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Carbromal
Carbromal
Carbromal
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Carbromal
Skeletal formula of carbromal
Skeletal formula of carbromal
Names
IUPAC name
2-Bromo-N-carbamoyl-2-ethylbutanamide
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.000.952 Edit this at Wikidata
EC Number
  • 201-046-6
KEGG
MeSH carbromal
UNII
  • InChI=1S/C7H13BrN2O2/c1-3-7(8,4-2)5(11)10-6(9)12/h3-4H2,1-2H3,(H3,9,10,11,12) checkY
    Key: OPNPQXLQERQBBV-UHFFFAOYSA-N checkY
  • CCC(Br)(CC)C(=O)NC(N)=O
Properties
C7H13BrN2O2
Molar mass 237.097 g·mol−1
Appearance White crystals
Odor Odorless
Density 1.544 g/cm3
Melting point 119 °C (246 °F; 392 K)
Soluble
Solubility soluble in chloroform, ether, acetone, benzene
log P 1.623
Acidity (pKa) 10.69
Basicity (pKb) 3.31
Structure
rhombic
Pharmacology
N05CM04 (WHO)
Related compounds
Related ureas
 Bromisoval
Related compounds
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Carbromal is a hypnotic/sedative originally synthesized in 1909 by Bayer and subsequently marketed as Adalin.[1][2] The drug was later sold by Parke-Davis in combination with pentobarbital, under the name Carbrital.[3] As of 2015, it was still used in Hungary in combination with aminophenazone under the name Demalgon.

Synthesis

[edit]
Carbromal synthesis:[2][4][5] Literature:[6][7]

Diethylmalonic acid [510-20-3] (1) is decarboxylated to 2-ethylvaleric acid [20225-24-5] (2). The Hell-Volhard-Zelinsky reaction converts this to 2-Bromo-2-Ethylbutyryl Bromide [26074-53-3] (3). Reaction with urea with affords carbromal (4).

See also

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Carbromal

View on Grokipedia
from Grokipedia
Carbromal is a synthetic nonbarbiturate sedative- agent with the C₇H₁₃BrN₂O₂ and the IUPAC name 2-bromo-2-ethylbutanoylurea, developed as a brominated derivative of the hypnotic diethylacetylurea. Originally synthesized in 1909 by researchers at , including contributions from Joseph von Mering and , it was patented in 1910 (German Patent 225710) and introduced to the market as Adalin for its calming and sleep-inducing properties. As a , carbromal was historically prescribed for short-term relief of , anxiety, and as a mild , particularly in elderly patients, with typical therapeutic doses producing serum levels of approximately 30 µmol/L. Its pharmacological activity is mediated in part by active metabolites, including bromoethylbutyramide ( potency relative to carbromal: 66%) and ethylbutyrylurea (33%), which enhance CNS depression, while inorganic accumulation from contributes to prolonged effects and potential toxicity. In , its intraperitoneal LD₅₀ in rats is 1.8 mmol/kg, comparable to phenobarbitone. Due to risks of —manifesting as neurological symptoms from buildup during extended use—along with the availability of safer alternatives like benzodiazepines, carbromal's therapeutic application has significantly diminished since the mid-20th century. It is not under international control but requires prescription in select countries, including , , , and , where it persists in limited formulations with minimal reported abuse. In many regions, including the , it holds experimental status without approved indications.

