CN1120046A - 洛巴铂三水合物 - Google Patents
洛巴铂三水合物 Download PDFInfo
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- CN1120046A CN1120046A CN94106670A CN94106670A CN1120046A CN 1120046 A CN1120046 A CN 1120046A CN 94106670 A CN94106670 A CN 94106670A CN 94106670 A CN94106670 A CN 94106670A CN 1120046 A CN1120046 A CN 1120046A
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims abstract description 7
- -1 Lobaplatinum trihydrate Chemical class 0.000 claims abstract description 4
- 229910052697 platinum Inorganic materials 0.000 claims abstract description 3
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 2
- 239000012736 aqueous medium Substances 0.000 claims 1
- 239000012050 conventional carrier Substances 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- WDFOGGXOXJPZGE-UHFFFAOYSA-N platinum(2+) trihydrate Chemical compound O.O.O.[Pt++] WDFOGGXOXJPZGE-UHFFFAOYSA-N 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 abstract description 2
- 150000004684 trihydrates Chemical class 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- XSMVECZRZBFTIZ-UHFFFAOYSA-M [2-(aminomethyl)cyclobutyl]methanamine;2-oxidopropanoate;platinum(4+) Chemical compound [Pt+4].CC([O-])C([O-])=O.NCC1CCC1CN XSMVECZRZBFTIZ-UHFFFAOYSA-M 0.000 description 9
- 229950008991 lobaplatin Drugs 0.000 description 9
- 150000008064 anhydrides Chemical class 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 238000003109 Karl Fischer titration Methods 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 239000000470 constituent Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010051779 Bone marrow toxicity Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 208000001382 Experimental Melanoma Diseases 0.000 description 1
- BKAYIFDRRZZKNF-VIFPVBQESA-N N-acetylcarnosine Chemical compound CC(=O)NCCC(=O)N[C@H](C(O)=O)CC1=CN=CN1 BKAYIFDRRZZKNF-VIFPVBQESA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229910021607 Silver chloride Inorganic materials 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 231100000366 bone marrow toxicity Toxicity 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 150000002500 ions Chemical class 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
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- UMFJAHHVKNCGLG-UHFFFAOYSA-N n-Nitrosodimethylamine Chemical compound CN(C)N=O UMFJAHHVKNCGLG-UHFFFAOYSA-N 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 239000012925 reference material Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
