Huagongshe화공사 화학 정보 인쇄 보고서 · 연구 참고용
도네페질
도네페질 · 5,6-Dimethoxy-2,3-dihydro-1H-inden-1-one · Donepenil · Donezepil · 2-[(1-benzyl-4-piperidyl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one · 2-((1-Benzylpiperidin-4-yl)Methyl)-5,6-diMethoxy-2,3-dihydro-1H-inden-1-one · Donepezilo · Donepezil hydrochloride monohydrate
식별자 및 물리적 특성
| CAS No. | 120014-06-4 |
|---|---|
| 분자식 | C24H29NO3 |
| 평균 분자량 | 379.5 g/mol |
| 단동위원소 질량 | 379.21474379 g/mol |
| SMILES | COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2 |
| InChIKey | ADEBPBSSDYVVLD-UHFFFAOYSA-N |
| PubChem CID | 3152 |
| ChEMBL | CHEMBL502 |
| ChEBI | CHEBI:53289 |
| EC No. | 601-651-9 |
| DTXSID | DTXSID8048317 |
| 현지명 | 도네페질 |
화학 및 물리적 성질
| XLogP | 4.3 |
|---|---|
| 극성 표면적 | 38.8 |
| 수소 결합 공여자 수 | 0 |
| 수소 결합 수용자 수 | 4 |
| 회전 가능 결합 수 | 6 |
| 무거운 원자 수 | 28 |
| 형식 전하 | 0 |
| 복잡도 | 510 |
| 의약품 | Pharmaceuticals |
| LogP(분배 계수) | 4.11 |
| 용해도 | 31mg/mL아세톤(약간 용해됨), 클로로포름(약간 용해됨) |
| Human Drugs | Pharmaceuticals |
| Endocrine Disruptors | Potential endocrine disrupting compound |
| 녹는점 | 223-227207°C |
| Physical Description | Solid |
| Dissociation Constants | 9.088.9 |
| Collision Cross Section | 198.1 Ų [M+H]+ [CCS Type: TWMethod: Major Mix IMS/Tof Calibration Kit (Waters)]195.62 Ų [M+H]+ [CCS Type: TWMethod: calibrated with polyalanine and drug standards] |
| Other Experimental Properties | Crystals from methanol/IPEmw 415.95mp 211-212 °C (decomposes) /Donepezil hydrochloride/White crystalline powder. Freely soluble in chloroform, soluble in water and glacial acetic acid, slightly soluble in ethanol and in acetonitrile and practically insoluble in ethyl acetate and in n-hexane. /Donezepil hydopchloride/ |
| 끓는 점 | 527.9±50.0 °C(Predicted) |
| 밀도 | 1.141±0.06 g/cm3(Predicted) |
| 저장 조건 | Sealed in dry,Room Temperature |
| 물리적 상태 | 고체 |
| pKa(산도 계수) | 8.84±0.10(Predicted) |
| 색상 | 흰색에서 황백색까지 |
| 용해도 | 2.931mg/L |
| 헨리 상수 | 8.2×106 mol/(m3Pa) at 25℃, HSDB (2015) |
| 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 |
| InChIKey | ADEBPBSSDYVVLD-UHFFFAOYSA-N |
| SMILES | C1(=O)C2=C(C=C(OC)C(OC)=C2)CC1CC1CCN(CC2=CC=CC=C2)CC1 |
안전 및 규제
| GHS 분류 | DangerH300 (88.9%): Fatal if swallowed [Danger Acute toxicity, oral]P261, P264, P264+P265, P270, P271, P273, P280, P301+P316, P301+P317, P302+P352, P304+P340, P305+P351+P338, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 9 reports by companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies. |
|---|---|
| FDA 요건 | The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl donepezil hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Donepezil hydrochloride/ |
| Hazard Classes and Categories | Acute Tox. 2 (88.9%) |
| 보관 조건 | Store at 20 to 25 °C (68 to 77 °F)Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). |
| 처리 방법 | SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. |
| Treatment | If the compound has been ingested, rapid gastric lavage should be performed using 5% sodium bicarbonate. For skin contact, the skin should be washed with soap and water. If the compound has entered the eyes, they should be washed with large quantities of isotonic saline or water. In serious cases, atropine and/or pralidoxime should be administered. Anti-cholinergic drugs work to counteract the effects of excess acetylcholine and reactivate AChE. Atropine can be used as an antidote in conjunction with pralidoxime or other pyridinium oximes (such as trimedoxime or obidoxime), though the use of '-oximes' has been found to be of no benefit, or possibly harmful, in at least two meta-analyses. Atropine is a muscarinic antagonist, and thus blocks the action of acetylcholine peripherally. |
| 상호 작용 | Ketoconazole and quinidine, inhibitors of CYP450, 3A4 and 2D6, respectively, inhibit donepezil metabolism in vitro. Whether there is a clinical effect of quinidine is not known. In a 7 day crossover study in 18 healthy volunteers, ketoconazole increased mean donepezil concentrations (AUC0-24 and Cmax) by 36%. The clinical relevance of this increase in concentration is unknown.A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol.Inducers of CYP 2D6 and CYP 3A4 (eg, phenytoin, carbamazepine, dexamethasone, rifampin, and phenobarbital) could increase the rate of elimination of donepezil hydrochloride.A 75-year-old man with Alzheimer's disease, treated with the cholinesterase inhibitor