WO2000009483A2 - Process and intermediates for production of donepezil and related compounds - Google Patents
Process and intermediates for production of donepezil and related compounds Download PDFInfo
- Publication number
- WO2000009483A2 WO2000009483A2 PCT/IL1999/000436 IL9900436W WO0009483A2 WO 2000009483 A2 WO2000009483 A2 WO 2000009483A2 IL 9900436 W IL9900436 W IL 9900436W WO 0009483 A2 WO0009483 A2 WO 0009483A2
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- WIPO (PCT)
- Prior art keywords
- formula
- compound
- mixture
- process according
- piperidyl
- Prior art date
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- 0 CC(C)C(c(c(*)c1*)c(*)c(*)c1S)=O Chemical compound CC(C)C(c(c(*)c1*)c(*)c(*)c1S)=O 0.000 description 4
- BUHNUVUYYUYZRG-UHFFFAOYSA-N CC(CC(CC(CC1CCN(Cc2ccccc2)CC1)C(O)=O)=C1)C(OC)=C1OC Chemical compound CC(CC(CC(CC1CCN(Cc2ccccc2)CC1)C(O)=O)=C1)C(OC)=C1OC BUHNUVUYYUYZRG-UHFFFAOYSA-N 0.000 description 1
- CRVLTDDCHATIIZ-UHFFFAOYSA-N CC(CCC1C)C(CC2CC3CCN(Cc4ccccc4)CC3)=C1C2=O Chemical compound CC(CCC1C)C(CC2CC3CCN(Cc4ccccc4)CC3)=C1C2=O CRVLTDDCHATIIZ-UHFFFAOYSA-N 0.000 description 1
- AEYTZUHWNIUVAG-UHFFFAOYSA-N COC1C(OC)=CC(C(C(CC2CCN(Cc3ccccc3)CC2)C2)=O)=C2C1 Chemical compound COC1C(OC)=CC(C(C(CC2CCN(Cc3ccccc3)CC2)C2)=O)=C2C1 AEYTZUHWNIUVAG-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
- C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Definitions
- the present invention relates to a new process for the preparation of acetylcholinesterase inhibitors (anti-AchE) such as Donepezil, to some novel intermediates used in this process and to their preparation.
- anti-AchE acetylcholinesterase inhibitors
- Dementia is a chronic progressive organic mental disorder in which there is disturbance of multiple higher cortical functions including memory, thinking, orientation, comprehension, calculation, learning capacity, language and judgement.
- Alzheimer's Disease is the commonest cause of dementia and is characterized by degeneration of specific nerve cells, presence of neurotic plaques, and neurofibrillary tangles. Definitive diagnosis of Alzheimer's Disease requires demonstration of these characteristic pathological features in brain tissue, although in the vast majority of cases diagnosis is made on clinical grounds alone, where it is more correctly called Senile Dementia of the Alzheimer Type (SDAT).
- SDAT Senile Dementia of the Alzheimer Type
- Donepezil is a new drug treatment for use in mild to moderate dementia due to SDAT.
- Donepezil acts by inhibiting acetylcholine esterase, the enzyme responsible for metabolising acetylcholine, thereby enhancing neurotransmitter levels.
- the general synthetic route to compounds [X] comprises the condensation of cyclic aromatic ketones [XI] with l-substituted-4-( ⁇ -formylalkyl)piperidines [XII] followed by reduction of the obtained compounds [XIII] (Scheme 1) (Sugimoto, H., et al., J. Med. Chem., v. 38, 481 (1995); Eisai Co., U.S. 5,100,901).
- the present invention relates to a process for preparing a compound of formula [I] or a salt thereof:
- R.1 is N-acyl-4-piperidyl; N-alkoxycarbonyl-4-piperidyl; 4-piperidyl; N-alkyl-4-piperidyl; N-benzyl-4-piperidyl; N-( ⁇ -aralkyl)-4-piperidyl; 4-pyridyl;
- R4, R.5, R6 and R ⁇ are identical or different and each represents hydrogen, straight-chain or branched alkyl, aryl, hydroxy, alkoxy, aryloxy, benzyloxy, acyloxy, alkylthio, arylthio, benzylthio, acylamino, phthalimido or halogen; n is 1, 2 or 3; m is 1, 2, 3, 4 or 5; which process comprises cyclisation of a compound of formula [II] or salts thereof
- Rl, R4, R5, R6 and R ⁇ , m and n are as defined above;
- R2 is selected from a derivatised or non-derivatised carboxyl, cyano, N-substituted aminocarbonyl groups or hydrogen;
- R3 is selected from a derivatised or non-derivatised carboxyl, cyano or N-substituted aminocarbonyl groups, optionally in the presence of acids and/or solvents.
