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Bromisoval
Bromisoval
Bromisoval
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Bromisoval
Skeletal formula of bromisoval
Skeletal formula of bromisoval
Names
IUPAC name
(RS)-2-Bromo-N-carbamoyl-3-methylbutanamide[citation needed]
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.007.115 Edit this at Wikidata
EC Number
  • 207-825-7
KEGG
MeSH Bromisovalum
UNII
  • InChI=1S/C6H11BrN2O2/c1-3(2)4(7)5(10)9-6(8)11/h3-4H,1-2H3,(H3,8,9,10,11) checkY
    Key: CMCCHHWTTBEZNM-UHFFFAOYSA-N checkY
  • CC(C)C(Br)C(=O)NC(N)=O
Properties
C6H11BrN2O2
Molar mass 223.070 g·mol−1
log P 1.057
Acidity (pKa) 10.536
Basicity (pKb) 3.461
Pharmacology
N05CM03 (WHO)
Oral
Related compounds
Related ureas
 Carbromal
Related compounds
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Bromisoval (INN), commonly known as bromovalerylurea, is a hypnotic and sedative of the bromoureide group discovered by Knoll in 1907 and patented in 1909.[1] It is marketed over the counter in Asia under various trade names (such as Brovarin[2]), usually in combination with nonsteroidal anti-inflammatory drugs.

Chronic use of bromisoval has been associated with bromine poisoning.[3][4][5][6]

Bromisoval can be prepared by bromination of isovaleric acid by the Hell-Volhard-Zelinsky reaction followed by reaction with urea.

See also

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Bromisoval

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from Grokipedia
Bromisoval, also known as bromovalerylurea, is a non-barbiturate hypnotic and sedative belonging to the bromoureide class of drugs, characterized by its chemical formula C₆H₁₁BrN₂O₂ and IUPAC name (2-bromo-3-methylbutanoyl)urea. Discovered in 1907 by Knoll and patented in 1909, it functions primarily as a central nervous system depressant with additional anti-inflammatory properties. Historically, bromisoval was developed as an alternative to barbiturates for inducing and reducing anxiety, gaining limited use in pharmaceutical preparations, particularly in and during the early to mid-20th century. Its administration typically involves oral doses of 100-200 mg for , with effects onsetting within 30-60 minutes, though it has largely been supplanted by safer modern alternatives due to risks of dependence and . Pharmacologically, bromisoval produces effects similar to barbiturates, including drowsiness, motor incoordination, and confusion, through presumed enhancement of inhibitory in the , though its exact mechanism remains incompletely elucidated. It is metabolized in the liver and excreted via and , with chronic use potentially leading to —a condition marked by neurological symptoms such as memory loss, hallucinations, and . Common side effects include , , and , while overdose can cause severe respiratory depression, cerebellar deficits, and even death, as documented in poisoning cases from the 1970s and 1980s in countries like and . As of 2024, bromisoval is rarely prescribed, holds no international scheduling under drug control conventions due to low abuse potential and limited concerns, alongside low therapeutic utility, and is available over-the-counter in some Asian countries, usually in combination with nonsteroidal anti-inflammatory drugs, though primarily for research purposes elsewhere.

Medical use

Indications

Bromisoval is primarily indicated as a agent for the short-term treatment of and other sleep initiation and maintenance disorders, where it facilitates the onset and maintenance of . This use leverages its depressant properties to induce drowsiness without significant residual effects upon awakening when administered appropriately. As a secondary indication, Bromisoval serves as a for managing anxiety disorders, restlessness, and mild agitation, providing calming effects to reduce psychological excitement. These applications are typically limited to acute situations due to the risk of tolerance and dependence with prolonged use. In certain formulations, Bromisoval is combined with non-steroidal drugs, such as in over-the-counter preparations available in some Asian markets, to offer pain relief enhanced by its properties for conditions involving discomfort and associated sleep disturbances. Historically, during the mid-20th century, Bromisoval was more widely prescribed for short-term and therapy, though its role has since been supplanted by modern agents with improved safety profiles.