洛巴铂三水合物是一种新的优良的有抗肿瘤作用的铂复合物。
Description
1，1—双(氨甲基)—环丁烷的铂复合物已知叙述于例如英国专利2024823中。这些化合物被建议治疗肿瘤病。
本发明化合物具有良好的抗肿瘤作用(例如对离体的AH135—瘤、B16—黑色素瘤、结肠癌115；在体的例如小鼠P388白血病)。此外，本发明化合物只有很低的毒性，尤其没有蓄积性毒性，对肾脏无毒性。而且对骨髓毒性很小，没有令人担心的血小板减少症。
欧洲专利324154叙述了作为强效抗肿瘤化合物的反式—1，2—双(氨甲基)环丁烷铂复合物。尤其是顺式—〔反式—1，2—环丁烷双(甲胺)—N，N′〕—〔(2S)—乳酸—O1，O2〕—铂(II)(INN：洛巴铂)比顺铂有更好的活性和耐受性(R.Voegeli等Drug of theFuture 1992，17：883—886，R.Voegeli等，J.Canc.Res.Clin.Oncol.，1990年1O月，166：439—442)。
洛巴铂的化学合成迄今是以无水物形式得到。如同在合成实施例(EP324154，实施例1a)中所述的，将水性反应溶液完全浓缩干，溶于甲醇，与活性碳搅拌，滤液中加入乙醚，于冰箱温度中结晶。这样得到的结晶真空干燥。用这样的方法难以做到纯度和含量的可重复性，并且难以建立内部的限量标准。此外，本物质还有潮解性，由于变粘，难以制成制剂。
本发明的内容是提供一种新形式的洛巴铂，操作简单安全，质量也有改善。另外重要的是，为医院工作人员提供了简便易处理的剂型，因为从组织保护的角度看，在涉及细胞毒药物时不是没有问题的。
现在发现，洛巴铂的三水合物在很大程度上满足了上述的要求。
洛巴铂水合物迄今尚属未知。经目标明确的研究表明，洛巴铂三水合物意外地有明显的优点。
本发明叙述了以三水合物形式的洛巴铂的制备以及由此得到的未预料的优点：较简便的合成方法，副产物减少了，无潮解性，可重复的和可控制的水含量，改善的贮存稳定性，改善的制剂可操作性。洛巴铂三水合物例如可制成如下的制剂：片剂、胶囊剂、锭剂、缓释剂型、冻干剂和注射液。
下面的研究内容说明了这优点。合成
完全类似于EP324154的实施例1a的方法合成的洛巴铂于乳酸水溶液中形成的二羟代—铂复合物的小液滴，按如下简便的方法处理：
水性反应液浓缩后，洛巴铂粗品析出，加入适量活性碳，在水—丙酮混合液中重结晶，这样得到三水合物结晶，在室温或略高的温度下空气中干燥。
15个样本中，7个是无水物，8个是三水合物，元素分析表明，作为三水合物的合成物有明显的优势。元素分析
| a)无水物： | 计算值 | 实测值 | 偏差* |
| CHNPtb)三水CHNPt | 27.21％4.57％7.05％49.40％合物：计算值23.95％5.36％6.21％43.22％ | 25.86％4.82％6.65％46.39％实测值23.92％5.25％6.06％43.44％ | 5.0％5.5％5.7％6.1％偏差*0.1％2.1％2.2％0.5％ |
*偏差＝100％*(计算值－实测值)/计算值含量测定a)无水物
用卡尔—费歇尔滴定法测定水含量值为3.75±1.55％，表明由于洛巴铂的潮解性，不可能达到完全干燥。此外，得到的数值非常分散。用HPLC测定的有效成分含量(减去经卡尔—费歇尔滴定法测定的水含量值)为标示量所需的有效成分含量的98.00±1.38％，也是很分散的。按照规定，有效物质的含量需在97％—102％之间。b)三水合物
三水合物样品中的水含量为12.09±0.09％，非常接近于理论量11.96％。有效成分含量分析也达到了99.76±0.83％的可接受的数值，其变化幅度在药学的常规范围之内。杂质检查
用薄层层析测定已知的和未知的杂质含量。无水物中杂质的总量为1.21±0.55％，三水合物的杂质总量为0.34±0.19％，杂质的绝对量和变动范围也都得到改进。
薄层层析是在市售的硅胶板上进行(制造厂：Merk，Darmstadt，No.5629)。
展开剂是由53％乙醇、30％氯仿、15％氨水(浓度25％)和1.5％水(体积/体积)的混合液组成。
薄板展开后放入常规用的碘缸中，并用对亚硝基二甲苯胺试剂溶液显色。混浊度
同时测定浊度、无水物为1.45±0.91FTU，三水合物为0.38±0.41FTU。
浊度是在Hach Ratio浊度计(型号18900—00)上测定的。
对照品和本发明物质均制成1％(重量/重量)的去离子水溶液进行测定。稳定性
无水物和三水合物二种样品分别存放在4℃、室温、31℃、41℃和31℃/相对空气湿度为80％(开口的试验瓶)的条件下贮存，于3、6和12个月后检查杂质(薄层)、有效成分含量(HPLC)、水份含量(卡尔—费歇尔滴定)和混浊度，确定所有存放条件的含量：
—无水物中的杂质含量增高，而三水合物中的杂质处于恒定的低水平。
—三水合物中有效物质的含量接近于100％，变动偏差很小。
—潮解性：无水物的水份含量增高，而本发明的三水合物的水份含量是绝对恒定的。
—无水物的冻干样品的混浊度于开始时就有明显的高浊度值，而且随着贮存的时间延长而更加增高，而三水合物样品的浊度值一直处于恒定的低水平。
冻干剂的制备方法可按照德国专利DEOS3843571所述进行。药剂可加工性
由于无水化合物的潮解作用，在处理时必须尽可能的隔绝空气，这是由于加入的湿气使无水物变成胶状物或粘连一起，而空气中稳定的三水合物具有良好的滑动性，因而显著改善了制剂和处理时的可操作性。制备洛巴铂三水合物的实施例
