Cyclazodone

Cyclazodone is a synthetic stimulant compound belonging to the 4-oxazolidinone class, chemically related to pemoline and aminorex, and known for its central nervous system effects.^[1]^[2] Developed by the American Cyanamid Company in the 1960s, it exhibits pharmacological properties as a monoaminomimetic agent, with stimulatory actions similar to those of dextroamphetamine, including enhancement of mental and physical performance.^[2]^[3] As a centrally acting dopaminergic stimulant, cyclazodone promotes increased dopaminergic and noradrenergic activity in the brain, leading to effects such as improved alertness and cognitive function, though its precise mechanism—potentially involving inhibition of monoamine reuptake—remains incompletely characterized in clinical settings.^[1]^[2] It has been studied for its ability to facilitate avoidance behaviors in animal models, mirroring amphetamine-like stimulation without widespread therapeutic approval.^[3] Despite early interest as a potential fatigue reducer or anorectic,^[4] cyclazodone is not approved by the U.S. Food and Drug Administration for medical use and has seen limited clinical application.^[1] In recent years, cyclazodone has emerged in the online research chemical market since around 2017, often marketed for forensic or laboratory analysis rather than human consumption, with analogs like N-methyl-cyclazodone also appearing as novel psychoactive substances.^[1] Its chemical formula is C₁₂H₁₂N₂O₂, and it is classified as a prohibited stimulant by the World Anti-Doping Agency due to its performance-enhancing potential.^[5]^[2] Toxicity data are sparse, but related compounds like pemoline have been associated with risks including hepatotoxicity and movement disorders, underscoring caution in its handling.^[1]

Chemistry

Chemical Structure

Cyclazodone is a synthetic compound with the molecular formula C₁₂H₁₂N₂O₂.^[4] Its IUPAC name is 2-(cyclopropylamino)-5-phenyl-1,3-oxazol-4(5H)-one.^[6] The compound belongs to the class of 4-oxazolidinone derivatives, characterized by a five-membered heterocyclic ring containing oxygen and nitrogen atoms, with a carbonyl group at the 4-position and a double bond between positions 4 and 5 in the tautomeric form.^[4] This structural motif is central to its chemical identity as a 2-amino-5-phenyl-4-oxazolinone.^[4] Cyclazodone shares significant structural similarities with pemoline, another 4-oxazolidinone derivative, particularly in the shared oxazolidinone ring system and the 5-phenyl substitution; however, cyclazodone features an N-cyclopropylamino group at the 2-position, whereas pemoline has a morpholino substituent.^[4] It also exhibits resemblance to thozalinone, which differs primarily by having a dimethylamino group at the 2-position instead of the N-cyclopropylamino moiety.^[6] Additionally, cyclazodone is structurally related to aminorex-class compounds such as 4-methylaminorex, with the key shared elements being the 5-phenyl substitution and the overall oxazoline/oxazolone framework, though cyclazodone includes the 4-carbonyl functionality and N-cyclopropyl group that distinguish it within this series.^[4] Regarding stereochemistry, cyclazodone possesses a chiral center at the 5-position of the oxazolone ring and is typically prepared and used as a racemic mixture.^[7]

Synthesis

The primary laboratory synthesis of cyclazodone (5-phenyl-2-cyclopropylamino-4-oxazolinone) follows a two-step process outlined in a key patent, involving the formation of an intermediate amide followed by cyclization. In the first step, α-chlorophenylacetyl chloride is reacted with 1-cyclopropylurea in the presence of a base to generate the amide intermediate. Specifically, α-chlorophenylacetyl chloride (33.3 g, 0.176 mol) is added to a solution of cyclopropylurea (17.6 g, 0.176 mol) and dimethylaniline (21.3 g, 0.176 mol) as the hydrogen halide acceptor in anhydrous benzene (310 mL). The mixture is stirred at ambient temperature for 1 hour, then heated under reflux on a water bath for 5 hours. This procedure yields N-cyclopropyl-N'-(α-chloro-α-phenylacetyl)urea as a white solid (55% yield, 24.7 g, melting point 134–135°C after recrystallization from benzene).^[4] The second step involves cyclization of the intermediate using sodium ethoxide. The amide (14.3 g, 0.056 mol) is dissolved in a sodium ethoxide solution (prepared by dissolving 1.5 g of sodium in 330 mL of absolute ethanol) and heated under reflux for 2 hours. Upon cooling and acidification with glacial acetic acid, the reaction mixture is concentrated, and the resulting solid is collected by filtration. This affords cyclazodone as a white crystalline product in 80% yield (11.4 g, melting point 139–140°C). Purification is achieved by recrystallization from a 1:4 (v/v) mixture of ethyl alcohol and hexane, yielding analytically pure material.^[4] An alternative synthesis route for cyclazodone, involving the chlorination of N-cyclopropyl-α-phenylacetamide followed by cyclization, has been documented in the chemical literature, though specific conditions and yields from this method are less detailed in available references.^[8]

Pharmacology

Pharmacodynamics

Cyclazodone exerts its stimulant effects primarily through activation of monoaminergic neurotransmitter systems in the central nervous system, functioning as a monoaminomimetic agent similar to dexamphetamine.^[9] It may involve the release or blockade of reuptake of monoamine neurotransmitters such as dopamine and norepinephrine.^[9] In animal models, cyclazodone exhibits stimulatory effects on continuous avoidance behavior similar to those of pemoline and D-amphetamine.^[3] Compared to amphetamines, cyclazodone provides comparable central nervous system stimulation.^[9] Its interactions are with monoaminergic systems.^[2]

Pharmacokinetics

Cyclazodone is primarily administered orally. Limited pharmacokinetic data exist due to its developmental status and lack of widespread clinical use. Metabolism is presumed hepatic, similar to its structural relative pemoline, but specific details are lacking. In research chemical contexts, reported dosage ranges include a threshold of 5 mg, common doses of 15-25 mg, and heavy doses exceeding 60 mg, though these are derived from user experiences rather than controlled trials.^[10] The pharmacology of cyclazodone remains incompletely characterized, with most data derived from 1960s animal studies and no human clinical trials available as of 2025.

