CN1064681C - 杂环化合物 - Google Patents
杂环化合物 Download PDFInfo
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- CN1064681C CN1064681C CN94192681A CN94192681A CN1064681C CN 1064681 C CN1064681 C CN 1064681C CN 94192681 A CN94192681 A CN 94192681A CN 94192681 A CN94192681 A CN 94192681A CN 1064681 C CN1064681 C CN 1064681C
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- thiadiazoles
- picoline
- tetrahydrochysene
- bitartrate
- hexyloxy
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- 150000002391 heterocyclic compounds Chemical class 0.000 title 1
- 239000003814 drug Substances 0.000 claims abstract description 3
- 238000002425 crystallisation Methods 0.000 claims description 9
- 230000008025 crystallization Effects 0.000 claims description 9
- 208000024827 Alzheimer disease Diseases 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims 1
- 238000005185 salting out Methods 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 4
- 229940124597 therapeutic agent Drugs 0.000 abstract 1
- JOLJIIDDOBNFHW-UHFFFAOYSA-N xanomeline Chemical compound CCCCCCOC1=NSN=C1C1=CCCN(C)C1 JOLJIIDDOBNFHW-UHFFFAOYSA-N 0.000 abstract 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 10
- 229940095064 tartrate Drugs 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 150000003839 salts Chemical class 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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- UQOFGTXDASPNLL-XHNCKOQMSA-N Muscarine Chemical compound C[C@@H]1O[C@H](C[N+](C)(C)C)C[C@H]1O UQOFGTXDASPNLL-XHNCKOQMSA-N 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 238000001816 cooling Methods 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
- 239000000284 extract Substances 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000003186 pharmaceutical solution Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Hospice & Palliative Care (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Psychiatry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines Containing Plant Substances (AREA)
- Compounds Of Unknown Constitution (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供结晶3-(4-己氧基-1，2，5-噻二唑-3-基)-1，2，5，6-四氢-1-甲基吡啶(+)L-酒石酸氢盐、它的制备及作为治疗剂的应用。
Description
本发明涉及结晶的在本文称作Xamoneline酒石酸盐的3-(4-己氧基-1，2，5-噻二唑-3-基)-1，2，5，6-四氢-1-甲基吡啶(+)L-酒石酸氢盐、它的制备及作为治疗剂的应用。
美国专利US5，043，345公开了一类本身为蕈毒碱胆碱能兴奋药，并因此可用作有识别功能的兴奋剂(特别是在治疗阿尔茨海默症时)的化合物。
在美国专利US5，043，345实施例9中描述了式Ⅰ的3-(4-己氧基-1，2，5-噻二唑-3-基)-1，2，5，6-四氢-1-甲基吡啶的制备过程：
在本说明书，式Ⅰ化合物称为Xamoneline。
由于Xamoneline为碱性，因而它优选以酸加成盐的形式用作治疗剂。在美国专利US5，043，345的实施例9中，Xamoneline以游离碱形式获得，然后转化为其草酸盐。
但是，草酸盐对病人的肾功能具有潜在的副作用，因而在药学上不宜(J．Pharm．Sci．1977，66(1)，1-19)。特别是在用于治疗老年人时尤为不宜。
另外，对于商业用途，很重要的一点是需具有一种可药用盐，该盐应具有好的生物利用率，好的处理性质和可重复的晶型。
已令人惊奇地发现在十二种可药用酸系列中，只有Xamoneline的酒石酸盐才有上述所需性质。
因此，本发明提供一种新物质形式的结晶Xamoneline酒石酸盐，特别是其可药用形式。
本发明还提供包含结晶Xamoneline酒石酸盐的药物组合物，所述组合物包含结晶Xamoneline酒石酸盐和可药用载体。
本发明的组合物通常适于口服给药，但用于非经肠给药的溶液制剂也在本发明范围之内。
本发明的组合物常以单位剂量组合物形式提供，其含有1～200mg，更常见为2～100mg，例如2～50mg，如2、4、8、10、20、25或30mg。这样的组合物一般每天服用1～6次，例如每天2、3或4次，这样服用的活性成分总量在4～400mg范围内。
优选的单位剂型包括片剂或胶囊剂。
本发明的组合物可以采用常规的混合方法配制，例如混合、填充和压制。