- enantiomerically enriched compounds of formula [ I ] or salts thereof are prepared by cyclisation of optically pure compounds of formula [ II ], wherein R 2 and R 3 are different.
- the present invention also relates to new compounds of formula
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R?, m and n are as defined above; including salts thereof and the optically active enantiomers thereof.
- the present invention further relates to a process for preparing a compound [II] which comprises reacting a compound of the formula [III]
- X is a facile leaving group, with a compound of the formula [IV] [ IV ] in the presence of a strong base.
- a compound of the formula [II] can be prepared by hydrogenation of a compound of formula [VHI] or [IX] or mixtures thereof
- R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , n and m are as defined above.
- Scheme 2 refers to a process for the preparation of a compound of formula [I] or salts thereof by cyclisation of a compound of formula [II] or salts thereof:
- ester, amido, cyano or ether protecting groups can be hydrolyzed under the conditions of the cyclisation reaction either in the starting compound [II] or in the desired compound [I].
- the cyclisation is carried out with a previously hydrolysed compound [II], wherein R is hydrogen or a carboxyl group and
- R is a carboxyl group.
- the cyclisation of the present invention is carried out in the presence of protic acids or Lewis acids or a mixture thereof.
- protic acids or Lewis acids or a mixture thereof examples include trifluoromethanesulfonic acid, methanesulfonic acid, polyphosphoric acid, fluoro- or chlorosulfonic acid, sulfuric acid, hydrogen fluoride, hydrogen chloride, zinc chloride, zinc bromide, aluminium chloride, aluminium bromide, titanium chloride, boron fluoride, phosphorus pentoxide, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thyonyl chloride and sulfuryl chloride.
- the cyclisation of the present invention can be carried out in the presence of a solvent.
- the solvent is selected from dichloromethane, chloroform, dichloroethane, tetrachloroethane, chlorobenzene, dichlorobenzene, nitromethane, nitroethane, nitrobenzene, ether or mixtures thereof.
- the present invention relates to new compounds of formula [II] including the optically active enantiomers thereof (R 7 ⁇ R 3 ) which are used in the cyclisation shown in Scheme 2 above.
- Schemes 5 and 6 below refer to processes for preparation of the new compounds of formula [U].
- X represents a facile leaving group and may be a sulfonate group or a halogen.
- X is selected from chlorine and bromine.
- the reactions according to Scheme 5 are usually carried out in the presence of a strong base, as for example metal alkoxides, metal amides, metal hydrides or mixtures thereof.
- a strong base as for example metal alkoxides, metal amides, metal hydrides or mixtures thereof.
- the strong base is selected from sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, sodium tert-pentoxide, sodium bis(trimehtylsilyl)amide, lithium diisopropylamide or mixtures thereof.
- the coupling reaction according to Scheme 6 is usually carried out in the presence of a base.
- the base is selected from metal carbonate, metal alkoxides, metal amides or metal hydrides. More preferably, the base is selected from potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, lithium diisopropylamide or mixture thereof.
- the above process can be carried out either without a solvent or in the presence of an organic solvent or water.
- the organic solvent is preferably selected from tetrahydrofuran (THF), 1,2-dimethoxy ethane, dichloromethane, benzene, toluene, N,N-dimethylformamide (DMF), N,N-dimethy lacetamide, 1 -methy 1-2-pyrrolidinone, dimethy lsulphoxide (DMSO), methanol, ethanol, isopropanol, tert-butyl alcohol or mixtures thereof.
- THF tetrahydrofuran
- 1,2-dimethoxy ethane 1,2-dimethoxy ethane
- dichloromethane benzene
- toluene N,N-dimethylformamide
- DMF N,N-dimethy lacetamide
- 1 -methy 1-2-pyrrolidinone dimethy lsulph
- Transition metals can be used as catalysts in said catalytic hydrogenation.
- Pd, Pt, Rh, Ru or Ni are used.
- some of the R groups are reduced (e.g. 4-pyridyl - to 4-piperidyl. In such a case it is preferred to protect the nitrogen of the piperidyl group).
- a compound of formula [Ha] (Scheme 3) may be prepared from the compounds [Ilia] and [IVa], as shown in the following Schemes 7 and 8.
- Enantiomerically enriched compounds of formula [I] are obtained from optically pure compounds [II] (Scheme 2), which in turn, are obtained from a racemic mixture of [II] (wherein R 7 ⁇ R 3 ) by either of the following reactions:
- the undesired enantiomer may be racemised and reused.
