CN1353712A - Nk－1－受体拮抗剂结晶(2－二苯甲基－1－氮杂双环[2.2.2]辛－3－基)－(5－异丙基－2－甲氧基苄基)－胺柠檬酸盐的多晶型 - Google Patents
Nk－1－受体拮抗剂结晶(2－二苯甲基－1－氮杂双环[2.2.2]辛－3－基)－(5－异丙基－2－甲氧基苄基)－胺柠檬酸盐的多晶型 Download PDFInfo
- Publication number
- CN1353712A CN1353712A CN00808340A CN00808340A CN1353712A CN 1353712 A CN1353712 A CN 1353712A CN 00808340 A CN00808340 A CN 00808340A CN 00808340 A CN00808340 A CN 00808340A CN 1353712 A CN1353712 A CN 1353712A
- Authority
- CN
- China
- Prior art keywords
- type
- monohydrate
- citric acid
- usp
- citrate trianion
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 102000002002 Neurokinin-1 Receptors Human genes 0.000 title description 4
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 title description 4
- 239000002464 receptor antagonist Substances 0.000 title description 4
- 229940044551 receptor antagonist Drugs 0.000 title description 4
- SWPMRUBXPAMUFU-UHFFFAOYSA-N C(CC(O)(C(=O)O)CC(=O)O)(=O)O.C(C1=CC=CC=C1)(C1=CC=CC=C1)N1C2CCC(C1NCC1=C(C=CC(=C1)C(C)C)OC)CC2 Chemical compound C(CC(O)(C(=O)O)CC(=O)O)(=O)O.C(C1=CC=CC=C1)(C1=CC=CC=C1)N1C2CCC(C1NCC1=C(C=CC(=C1)C(C)C)OC)CC2 SWPMRUBXPAMUFU-UHFFFAOYSA-N 0.000 title 1
- 150000004682 monohydrates Chemical class 0.000 claims abstract description 17
- 206010047700 Vomiting Diseases 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 74
- 238000002425 crystallisation Methods 0.000 claims description 34
- 230000008025 crystallization Effects 0.000 claims description 34
- -1 methoxy-benzyl Chemical group 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 23
- 239000000843 powder Substances 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 239000013078 crystal Substances 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- 238000002050 diffraction method Methods 0.000 claims description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- 230000008673 vomiting Effects 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 238000001291 vacuum drying Methods 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 6
- 230000003474 anti-emetic effect Effects 0.000 claims description 5
- 239000002111 antiemetic agent Substances 0.000 claims description 5
- 239000005557 antagonist Substances 0.000 claims description 4
- 230000004927 fusion Effects 0.000 claims description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 3
