CN1297448A - 帕罗西汀抗坏血酸盐 - Google Patents
帕罗西汀抗坏血酸盐 Download PDFInfo
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- CN1297448A CN1297448A CN99805160A CN99805160A CN1297448A CN 1297448 A CN1297448 A CN 1297448A CN 99805160 A CN99805160 A CN 99805160A CN 99805160 A CN99805160 A CN 99805160A CN 1297448 A CN1297448 A CN 1297448A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
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- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- 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
- A61P25/22—Anxiolytics
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- 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
- A61P25/24—Antidepressants
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- 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
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Abstract
帕罗西汀抗坏血酸盐可有效用于一些中枢神经***疾病(CNS)的治疗。
Description
本发明涉及一种新化合物,制备该化合物的方法及其在治疗内科疾病中的应用。
美国专利US-A-3912743和US-A-4007196中描述了具有抗抑郁和抗帕金森氏症的性质的药物。其中披露的一种特别重要的化合物为帕罗西汀,即4-(4′-氟苯基)-3-(3′,4′-亚甲基二氧苯氧甲基)-哌啶的反式异构体。该化合物以盐酸盐的形式在治疗中使用,用于治疗和特别是预防抑郁,强迫性神经失调(OCD)和恐慌症。
我们现在惊奇地发现了帕罗西汀的一种新盐,可用于作为目前市场上使用的盐酸盐的替代物,或用于作为制备盐酸盐的中间体。
根据本发明,所提供的是帕罗西汀抗坏血酸盐。
一方面本发明的新型盐以非结晶形式提供,可以为固体或油状物。油状物最好以一种固体载体吸收,特别的可使用一种可作为药物组合物的一种组分的载体。
另一方面,本发明的新型盐以结晶形式提供。当结晶形式以超过一种多晶型物存在时,每一种多晶型物构成本发明的另一方面。
帕罗西汀抗坏血酸盐可通过将计量的抗坏血酸与帕罗西汀游离碱接触来制备。优选酸或碱之一在溶液中,更优选二者都在溶液中。为将酸制成溶液,可提高温度,但要想获得盐的好的收率,可通过蒸发部分或全部溶剂,或控制冷却,最好是阶段冷却的方法获得。最常使用的溶剂是适于帕罗西汀游离碱流动的溶剂,例如甲苯,醇类例如甲醇,乙醇,异丙醇,酯类如乙酸乙酯,酮类如丙酮和丁酮,卤代烷烃如二氯甲烷以及醚类如四氢呋喃和***,但最好避免使用抗坏血酸在其中极不溶解的溶剂。对抗坏血酸合适的溶剂包括水和低级醇。
该盐可以通过常规的方法从上述所获得的溶液中以固体形式分离出来。例如,非结晶态盐可通过沉淀、喷雾干燥、及溶液的冷冻干燥,或油状物的真空干燥,或将游离碱和酸反应所获得的熔化物固化得到。结晶盐可用适当的溶剂结晶或重结晶得到。
当该盐与其所溶于的溶剂一起以溶剂化物得到时,这种溶剂化物构成本发明的又一方面。溶剂化物可以通过加热转变为非溶剂化物的盐,例如,通过炉干燥,或用一种不能形成溶剂化物的溶剂置换处理。
在分离出帕罗西汀盐之前,可先将水用共沸物蒸馏方法除去,以避免水合物的形成,或获得以无水物形式存在的产品。在这种情况下,盐溶液的合适溶剂为那些可与水形成共沸物的溶剂如甲苯和异丙醇。也应该理解溶剂的混合物也可以用于帮助共沸除水。
更通常地,结晶可在任何可形成所需要的晶体结构的溶剂中进行,有需要或有要求时可以使用所需结构的晶种。当多晶型物存在时,每种多晶型物最好从盐的溶液中直接结晶出来,尽管使用另一种多晶型物的晶种将一种多晶型物从溶液中重结晶出来也可以。
帕罗西汀游离碱可以按照美国专利4,007,196和EP-B-0223403所概述的方法制备。抗坏血酸可在市场上获得。
本发明的化合物可用于治疗和预防以下疾病:
酒精中毒;焦虑;抑郁症;强迫性神经失调;恐慌症;慢性疼痛;肥胖症;老年痴呆;偏头痛;饥饿症;厌食症;社交恐怖症;月前期综合症(PMS);***抑郁症;拔毛发癖;精神抑郁症;物质滥用症。
这些疾病在下文中称为“这些疾病”。
本发明进一步提供了一种治疗和/或预防“这些疾病”中的一种或多种疾病的方法,该方法可通过给予需要治疗的患者有效量和/或预防量的本发明的盐进行。
本发明进一步提供了一种用于治疗和/或预防“这些疾病”的药物组合物,该组合物包含一种本发明的盐和一种可药用的载体的共混物。