- Phosphorous pentoxide (1.0 g) was dissolved in methanesulfonic acid (10.0 g) at 90 °C. (3,4-Dimethoxybenzyl)(N-benzyl- 4-piperidylmethyl)malonic acid p-toluenesulfonate [XVa] (2.0 g) were added to the solution at 55°C. The mixture was stirred vigorously for 2 hours at 55-65°C and poured on crushed ice. The obtained mixture was extracted with dichloromethane. The organic layer was washed with 5 % aqueous sodium carbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
- donepezil was purified by column chromatography on silica gel (dichloromethane : methanol from 100 : 0 to 96 : 4 v/v) to give donepezil [VII]. *H NMR is in agreement with the literature.
- reaction mixture was concentrated under reduced pressure to about half volume and treated with a mixture of ice and 5 % aqueous citric acid followed by neutralization with aqueous sodium hydrogen carbonate solution.
- Phosphorous pentoxide (1.0 g) was added to methanesulfonic acid (10.0 g, 104 mmol) and the mixture was stirred at 90 °C to complete dissolution of phosphorous pentoxide.
- the mixture was cooled to 55°C and (3,4-dimethoxybenzyl)(N-benzyl-4-piperidylmethyl)malonic acid [XV] (2.0 g) was added over a period of 10 min.
- the obtained mixture was stirred vigorously for 2 hours at 55 - 65 °C.
- the reaction mixture was poured into crushed ice and extracted with dichloromethane. The organic layer was washed with aqueous sodium carbonate, dried over sodium sulfate, filtered and concentrated under reduced pressure.
- a 100 L glass reactor equipped with a mechanical stirrer, a dropping funnel, a thermometer and a bubbler was charged with veratraldehyde (1445.5 g), triethyl phosphonoacetate (1950.0 g) and dichloromethane (26.76 Kg) and filled with argon.
- the solution of titanium (IV) chloride (3300 g) in dichloromethane (6700 g) was added dropwise to the stirred mixture while keeping the temperature between - 5 °C and 0 °C.
- the mixture was stirred for an additional 1.5 hours at the same temperature.
- Triethylamine (3521 g) was added dropwise to the stirred mixture while keeping the temperature between - 5 and 0 °C.
- the obtained mixture was stirred for an additional 0.5 hour at the same temperature.
- the reaction mixture was poured under stirring into water at 20 ⁇ 25 °C.
- the organic layer was separated and aqueous layer was extracted with dichloromethane.
- the combined organic extracts were consequently washed with water, sodium hydrogencarbonate aqueous solution and again with water.
- the organic layer was dried over sodium sulfate, passed through silica gel column and the solvent was removed under reduced pressure to afford triethyl 3,4-dimethoxy- ⁇ -phosphonocinnamate [XXX] as yellow oil.
- a 20 L glass reactor equipped with a mechanical stirrer, a thermometer, a dropping funnel and a bubbler was charged with triethyl (3,4-dimethoxybenzyl)phosphonoacetate [XXIIIa] (4400 g) and 4-pyridinecarboxaldehyde (1633 g) and filled with argon.
- a solution of potassium carbonate (4900 g) in water (4900 g) was added dropwise to the mixture under stirring while keeping the temperature of the mixture at 10- 15°C. The obtained mixture was stirred overnight at 15-20°C and kept without stirring for 3 hours at the same temperature. Upper organic layer was separated and water was added to the aqueous layer. The obtained aqueous solution was extracted with dichloromethane.
- a 18 L stainless steel high pressure "Parr" reactor was charged with 10 wt. % palladium on activated carbon (60.0 g), sodium acetate (180 g), glacial acetic acid (330 g), a mixture of [XXVa] and [XXVIa] (1200 g), abs. ethanol (12 L) and filled consequently with nitrogen and hydrogen.
- the hydrogenation was carried out at hydrogen pressure of 250 psi at 90 °C. Then, the reactor was cooled to room temperature and the catalyst was filtered off. The obtained solution of [XXVIIa] was used for the next step without further purification.
- Ethyl 2-(3,4-dimethoxybenzyl)-3-(4-piperidine)propionate hydrochloride [XXVHb] was prepared from [XXVIIa] by the standard procedure.
- a 100 L glass reactor equipped with a mechanical stirrer, a thermometer and a condenser connected to a bubbler was charged with ethyl 2-(3,4-dimethoxybenzyl)-3-(N-benzyl-4-piperidine)propionate [XVIIa] (2938 g), 90 % potassium hydroxide (656.0 g), methanol (6327 g) and water (3163 g) and filled with argon.