Medical Uses and Effects

Therapeutic Applications

Carbromal is a short-acting and drug from the ureide class, primarily employed for short-term management of and anxiety relief. It functions as a , offering a non-barbiturate alternative with milder effects compared to barbiturates, which contributed to its historical preference in certain patient populations. The primary indications for carbromal include the treatment of and mild anxiety disorders, particularly in short-term scenarios where rapid onset of is desired without the risks associated with stronger agents. It was often prescribed to elderly patients due to its relatively benign profile as a non-barbiturate , minimizing concerns over respiratory depression or dependency seen with barbiturates. In clinical practice, the typical oral dosing regimen consists of 250-500 mg administered at , with a maximum daily intake not exceeding 1 g to avoid accumulation and potential . Carbromal is classified under the Anatomical Therapeutic Chemical (ATC) code N05CM04 within the hypnotics and sedatives category. Historically, carbromal was incorporated into combination products to enhance its effects or provide multifaceted relief. Notable formulations include Carbrital, which pairs carbromal with for prolonged and , typically in form containing approximately 48 mg carbromal and 16 mg per teaspoonful. In , it was combined with in the product Demalgon for and applications, with each tablet containing 180 mg carbromal and 270 mg . These combinations were used to leverage carbromal's properties alongside other agents for broader therapeutic utility in the mid-20th century.

Adverse Effects and Toxicity

Carbromal, a bromine-containing , is associated with common side effects including , , weakness, and gastrointestinal disturbances such as and . These effects stem from its (CNS) depressant properties and are typically mild but can impair daily functioning. Prolonged use of carbromal poses serious risks due to accumulation, leading to , a form of chronic intoxication. Symptoms of bromism include neurological manifestations like , , and , as well as psychiatric effects such as , , and hallucinations; dermatological issues, including rashes and eruptions, are also prominent. A documented case from highlighted purpuric drug eruptions as a specific complication attributable to carbromal, presenting as hemorrhagic lesions on the . Bromism arises from slow renal excretion of , exacerbating in susceptible individuals. Rare but severe complications from carbromal include renal insufficiency and liver damage, often linked to overdose or chronic exposure. The drug has been implicated in attempts, where acute overdose can result in profound CNS depression, , apnea, and potentially fatal . In poisoning cases, symptoms are primarily driven by unchanged carbromal and its bromoethylbutyramide, with serum levels correlating to the degree of and observed. Carbromal is contraindicated in patients with renal impairment, due to impaired bromide clearance increasing bromism risk, and in those with known bromide sensitivity or hypersensitivity to carbamic acid derivatives. It should also be avoided in individuals with severe or when combined with other CNS depressants, as this heightens the potential for excessive . Drug interactions with carbromal significantly amplify CNS depression; concurrent use with alcohol, barbiturates, or other sedatives like benzodiazepines can lead to additive effects, including severe drowsiness, respiratory depression, and impaired psychomotor skills. For instance, combining carbromal with indalpine or increases the severity of adverse CNS outcomes. Overdose management for carbromal involves supportive care, including airway protection and ventilation to address respiratory depression. Bromide levels should be monitored, with serum concentrations above 50 mg/dL confirming ; is recommended for severe cases to enhance elimination of ions, while hemoperfusion effectively removes the parent compound and organic metabolites. In documented suicidal overdoses, a combination of these interventions has been crucial for recovery.

Pharmacology

Pharmacodynamics

Carbromal functions as a central nervous system (CNS) depressant, exerting sedative and hypnotic effects similar to those of barbiturates. Structurally related to bromisoval as a brominated acylurea derivative, carbromal shares functional similarities in producing hypnotic effects, though with distinct metabolic patterns that influence its toxicity profile. As a short-acting hypnotic, carbromal typically exhibits an onset of action within 30 to 60 minutes following oral administration, yielding sedation that lacks notable analgesic activity. Chronic administration of carbromal stimulates hepatic microsomal enzymes, a process that mirrors effects and may contribute to the development of tolerance over time.