- 239000012141 concentrate Substances 0.000 claims description 3
- 238000000354 decomposition reaction Methods 0.000 claims description 3
- ADNPLDHMAVUMIW-CUZNLEPHSA-N substance P Chemical group C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000010521 absorption reaction Methods 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 238000002512 chemotherapy Methods 0.000 abstract description 2
- 238000009472 formulation Methods 0.000 abstract description 2
- 230000001154 acute effect Effects 0.000 abstract 1
- 239000002775 capsule Substances 0.000 abstract 1
- 238000001990 intravenous administration Methods 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 235000015165 citric acid Nutrition 0.000 description 17
- 229960004106 citric acid Drugs 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 238000005755 formation reaction Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000002441 X-ray diffraction Methods 0.000 description 3
- 229960002303 citric acid monohydrate Drugs 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 208000005156 Dehydration Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009838 combustion analysis Methods 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000012521 purified sample Substances 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 230000010512 thermal transition Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Hospice & Palliative Care (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Psychiatry (AREA)
- Otolaryngology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
(2－二苯甲基－1－氮杂双环[2.2.2]辛－3－基)－(5－异丙基－2－甲氧基苄基)－胺柠檬酸盐一水合物的两种结晶多晶型是A型和B型。含有至少一种这种多晶型的药物组合物具有配制稳定性,可用于治疗接受化疗患者的急性呕吐。该药物组合物通常优选以片剂或胶囊形式口服给药或者经静脉内给药。还公开了制备A和B型多晶型的方法。
Description
发明背景
本发明涉及结晶(2-二苯甲基-1-氮杂双环[2.2.2]辛-3-基)-(5-异丙基-2-甲氧基苄基)-胺柠檬酸盐的某些多晶型和结晶形式及它们的药物组合物。该柠檬酸盐是一种CNS活性NK-1受体拮抗剂，因此本发明涉及治疗受P物质介导的神经传递降低的影响或与此有关的适应症的方法。本发明还涉及P物质拮抗剂，据认为该物质对接受化疗的包括人在内的哺乳动物具有立即或者延缓的止吐效力。在此，治疗被定义为预防和治疗。
美国专利5393762和序号为08/816016的美国申请均引入本文以供参考，它们都描述了NK-1受体拮抗剂的药物组合物和使用该拮抗剂治疗呕吐的方法。结晶无水柠檬酸盐是不吸湿的，表现出独特的X-线粉末衍射类型，在159.9℃熔融。该无水柠檬酸盐在水中转化为一水合物。
发明概述
本发明涉及(2-二苯甲基-1-氮杂双环[2.2.2]辛-3-基)-(5-异丙基-2-甲氧基苄基)-胺的无水柠檬酸盐、柠檬酸盐一水合物和其两种多晶型。
在本发明的一个方案中，无水柠檬酸盐是一种晶体稳定的不吸湿的单体形式。该无水柠檬酸盐晶型呈片状微晶形式并以下面的X-线粉末衍射图样为特征。
无水柠檬酸盐