- the mixture was refluxed under stirring for 2 hours, concentrated under reduced pressure to the volume of about 11 L and washed with toluene (2 x 2.5 L).
- An aqueous layer was acidified to pH 8 with 20 % aqueous solution of citric acid and extracted with dichloromethane.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/763,245 US6492522B1 (en) | 1998-08-17 | 1999-08-11 | Process and intermediates for production of donepezil and related compounds |
EP99936948A EP1129073A2 (en) | 1998-08-17 | 1999-08-11 | Process and intermediates for production of donepezil and related compounds |
HU0103253A HUP0103253A3 (en) | 1998-08-17 | 1999-08-11 | Novel process and intermediates for production of donepezil and related compounds |
JP2000564937A JP2002525264A (en) | 1998-08-17 | 1999-08-11 | Novel methods and intermediates for the preparation of donepezil and related compounds |
AU51910/99A AU5191099A (en) | 1998-08-17 | 1999-08-11 | Novel process and intermediates for production of donepezil and related compounds |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IL125809 | 1998-08-17 | ||
IL12580998A IL125809A (en) | 1998-08-17 | 1998-08-17 | Process and intermediates for production of donepezil and related compounds |
Publications (2)
Publication Number | Publication Date |
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WO2000009483A2 true WO2000009483A2 (en) | 2000-02-24 |
WO2000009483A3 WO2000009483A3 (en) | 2001-06-21 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IL1999/000436 WO2000009483A2 (en) | 1998-08-17 | 1999-08-11 | Process and intermediates for production of donepezil and related compounds |
Country Status (7)
Country | Link |
---|---|
US (1) | US6492522B1 (en) |
EP (1) | EP1129073A2 (en) |
JP (1) | JP2002525264A (en) |
AU (1) | AU5191099A (en) |
HU (1) | HUP0103253A3 (en) |
IL (1) | IL125809A (en) |
WO (1) | WO2000009483A2 (en) |
Cited By (21)
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WO2004016589A2 (en) * | 2002-08-14 | 2004-02-26 | Finetech Laboratories Ltd. | Process for production of highly pure donepezil hydrochloride |
JP2004131465A (en) * | 2002-07-30 | 2004-04-30 | Chemagis Ltd | Production method of donepezil |
WO2004075916A1 (en) * | 2003-02-27 | 2004-09-10 | Shirankai Kyoto University Faculty Of Medicine Alumni Association Inc. | Pharmaceutical composition for treatment of drug dependence |
WO2007077443A1 (en) * | 2006-01-04 | 2007-07-12 | Cipla Limited | Process and intermediate for preparation of donepezil |
WO2008055945A1 (en) | 2006-11-09 | 2008-05-15 | Probiodrug Ag | 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases |
WO2008065141A1 (en) | 2006-11-30 | 2008-06-05 | Probiodrug Ag | Novel inhibitors of glutaminyl cyclase |
WO2008104580A1 (en) | 2007-03-01 | 2008-09-04 | Probiodrug Ag | New use of glutaminyl cyclase inhibitors |
EP1992616A1 (en) | 2005-07-30 | 2008-11-19 | Pliva Hrvastka D.O.O. | Process for the preparation of donepezil and intermediate compounds thereof as well as hydrates of donepezil |
WO2011100373A1 (en) | 2010-02-09 | 2011-08-18 | The Johns Hopkins University | Methods and compositions for improving cognitive function |
WO2011107530A2 (en) | 2010-03-03 | 2011-09-09 | Probiodrug Ag | Novel inhibitors |
WO2011110613A1 (en) | 2010-03-10 | 2011-09-15 | Probiodrug Ag | Heterocyclic inhibitors of glutaminyl cyclase (qc, ec 2.3.2.5) |
WO2011131748A2 (en) | 2010-04-21 | 2011-10-27 | Probiodrug Ag | Novel inhibitors |
US8247563B2 (en) | 2006-12-11 | 2012-08-21 | Reviva Pharmaceuticals, Inc. | Compositions, synthesis, and methods of using indanone based cholinesterase inhibitors |
WO2012123563A1 (en) | 2011-03-16 | 2012-09-20 | Probiodrug Ag | Benz imidazole derivatives as inhibitors of glutaminyl cyclase |
WO2014005421A1 (en) | 2012-07-03 | 2014-01-09 | 浙江海正药业股份有限公司 | Benzodioxole derivative and preparation method and use thereof |
WO2014144801A1 (en) | 2013-03-15 | 2014-09-18 | Agenebio Inc. | Methods and compositions for improving cognitive function |