Dosage and administration

Bromisoval is administered orally, typically in tablet form, and is usually taken at bedtime to induce in patients with indicated sleep disorders. The standard adult dosage ranges from 0.2 to 1 g per night. Use in elderly, debilitated patients, young adults, and children is contraindicated due to heightened risk of adverse reactions; if deemed necessary under strict medical supervision, lower doses starting at 0.1–0.5 g may be considered with close monitoring, though this is not standard practice. Bromisoval should be prescribed for short-term use only, generally 1–2 weeks, to prevent development of tolerance and dependence. Dosage adjustments are required for patients with hepatic or renal impairment: it is contraindicated in severe hepatic impairment and used with caution in renal insufficiency, potentially requiring reduced doses based on clinical response. It may be taken with or without food, but concomitant use with alcohol or other central nervous system depressants must be avoided to prevent enhanced and respiratory depression.

Adverse effects

Common side effects

Bromisoval, as a sedative-hypnotic agent, commonly produces central nervous system effects such as drowsiness and , which are the most frequently reported adverse reactions during standard therapeutic dosing. These effects often manifest as residual or mild , particularly in the morning following evening administration, reflecting the drug's prolonged CNS action akin to other bromoureides. , , and also occur regularly, contributing to impaired coordination and balance in affected individuals. Dependence and tolerance can develop with prolonged use, leading to withdrawal symptoms such as anxiety, agitation, and tremors upon discontinuation. Gastrointestinal disturbances represent another common category of side effects, including , , and stomach discomfort, which may arise shortly after . has been noted in some users, likely due to the drug's impact on tone. Additional mild effects encompass skin reactions such as or itching, as well as occasional paradoxical responses like in sensitive patients. Haematologic disorders have also been reported rarely. These side effects are generally dose-dependent, mild in nature, and resolve upon discontinuation of the , with overall incidence varying but commonly affecting a notable proportion of users under routine treatment.

Contraindications and special populations

Bromisoval is contraindicated in patients with severe hepatic impairment, , , and due to risks of neonatal intoxication, symptoms, and congenital malformations. Caution is advised in renal insufficiency and elderly or debilitated patients, as well as those with preexisting CNS depression, pulmonary insufficiency, or sleep apnoea.

Toxicity and overdose

Acute overdose of Bromisoval can lead to severe , manifesting as profound drowsiness, , , slurred speech, and respiratory depression, potentially progressing to and . In severe cases, patients may exhibit , seizures, , and pseudohyperchloremia due to interference with chloride assays. Management of acute overdose involves supportive care, including airway protection and if occurs, along with administration of activated charcoal to reduce absorption if ingestion was recent. There is no specific , and for life-threatening presentations, is recommended to rapidly remove from the bloodstream. Chronic intoxication with Bromisoval, known as , results from bromide accumulation and primarily affects the , causing neurological deficits such as , , gait disturbances, , and . Psychiatric symptoms including , hallucinations, and confusion may occur, alongside gastrointestinal issues like anorexia and , and dermatological manifestations such as rashes. Brain imaging often reveals symmetrical lesions in the , , or matter, with potential long-term sequelae like and even after treatment. Risk factors for bromism include prolonged or excessive use of Bromisoval, particularly in over-the-counter preparations, and renal impairment, which hinders bromide excretion due to its long plasma half-life of up to 12 days. Historical cases in highlight overuse of bromide-containing sedatives like Bromisoval, leading to outbreaks of chronic intoxication with neurological and psychiatric symptoms. focuses on drug cessation, aggressive hydration with chloride-rich saline to promote renal excretion, and diuretics; is employed for severe or refractory cases to accelerate clearance. Death from Bromisoval overdose is rare, though acute ingestions exceeding typical therapeutic doses by several fold can be fatal due to or complications.