本发明也提供了一种本发明的盐用于治疗和/或预防“这些疾病”的用途。
本发明也提供了本发明的盐用于制造一种治疗和/或预防“这些疾病”的药物的用途。
本发明更适宜于在治疗抑郁症,OCD和恐慌症上的应用。
本发明的组合物通常适合口服给药,但组合物溶解后用于胃肠外给药的方法也在本发明的保护范围内。
组合物通常以一单位剂量组合物的形式用于病人,该单位剂量组合物包含1到200mg以游离碱量计算的活性组分,更通常为5到100mg,例如10到50mg比如10、12.5、15、20、25、30或40mg。更优选的单位剂量组合物包含20mg以游离碱量计算的活性组分。这种组合物正常情况下每天给药1到6次,例如每天2、3或4次以使所给的活性剂的总量在活性组分以游离碱量计算的5到400mg的范围内。最优选的单位剂量为每天给药一次。
优选的单位剂量形式包括片剂或胶囊。
本发明的组合物可通过通用的混合方法制剂,例如混合,填料和压片。
用于本发明的适宜载体包括一种稀释剂,一种粘合剂,一种崩解剂,一种着色剂,一种香味剂和/或防腐剂。这些试剂可按通用方法使用,例如按照与市场上销售的抗抑郁剂类似的方法使用。
药物组合物的特例包括EP-B-0223403和US4,007,196中所描述的,本发明产物可用作其中的活性组分。
下面举例说明本发明:实施例1:帕罗西汀抗坏血酸盐的制备
向抗坏血酸(1.12g,6.38mmol)的甲醇(15ml)溶液中加入含1.28mol帕罗西汀碱的甲苯(5ml,6.38mmol)溶液。用真空的方法除去溶剂,残余油状物用甲苯(15ml)稀释,并将溶剂真空除去。用***(约15ml)研磨,并在氮气保护下过滤,得到淡黄色固体,用***(2×10ml)洗涤,在真空干燥器中干燥3小时。收率2.99g。
IR(液体石蜡研磨):1716,1603,1510,1465,1377,1224,1186,1136,1037,930,831,722,540cm-1实施例2:片剂的制备
组分 | 20mg片 | 30mg片 |
帕罗西汀抗坏血酸盐磷酸二钙(DCP)微晶纤维素淀粉羟乙酸钠硬脂酸镁 | 20.00mg(以游离碱计算)83.34mg50.67mg8.34mg1.67mg | 30.00mg(以游离碱计算)125.0mg76.0mg12.5mg2.5mg |
组分的商业来源:磷酸二钙二水合物-Emcompress或Ditab*微晶纤维素-Avicel PH102*淀粉羟乙酸钠-Explotab**商品名方法1.将DCP过筛后称重,加入一轨道式混合机中。2.向混合机中加入30目的帕罗西汀抗坏血酸盐。3.加入20目的Avieel和Explotab,并将所有粉末混合10分钟。4.加入硬脂酸镁并混合10分钟。
制成五角型片剂的片所需的下列冲头:
30mg片9.5mm外接圆
20mg片8.25mm外接圆
此片剂在单冲杆压机或滚压机上就可以满意地制造出来。实施例3:片剂的制备
方法1.将帕罗西汀抗坏血酸盐、淀粉羟乙酸钠和磷酸二钙二水合物过筛,并在一合适的混合机中混合。(轨道式,Cuble式或高能剪切混合机)2.加入硬脂酸镁,并将其用单冲杆压机或滚压机压成片。
组分 | 10mg片 | 20mg片 | 30mg片 |
帕罗西汀抗坏血酸盐淀粉羟乙酸钠颗粒磷酸二钙(DITAB)或Dicafos硬脂酸镁 | 10mg(以游离碱计算)2.98mg158.88mg1.75mg | 20mg(以游离碱计算)5.95mg317.75mg3.50mg | 30mg(以游离碱计算)8.93mg476.63mg5.25mg |
Claims (7)
1.帕罗西汀抗坏血酸盐。
2.根据权利要求1的化合物,该化合物是以非结晶状态存在的。
3.根据权利要求1的化合物,该化合物是以结晶状态存在的。
4.一种制备权利要求1或2的化合物的方法,该方法通过帕罗西汀抗坏血酸盐溶液的沉淀,喷雾干燥或冷冻干燥,或通过帕罗西汀抗坏血酸盐油状物的真空干燥,或帕罗西汀抗坏血酸盐熔化物的固化来制备。
5.制备权利要求1或3的化合物的方法,该方法通过从帕罗西汀抗坏血酸盐的溶液进行结晶或重结晶来制备。
6.根据权利要求4或5的制备方法,其中帕罗西汀抗坏血酸盐的溶液,油状物或熔化物通过用抗坏血酸处理帕罗西汀游离碱来制备。
7.一种治疗和/或预防任何一种或多种“这些疾病”的方法,该方法通过给予患者有效量和/或预防量的帕罗西汀抗坏血酸盐来进行。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9808896.6A GB9808896D0 (en) | 1998-04-25 | 1998-04-25 | Novel compound |
GB9808896.6 | 1998-04-25 |
Publications (1)
Publication Number | Publication Date |
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CN1297448A true CN1297448A (zh) | 2001-05-30 |
Family
ID=10831008
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CN99805160A Pending CN1297448A (zh) | 1998-04-25 | 1999-04-23 | 帕罗西汀抗坏血酸盐 |
Country Status (20)