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US10154988B2 (en) | 2012-11-14 | 2018-12-18 | The Johns Hopkins University | Methods and compositions for treating schizophrenia |
US10159648B2 (en) | 2015-05-22 | 2018-12-25 | Agenebio, Inc. | Extended release pharmaceutical compositions of levetiracetam |
EP3461819A1 (en) | 2017-09-29 | 2019-04-03 | Probiodrug AG | Inhibitors of glutaminyl cyclase |
US10806717B2 (en) | 2013-03-15 | 2020-10-20 | The Johns Hopkins University | Methods and compositions for improving cognitive function |
Families Citing this family (8)
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US20040192919A1 (en) * | 2002-08-14 | 2004-09-30 | Finetech Laboratories, Ltd. | Process for production of highly pure donepezil hydrochloride |
AU2003247158A1 (en) * | 2003-07-01 | 2005-01-21 | Hetero Drugs Limited | Preparation of intermediates for acetyl cholinesterase inhibitors |
JP2007519733A (en) * | 2004-01-26 | 2007-07-19 | コーテックス ファーマシューティカルズ インコーポレーティッド | A method to enhance the stimulation of synaptic response induced by ampakine by cholinesterase inhibitors |
US20060122226A1 (en) * | 2004-12-08 | 2006-06-08 | Itai Adin | Crystalline forms of Donepezil base |
CN100436416C (en) * | 2005-07-29 | 2008-11-26 | 西南合成制药股份有限公司 | Novel donepezil synthesis process |
HU227474B1 (en) * | 2005-12-20 | 2011-07-28 | Richter Gedeon Nyrt | Process for industrial scale production of high purity donepezil hydrochloride polymorph i. |
US20100113793A1 (en) * | 2006-03-20 | 2010-05-06 | Ind-Swift Laboratories Limited | Process for the Preparation of Highly Pure Donepezil |
WO2011151359A1 (en) | 2010-06-02 | 2011-12-08 | Noscira, S.A. | Combined treatment with a cholinesterase inhibitor and a thiadiazolidinedione derivative |
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JP2893893B2 (en) * | 1990-02-02 | 1999-05-24 | 三菱化学株式会社 | Method for producing cyclic ketones |
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1998
- 1998-08-17 IL IL12580998A patent/IL125809A/en not_active IP Right Cessation
-
1999
- 1999-08-11 EP EP99936948A patent/EP1129073A2/en not_active Withdrawn
- 1999-08-11 US US09/763,245 patent/US6492522B1/en not_active Expired - Fee Related
- 1999-08-11 JP JP2000564937A patent/JP2002525264A/en active Pending
- 1999-08-11 WO PCT/IL1999/000436 patent/WO2000009483A2/en not_active Application Discontinuation
- 1999-08-11 AU AU51910/99A patent/AU5191099A/en not_active Abandoned
- 1999-08-11 HU HU0103253A patent/HUP0103253A3/en unknown
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Cited By (29)
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JP2004131465A (en) * | 2002-07-30 | 2004-04-30 | Chemagis Ltd | Production method of donepezil |
WO2004016589A3 (en) * | 2002-08-14 | 2004-06-10 | Finetech Lab Ltd | Process for production of highly pure donepezil hydrochloride |
WO2004016589A2 (en) * | 2002-08-14 | 2004-02-26 | Finetech Laboratories Ltd. | Process for production of highly pure donepezil hydrochloride |
WO2004075916A1 (en) * | 2003-02-27 | 2004-09-10 | Shirankai Kyoto University Faculty Of Medicine Alumni Association Inc. | Pharmaceutical composition for treatment of drug dependence |
EP1992616A1 (en) | 2005-07-30 | 2008-11-19 | Pliva Hrvastka D.O.O. | Process for the preparation of donepezil and intermediate compounds thereof as well as hydrates of donepezil |
US8030491B2 (en) | 2006-01-04 | 2011-10-04 | Cipla Limited | Process and intermediate for preparation of donepezil |
WO2007077443A1 (en) * | 2006-01-04 | 2007-07-12 | Cipla Limited | Process and intermediate for preparation of donepezil |
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EP1129073A2 (en) | 2001-09-05 |
JP2002525264A (en) | 2002-08-13 |
US6492522B1 (en) | 2002-12-10 |
AU5191099A (en) | 2000-03-06 |
IL125809A0 (en) | 1999-04-11 |
IL125809A (en) | 2005-08-31 |
WO2000009483A3 (en) | 2001-06-21 |
HUP0103253A3 (en) | 2002-02-28 |
HUP0103253A2 (en) | 2002-01-28 |
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