Huagongshe화공사 화학 정보 인쇄 보고서 · 연구 참고용
클로나제팜
클로나제팜 · Klonopin · Rivotril · 5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2h-4-benzodiazepin-2-one · 5-(2-Chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one · RO4023 · Sentil · Landsen
식별자 및 물리적 특성
| CAS No. | 106955-87-7 |
|---|---|
| 분자식 | C15H10ClN3O3 |
| 평균 분자량 | 315.71 g/mol |
| 단동위원소 질량 | 315.0410689 g/mol |
| SMILES | O=C1CN=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N1 |
| InChIKey | DGBIGWXXNGSACT-UHFFFAOYSA-N |
| PubChem CID | 2802 |
| ChEMBL | CHEMBL452 |
| ChEBI | CHEBI:3756 |
| EC No. | 216-596-2 |
| DTXSID | DTXSID1022845 |
| 현지명 | 클로나제팜 |
화학 및 물리적 성질
| XLogP | 2.4 |
|---|---|
| 극성 표면적 | 87.3 |
| 수소 결합 공여자 수 | 1 |
| 수소 결합 수용자 수 | 4 |
| 회전 가능 결합 수 | 1 |
| 무거운 원자 수 | 22 |
| 형식 전하 | 0 |
| 복잡도 | 491 |
| LogP(분배 계수) | 2.41log Kow = 2.412.7 |
| 냄새 | Faint odor |
| Color/Form | White crystals from ethanol-methylene chlorideOff-white to light yellow crystalline powder |
| 용해도 | 100In water, <100 mg/L at 25 °CInsoluble in benzeneslightly soluble in acetone, methanol, chloroformSolubility in mg/mL at 25 °C: acetone 31chloroform 15methanol 8.6ether 0.7benzene 0.51.06e-02 g/L물에는 거의 녹지 않으며 알코올과 메탄올에는 약간 녹습니다. |
| Decomposition | When heated to decomposition it emits very toxic fumes of /hydrogen chloride and nitrogen oxides/. |
| 녹는점 | 238-240237.5 °C236.5 - 238.5 °C236.5-238.50C |
| Physical Description | Solid |
| Stability/Shelf Life | The commercially available conventional tablets have an expiration date of 5 years following the date of manufacture.Stable under recommended storage conditions. |
| Dissociation Constants | pK1 = 1.5pK2 = 10.5 |
| Kovats Retention Index | 2803286028062833283228562878281328852857.12843.3282728142934.628532835.228632848.42879 |
| Collision Cross Section | 168.2 Ų [M+H]+ [CCS Type: TWMethod: Major Mix IMS/Tof Calibration Kit (Waters)]171 Ų [M+H]+ [CCS Type: DTMethod: single field calibrated] |
| 끓는 점 | 524.5±50.0 °C(Predicted) |
| 밀도 | 1.4592 (rough estimate) |
| 굴절률 | 1.6470 (estimate) |
| 인화점 | 11 °C |
| 저장 조건 | 2-8°C |
| 물리적 상태 | 가루 |
| pKa(산도 계수) | 1.5, 10.5(at 25℃) |
| 색상 | 연노랑 |
| 헨리 상수 | 1.4×107 mol/(m3Pa) at 25℃, HSDB (2015) |
| 주요 응용 | 의약품(소분자) |
| InChI | 1S/C15H10ClN3O3/c16-12-4-2-1-3-10(12)15-11-7-9(19(21)22)5-6-13(11)18-14(20)8-17-15/h1-7H,8H2,(H,18,20) |
| InChIKey | DGBIGWXXNGSACT-UHFFFAOYSA-N |
| SMILES | Clc1ccccc1C2=NCC(=O)Nc3ccc(cc23)N(=O)=O |
| NIST | Clonazepam(1622-61-3) |
| EPA | 2H-1,4-Benzodiazepin-2-one, 5-(2-chlorophenyl)-1,3-dihydro-7-nitro- (1622-61-3) |
화학적 성질
Tan Solid
안전 및 규제
| GHS 분류 | This chemical does not meet GHS hazard criteria for 12.5% (1 of 8) of reports.DangerH336 (50%): May cause drowsiness or dizziness [Warning Specific target organ toxicity, single exposureNarcotic effects]H360 (12.5%): May damage fertility or the unborn child [Danger Reproductive toxicity]H361 (50%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]H362 (25%): May cause harm to breast-fed children [Reproductive toxicity, effects on or via lactation]H412 (50%): Harmful to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]H413 (12.5%): May cause long lasting harmful effects to aquatic life [Hazardous to the aquatic environment, long-term hazard]P203, P260, P261, P263, P264, P270, P271, P273, P280, P304+P340, P318, P319, P403+P233, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 8 reports by companies from 8 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.Reported as not meeting GHS hazard criteria per 1 of 8 reports by companies.There are 7 notifications provided by 7 of 8 reports by companies with hazard statement code(s).Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website. |
|---|---|
| 규제 정보 | DEA schedule IV controlled substanceClonazepam: Does not have an individual approval but may be used as a component in a product covered by a group standard. It is not approved for use as a chemical in its own right. |
| 기타 안전 정보 | IMAP assessments - 2H-1,4-Benzodiazepin-2-one, 5-(2-chlorophenyl)-1,3-dihydro-7-nitro-: Environment tier I assessmentIMAP assessments - 2H-1,4-Benzodiazepin-2-one, 5-(2-chlorophenyl)-1,3-dihydro-7-nitro-: Human health tier I assessment |
