-05-24 | 2015-05-08 | Phosplatin Therapeutics Llc |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS55120594A (en) * | 1979-03-07 | 1980-09-17 | Engelhard Min & Chem | Ethylene diamine platinum*ii* and 1*22diaminoocyclohexane platinum*ii* pyrophosphate complex |
JP2013529219A (ja) * | 2010-06-04 | 2013-07-18 | オハイオ ユニバーシティー | ホスファプラチン、及び癌治療のためのそれらの使用 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PT2173337E (pt) | 2007-08-06 | 2014-09-03 | Univ Ohio | Fosfoplatinas e a sua utilização no tratamento de cancros resistentes à cisplantina e carboplatina |
US20110092465A1 (en) * | 2009-10-21 | 2011-04-21 | Syracuse University | Monomeric pyrophosphate complexes and methods of treatment using the complexes |
-
2012
- 2012-10-05 US US13/646,152 patent/US9012669B2/en not_active Expired - Fee Related
- 2012-10-05 MX MX2014004181A patent/MX357865B/es active IP Right Grant
- 2012-10-05 JP JP2014534791A patent/JP6027619B2/ja not_active Expired - Fee Related
- 2012-10-05 EP EP12838315.5A patent/EP2763537B1/en not_active Not-in-force
-
2015
- 2015-01-12 HK HK15100298.2A patent/HK1199795A1/xx not_active IP Right Cessation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS55120594A (en) * | 1979-03-07 | 1980-09-17 | Engelhard Min & Chem | Ethylene diamine platinum*ii* and 1*22diaminoocyclohexane platinum*ii* pyrophosphate complex |
JP2013529219A (ja) * | 2010-06-04 | 2013-07-18 | オハイオ ユニバーシティー | ホスファプラチン、及び癌治療のためのそれらの使用 |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2019510831A (ja) * | 2016-04-06 | 2019-04-18 | フォスプラティン・セラピューティクス・エルエルシー | ホスファプラチン液体製剤 |
JP2020504140A (ja) * | 2017-01-06 | 2020-02-06 | フォスプラティン・セラピューティクス・エルエルシー | 骨がんまたは血液がんの治療のための治療薬としてのホスファプラチン化合物 |
JP7023968B2 (ja) | 2017-01-06 | 2022-02-22 | フォスプラティン・セラピューティクス・インコーポレーテッド | 骨がんまたは血液がんの治療のための治療薬としてのホスファプラチン化合物 |
Also Published As
Publication number | Publication date |
---|---|
MX357865B (es) | 2018-07-25 |
HK1199795A1 (en) | 2015-07-24 |
MX2014004181A (es) | 2015-02-05 |
EP2763537A4 (en) | 2015-03-25 |
US20130165680A1 (en) | 2013-06-27 |
EP2763537B1 (en) | 2018-01-10 |
US9012669B2 (en) | 2015-04-21 |
JP6027619B2 (ja) | 2016-11-16 |
EP2763537A1 (en) | 2014-08-13 |
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