| 峰号 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 |
| D间距 | 17.61 | 10.95 | 8.78 | 7.96 | 7.37 | 6.80 | 6.57 | 5.87 | 5.46 |
在其它的两个方案中，柠檬酸盐一水合物是A或B型的结晶。A型以下面的X-线衍射图样为特征。
A型柠檬酸盐一水合物
| 峰号 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 |
| D间距 | 17.74 | 10.93 | 9.65 | 8.25 | 6.71 | 5.98 | 5.67 | 5.45 | 4.83 |
A型结晶型是双折射针晶，它在约84℃时挥发，重结晶得到板型结晶，其熔点为约162.6℃。B型结晶型是双折射片晶，它在约102℃下挥发，重结晶得到基本上不产生双折射的结晶，特征熔点为约120℃，再重结晶得到熔点为约149℃(降解)的微晶形式。B型以下面的X-线衍射图样为特征。
B型柠檬酸盐一水合物
| 峰号 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
| D间距 | 12.3 | 11.3 | 6.9 | 5.9 | 4.3 | 4.1 | 3.5 | 3.2 |
另一方面，本发明涉及一种具有药物活性的药物组合物，它含有至少一种用于治疗呕吐的A和B型的多晶型形式的柠檬酸盐一水合物和无水柠檬酸盐。一种治疗呕吐的方法，包括给需此治疗的对象施用止吐有效量的A或B型的多晶型或者无水柠檬酸盐。
(2-二苯甲基-1-氮杂双环[2.2.2]辛-3-基)-(5-异丙基-2-甲氧基苄基)-胺柠檬酸盐一水合物的A型多晶型的制备包括将无水柠檬酸盐溶于异丙醇和水中并将该混合物在室温搅拌过夜。使柠檬酸盐一水合物结晶，过滤收集得到A型结晶。然后在约20-80℃下真空干燥A型结晶。在室温条件下，合成反应进行约1.5-72小时。晶体较大的A型片晶生长于乙醚/水溶液中，A型针晶生长于丙酮/二异丙基醚/水中。制备柠檬酸盐一水合物的B型多晶型的方法包括在室温下浓缩柠檬酸盐一水合物的甲醇溶液约48-72小时。
发明详述
在室温下，通过将1.1当量柠檬酸加到搅拌着的游离碱在异丙醇(15倍体积)中的浆状物中合成无水柠檬酸盐。搅拌所得溶液并用差示扫描量热计监测，待所有的游离碱反应(18小时)后，经过滤并在45℃和氮气氛下真空干燥得到白色结晶形式的无水柠檬酸盐(产率83％)。X-线粉末衍射和PLM显示该盐是结晶形式的。常见的晶型为片状微晶形式。通过X-线粉末衍射观察到的最强反射，d间距是17.608，10.953，8.782，7.956，7.371，6.802，6.571，5.866，5.462，4.907，4.415，4.188，3.635和3.512埃。该结晶的熔点为159.8℃(分解)。吸湿性测定表明在90％RH时，它吸附1.11％wt./wt.的水。
制备结晶柠檬酸一水合物A型多晶型的方法包括将13.9kg柠檬酸(无水，99.5+％)的丙酮(125L)溶液加到50kg游离碱的异丙醇(250L)溶液中。将该透明溶液过滤、搅拌，蒸除丙酮。在室温搅拌所得混合物直至开始结晶，然后在接下来的16小时内，使其形成结晶颗粒。过滤收集形成的白色结晶状的无水柠檬酸盐并在25℃下真空干燥(产率80％)。
无水柠檬酸盐(26.4kg)溶于异丙醇(264L)，加入水(13.2L)并将该混合物在室温搅拌过夜。柠檬酸盐一水合物产生结晶，过滤收集并于25℃真空干燥。获得24.9kg产物(91.8％)。
将所得A型柠檬酸盐一水合物与纯净的样品通过PLM、X-线粉末衍射、质子NMR、卡尔·费歇尔法、DSC和元素分析进行比较。X-线粉末衍射和PLM表明其是结晶形式的。具有类似折射图的两种晶型是板晶和针晶。针晶型是晶面在水中以不同速率生长的结果，晶面在异丙醇/水中以较平衡的速率生长则产生片晶。通过X-线粉末衍射观察到的最强反射，d间距为17.736，10.928，9.651，8.253，6.707，5.981，5.666，5.450，4.833，4.488和3.646埃。该结晶在84℃下挥发并在159.9℃熔融分解。吸湿性测定表明，在90％RH时，它吸附2.44％wt./wt.的水。卡尔·费歇尔法显示含有2.7％的水(理论值为2.66％)，证实合成的是一水合物。元素分析验证了合成得到的盐的纯度。
通过在室温下在甲醇中浆化1.5-72小时实现B型柠檬酸盐一水合物的制备。过滤收集产物。将柠檬酸盐一水合物回流18小时得到相同的结果。
B型是柠檬酸盐一水合物的多晶型。通过分离，B型的典型结晶形式是双折射片晶。在室温下、乙酸乙酯中，B型可转化为A型。差示扫描量热法表明B型在76℃下失水，在120℃下发生脆弱的重结晶，在138.8℃熔融，重结晶，其最终熔点为159.9℃。
将A型溶于甲醇可回转为B型，它易于干燥得到相当稳定的多晶型。将该多晶型在乙酸乙酯中桥接(bridging)得到A型。桥接是显微化学和结晶学中有关溶液相转变的普通术语，是一种测定最低能量(最稳定)结晶形式的常用方法。结晶通常出现在各种预先饱和的溶剂中(以化合物饱和的溶剂，它产生结晶)。结晶浆化一段时间后，收集结晶并监测获得了何种形式的结晶。在实验条件下，晶型应是最低能量形式的。
在乙酸乙酯和丙酮中桥接A型结晶，可由A型结晶得到B型结晶，随后在下列的溶剂中又可转化为原始的混合结晶形式：四氢呋喃、乙酸乙酯、环己烷、己烷、乙腈和甲基乙基酮。