| FDA 요건 | Schedule IV shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. ... Depressants. Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of the following substances, including its salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible within the specific chemical designation: Clonazepam (DEA Code Number: 2737) is included on this list.The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including clonazepam, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. |
| Special Reports | Teboul E, Chouinard GA Guide to Benzodiazepine Selection. Part II: Clinical Aspects. Can J Psychiatry 36 (1): 62-73 (1991). To suit the specific needs of various clinical situations, selection of an appropriate benzodiazepine derivative should be based on consideration of their different pharmacokinetic and pharmacodynamic properties. Benzodiazepine derivatives that are rapidly eliminated produce the most pronounced rebound and withdrawal syndromes. Benzodiazepines that are slowly absorbed and slowly eliminated are most appropriate for the anxious patient, since these derivatives produce a gradual and sustained anxiolytic effect. Rapidly absorbed and slowly eliminated benzodiazepines are usually more appropriate for patients with sleep disturbances, since the rapid absorption induces sleep and the slower elimination rate may induce less tolerance to the sedative effect. Rational selection of a benzodiazepine for the elderly and for the suspected drug abuser is more problematic. The relevant pharmacokinetic and clinical considerations for these users are discussed. Certain derivatives may possess pharmacodynamic properties not shared by the entire benzodiazepine classempirical studies have suggested the existence of anti-panic properties for alprazolam and clonazepam, antidepressant properties for alprazolam, and anti-manic properties for clonazepam and possibly lorazepam.Trimble MR, Cull CChildren of School age: The Influence of Antiepileptic Drugs on Behavior and Intellect. Epilepsia 29 (Suppl 3): S15-9 (1988). The role of antiepileptic drugs in behavior and cognitive function in children is well documented the literature. In general, behavioral problems occur most frequently with phenobarbital and clonazepam, and appear least often with valproate and carbamazepine. Cognitive impairments occur with phenytoin, are less evident with valproate, and minimal with carbamazepine. Monotherapy, as with adults, leads to improvements in both cognitive abilities and behavior. |
| Toxic Combustion Products | Special hazards arising from the substance or mixture: Carbon oxides, nitrogen oxides (NOx), hydrogen chloride gas. |
| Hazard Classes and Categories | STOT SE 3 (50%)Repr. 2 (12.5%)Repr. 2 (50%)Lact. (25%)Aquatic Chronic 3 (50%)Aquatic Chronic 4 (12.5%) |
| 소화 절차 | Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary. |
| 보관 조건 | Keep container tightly closed in a dry and well-ventilated place.Clonazepam tablets and orally disintegrating tablets should be stored in air-tight, light-resistant containers at 25 °C, but may be exposed to temperatures ranging from 15-30 °C. The commercially available conventional tablets have an expiration date of 5 years following the date of manufacture. |
| 정리 방법 | ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Sweep up and shovel. Keep in suitable, closed containers for disposal. |
| 처리 방법 | SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contaminated packaging: Dispose of as unused product. |
| Preventive Measures | ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: Do not let product enter drains.Precautions for safe handling: Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection.Appropriate engineering controls: General industrial hygiene practice.Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker. |
| Personal Protective Equipment (PPE) | Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).Skin protection: Handle with gloves.Body Protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place.Respiratory protection: Respiratory protection is not required. Where protection from nuisance levels of dusts are desired, use type N95 (US) or type P1 (EN 143) dust masks. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). |
| 체내 부담 | Cord and maternal serum levels of clonazepam at delivery were 32 and 19 ng/mL in a woman that had been treated with clonazepam throughout her pregnancy (36 weeks)(1). Clonazepam was detected at 11-13 ng/mL in breast milk from this woman(1). |
| Treatment | Treatment includes monitoring of respiration, pulse and blood pressure, general supportive measures and immediate gastric lavage. Intravenous fluids should be administered and an adequate airway maintained. Hypotension may be combated by the use of levarterenol or metaraminol. Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. (L1712) |
| 상호 작용 | Increased salivation, hypersecretion in upper respiratory passages, chest congestion, rhinorrhea, and shortness of breath may occur in patients receiving clonazepam. In one study, increased salivation, mucous obstruction of the nasopharynx and bronchi, and difficulty in swallowing occurred in infants receiving the drug. The investigator reported that these effects occurred most frequently when clonazepam was used in conjunction with phenobarbital.The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABAA sites, and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and follow patients closely for respiratory depression and sedation.Additive CNS depression may occur when clonazepam is administered concomitantly with other CNS depressants, including alcohol, opiate agonists, barbiturates, anxiolytics, sedatives and hypnotics, some antipsychotic agents, monoamine oxidase (MAO) inhibitors, tricyclic antidepressants, and other anticonvulsants. If clonazepam is used concomitantly with other CNS depressants, caution should be used to avoid excessive CNS depression. Patients also should be advised to avoid alcohol while receiving clonazepam therapy.In one study, increased serum phenytoin concentrations were reported to occur when clonazepam and phenytoin were administered concomitantly. In another study, plasma clonazepam concentrations decreased when the two drugs were administered. Although the clinical importance of these reports has not been established, it may be desirable to monitor serum concentrations of both drugs during initial concomitant therapy, making dosage adjustments as necessary.For more Interactions (Complete) data for Clonazepam (8 total), please visit the HSDB record page. |
| 건강 영향 | May cause a potentially dangerous rash that may develop into Stevens Johnson syndrome, an extremely rare but potentially fatal skin disease. |
| Hepatotoxicity | Clonazepam, as with other benzodiazepines, is rarely associated with serum ALT elevations, and clinically apparent liver injury from clonazepam is extremely rare. However, at least one convincing case report of acute liver injury from clonazepam with recurrence on reexposure has been reported. Rare instances of drug induced liver injury has been reported with other benzodiazepines, such as chlordiazepoxide, diazepam, flurazepam, triazolam, clorazepate and alprazolam. In benzodiazepine related cases of acute liver injury, the latency has ranged from a few weeks to 6 monthsthe typical pattern of liver enzyme elevations has been cholestatic or mixed, but hepatocellular patterns have also been reported. The injury is usually mild to moderate in severity and self-limited. Fever and rash have not been described nor has autoantibody formation.Likelihood score: D (possible but rare cause of clinically apparent liver injury). |