Pharmacokinetics

Carbromal is rapidly absorbed from the after , achieving peak plasma concentrations of the parent compound within approximately 0.5 to 1 hour in healthy volunteers following a 1 g dose. Doses exceeding 20 mg/kg result in delayed absorption due to retardation of gastric emptying, as demonstrated in rat studies where stomach absorption was 5-8 times lower than in the . The drug distributes widely throughout the body, with even concentrations in serum, , and , and higher levels in ; it readily crosses the blood-brain barrier to mediate its effects. The bromine moiety accumulates in tissues with chronic use, contributing to prolonged exposure. Carbromal is extensively metabolized in the liver to primary metabolites including bromoethylbutyramide and ethylbutyrylurea, with only trace amounts of the unchanged drug appearing in urine or feces. These metabolic processes involve , and repeated dosing leads to induction, accelerating clearance over time. Elimination of the parent compound and its metabolites occurs primarily via renal excretion, with a of 3-7 hours in serum and tissues based on animal data; however, the ion exhibits a much longer of 12-14 days in humans, allowing for significant accumulation upon repeated administration. Pharmacokinetic parameters are altered in vulnerable populations, with slower clearance observed in elderly patients due to reduced renal function and frequent prescribing of carbromal as a , heightening the risk of accumulation; similarly, individuals with renal impairment experience prolonged elimination, exacerbating potential.

Chemistry

Chemical Properties

Carbromal has the molecular formula C7H13BrN2O2 and a of 237.09 g/mol. Its systematic name is 2-bromo-N-carbamoyl-2-ethylbutanamide, classifying it as an N-acylurea derivative rather than a traditional ester. This features a brominated alpha-carbon in the ethylbutyryl chain attached to a moiety, distinguishing it from barbiturates, which are based on the cyclic scaffold. Physically, carbromal appears as a white, odorless crystalline powder with a of 1.544 g/cm3. It has a of 119 °C. The compound exhibits low solubility in (approximately 1 g dissolves in 3000 mL), rendering it sparingly soluble, while it is more soluble in organic solvents such as alcohol (1 g in 18 mL), (1 g in 3 mL), and (1 g in 14 mL). Carbromal is chemically stable under normal storage conditions, including and pressure, though it may be sensitive to prolonged exposure to air and light. As an N-acyl, it can undergo in the presence of strong acids or bases, leading to decomposition, consistent with the reactivity of similar urea derivatives.

Synthesis

Carbromal was originally synthesized in through a multi-step process beginning with the of diethylmalonic acid, which yields 2-ethylbutanoic acid upon heating. This then undergoes the Hell-Volhard-Zelinsky (HVZ) reaction, involving treatment with and , to introduce a bromine atom at the alpha position, forming 2-bromo-2-ethylbutyryl bromide as the key intermediate. The final step entails the reaction of this alpha-bromo acyl bromide with at approximately 50°C, resulting in the formation of the acylurea structure of carbromal. The synthesis was detailed in German patent DRP 225710, filed on September 17, 1910, by , which described the preparation method and claimed the compound for its properties. Due to regulatory restrictions and the obsolescence of carbromal as a pharmaceutical agent, it is no longer produced commercially; however, laboratory-scale syntheses continue to employ the original HVZ-based route with minor adaptations for safety and yield optimization.

History and Society

Development and Introduction

Carbromal was first synthesized in 1909 by chemists at in as a non-barbiturate sedative-hypnotic, designed to offer a safer alternative to barbiturates for inducing and relieving anxiety without the risk of dependency associated with the latter class of drugs. Bayer quickly commercialized the compound, introducing it to the German market under the brand name Adalin shortly after its synthesis, where it was marketed as a mild valued for its and minimal side effects compared to earlier sedatives like bromides or . The drug entered the market in the through 's distribution efforts, with samples of Adalin documented in pharmaceutical collections by , reflecting early availability for clinical use. By the , had taken over marketing in the U.S., promoting carbromal for short-term treatment of amid rising public health concerns over and overdose risks. It was frequently formulated in combination with as Carbrital to potentiate effects while aiming to reduce the dosage of the more addictive component.