适用于本发明的载体包括稀释剂、粘合剂、崩解剂、着色剂、调味剂和／或防腐剂。这些试剂可以以常规方式使用，例如以类似于用于治疗阿尔茨海默症的已用于临床药剂的方式使用。
本发明还提供治疗哺乳动物、包括人的阿尔茨海默症的方法，所述方法包括施用有效量的可药用结晶Xamoneline酒石酸盐。
本发明还提供用于治疗阿尔茨海默症的可药用结晶Xamoneline酒石酸盐。
Xamoneline酒石酸盐如下列实施例中所述进行合成、纯化和结晶。
实施例1
3-(4-已氧基-1，2，5-噻二唑-3-基)-1，2，5，6-四氢-1-甲基吡啶(+)L-酒石酸氢盐(Xamoneline酒石酸盐)
在0～5℃、氮气氛下，经3小时向搅拌着的碘化3-(4-己氧基-1，2，5-噻二唑-3-基)-1-甲基吡啶鎓(1．00kg，2．47mol)(US5，043，345)的甲醇(4升)溶液中加入硼氢化钠(113g，2．99mol)的0．1N氢氧化钠(500ml)溶液。反应混合物继续搅拌30分钟，然后用4N盐酸(800ml)中和。调PH值在7～8之间，并加入水(8升)。混合物用二氯甲烷(2×2升)萃取。合并有机相，用水洗涤，蒸发，得到游离碱态的标题化合物，产量700g。将残留物溶于2-丙醇(2．5升)中，加入富马酸(290g，2．50mol)。加热混合物至变成透明溶液，然后加入丙酮(2．5升)。搅拌该溶液并同时冷却至5-10℃，过滤收集沉淀的富马酸盐。
将沉淀(1kg，2．52mol)悬浮于二氯甲烷(4升)中，加入水(2升)和氢氧化钠溶液(560ml，27．65％，5．04mol)。搅拌反应混合物，直至得到透明溶液，然后分出二氯甲烷相，用水(2升)洗涤两次。过滤有机相，蒸发得到油状的游离碱标题化合物。将油状物溶于2-丙醇(5升)中，并加入(+)L-酒石酸(416g，2．77mol)。加热混合物直至形成透明溶液。在搅拌下缓缓冷却溶液至5～10℃，过滤收集沉淀物，干燥得到980g(90％)所需产物。用加有活性碳(10g)的热(80℃)2-丙醇(5升)重结晶，过滤、冷却至5～10℃后得到标题化合物的纯晶体。过滤收集晶体，在40℃干燥，得到900g(90％)产物。
熔点：95．5℃(DSC)1H-NMR(CD3OD，TMS)：δ7．3(1H，t)，4．9(4H，s)，4．5(2H，t)，4．4(2H，s)，4．2(2H，s)，3．4(2H，t)，3．3(CH3OD)，3．0(3H，s)，2．7(2H，q)，1．9(2H，m)，1．5(2H，m)，1．4(4H，m)，0．9(3H，t)．13C-NMR(DMSO-d6，TMS)：δ173．8，162．0，145．6，128．1，126．7，72．0，70．9，52．8，49．5，43．7，30．7，28．1，25．0，24．3，21．9，13．8．MS：281(M+)．
Claims (5)
1．结晶3-(4-己氧基-1，2，5-噻二唑-3-基)-1，2，5，6-四氢-1-甲基吡啶(+)L-酒石酸氢盐。
2．制备3-(4-己氧基-1，2，5-噻二唑-3-基)-1，2，5，6-四氢-1-甲基吡啶(+)L-酒石酸氢盐的方法，所述方法包括形成3-(4-已氧基-1，2，5-噻二唑-3-基)-1，2，5，6-四氢-1-甲基吡啶的溶液，和经沉淀或重结晶由溶液中结晶所述3-(4-已氧基-1，2，5-噻二唑-3-基)-1，2，5，6-四氢-1-甲基吡啶(+)L-酒石酸氢盐。
3．用于治疗阿尔茨海默症的药物组合物，包括与可药用载体或稀释剂结合的有效量的结晶3-(4-己氧基-1，2，5-噻二唑-3-基)-1，2，5，6-四氢-1-甲基吡啶(+)L-酒石酸氢盐。
4．权利要求3的药物组合物，该药物组合物为口服单位剂型，含有1-200mg 3-(4-己氧基-1，2，5-噻二唑-3-基)-1，2，5，6-四氢-1-甲基吡啶(+)L-酒石酸氢盐。
5．3-(4-己氧基-1，2，5-噻二唑-3-基)-1，2，5，6-四氢-1-甲基吡啶(+)L-酒石酸氢盐用于制备可用于治疗阿尔茨海默症的药物的用途。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US7257293A | 1993-06-04 | 1993-06-04 | |
| US08/072,572 | 1993-06-04 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1128999A CN1128999A (zh) | 1996-08-14 |
| CN1064681C true CN1064681C (zh) | 2001-04-18 |
Family
ID=22108479
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN94192681A Expired - Fee Related CN1064681C (zh) | 1993-06-04 | 1994-05-26 | 杂环化合物 |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US5834495A (zh) |
| EP (1) | EP0703915B1 (zh) |
| JP (1) | JP3190679B2 (zh) |
| KR (1) | KR100339115B1 (zh) |
| CN (1) | CN1064681C (zh) |
| AT (1) | ATE196631T1 (zh) |
| AU (1) | AU698673B2 (zh) |
| CA (1) | CA2164296C (zh) |
| CZ (1) | CZ290550B6 (zh) |
| DE (1) | DE69426021T2 (zh) |
| DK (1) | DK0703915T3 (zh) |
| ES (1) | ES2152315T3 (zh) |
| FI (1) | FI955829A0 (zh) |
| GR (1) | GR3035033T3 (zh) |
| HU (1) | HUT75038A (zh) |
| IL (1) | IL109866A (zh) |
| NO (1) | NO305560B1 (zh) |
| NZ (2) | NZ267062A (zh) |
| PT (1) | PT703915E (zh) |
| SK (1) | SK281980B6 (zh) |
| WO (1) | WO1994029303A1 (zh) |
| ZA (1) | ZA943904B (zh) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6043258A (en) * | 1996-08-01 | 2000-03-28 | Eli Lilly And Company | Method for treating disruptive behavior disorders with xanomeline |