通过在室温条件下在乙酸乙酯中搅拌不太稳定的形式，例如B型结晶可转化得到A型结晶。
在水中结晶浆化无水形式或者各种形式的混合物得到结晶一水合物，该一水合物在干燥条件下，例如于45℃真空干燥下不失水。
A和B型结晶形式的柠檬酸盐一水合物具有有价值的和非显而易见的特性。由于A型柠檬酸盐一水合物具有吸湿稳定性，减小了在制片和包囊操作中由于活性成分的重量变化带来的配制问题。在低于约85％相对湿度下，B型也具有相似的优点。A和B型结晶及无水柠檬酸盐还可通过静脉给药。
柠檬酸盐一水合物的药物组合物的有效剂量取决于期望的给药途径、指标、治疗的适应症和其它因素，如被治疗对象的年龄和体重。在下列剂量范围内，术语“mg A”是指一水合物的毫克数。口服给药的推荐剂量为5-300mg A/天，优选40-200mg A/天，更优选40-80mg A/天，可一次性或分次给药。以口服剂型，如丸剂或片剂，口服给药的推荐剂量是2.5mg A/天-160mg A/天，优选5-80mg A/天。由于A型结晶不具有吸湿性和较低的能量桥接和热转化，证实了其相对于其它各种形式的稳定性。
下列实施例说明本发明的方法和化合物。但是应该理解，本发明不受具体实施例的限制。
实施例1
A型结晶柠檬酸一水合物的制备
将13.9kg柠檬酸(无水，99.5+％)的丙酮(125L)溶液加到50kg游离碱的异丙醇(250L)中。将该透明溶液过滤、搅拌并蒸馏除去丙酮。在室温搅拌所得混合物直至开始结晶，然后在使其粒化16个小时。过滤收集形成的无水柠檬酸盐白色结晶并在25℃下真空干燥(产率80％)。
实施例2
B型结晶柠檬酸一水合物的制备
将A型结晶一水合物样品溶于甲醇。在室温下搅拌该溶液后，浓缩蒸发溶剂。过滤收集所得的B型结晶。通过X-线衍射图、Hnmr和燃烧分析证实该化合物是B型结晶形式的一水合物。
Claims (19)
1.下式的(2-二苯甲基-1-氮杂双环[2.2.2]辛-3-基)-(5-异丙基-2-甲氧基苄基)-胺柠檬酸盐的结晶形式，
其中所说结晶形式选自：
(a)表现出下面的X-线粉末衍射图样的稳定的非吸湿性无水柠檬酸盐
峰号
1
2
3
4
5
6
7
8
9
D间距
17.61
10.95
8.78
7.96
7.37
6.80
6.57
5.87
5.46
(b)表现出下面的X-线粉末衍射图样的柠檬酸盐一水合物的A型多晶型
峰号
1
2
3
4
5
6
7
8
9
D间距
17.74
10.93
9.65
8.25
6.71
5.98
5.67
5.45
4.83
(c)表现出下面的X-线粉末衍射图样的柠檬酸盐一水合物的B型多晶型
峰号
1
2
3
4
5
6
7
8
9
D间距
12.3
11.3
6.5
6.9
5.9
4.3
4.1
3.5
3.2
2.权利要求1的一水合物多晶型，其中A晶型是针状针晶或片晶。
3.权利要求1的一水合物B型多晶型，其中B晶型是片晶。
4.通过浓缩柠檬酸盐一水合物的甲醇溶液获得的权利要求1的一水合物B型多晶型。
5.权利要求1的无水柠檬酸盐，具有约159.9℃的熔点。
6.权利要求1的无水柠檬酸盐，其在水中转化为一水合物。
7.权利要求1的无水柠檬酸盐，其中吸湿测定表明在约90％相对湿度下它含有约1.11％重量/重量的水。
8.权利要求1的无水柠檬酸盐，其中其晶型是薄片状微晶。
9.权利要求1的一水合物A型多晶型，特征在于其熔点为约162.6℃。
10.权利要求1的一水合物B型多晶型，特征在于其熔融分解点为约149℃。
11.一种具有P物质拮抗剂活性的药物组合物，它含有有效治疗呕吐量的至少一种权利要求1的A或B型多晶型和可药用载体。
12.一种治疗呕吐的方法，包括给需此治疗的对象施用止吐有效量的权利要求1的A型多晶型化合物。
13.一种治疗呕吐的方法，包括给需此治疗的对象施用止吐有效量的权利要求1的B型多晶型化合物。
14.一种具有P物质拮抗剂活性的药物组合物，它含有有效治疗呕吐量的权利要求1的无水柠檬酸盐。
15.一种治疗呕吐的方法，包括给需此治疗的对象施用止吐有效量的权利要求1的无水柠檬酸盐化合物。
16.一种制备(2-二苯甲基-1-氮杂双环[2.2.2]辛-3-基)-(5-异丙基-2-甲氧基苄基)-胺柠檬酸盐一水合物的A型多晶型结晶的方法，包括：
将无水柠檬酸盐溶于异丙醇和水中；在室温下将该混合物搅拌过夜；使柠檬酸盐一水合物结晶并经过滤收集A型结晶；和在约20-80℃下真空干燥。
17.权利要求16的方法，其中合成在室温下进行约1.5-72小时。
18.权利要求16的方法，其中A型的晶体较大的片晶型生长于异丙醇/水溶液中，针晶型生长于丙酮/二异丙基醚/水中。
19.一种制备(2-二苯甲基-1-氮杂双环[2.2.2]辛-3-基)-(5-异丙基-2-甲氧基苄基)-胺柠檬酸盐一水合物的B型多晶型结晶的方法，包括：
在室温下将柠檬酸盐一水合物的甲醇溶液浓缩48-72小时。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13699599P | 1999-06-01 | 1999-06-01 | |
| US60/136,995 | 1999-06-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1353712A true CN1353712A (zh) | 2002-06-12 |