Country | Link |
---|---|
EP (1) | EP1089995A1 (zh) |
JP (1) | JP2002513019A (zh) |
KR (1) | KR20010042977A (zh) |
CN (1) | CN1297448A (zh) |
AP (1) | AP2000001963A0 (zh) |
AU (1) | AU3618499A (zh) |
BG (1) | BG104940A (zh) |
BR (1) | BR9909868A (zh) |
CA (1) | CA2330055A1 (zh) |
EA (1) | EA200001104A1 (zh) |
GB (1) | GB9808896D0 (zh) |
HU (1) | HUP0102116A3 (zh) |
ID (2) | ID26083A (zh) |
IL (1) | IL139081A0 (zh) |
NO (1) | NO20005352D0 (zh) |
PL (1) | PL343677A1 (zh) |
SK (1) | SK15912000A3 (zh) |
TR (1) | TR200003084T2 (zh) |
WO (1) | WO1999055698A1 (zh) |
ZA (1) | ZA200005912B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110607553A (zh) * | 2018-10-30 | 2019-12-24 | 中国科学院化学研究所 | 一种制备粒径可调的药物或药物中间体单晶或无定型物的方法 |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
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GB0003232D0 (en) * | 2000-02-11 | 2000-04-05 | Smithkline Beecham Plc | Novel composition |
IL159280A0 (en) * | 2001-06-14 | 2004-06-01 | Teva Pharma | A process for preparing paroxetine hcl which limits formation of pink colored compounds |
ES2664189T3 (es) | 2002-01-09 | 2018-04-18 | Emisphere Technologies, Inc. | Polimorfos de 4-(4-cloro-2-hidroxibenzoil)aminobutanoato de sodio |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
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GB1422263A (en) * | 1973-01-30 | 1976-01-21 | Ferrosan As | 4-phenyl-piperidine compounds |
EP0223403B1 (en) * | 1985-10-25 | 1993-08-04 | Beecham Group Plc | Piperidine derivative, its preparation, and its use as medicament |
US5276042A (en) * | 1993-04-16 | 1994-01-04 | Crenshaw Roger T | Treatment of premature ejaculation |
ES2117557B1 (es) * | 1996-02-29 | 1999-07-01 | Ferrer Int | Nuevo procedimiento de obtencion de (-)-trans -n-p-fluorobenzoilmetil-4-(p-fluorofenil)-3- ((3,4-(metilendioxi)fenoxi ) metil)-piperidina. |
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1998
- 1998-04-25 GB GBGB9808896.6A patent/GB9808896D0/en not_active Ceased
-
1999
- 1999-04-23 EP EP99918151A patent/EP1089995A1/en not_active Withdrawn
- 1999-04-23 KR KR1020007011809A patent/KR20010042977A/ko not_active Application Discontinuation
- 1999-04-23 CN CN99805160A patent/CN1297448A/zh active Pending
- 1999-04-23 SK SK1591-2000A patent/SK15912000A3/sk unknown