3.8g(10mmol)顺式—〔反式—1，2—环丁基双(甲胺)—N，N′)—二氯铂(II)悬浮于20ml水中，加热至40℃，加入3.39g(20mmol)硝酸银。搅拌1.5小时后，于冰箱中冷却，滤除析出的氯化银，并用10ml水洗涤，滤液通过含100ml碱性离子交换柱，用150ml水洗涤，离子交换剂可用各种可买到的碱性离子交换剂。然后滴加到4.5g(10mmol，20％水溶液)的L—乳酸中。搅拌3天后，浓缩至大约20ml，冰箱中放置过夜。吸滤析出的结晶，滤液浓缩，冰箱放置过夜，又析出结晶，再滤集，合并结晶后，用20ml水/丙酮(1/1，V/V)重结晶，得量2.3g(51％)，mp.210℃(分解)。C9H24N2O6Pt M＝451.38计算值： C23.95％ H5.36％ N6.21％ Pt43.22％实测值： C23.94％ H5.28％ N6.15％ Pt43.05％
C23.99％ H5.25％ N6.05％水份含量(卡尔-费歇尔滴定法)：12.24％(计算值1.96％)1H-NMR(500MHz，D2O)：δ(ppm)＝1.2(d，3H，CH3)，1.6(m，2H，CH2-CH2)，1.9(m，2H，CH2-CH2)，2.4(m，2H，CH2-NH2)，2.65(m，2H，CH-CH)，2.85(m，2H，CH2-NH2)，4.05(q，1H，CH-CH3)，4.3...5.0(br，重叠，NH2)
Claims (5)
1.顺式—〔反式—1，2—环丁基双(甲胺)—N，N′〕—〔(2S)—乳酸—O1，O2〕—铂(II)—三水合物(洛巴铂三水合物)
2.制备洛巴铂三水合物的方法，其特征是，顺式—〔反式—1，2—环丁基双(甲胺)—N，N′〕二卤铂(II)通过对卤素配位基的交换反应，然后于水溶液介质中转变成顺式—〔反式—1，2—环丁基双(甲胺)N，N′〕—〔(2S)—乳酸—O1，O2〕—铂(II)三水合物。
3.由顺式—〔反式—1，2—环丁基双(甲胺)—N，N′〕—〔(2S)—乳酸—O1，O2〕铂(II)—三水合物和常规的载体、稀释剂和/或辅料制成的药剂。
4.洛巴铂三水合物用于制备药剂的用途。
5.由洛巴铂三水合物制备药剂的方法。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4415263A DE4415263C1 (de) | 1994-04-15 | 1994-04-15 | Cis-[trans-1,2-Cyclobutanbis(methylamin)-N,N']-[(2S)-lactato-O·1·, O·2·]-platin(II)-trihydrat (Lobaplatin-Trihydrat), seine Herstellung und arzneiliche Verwendung |
| DEP4415263.9 | 1994-04-15 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1120046A true CN1120046A (zh) | 1996-04-10 |
| CN1041094C CN1041094C (zh) | 1998-12-09 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN94106670A Expired - Lifetime CN1041094C (zh) | 1994-04-15 | 1994-06-20 | 洛巴铂三水合物,其制备方法及其应用 |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US5747534A (zh) |
| EP (1) | EP0755399B1 (zh) |
| JP (1) | JP3579423B2 (zh) |
| CN (1) | CN1041094C (zh) |
| AT (1) | ATE185142T1 (zh) |
| AU (1) | AU2256195A (zh) |
| DE (2) | DE4415263C1 (zh) |
| DK (1) | DK0755399T3 (zh) |
| ES (1) | ES2138199T3 (zh) |
| GR (1) | GR3032061T3 (zh) |
| IL (1) | IL113360A (zh) |
| TW (1) | TW367329B (zh) |
| WO (1) | WO1995028407A1 (zh) |
| ZA (1) | ZA953095B (zh) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102020679A (zh) * | 2010-11-24 | 2011-04-20 | 贵州益佰制药股份有限公司 | 一种以草酸盐制备洛铂三水合物的方法 |
| WO2015192606A1 (zh) * | 2014-06-20 | 2015-12-23 | 贵州益佰制药股份有限公司 | 洛铂晶体、制备方法及药物应用 |
| CN105198932A (zh) * | 2014-06-20 | 2015-12-30 | 贵州益佰制药股份有限公司 | 洛铂二水合物、制备方法及药物应用 |
| CN105218587A (zh) * | 2014-06-20 | 2016-01-06 | 贵州益佰制药股份有限公司 | 一种洛铂晶体、制备方法及药物应用 |
| CN105330702A (zh) * | 2014-06-20 | 2016-02-17 | 贵州益佰制药股份有限公司 | 一种洛铂晶体、制备方法及药物应用 |
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| KR100314720B1 (ko) * | 1999-03-26 | 2001-11-26 | 박호군 | 포스파젠 삼합체에 도입된 백금 착물, 그의 제조방법 및 그를 유효성분으로 하는 항암제 |