Family
ID=22475353
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00808340A Pending CN1353712A (zh) | 1999-06-01 | 2000-05-17 | Nk－1－受体拮抗剂结晶(2－二苯甲基－1－氮杂双环[2.2.2]辛－3－基)－(5－异丙基－2－甲氧基苄基)－胺柠檬酸盐的多晶型 |
Country Status (38)
| Country | Link |
|---|---|
| US (1) | US6387925B1 (zh) |
| EP (1) | EP1181289A1 (zh) |
| JP (1) | JP2003501353A (zh) |
| KR (1) | KR20020005055A (zh) |
| CN (1) | CN1353712A (zh) |
| AP (1) | AP2001002350A0 (zh) |
| AR (1) | AR029753A1 (zh) |
| AU (1) | AU767331B2 (zh) |
| BG (1) | BG106139A (zh) |
| BR (1) | BR0011125A (zh) |
| CA (1) | CA2372236A1 (zh) |
| CO (1) | CO5170468A1 (zh) |
| CR (1) | CR6513A (zh) |
| CZ (1) | CZ20014270A3 (zh) |
| DZ (1) | DZ3051A1 (zh) |
| EA (1) | EA004206B1 (zh) |
| EE (1) | EE200100655A (zh) |
| GT (1) | GT200000086A (zh) |
| HK (1) | HK1046407A1 (zh) |
| HN (1) | HN2000000076A (zh) |
| HR (1) | HRP20010884A2 (zh) |
| HU (1) | HUP0201798A3 (zh) |
| IL (1) | IL145952A0 (zh) |
| IS (1) | IS6129A (zh) |
| MX (1) | MXPA01012328A (zh) |
| NO (1) | NO20015845L (zh) |
| NZ (1) | NZ514762A (zh) |
| OA (1) | OA11955A (zh) |
| PA (1) | PA8496001A1 (zh) |
| PE (1) | PE20010155A1 (zh) |
| PL (1) | PL352715A1 (zh) |
| SK (1) | SK17342001A3 (zh) |
| SV (1) | SV2002000092A (zh) |
| TN (1) | TNSN00119A1 (zh) |
| TR (1) | TR200103472T2 (zh) |
| UY (1) | UY26177A1 (zh) |
| WO (1) | WO2000073303A1 (zh) |
| ZA (1) | ZA200109839B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110577522A (zh) * | 2018-06-07 | 2019-12-17 | 广东东阳光药业有限公司 | 马罗匹坦柠檬酸盐新晶型及其制备方法 |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006503859A (ja) * | 2002-10-04 | 2006-02-02 | メルク シャープ エンド ドーム リミテッド | 受容体拮抗薬としてのアザ二環式スピロエーテル誘導体 |
| US7414140B2 (en) * | 2003-06-18 | 2008-08-19 | Teva Pharmaceutical Industries Ltd. | Fluvastatin sodium crystal forms, processes for preparing them, compositions containing them and methods of using them |
| US7371906B2 (en) | 2004-08-24 | 2008-05-13 | Eastman Kodak Company | Process for photo-oxidative stability improvements |
| US9446029B2 (en) | 2010-07-27 | 2016-09-20 | Colorado State University Research Foundation | Use of NK-1 receptor antagonists in management of visceral pain |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX18467A (es) * | 1988-11-23 | 1993-07-01 | Pfizer | Agentes terapeuticos de quinuclidinas |