| 환경 거동 | TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 12,000(SRC), determined from a structure estimation method(2), indicates that clonazepam is expected to be immobile in soil(SRC). Volatilization of clonazepam from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 7.0X10-13 atm-cu m/mole(SRC), using a fragment constant estimation method(2). Clonazepam is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 7.3X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2017).AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 12,000(SRC), determined from a structure estimation method(2), indicates that clonazepam 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 7.0X10-13 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). Clonazepam is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(3). According to a classification scheme(4), an estimated BCF of 18(SRC), from its log Kow of 2.41(5) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low. Biodegradation data in water were not available(SRC, 2017).ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), clonazepam, which has an estimated vapor pressure of 7.3X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase clonazepam may be removed from the air by wet or dry deposition(SRC). Clonazepam contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC). |
| 유해 작용 | The adverse effects of clonazepam derive from its property to act as a central nervous system depressant like all the other BZD drugs.Common Side EffectsThe use of clonazepam is most commonly associated with lethargy, fatigue, sedation, drowsiness, and motor impairment (impaired coordination, impaired balance, dizziness).Less Common Side EffectsClonazepam can cause blurred vision, confusion, irritability, loss of libido, lack of motivation, psychomotor agitation, hallucination, worsening of depression, short-term memory loss, and anterograde amnesia, especially with high doses.Occasional Side EffectsOccasional adverse effects of clonazepam include personality changes, behavioral disturbance, ataxia, increased frequency of seizures, thrombocytopenia, and dysphoria.Rare Side EffectsRare but important side effects of clonazepam include paradoxical disinhibition, i.e., excitement, rage, and impulsive behavior. Older patients are especially prone to this side effect. Other side effects are suicide, psychosis, and incontinence. Long-term use of benzodiazepine can lead to depression and sexual dysfunction. There have been reports of Lichenoid drug eruption with the use of clonazepam. Paradoxical sleep-related eating disorder (SRED) has been described, although clonazepam is used to treat SRED.Drug-Drug Interactions* Concurrent use of benzodiazepines and opioids may result in sedation, respiratory depression, coma, and death. Avoid combination.* The use of clonazepam along with kratom may lead to increased CNS depression and death. Avoid combination.* Concurrent use of clonazepam with antidepressants, antipsychotics, hypnotics, antiepileptic drugs, and antihistamines leads to increased sedation due to pharmacodynamic synergism. Monitor the therapy.* Concurrent administration of clonazepam with CYP3A4 inducers like carbamazepine, phenobarbital, phenytoin, and primidone can reduce the concentration of clonazepam.* Concurrent administration of clonazepam with CYP3A4 inhibitors like clarithromycin, itraconazole, ketoconazole, nirmatrelvir/ritonavir, telithromycin, and voriconazole can increase the serum concentration of clonazepam. |
| 노출 경로 | Clonazepam is rapidly and completely absorbed after oral administration. The absolute bioavailability of clonazepam is about 90%. Cmax, oral administration = 1 -4 hours. |
| Milk Concentrations | Clonazepam was detected at 11-13 ng/mL in breast milk from a woman that had been treated with clonazepam throughout her pregnancy (36 weeks)(1). |
| 독성 요약 | IDENTIFICATION AND USE: Clonazepam is off-white to light yellow crystalline powder with a faint odor. It is a Schedule IV Controlled Substance. It is anticonvulsant and gamma-aminobutyric acid (GABA) modulator. A significant increase in the illegal use of clonazepam has been seen. HUMAN STUDIES: Overdosage of clonazepam may produce somnolence, confusion, ataxia, diminished reflexes, or coma. The shortcomings of clonazepam therapy include tolerance, withdrawal symptoms, and adverse effects such as drowsiness, dizziness, and confusion leading to increased risk of falls. Inter-individual variability in the incidence of adverse events in patients partly originates from the differences in clonazepam metabolism due to genetic and nongenetic factors. Because of experience with other members of the benzodiazepine