| US6090829A (en) * | 1996-08-01 | 2000-07-18 | Eli Lilly And Company | Method for treating excessive aggression |
| EP0821956A1 (en) * | 1996-08-01 | 1998-02-04 | Eli Lilly And Company | Method for treating disruptive behavior disorders |
| EP0821954A1 (en) * | 1996-08-01 | 1998-02-04 | Eli Lilly And Company | Method for treating mental retardation |
| US6117890A (en) * | 1996-08-01 | 2000-09-12 | Eli Lilly And Company | Method for treating bipolar disorder |
| US6034108A (en) * | 1997-07-28 | 2000-03-07 | Eli Lilly And Company | Method for treating mental retardation |
| CA2978201A1 (en) | 2015-03-06 | 2016-09-15 | Chase Pharmaceuticals Corporation | Use of oxybutynin transdermal formulations to reduce side effects associated with muscarinic agonists |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5043345A (en) * | 1989-02-22 | 1991-08-27 | Novo Nordisk A/S | Piperidine compounds and their preparation and use |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5260311A (en) * | 1989-02-22 | 1993-11-09 | Novo Nordisk A/S | Piperidine compounds and their use |
| US5264444A (en) * | 1989-02-22 | 1993-11-23 | Novo Nordisk A/S | Piperidine compounds and use |
-
1994
- 1994-05-26 WO PCT/DK1994/000205 patent/WO1994029303A1/en active IP Right Grant
- 1994-05-26 CN CN94192681A patent/CN1064681C/zh not_active Expired - Fee Related
- 1994-05-26 EP EP94917567A patent/EP0703915B1/en not_active Expired - Lifetime
- 1994-05-26 AU AU69242/94A patent/AU698673B2/en not_active Ceased
- 1994-05-26 DE DE69426021T patent/DE69426021T2/de not_active Expired - Fee Related
- 1994-05-26 NZ NZ267062A patent/NZ267062A/en unknown
- 1994-05-26 DK DK94917567T patent/DK0703915T3/da active
- 1994-05-26 HU HU9503453A patent/HUT75038A/hu unknown
- 1994-05-26 PT PT94917567T patent/PT703915E/pt unknown
- 1994-05-26 CA CA002164296A patent/CA2164296C/en not_active Expired - Fee Related
- 1994-05-26 ES ES94917567T patent/ES2152315T3/es not_active Expired - Lifetime
- 1994-05-26 CZ CZ19953210A patent/CZ290550B6/cs not_active IP Right Cessation
- 1994-05-26 JP JP50120095A patent/JP3190679B2/ja not_active Expired - Fee Related
- 1994-05-26 AT AT94917567T patent/ATE196631T1/de not_active IP Right Cessation
- 1994-05-26 SK SK1520-95A patent/SK281980B6/sk unknown
- 1994-05-26 KR KR1019950705467A patent/KR100339115B1/ko not_active IP Right Cessation
- 1994-06-02 IL IL10986694A patent/IL109866A/xx not_active IP Right Cessation
- 1994-06-03 ZA ZA943904A patent/ZA943904B/xx unknown
-
1995
- 1995-12-01 NO NO954892A patent/NO305560B1/no not_active IP Right Cessation
- 1995-12-04 FI FI955829A patent/FI955829A0/fi not_active Application Discontinuation
-
1996
- 1996-11-26 US US08/756,835 patent/US5834495A/en not_active Expired - Fee Related
-
1999
- 1999-07-09 NZ NZ336733A patent/NZ336733A/en unknown
-
2000
- 2000-12-12 GR GR20000402720T patent/GR3035033T3/el not_active IP Right Cessation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5043345A (en) * | 1989-02-22 | 1991-08-27 | Novo Nordisk A/S | Piperidine compounds and their preparation and use |
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