| DE9290063U1 (de) * | 1991-05-31 | 1994-02-24 | Pfizer Inc., New York, N.Y. | Chinuclidin-Derivate |
| AU676489B2 (en) * | 1992-11-12 | 1997-03-13 | Pfizer Inc. | Quinuclidine derivative as substance P antagonist |
| US5393762A (en) * | 1993-06-04 | 1995-02-28 | Pfizer Inc. | Pharmaceutical agents for treatment of emesis |
| US6262067B1 (en) * | 1999-06-22 | 2001-07-17 | Pfizer Inc. | Polymorphs of a crystalline azo-bicyclo 2,2,2 OCT-3-yl amine dihydrochloride and their pharmaceutical compositions |
-
2000
- 2000-05-12 US US09/887,682 patent/US6387925B1/en not_active Expired - Fee Related
- 2000-05-17 TR TR2001/03472T patent/TR200103472T2/xx unknown
- 2000-05-17 BR BR0011125-2A patent/BR0011125A/pt not_active IP Right Cessation
- 2000-05-17 KR KR1020017015324A patent/KR20020005055A/ko not_active Application Discontinuation
- 2000-05-17 CA CA002372236A patent/CA2372236A1/en not_active Abandoned
- 2000-05-17 NZ NZ514762A patent/NZ514762A/xx unknown
- 2000-05-17 EP EP00925526A patent/EP1181289A1/en not_active Withdrawn
- 2000-05-17 SK SK1734-2001A patent/SK17342001A3/sk unknown
- 2000-05-17 MX MXPA01012328A patent/MXPA01012328A/es not_active Application Discontinuation
- 2000-05-17 HU HU0201798A patent/HUP0201798A3/hu unknown
- 2000-05-17 CN CN00808340A patent/CN1353712A/zh active Pending
- 2000-05-17 AU AU44246/00A patent/AU767331B2/en not_active Ceased
- 2000-05-17 OA OA1200100317A patent/OA11955A/en unknown
- 2000-05-17 JP JP2001500628A patent/JP2003501353A/ja active Pending
- 2000-05-17 EE EEP200100655A patent/EE200100655A/xx unknown
- 2000-05-17 CZ CZ20014270A patent/CZ20014270A3/cs unknown
- 2000-05-17 HN HN2000000076A patent/HN2000000076A/es unknown
- 2000-05-17 AP APAP/P/2001/002350A patent/AP2001002350A0/en unknown
- 2000-05-17 WO PCT/IB2000/000663 patent/WO2000073303A1/en not_active Application Discontinuation
- 2000-05-17 PL PL00352715A patent/PL352715A1/xx not_active Application Discontinuation
- 2000-05-17 EA EA200100982A patent/EA004206B1/ru not_active IP Right Cessation
- 2000-05-17 IL IL14595200A patent/IL145952A0/xx unknown
- 2000-05-19 PA PA20008496001A patent/PA8496001A1/es unknown
- 2000-05-26 CO CO00039192A patent/CO5170468A1/es not_active Application Discontinuation