class, clonazepam is assumed to be capable of causing an increased risk of congenital abnormalities when administered to a pregnant woman during the first trimester. In a study of 118 liveborn infants, there were 6 (5.1%) with major malformations, 4 of whom were prenatally exposed to clonazepam monotherapy and all of whom were full term infants. These included two with bilateral inguinal hernias requiring surgery, one with bilateral communicating hydroceles requiring surgery, one with midline pit over the nasal bridge, one with a uretero-pelvic junction obstruction requiring surgery and one with a PDA and ASD diagnosed at one day of age for which no follow-up is available. Sixty five (55.1%) of liveborn infants received a dysmorphological exam performed by an examiner who was blinded to the prenatal exposure. Although 16 (13.6%) children had 3 or more minor malformations, only one of the 16 was exposed to monotherapy. It is notable that 3 fullterm infants, all of whom were prenatally exposed to clonazepam monotherapy, had either inguinal hernias or communicating hydroceles requiring surgery. ANIMAL STUDIES: No adverse maternal or embryo-fetal effects were observedThe therapeutic range of clonazepam is from 0.02 to 0.08 mcg/mL. Any level over 0.08 mcg/mL is considered toxic. The symptoms of overdose develop rapidly.Initial PresentationThe initial symptoms appear within a few hours with symptoms of CNS depression such as:* Somnolence* Diplopia* Slurred speech* Motor impairmentSevere PresentationIf the overdose is severe, then it may result in severe symptoms such as:* Respiratory depression* Hypoxemia* Apnea* Hypotension* Bradycardia* Cardiac arrest* Pulmonary aspiration* ComaSevere consequences of clonazepam use alone are rare, but the toxicity increases significantly if other CNS depressants, such as opioids, ethanol, barbiturates, etc., are coadministered.Treatment of ToxicitySupportive care and medical observation are the mainstays of the treatment. The supportive care includes monitoring vitals, IV fluids for hypotension, atropine for bradycardia, and maintaining the patency of the airway by intubation or artificial respiration if respiratory depression develops.Allosteric interactions between central benzodiazepine receptors and gamma-aminobutyric acid (GABA) receptors potentiate the effects of GABA. As GABA is an inhibitory neurotransmitter, this results in increased inhibition of the ascending reticular activating system. Benzodiazepines, in this way, block the cortical and limbic arousal that occurs following stimulation of the reticular pathways. |
| Signs and Symptoms | Somnolence, confusion, coma, and diminished reflexes. The most commonly reported adverse event when clonazepam is used for seizure disorders is CNS depression. |
| Effluent Concentrations | Clonazepam was detected in 9% of effluent samples collected in 2010 from 90 European wastewater treatment plants at <5-43.7 ng/L (average 1.6 ng/L)(1). Based on studies, clonazepam removal is about 10.3% in wastewater treatment plants(2). |
| 수질 위해 등급(WGK) | 2 |
| RTECS 번호 | DF2100000 |
| 운송 번호(UN) | UN 1230 3/PG 2 |
| 독성 | LD50 orally in mice: >4000 mg/kg (Blum) |
| 관세 코드 | 2933910000 |
| 위험 문구(R) | 11-23/24/25-39/23/24/25 |
| 위험 표시 | F,T |
| 안전 문구(S) | 7-16-36/37-45-24/25-22 |
| 포장분류 | III |
| 위험 등급 | 6.1(b)Aquatic Chronic 3STOT SE 3 |
| 저장 분류 | 11 - Combustible Solids |
| 유해 물질 데이터 | 1622-61-3(Hazardous Substances Data) |
용도
개요
Clonazepam (Item No. 14263) is an analytical reference material categorized as a benzodiazepine. Clonazepam is regulated as a Schedule IV compound in the United States. This product is intended for research and forensic applications.
용도
Antiepileptic agent with anxiolytic and antimanic properties. Anticonvulsant. This is a controlled substance (depressant)
일반 설명
Clonazepam is useful in absence seizures and in myoclonicseizures. Tolerance to the anticonvulsant effect of the clonazepamoften developed rather quickly, and it is a commonproblem with the BZDs. Metabolism involves hydroxylationof the C-3 position, followed by glucuronidation andnitro group reduction, followed by acetylation.