donepezil for 14 months, was scheduled for left colectomy under general anesthesia. During the procedure, succinylcholine-induced relaxation was prolonged and the effect of atracurium besylate was inadequate even at higher doses than those indicated for the patient's weight. Cholinesterase blood tests performed 10 months, 1 month and 10 days before surgery had demonstrated a gradual decrease in the duration of activity of the enzyme. Such an effect, which has been described for cholinesterase inhibitors like neostigmine and donepezil, would explain the prolonged effect of succinylcholine. After ruling out other causes for resistance to atracurium, we conclude that donepezil or its metabolites acted on muscle plaque, blocking acetylcholine hydrolysis and antagonizing atracurium.For more Interactions (Complete) data for Donepezil (7 total), please visit the HSDB record page. |
| 건강 영향 | Acute exposure to cholinesterase inhibitors can cause a cholinergic crisis characterized by severe nausea/vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Accumulation of ACh at motor nerves causes overstimulation of nicotinic expression at the neuromuscular junction. When this occurs symptoms such as muscle weakness, fatigue, muscle cramps, fasciculation, and paralysis can be seen. When there is an accumulation of ACh at autonomic ganglia this causes overstimulation of nicotinic expression in the sympathetic system. Symptoms associated with this are hypertension, and hypoglycemia. Overstimulation of nicotinic acetylcholine receptors in the central nervous system, due to accumulation of ACh, results in anxiety, headache, convulsions, ataxia, depression of respiration and circulation, tremor, general weakness, and potentially coma. When there is expression of muscarinic overstimulation due to excess acetylcholine at muscarinic acetylcholine receptors symptoms of visual disturbances, tightness in chest, wheezing due to bronchoconstriction, increased bronchial secretions, increased salivation, lacrimation, sweating, peristalsis, and urination can occur. Certain reproductive effects in fertility, growth, and development for males and females have been linked specifically to organophosphate pesticide exposure. Most of the research on reproductive effects has been conducted on farmers working with pesticides and insecticdes in rural areas. In females menstrual cycle disturbances, longer pregnancies, spontaneous abortions, stillbirths, and some developmental effects in offspring have been linked to organophosphate pesticide exposure. Prenatal exposure has been linked to impaired fetal growth and development. Neurotoxic effects have also been linked to poisoning with OP pesticides causing four neurotoxic effects in humans: cholinergic syndrome, intermediate syndrome, organophosphate-induced delayed polyneuropathy (OPIDP), and chronic organophosphate-induced neuropsychiatric disorder (COPIND). These syndromes result after acute and chronic exposure to OP pesticides. |
| Hepatotoxicity | In several large clinical trials, donepezil therapy was not associated with an increased rate of serum enzyme elevations compared to placebo treatment. Furthermore, escalation of the dose from 10 to 23 mg daily was not followed by an increased rate of ALT elevations compared to patients maintained on the lower dose. Nevertheless, since its introduction into clinical use, donepezil has been implicated in several isolated case reports of clinically apparent hepatotoxicity. The time to onset was short (1 to 6 weeks) and the pattern of serum enzyme elevations was cholestatic or mixed. The course of illness can be severe with prolonged jaundice and itching (Case 1), but fatal instances have not been published. Immunoallergic and autoimmune features are not common. |
| 환경 거동 | TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 4.0X10+4(SRC), determined from a structure estimation method(2), indicates that donepezil is expected to be immobile in soil(SRC). Volatilization of donepezil from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.2X10-12 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Donepezil is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.8X10-10 mm Hg at 25 °C(SRC), determined from a fragment constant method(4). Biodegradation data were not available(SRC, 2009).AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 4.0X10+4(SRC), determined from a structure estimation method(2), indicates that donepezil is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.2X10-12 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 190(SRC), from an estimated log Kow of 4.9(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is high, provided the compound is not metabolized by the organism(SRC). Biodegradation data were not available(SRC, 2009).ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), donepezil, which has aan estimated vapor pressure of 6.8X10-10 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phasein the ambient atmosphere. Particulate-phase donepezil may be removed from the air by wet or dry deposition(SRC). Donepezil does not contain chromophores that absorb at wavelengths >290 nm(4) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC). |
| 유해 작용 | The most common adverse effects of donepezil are gastrointestinal (GI), which may include nausea, diarrhea, and vomiting. In addition, other common adverse effects such as insomnia, muscle cramps, fatigue, and anorexia are more frequently reported with higher doses of donepezil. However, these adverse effects are typically mild and transient in most patients, lasting for up to 3 weeks, and they usually resolve even with continued use of the medication. |
| 노출 경로 | Donepezil is well absorbed with a relative oral bioavailability of 100% and reaches peak plasma concentrations in 3 to 4 hours. |
| 독성 요약 | General supportive measures are crucial for a donepezil overdose, and the clinician should immediately contact the poison control center. An overdose of donepezil can trigger a cholinergic crisis, leading to severe symptoms like nausea, vomiting, excessive sweating, and salivation. Furthermore, bradycardia, hypotension, respiratory depression, collapse, and seizures are potential manifestations of an overdose.Donepezil is a cholinesterase or acetylcholinesterase (AChE) inhibitor. A cholinesterase inhibitor (or 'anticholinesterase') suppresses the action of acetylcholinesterase. Because of its essential function, chemicals that interfere with the action of acetylcholinesterase are potent neurotoxins, causing excessive salivation and eye-watering in low doses, followed by muscle spasms and ultimately death. Nerve gases and many substances used in insecticides have been shown to act by binding a serine in the active site of acetylcholine esterase, inhibiting the enzyme completely. Acetylcholine esterase breaks down the neurotransmitter acetylcholine, which is released at nerve and muscle junctions, in order to allow the muscle or organ to relax. The result of acetylcholine esterase inhibition is that acetylcholine builds up and continues to act so that any nerve impulses are continually transmitted and muscle contractions do not stop. Among the most common acetylcholinesterase inhibitors are phosphorus-based compounds, which are designed to bind to the active site of the enzyme. The structural requirements are a phosphorus atom bearing two lipophilic groups, a leaving group (such as a halide or thiocyanate), and a terminal oxygen. |
| Signs and Symptoms | Symptoms of overdose include severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. |
| Soil Adsorption/Mobility | Using a structure estimation method based on molecular connectivity indices(1), the Koc of donepezil can be estimated to be 4.0X10+4(SRC). According to a classification scheme(2), this estimated Koc value suggests that donepezil is expected to be immobile in soil. |
| Human Toxicity Excerpts | /SIGNS AND SYMPTOMS/ Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved./CASE REPORTS/ A 79-year-old woman with Alzheimer's disease was admitted due to acute cholinergic symptoms induced by overdose (45 mg) of donepezil (DPZ). Physical examination showed bradycardia, sinus arrhythmia, vomiting, and respiratory insufficiency. She was treated with atropine intravenously and her cholinergic symptoms subsided in the next evening. After 5 days she was discharged from the hospital and DPZ was withheld for about 4 wk. The plasma concentration of DPZ was 54.6 ng/mL on admission and gradually decreased to the normal limits in about 90 hr. The calculative half-life of DPZ was about 55 hr .../CASE REPORTS/ ... An 82 year old woman was seen with a two year history of memory problems. She