- 2000-05-29 UY UY26177A patent/UY26177A1/es not_active Application Discontinuation
- 2000-05-30 AR ARP000102664A patent/AR029753A1/es unknown
- 2000-05-30 GT GT200000086A patent/GT200000086A/es unknown
- 2000-05-30 PE PE2000000517A patent/PE20010155A1/es not_active Application Discontinuation
- 2000-05-31 TN TNTNSN00119A patent/TNSN00119A1/fr unknown
- 2000-05-31 SV SV2000000092A patent/SV2002000092A/es unknown
- 2000-05-31 DZ DZ000102A patent/DZ3051A1/xx active
-
2001
- 2001-10-26 IS IS6129A patent/IS6129A/is unknown
- 2001-11-23 BG BG106139A patent/BG106139A/bg unknown
- 2001-11-27 CR CR6513A patent/CR6513A/es not_active Application Discontinuation
- 2001-11-27 HR HR20010884A patent/HRP20010884A2/hr not_active Application Discontinuation
- 2001-11-29 ZA ZA200109839A patent/ZA200109839B/xx unknown
- 2001-11-30 NO NO20015845A patent/NO20015845L/no not_active Application Discontinuation
-
2002
- 2002-10-30 HK HK02107840.5A patent/HK1046407A1/zh unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110577522A (zh) * | 2018-06-07 | 2019-12-17 | 广东东阳光药业有限公司 | 马罗匹坦柠檬酸盐新晶型及其制备方法 |
| CN110577522B (zh) * | 2018-06-07 | 2022-12-27 | 东莞市东阳光动物保健药品有限公司 | 马罗匹坦柠檬酸盐新晶型及其制备方法 |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AT7110U2 (de) | Verfahren zur herstellung von amlodipinmaleat | |
| CN1353712A (zh) | Nk－1－受体拮抗剂结晶(2－二苯甲基－1－氮杂双环[2.2.2]辛－3－基)－(5－异丙基－2－甲氧基苄基)－胺柠檬酸盐的多晶型 | |
| CA2403264A1 (en) | Chiral fluoroquinolizinone arginine salt forms | |
| CN112094249A (zh) | 磺胺甲噻二唑-糖精共晶及其制备方法与应用 | |
| AU767334B2 (en) | Polymorphs of a crystalline azabicyclo (2,2,2) octan-3-amine citrate and their pharmaceutical compositions | |
| CN1390216A (zh) | 作为nk－1受体拮抗剂的结晶性(2－二苯甲基－1－氮杂双环[2,2,2]辛－3－基)－(5－异丙基－2甲氧基苄基)氯化铵多晶型物 | |
| CA2315835C (en) | New crystalline form of 1-methyl-5-p-toluoylpyrrole-2-acetamidoacetic acid guaiacyl ester | |
| MXPA05001241A (es) | Sal acida organica de amilodipina. | |
| US2781346A (en) | Omricn-(phenyl carbamyl)-nu-methyl scopolamine quaternary ammonium salts | |
| JPH09176119A (ja) | ピペリジン誘導体の結晶並びにその製造中間体及び製造方法 | |
| JPH0971575A (ja) | 新規な結晶型スルホンアミド化合物 | |
| WO2009113081A1 (en) | Tris (hydroxymethyl ) amino methane salt of quinapril and ramipril |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C06 | Publication | ||
| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |