Donepezil
カタログ番号:
B133215
CAS番号:
142057-79-2
分子量:
379.5 g/mol
InChIキー:
ADEBPBSSDYVVLD-UHFFFAOYSA-N
注意:
研究専用です。人間または獣医用ではありません。
概要
説明
Donepezil is a medication primarily used to treat dementia associated with Alzheimer’s disease. It is a centrally acting reversible acetylcholinesterase inhibitor, which means it works by inhibiting the enzyme acetylcholinesterase, thereby increasing the concentration of acetylcholine in the brain. This increase in acetylcholine helps improve cognitive function and memory in patients with Alzheimer’s disease .
準備方法
Synthetic Routes and Reaction Conditions: The synthesis of donepezil typically involves the aldol condensation of benzylpiperidine-carboxyaldehyde with dimethoxyindanone, utilizing the Wittig reaction. This is followed by a subsequent dehydration step and catalytic reduction of the exocyclic double bond, yielding the desired product .
Industrial Production Methods: Industrial production of this compound involves similar synthetic routes but on a larger scale. The process is optimized for efficiency, cost-effectiveness, and scalability. Eco-friendly strategies are also being explored to reduce the environmental impact of the production process .
化学反応の分析
反応の種類： ドネペジルは、酸化、還元、置換など、さまざまな化学反応を起こします。
一般的な試薬と条件：
酸化： ドネペジルは、酸性媒体中のクロラミンTなどの穏やかな酸化剤を使用して酸化できます。
主要な生成物： これらの反応から生成される主要な生成物には、さまざまなドネペジル類似体および誘導体があり、それらは潜在的な治療上の利点について研究されています .
4. 科学研究への応用
ドネペジルは、科学研究において幅広い用途があります。
化学： ドネペジルとその誘導体は、その化学的特性と、その有効性を高め、副作用を軽減する可能性のある修飾について研究されています.
生物学： 研究は、脳内のさまざまな酵素や受容体とのドネペジルの生物学的経路と相互作用を理解することに焦点を当てています.
科学的研究の応用
作用機序
ドネペジルは、通常アセチルコリンを分解するアセチルコリンエステラーゼを、選択的かつ可逆的に阻害します。この酵素を阻害することにより、ドネペジルは脳内のアセチルコリン濃度を高め、コリン作動性伝達を強化します。これは、認知機能と記憶を改善することにより、アルツハイマー病性認知症の症状を軽減するのに役立ちます .
類似化合物：
リバスチグミン： 認知症の治療に使用されるもう1つのアセチルコリンエステラーゼ阻害剤。ドネペジルとは異なり、ブチリルコリンエステラーゼも阻害します。
ガランタミン： ニコチン性受容体を調節するアセチルコリンエステラーゼ阻害剤。
ドネペジルの独自性： ドネペジルは、アセチルコリンエステラーゼを選択的かつ可逆的に阻害するという点でユニークであり、脳内のアセチルコリンレベルを効果的に増加させることができます。その長い半減期と血液脳関門を通過する能力は、アルツハイマー病の症状の管理におけるその有効性に貢献しています .
類似化合物との比較
Rivastigmine: Another acetylcholinesterase inhibitor used to treat dementia. Unlike donepezil, it also inhibits butyrylcholinesterase.
Galantamine: An acetylcholinesterase inhibitor that also modulates nicotinic receptors.
Uniqueness of this compound: this compound is unique in its selective and reversible inhibition of acetylcholinesterase, which makes it highly effective in increasing acetylcholine levels in the brain. Its long half-life and ability to cross the blood-brain barrier contribute to its effectiveness in managing Alzheimer’s disease symptoms .
特性
IUPAC Name |
2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C24H29NO3/c1-27-22-14-19-13-20(24(26)21(19)15-23(22)28-2)12-17-8-10-25(11-9-17)16-18-6-4-3-5-7-18/h3-7,14-15,17,20H,8-13,16H2,1-2H3 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
ADEBPBSSDYVVLD-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
COC1=C(C=C2C(=C1)CC(C2=O)CC3CCN(CC3)CC4=CC=CC=C4)OC |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C24H29NO3 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Related CAS |
120011-70-3 |
Source
|
| Record name | Donepezil [INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0120014064 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
DSSTOX Substance ID |
DTXSID8048317 |
Source
|
| Record name | Donepezil | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID8048317 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
379.5 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Physical Description |
Solid |
Source
|
| Record name | Donepezil | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0005041 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Solubility |
31mg/mL |
Source
|
| Record name | Donepezil | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00843 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
Mechanism of Action |
The commonly accepted cholinergic hypothesis proposes that a portion of the cognitive and behavioral decline associated with Alzheimer's are the result of decreased cholinergic transmission in the central nervous system. Donepezil selectively and reversibly inhibits the acetylcholinesterase enzyme, which normally breaks down acetylcholine. The main pharmacological actions of this drug are believed to occur as the result of this enzyme inhibition, enhancing cholinergic transmission, which relieves the symptoms of Alzheimer's dementia. In addition to the above, other mechanisms of action of donepezil are possible, including the opposition of glutamate-induced excitatory transmission via downregulation of NMDA receptors and the regulation of amyloid proteins, which have demonstrated significant effects on the disease process of Alzheimer's. Other possible targets for donepezil may also include the inhibition various inflammatory signaling pathways, exerting neuroprotective effects., Donepezil hydrochloride, a piperidine derivative, is a centrally active, reversible inhibitor of acetylcholinesterase. The drug is structurally unrelated to other anticholinesterase agents (eg, tacrine, physostigmine)., The precise mechanism(s) of action of donepezil in patients with dementia of the Alzheimer's type (Alzheimer's disease) has not been fully elucidated. The drug is an anticholinesterase agent that binds reversibly with and inactivates cholinesterases (eg, acetylcholinesterase), thus inhibiting hydrolysis of acetylcholine. As a result, the concentration of acetylcholine increases at cholinergic synapses. In vitro data and data in animals indicate that the anticholinesterase activity of donepezil is relatively specific for acetylcholinesterase in the brain compared with butyrylcholinesterase inhibition in peripheral tissues., A deficiency of acetylcholine caused by selective loss of cholinergic neurons in the cerebral cortex, nucleus basalis, and hippocampus is recognized as one of the early pathophysiologic features of Alzheimer's disease associated with memory loss and cognitive deficits. Because the resultant cortical deficiency of this neurotransmitter is believed to account for some of