was also hypertensive and receiving long term treatment with atenolol and doxazosin. On examination she was normotensive (140/80 mm Hg) and had moderate cognitive impairment (score in mini-mental state examination 15/30 and on the cognitive subscale of the Alzheimer's disease assessment scale 46/75). Routine haematological and biochemical tests gave normal results (platelet count 146 X 10+9/L), and a computed tomogram of the brain was normal. Probable Alzheimer's disease was diagnosed according to published criteria,2 and treatment with donepezil 5 mg daily was started. After 4 days she developed diarrhea and vomiting. On review she had a purpuric rash on her trunk and her arms and legs. Donepezil treatment was stopped, with resolution of the gastrointestinal symptoms, which were thought to be a result of gastroenteritis as another family member was affected. The rash began to fade.After discussion with the patient and her carer we cautiously restarted donepezil treatment. On review 16 days later an obvious recurrence of the purpuric rash was noted on her trunk and legs, although she had not had a recurrence of the gastrointestinal symptoms. Donepezil treatment was stopped. Successive platelet counts were 119 X 10+9/L and 157 X 10+9/L, and the rash had almost resolved when she was reviewed six weeks after rechallenge with donepezil. Donepezil was thought to be the cause of this rash because of the temporal association with treatment and its recurrence on rechallenge./CASE REPORTS/ ... A 79-year-old white nursing home patient with a history of Alzheimer disease and hypertension was inadvertently given 50 mg of donepezil instead of her usual 5-mg dose. She presented to the emergency department with nausea, vomiting, and persistent bradycardia (HR in the 40s). Routine laboratory studies were all within normal limits. Basilar rales were noted five hours after arrival. She was treated with atropine 0.2 mg as needed for bradycardia (HR <50 beats/min)a total of 3.0 mg was administered over 18 hours. Each bolus kept her HR >60 beats/min for one-half to two hours. No further vomiting or evidence of pulmonary edema occurred after her initial episodes. She returned to baseline by day 2 (HR in the 70s) and was returned to the nursing home. ...For more Human Toxicity Excerpts (Complete) data for Donepezil (9 total), please visit the HSDB record page. |
| Artificial Pollution Sources | Donepezil's production and use as a nootropic(1) (memory or cognition enhancer) may result in its release to the environment through various waste streams(SRC). |
| 수질 위해 등급(WGK) | WGK 3 |
| 운송 번호(UN) | UN 2811 |
| 관세 코드 | 29333990 |
| 위험 문구(R) | 36/37/38 |
| 위험 표시 | Xi |
| 안전 문구(S) | 26-36-36/37/39 |
| 위험 등급 | Acute Tox. 2 OralEye Irrit. 2 |
| 저장 분류 | 6.1A - Combustible acute toxic Cat. 1 and 2very toxic hazardous materials |
| 유해 물질 데이터 | 120014-06-4(Hazardous Substances Data) |
용도
개요
Donepezil is another “nonclassic,” centrally acting, reversible, noncompetitive AChEI that was approved in 1997 for treatment of mild-to-moderate AD and dementia. Its selectivity for AChE is 570- to 1,250-fold that for butyrylcholinesterase, and it also exhibits greater affinity for brain AChE than for AChE in the periphery.
용도
Acetylcholine is a neurotransmitter involved in neural signaling throughout the body. Donepezil is a reversible acetylcholinesterase inhibitor that readily crosses the blood-brain barrier to reduce the breakdown of acetylcholine. It has a half-life in circulation of about 70 hours. As acetylcholine modulates plasticity, excitability, and arousal in the central nervous system, donepezil is commonly used in the treatment of Alzheimer’s disease to improve cognition, memory, and behavior. In this way, it is intended to prevent or reverse dementia. Studies on these effects have been equivocal, indicating that more research into the therapeutic potential of donepezil is warranted.[Cayman Chemical]
일반 설명
Donepezil, (±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one (Aricept), commonly referred to in the literature asE2020, is a reversible inhibitor of AChE. It is indicated forthe treatment of symptoms of mild-to-moderate Alzheimerdisease. Donepezil is approximately 96% bound to plasmaproteins, with an elimination half-life of 70 hours. It is metabolizedprincipally by the 2D6 and 3A4 isozymes of theP450 system.