| CA2385528C (en) | 1999-10-01 | 2013-12-10 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
| CN103467528B (zh) * | 2013-08-21 | 2016-06-08 | 江苏奥赛康药业股份有限公司 | 一种洛铂的制备方法 |
| DK3689899T3 (da) | 2014-04-25 | 2021-11-22 | 2Seventy Bio Inc | Kimære mnd-promotor-antigenreceptorer |
| WO2015188119A1 (en) | 2014-06-06 | 2015-12-10 | Bluebird Bio, Inc. | Improved t cell compositions |
| AU2015292590B2 (en) | 2014-07-24 | 2020-01-16 | 2Seventy Bio, Inc. | BCMA chimeric antigen receptors |
| NZ733025A (en) | 2014-12-12 | 2022-01-28 | 2Seventy Bio Inc | Bcma chimeric antigen receptors |
| WO2017099712A1 (en) | 2015-12-07 | 2017-06-15 | Bluebird Bio, Inc. | Improved t cell compositions |
| CN111721843B (zh) * | 2019-03-19 | 2022-05-17 | 海南长安国际制药有限公司 | 与洛铂有关物质的检测方法 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL7807334A (nl) * | 1978-07-06 | 1980-01-08 | Tno | Platina-diaminecomplexen, werkwijze voor het bereiden daarvan, werkwijze voor het bereiden van een genees- middel met toepassing van een dergelijk platina-dia- minecomplex voor de behandeling van kanker, alsmede al- dus verkregen gevormd geneesmiddel. |
| NL181434C (nl) * | 1980-01-03 | 1987-08-17 | Tno | Platina(iv)-diamine-complexen, alsmede hun bereiding en toepassing. |
| SU1186617A1 (ru) * | 1980-01-03 | 1985-10-23 | Нидерландзе Сентрале Организати Фор Тегепаст-Натурветеншаппелийк Ондерцоек (Фирма) | Платино ( @ )-диаминовые комплексы,про вл ющие противоопухолевую активность |
| US4912100A (en) * | 1986-10-15 | 1990-03-27 | Toray Industries, Inc. | Platinum complex, process for preparing same and antitumor agent |
| DE3843571A1 (de) * | 1988-01-09 | 1989-07-20 | Asta Pharma Ag | 1,2-bis(aminomethyl)cyclobutan-platin-komplexe |
| JPH02275891A (ja) * | 1988-12-29 | 1990-11-09 | Tsumura & Co | 新規な複核白金錯体および該錯体を有効成分とする抗腫瘍剤 |
| DE4115559A1 (de) * | 1990-05-15 | 1991-11-21 | Deutsches Krebsforsch | Antitumormittel mit verminderter toxizitaet auf der basis von cytostatika und xanthogenaten |
-
1994
- 1994-04-15 DE DE4415263A patent/DE4415263C1/de not_active Expired - Fee Related
- 1994-06-20 CN CN94106670A patent/CN1041094C/zh not_active Expired - Lifetime
-
1995
- 1995-03-31 WO PCT/EP1995/001214 patent/WO1995028407A1/de active IP Right Grant
- 1995-03-31 DE DE59506958T patent/DE59506958D1/de not_active Expired - Fee Related
- 1995-03-31 DK DK95915838T patent/DK0755399T3/da active