- 1999-04-23 AU AU36184/99A patent/AU3618499A/en not_active Abandoned
- 1999-04-23 PL PL99343677A patent/PL343677A1/xx not_active Application Discontinuation
- 1999-04-23 JP JP2000545858A patent/JP2002513019A/ja active Pending
- 1999-04-23 WO PCT/GB1999/001244 patent/WO1999055698A1/en not_active Application Discontinuation
- 1999-04-23 TR TR2000/03084T patent/TR200003084T2/xx unknown
- 1999-04-23 IL IL13908199A patent/IL139081A0/xx unknown
- 1999-04-23 ID IDW20002168A patent/ID26083A/id unknown
- 1999-04-23 CA CA002330055A patent/CA2330055A1/en not_active Abandoned
- 1999-04-23 ID IDW20002169A patent/ID26654A/id unknown
- 1999-04-23 AP APAP/P/2000/001963A patent/AP2000001963A0/en unknown
- 1999-04-23 EA EA200001104A patent/EA200001104A1/ru unknown
- 1999-04-23 BR BR9909868-7A patent/BR9909868A/pt not_active Application Discontinuation
- 1999-04-23 HU HU0102116A patent/HUP0102116A3/hu unknown
-
2000
- 2000-10-23 ZA ZA200005912A patent/ZA200005912B/en unknown
- 2000-10-24 NO NO20005352A patent/NO20005352D0/no not_active Application Discontinuation
- 2000-11-13 BG BG104940A patent/BG104940A/bg unknown
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110607553A (zh) * | 2018-10-30 | 2019-12-24 | 中国科学院化学研究所 | 一种制备粒径可调的药物或药物中间体单晶或无定型物的方法 |
CN110607554A (zh) * | 2018-10-30 | 2019-12-24 | 中国科学院化学研究所 | 一种制备药物或药物中间体单晶或无定型物的方法 |
CN110607554B (zh) * | 2018-10-30 | 2024-03-22 | 中国科学院化学研究所 | 一种制备药物或药物中间体单晶或无定型物的方法 |
CN110607553B (zh) * | 2018-10-30 | 2024-03-22 | 中国科学院化学研究所 | 一种制备粒径可调的药物或药物中间体单晶或无定型物的方法 |
Also Published As
Publication number | Publication date |
---|---|
ID26083A (id) | 2000-11-23 |
AP2000001963A0 (en) | 2000-12-31 |
BG104940A (bg) | 2001-09-28 |
NO20005352L (no) | 2000-10-24 |
TR200003084T2 (tr) | 2001-02-21 |
ZA200005912B (en) | 2001-12-19 |
ID26654A (id) | 2001-01-25 |
AU3618499A (en) | 1999-11-16 |
IL139081A0 (en) | 2001-11-25 |
PL343677A1 (en) | 2001-08-27 |
EA200001104A1 (ru) | 2001-04-23 |
KR20010042977A (ko) | 2001-05-25 |
NO20005352D0 (no) | 2000-10-24 |
HUP0102116A2 (hu) | 2002-05-29 |
HUP0102116A3 (en) | 2002-12-28 |
CA2330055A1 (en) | 1999-11-04 |
BR9909868A (pt) | 2000-12-19 |
GB9808896D0 (en) | 1998-06-24 |
EP1089995A1 (en) | 2001-04-11 |
JP2002513019A (ja) | 2002-05-08 |
WO1999055698A1 (en) | 1999-11-04 |
SK15912000A3 (sk) | 2001-04-09 |
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