Regulatory Status and Decline

Carbromal reached peak usage in the mid-20th century, particularly in and the , where it was widely prescribed as a non-barbiturate and for and anxiety until the . Its popularity stemmed from its perceived milder effects compared to barbiturates, leading to routine use both alone and in combination formulations like Carbrital (with ). The drug's decline accelerated in the and 1970s due to growing reports of from its inorganic , which accumulates with chronic use and causes neurological symptoms such as confusion, , and , alongside risks of acute overdose leading to respiratory depression. These safety concerns, compounded by the introduction of safer alternatives like benzodiazepines (e.g., chlordiazepoxide in 1960 and in 1963), prompted regulatory restrictions and market withdrawals in many countries; for instance, it was moved to prescription-only status in response to high intoxication rates, and formulations were discontinued amid broader scrutiny of -containing sedatives. In the , heightened awareness followed high-profile incidents, including the 1967 accidental overdose death of from Carbrital, contributing to restrictions and eventual withdrawals of bromoureides like carbromal in the 1970s and later. By the 1970s, carbromal had been withdrawn from most major markets, including the , where the FDA cited safety issues related to and lack of data under modern standards, leading to no active approvals. Globally, it is now discontinued, with only limited historical use noted in as the combination product Demalgon (with ) in studies up to 2011; as of 2025, it is absent from major pharmacopeias and registries due to obsolescence and unresolved risks. Carbromal's regulatory history heightened early medical awareness of cumulative toxicity in medications, particularly the dangers of bromide accumulation, influencing stricter oversight of similar agents and paving the way for non-bromide alternatives. Due to its obsolescence and low abuse potential post-withdrawal, it is no longer classified as a in most jurisdictions, including under the .

References

  1. https://pharmacy.hebmu.edu.cn/trywhx/resources/43/2019521163354.pdf
  2. https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/carbromal
  3. https://pubmed.ncbi.nlm.nih.gov/28110/
  4. https://ecddrepository.org/en/carbromal
  5. https://go.drugbank.com/drugs/DB13817
  6. https://git-readonly.openmodelica.org/Documentation/Pharmacolibrary.Drugs.ATC.N.N05CM04.html
  7. https://drugcentral.org/drugcard/504
  8. https://ntp.niehs.nih.gov/sites/default/files/ntp/htdocs/lt_rpts/tr173.pdf
  9. https://atcddd.fhi.no/atc_ddd_index/?code=N05CM04
  10. https://aihp.omeka.net/items/show/282
  11. https://pillintrip.com/medicine/demalgon
  12. https://onlinelibrary.wiley.com/doi/10.1111/j.1741-4520.2011.00319.x
  13. https://synapse.patsnap.com/article/what-is-carbromal-used-for
  14. https://pubmed.ncbi.nlm.nih.gov/6145280/
  15. https://pubmed.ncbi.nlm.nih.gov/13230580/
  16. https://www.sciencedirect.com/topics/medicine-and-dentistry/carbromal
  17. https://pubmed.ncbi.nlm.nih.gov/2865375/
  18. https://www.bmj.com/content/2/5602/409
  19. https://www.drugs.com/drug-interactions/acetylcarbromal-with-bellamine-s-95-0-330-8737.html
  20. https://pubmed.ncbi.nlm.nih.gov/33323/
  21. https://pubmed.ncbi.nlm.nih.gov/31153/
  22. https://academic.oup.com/jpp/article/21/5/287/6202318
  23. https://pubmed.ncbi.nlm.nih.gov/9922/
  24. https://pubmed.ncbi.nlm.nih.gov/20868/
  25. https://gulflink.health.mil/library/randrep/pb_paper/mr1018.2.chap10.html
  26. https://webbook.nist.gov/cgi/cbook.cgi?ID=C77656
  27. https://pubchem.ncbi.nlm.nih.gov/compound/6488
  28. https://www.chemeo.com/cid/10-051-3/Carbromal
  29. https://www.benchchem.com/product/b1668436
  30. https://static.cymitquimica.com/products/86/pdf/sds-MM1686.00.pdf
  31. https://pubs.acs.org/doi/10.1021/jm501371s
  32. https://pmc.ncbi.nlm.nih.gov/articles/PMC6046508/
  33. https://americanhistory.si.edu/collections/object/nmah_715045
  34. https://pubchem.ncbi.nlm.nih.gov/compound/Hoggar
  35. https://www.researchgate.net/publication/26717493_Case_files_of_the_medical_toxicology_fellowship_at_the_New_York_City_Poison_Control_Bromism_Forgotten_but_not_gone
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