Pharmacology

Pharmacodynamics

Bromisoval, also known as bromovalerylurea, exerts its primary pharmacological effects through potentiation of γ-aminobutyric acid type A (GABA_A) receptor-mediated inhibitory neurotransmission in the central nervous system (CNS). This modulation occurs by prolonging the duration of GABA_A receptor-mediated inhibitory postsynaptic currents (IPSCs) in cortical pyramidal neurons, thereby enhancing chloride ion influx and hyperpolarizing neurons to reduce their excitability. The resulting CNS depression leads to sedative and hypnotic effects, characterized by increased non-rapid eye movement (NREM) sleep duration and decreased rapid eye movement (REM) sleep at doses exceeding 125 mg/kg in rat models. Unlike benzodiazepines, bromisoval's enhancement of activity is not mediated through the classical binding site on the GABA_A receptor, as its effects on IPSCs are unaffected by the flumazenil. This distinguishes it from -class drugs while sharing functional similarities with barbiturates and other GABA_A-positive allosteric modulators in promoting inhibitory . Classified as a non-barbiturate bromoureide, bromisoval's actions focus primarily on GABA_A channels. In addition to its CNS effects, bromisoval exhibits weak properties, suppressing release and proinflammatory expression in activated macrophages and , which may contribute to therapeutic benefits in inflammatory conditions at lower doses. This action appears independent of its primary mechanism but aligns with the broader profile of bromoureides. Bromisoval undergoes metabolic that releases ions, which may further enhance inhibitory effects, though the exact mechanism remains unclear.

Pharmacokinetics

Bromisoval is administered orally and is absorbed from the gastrointestinal tract, with plasma concentrations detectable shortly after dosing in healthy volunteers. Following absorption, bromisoval is widely distributed to the central nervous system, consistent with its sedative effects, though specific volume of distribution data in humans is limited. The bromide ion released during metabolism accumulates in tissues due to its long elimination half-life. Bromisoval undergoes hepatic primarily via conjugation, a stereoselective process in which the alpha-bromo group is displaced by , releasing the and forming mercapturate conjugates; the R-enantiomer is cleared approximately 12 times faster than the S-enantiomer. This occurs mainly in the liver, similar to barbiturates, with potential partial first-pass effects contributing to enantiomer-specific handling. Excretion occurs primarily via the kidneys, with 8–26% of the dose recovered in as mercapturate conjugates (8% ± 3% for the S-enantiomer and 26% ± 4% for the R-enantiomer) and the remainder largely as ion; biliary excretion of conjugates also contributes. The ion has a of 9–12 days. Pharmacokinetic parameters are affected by renal and hepatic function, with reduced clearance in impairment leading to prolonged exposure and increased risk of accumulation; dosing adjustments are necessary in such patients to avoid extended effects.

Chemistry

Chemical properties

Bromisoval, systematically named 2-bromo-N-carbamoyl-3-methylbutanamide and commonly referred to as bromovaleryl, possesses the molecular C₆H₁₁BrN₂O₂ and a molecular weight of 223.07 g/mol. The compound is an acyl , characterized by an α-bromo isovaleryl group attached to the urea functionality. In its physical form, Bromisoval presents as a white to off-white crystalline powder or needle-like crystals, with a of 152 °C. It is slightly soluble in cold water (but freely soluble in hot water), while being readily soluble in organic solvents including , , and acetone. For stability, Bromisoval is recommended to be stored as a sealed solid at in a dry environment to prevent degradation.

Synthesis

The classical synthesis of bromisoval, also known as bromovalerylurea, involves the Hell-Volhard-Zelinsky (HVZ) bromination of isovaleric to produce 2-bromoisovaleryl bromide, followed by condensation with . This method was first described in a German filed by Knoll in 1907 and granted in 1909 (DE185962). In the initial HVZ step, isovaleric acid reacts with in the presence of phosphorus or at controlled temperatures (typically 20–60°C) to form the alpha-bromo acid bromide intermediate, with as a . The intermediate then undergoes condensation with , often in a 1:0.6 molar ratio, by heating the mixture to 70°C for several hours, liberating HBr gas. The reaction mixture is subsequently neutralized with to adjust the and facilitate product isolation. Typical yields for this range from 70–80%, with the product purified by recrystallization from solvents such as or to achieve high purity. The method, while effective, can produce hazardous byproducts like HBr and requires careful handling of compounds. Modern industrial methods improve upon the classical approach by using in the HVZ step to avoid chloro by-products that arise from alternative halogenating agents like or sulfur oxychloride. For instance, one optimized involves direct conversion of the alpha-bromo acid to the acid bromide without isolation, followed by at 60–72°C, achieving yields up to 96% for the bromination stages and overall purity exceeding 99% after and . Another variant starts from pre-formed alpha-bromo isovaleric acid, converting it to the acid chloride with at 30–50°C under DMF , then reacting with at similar temperatures, yielding 82–86% overall while minimizing waste and equipment corrosion. These adaptations emphasize milder conditions and byproduct recovery, such as absorbing HBr into for reuse.