the clinical manifestations of mild to moderate dementia, enhancement of cholinergic function with an anticholinesterase agent, such as tacrine or donepezil, is one of the pharmacologic approaches to treatment. Because widespread degeneration of multiple central neuronal systems eventually occurs in patients with Alzheimer's disease, potentially beneficial effects of anticholinesterase agents theoretically would diminish as the disease process advances and fewer cholinergic neurons remain functioning., Current theories on the pathogenesis of the cognitive signs and symptoms of Alzheimer's Disease attribute some of them to a deficiency of cholinergic neurotransmission. Donepezil hydrochloride is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by acetylcholinesterase. There is no evidence that donepezil alters the course of the underlying dementing process., For more Mechanism of Action (Complete) data for Donepezil (6 total), please visit the HSDB record page. |
Source
|
| Record name | Donepezil | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00843 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | Donepezil | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7743 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
CAS No. |
120014-06-4 |
Source
|
| Record name | Donepezil | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=120014-06-4 | |
| Description | CAS Common Chemistry is an open community resource for accessing chemical information. Nearly 500,000 chemical substances from CAS REGISTRY cover areas of community interest, including common and frequently regulated chemicals, and those relevant to high school and undergraduate chemistry classes. This chemical information, curated by our expert scientists, is provided in alignment with our mission as a division of the American Chemical Society. | |
| Explanation | The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated. | |
| Record name | Donepezil [INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0120014064 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
| Record name | Donepezil | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00843 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | Donepezil | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID8048317 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | DONEPEZIL | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/8SSC91326P | |
| Description | The FDA Global Substance Registration System (GSRS) enables the efficient and accurate exchange of information on what substances are in regulated products. Instead of relying on names, which vary across regulatory domains, countries, and regions, the GSRS knowledge base makes it possible for substances to be defined by standardized, scientific descriptions. | |
| Explanation | Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required. | |
| Record name | Donepezil | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7743 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Donepezil | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0005041 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Melting Point |
223-227 |
Source
|
| Record name | Donepezil | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00843 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
Synthesis routes and methods I
Procedure details
Donepezil oxalate is dissolved in water and basified. Donepezil base thus obtained, is extracted in a suitable solvent and acidified with aqueous hydrochloric acid. The solvent is evaporated and aqueous acidic solution of Donepezil hydrochloride is lyophilized to obtain Donepezil hydrochloride amorphous form.
Name
Synthesis routes and methods II
Procedure details
Quantity
Extracted from reaction SMILES
Type
reactant
Reaction Step One
Synthesis routes and methods III
Procedure details
As it was disclosed in Example 3 and 4 of JP-A 64-79151(1989), indanone derivative was produced by reacting 5,6-dimethoxy-1-indanone with 1-benzyl-4-formylpiperidine in the presence of strong base such as lithium diisopropylamide (Example 3), followed by reduction (Example 4) for example. According to this method, yield for Donepezil through Example 3 and 4 was 50.8% (62%×82%).
Name
Synthesis routes and methods IV
Procedure details
4-[(5,6-Dimethoxy-1-indanon-2-yl)methyl]piperidine (4 g) was taken in acetone (60 ml). To which benzyl chloride (1.92 g), potassium carbonate (2.28 g) and a catalytic quantity of tetrabutylammonium iodide (TBAI) were added. The reaction mixture was heated at 60° C. and reaction was monitored on TLC. Solvent was removed by distillation after reaction completion and the residue was taken in water and extracted with ethyl acetate (100 ml). The organic extract was acidified with cone. HCl. The solvent was evaporated under vacuum to yield the salt as a residue. Yield: 5.14 g.
Quantity
4 g
Type
reactant
Reaction Step One
Synthesis routes and methods V
Procedure details
There are many processes as disclosed in the prior arts for producing donepezil of formula 1. U.S. Pat. No. 4,895,841 wherein substituted 1-indanone-2-phosphonate prepared from 2-bromo-5,6-dimethoxyindanone and triethyl phosphite, is treated with 1-benzylpiperidine-4-carboxaldehyde in the presence of a strong base, such as lithium diisopropylamide (LDA), followed by catalytic reduction using palladium on carbon in tetrahydrofuran (40 volumes) to yield donepezil with an overall yield of 50.8%. This process however suffers with few limitations i.e. it employs triphenylphosphonium methoxymethyl chloride, which is expensive and toxic and the overall yield of this process is quite low. (scheme 1).
[Compound]
Name
substituted 1-indanone-2-phosphonate
Quantity
0 (± 1) mol
Type
reactant
Reaction Step One
Name
Yield
50.8%
Retrosynthesis Analysis
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Strategy Settings
| Precursor scoring | Relevance Heuristic |
|---|---|
| Min. plausibility | 0.01 |
| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
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