- 1995-03-31 ES ES95915838T patent/ES2138199T3/es not_active Expired - Lifetime
- 1995-03-31 JP JP52666395A patent/JP3579423B2/ja not_active Expired - Fee Related
- 1995-03-31 AT AT95915838T patent/ATE185142T1/de not_active IP Right Cessation
- 1995-03-31 AU AU22561/95A patent/AU2256195A/en not_active Abandoned
- 1995-03-31 EP EP95915838A patent/EP0755399B1/de not_active Expired - Lifetime
- 1995-04-13 IL IL11336095A patent/IL113360A/xx not_active IP Right Cessation
- 1995-04-13 ZA ZA953095A patent/ZA953095B/xx unknown
- 1995-04-14 TW TW084103672A patent/TW367329B/zh not_active IP Right Cessation
-
1996
- 1996-09-16 US US08/714,456 patent/US5747534A/en not_active Expired - Lifetime
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1999
- 1999-12-07 GR GR990403150T patent/GR3032061T3/el unknown
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102020679A (zh) * | 2010-11-24 | 2011-04-20 | 贵州益佰制药股份有限公司 | 一种以草酸盐制备洛铂三水合物的方法 |
| CN102020679B (zh) * | 2010-11-24 | 2013-12-25 | 贵州益佰制药股份有限公司 | 一种以草酸盐制备洛铂三水合物的方法 |
| WO2015192606A1 (zh) * | 2014-06-20 | 2015-12-23 | 贵州益佰制药股份有限公司 | 洛铂晶体、制备方法及药物应用 |
| CN105198932A (zh) * | 2014-06-20 | 2015-12-30 | 贵州益佰制药股份有限公司 | 洛铂二水合物、制备方法及药物应用 |
| CN105218587A (zh) * | 2014-06-20 | 2016-01-06 | 贵州益佰制药股份有限公司 | 一种洛铂晶体、制备方法及药物应用 |
| CN105330702A (zh) * | 2014-06-20 | 2016-02-17 | 贵州益佰制药股份有限公司 | 一种洛铂晶体、制备方法及药物应用 |
| US9889112B2 (en) | 2014-06-20 | 2018-02-13 | Guizhou Yibai Pharmaceutical Company Limited | Lobaplatin crystal, preparation method and pharmaceutical application |
| CN105218587B (zh) * | 2014-06-20 | 2018-08-14 | 贵州益佰制药股份有限公司 | 一种洛铂晶体、制备方法及药物应用 |
| CN105330702B (zh) * | 2014-06-20 | 2018-08-14 | 贵州益佰制药股份有限公司 | 一种洛铂晶体、制备方法及药物应用 |
| CN105198932B (zh) * | 2014-06-20 | 2018-09-21 | 贵州益佰制药股份有限公司 | 洛铂二水合物、制备方法及药物应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| DE59506958D1 (de) | 1999-11-04 |
| IL113360A (en) | 1999-09-22 |
| GR3032061T3 (en) | 2000-03-31 |
| EP0755399A1 (de) | 1997-01-29 |
| ATE185142T1 (de) | 1999-10-15 |
| TW367329B (en) | 1999-08-21 |
| EP0755399B1 (de) | 1999-09-29 |
| DK0755399T3 (da) | 2000-03-27 |
| JPH09511991A (ja) | 1997-12-02 |
| WO1995028407A1 (de) | 1995-10-26 |
| US5747534A (en) | 1998-05-05 |
| CN1041094C (zh) | 1998-12-09 |
| ES2138199T3 (es) | 2000-01-01 |
| AU2256195A (en) | 1995-11-10 |
| JP3579423B2 (ja) | 2004-10-20 |
| DE4415263C1 (de) | 1995-11-30 |
| IL113360A0 (en) | 1995-07-31 |
| ZA953095B (en) | 1996-01-05 |
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