History

Development

Bromisoval, chemically known as bromovalerylurea, was first synthesized in 1907 by the German pharmaceutical company Knoll as part of systematic research into bromoureides, a group of bromine-containing urea derivatives investigated for their potential as sedatives and hypnotics. This synthesis occurred amid the early 20th-century push to develop safer alternatives to emerging barbiturates, such as introduced in 1903, within the broader historical context of bromide-based compounds that had been used for sedation since the mid-19th century. The compound's development reflected efforts to harness bromide's calming effects while aiming to mitigate the toxicity and dependency issues associated with inorganic bromides like . A for bromisoval was granted to Knoll in 1909 (Deutsches Reichspatent No. 185962), highlighting its properties and positioning it as a non-barbiturate option for inducing and relieving anxiety. Initial testing focused on its effects, with early pharmacological studies, including those published in 1907, exploring the hypnotic activity of derivatives like bromovalerylurea. These efforts underscored the search for agents with reduced risk profiles compared to barbiturates, which were already showing signs of habit-forming potential in preliminary clinical observations. In the , clinical trials conducted in evaluated bromisoval for , confirming its efficacy in treating and nervous tension with a reportedly lower potential than barbiturates, owing to its milder . Key milestones included its market introduction in the under trade names such as Brovarin, initially in and later exported to regions like during the late . Usage peaked in the mid-20th century as a widely available over-the-counter before the rise of benzodiazepines in the shifted preferences toward newer agents with improved safety margins.

Regulation and availability

Bromisoval has faced significant regulatory scrutiny due to its potential for causing , a form of toxicity associated with chronic use, as well as risks of dependence and overdose. In the United States, it is not approved by the (FDA) for medical use and is considered an unapproved drug, with importation prohibited under federal regulations. In the , bromisoval is classified as a controlled psychotropic substance in several member states, including , , , the , , and , where it is subject to scheduling under national narcotics laws. It was voluntarily withdrawn from the market in the in January 1987 by manufacturers at the request of the Board for the Evaluation of Medicines, citing concerns over dependence potential and chronic intoxication from ion release. Despite these restrictions, as of November 2025, bromisoval remains available in limited forms in parts of . In , it is sold over-the-counter as a component of certain combinations, such as Naron Ace T and others, though its use is declining amid growing awareness of toxicity risks. In and some other Asian countries, it may be accessible through pharmacies, but therapeutic uses, prescribing information, and availability vary by jurisdiction. Where permitted, bromisoval is typically classified as a prescription-only due to its sedative-hypnotic properties and potential, though over-the-counter formulations persist in select markets. It is not scheduled under the U.S. Drug Enforcement Administration's federal controlled substances list but is designated a "dangerous drug" in certain states, such as Georgia, requiring strict oversight. Known brand names include Brovarin, Bromoval, and Isobromyl, often appearing historically in combination products with nonsteroidal anti-inflammatory drugs for pain relief and sedation. The societal impact of bromisoval has been marked by a sharp decline in use following the introduction of safer alternatives like benzodiazepines in the mid-20th century, leading to its phased withdrawal from Western markets between the 1980s and 2000s. Modern applications are rare, confined largely to niche formulations in , with occasional reports of misuse, accidental , and cases—including a 2025 incident involving AI-influenced overuse—highlighting ongoing concerns.

References

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