Research and Potential Uses

Cognitive and Performance Enhancement

In rodent models, cyclazodone produced stimulant-like behavioral effects, including increased locomotor activity, comparable to those of amphetamine.^[9]^[3] Early patents noted its anorectic properties as a central nervous system stimulant.^[11] Regarding performance enhancement, cyclazodone's ability to boost alertness and mitigate fatigue has led to its prohibition by the World Anti-Doping Agency (WADA) in competitive sports, as these properties could confer unfair advantages to athletes. The key 1967 study by Segal et al. on rodents provided foundational evidence for these stimulant effects, influencing subsequent evaluations of its ergogenic potential.^[9]

Other Investigational Applications

Cyclazodone was initially developed as a central nervous system stimulant with potential applications in countering central fatigue, particularly in conditions resembling narcolepsy. Early pharmacological evaluations described its efficacy in enhancing wakefulness and motor performance.^[11] In terms of anxiolytic potential, patent applications have explored cyclazodone in combinations that promote reduced anxiety without sedation, suggesting utility in inducing states characterized by a peaceful mental state.^[12] Animal model studies from the 1960s demonstrated cyclazodone's stimulatory effects on locomotor activity and avoidance behavior in rats, showing potency comparable to D-amphetamine. In these experiments, cyclazodone enhanced continuous avoidance performance similarly to D-amphetamine, indicating central dopaminergic stimulation.^[3] Despite early interest, cyclazodone has not undergone modern clinical trials, and there is no robust human data supporting therapeutic applications.

Safety and Toxicity

Adverse Effects

Cyclazodone, as a sympathomimetic stimulant chemically related to pemoline, produces cardiovascular effects including increased heart rate (tachycardia) and palpitations, along with potential elevations in blood pressure. These effects are attributed to its monoaminomimetic actions on noradrenergic and dopaminergic systems.^[2] Animal studies indicate that cyclazodone induces less severe cardiovascular responses compared to amphetamines, with a safer profile for cardiotoxicity in mice.^[3] Neurological adverse effects may include anxiety and insomnia, stemming from its central stimulant properties similar to dexamphetamine. Concerns for psychological dependence exist with chronic use, consistent with patterns observed in other prohibited stimulants.^[2] Gastrointestinal side effects encompass appetite suppression, a hallmark of its anorectic-like activity, and possible nausea at higher doses.^[2] Additional acute effects may include salivation and cold extremities. Human data on cyclazodone remains sparse due to its status as a research chemical without approved medical use, suggesting a low incidence of severe acute adverse events based on available anecdotal and preclinical reports. No cases of human toxicity from cyclazodone have been reported, though its analog N-methyl-cyclazodone has been associated with severe effects including choreoathetosis.^[2]^[1]

Hepatotoxicity and Long-term Risks

Cyclazodone, as a structural analog of pemoline within the oxazolidinone class of stimulants, raises concerns for hepatotoxicity primarily inferred from the well-documented risks associated with pemoline. Pemoline therapy has been linked to elevations in liver enzymes, acute hepatitis, and severe outcomes including fulminant hepatic failure, with postmarketing surveillance reporting 12 cases of jaundice and 6 fatalities among pediatric patients between 1975 and 1989. Early 1970s clinical reports described reversible liver abnormalities in patients rechallenged with pemoline, highlighting the potential for idiosyncratic reactions that could manifest after prolonged exposure. Although no direct human cases of cyclazodone-induced hepatotoxicity have been reported, its chemical similarity suggests a comparable risk profile, particularly at higher doses or with chronic use, warranting liver function monitoring in any investigational contexts. Regarding dopaminergic neurotoxicity, cyclazodone, as a monoaminomimetic stimulant potentially involving monoamine release or reuptake inhibition, may predispose it to neuronal damage at elevated doses, akin to other stimulants in its class. High-dose administration of such agents can induce oxidative stress through the generation of reactive oxygen species, leading to mitochondrial dysfunction and potential neurodegeneration in dopamine-rich brain regions. Animal models of amphetamine-like releasers demonstrate this oxidative burden, which could theoretically extend to cyclazodone given its pharmacological overlap, though specific studies on cyclazodone are absent. Long-term risks of cyclazodone remain poorly characterized due to the absence of human longitudinal studies and has not received regulatory approval, unlike related pemoline which was withdrawn in 2005 due to safety concerns including hepatotoxicity. Preclinical data suggest a potential for tolerance development, requiring escalating doses to maintain stimulant effects, as observed with other dopamine releasers. Dependence and withdrawal symptoms, including fatigue and dysphoria, may parallel those of amphetamines, driven by neuroadaptations in reward pathways. Overall, the limited evidence underscores the need for caution in non-clinical use, with no established safety profile for extended exposure.

History and Development

Discovery and Early Research

Cyclazodone, chemically known as 2-(cyclopropylamino)-5-phenyl-2-oxazolin-4-one, was synthesized in the early 1960s by researchers at Les Laboratoires Dausse in France as part of efforts to develop novel central nervous system stimulants related to pemoline. This work aimed to explore structural analogs with enhanced stimulant activity for potential therapeutic applications. The compound emerged from synthetic chemistry focused on oxazolinone derivatives, building on prior research into pemoline-like agents for improving alertness and performance.^[11] The initial pharmacological profile of cyclazodone was detailed in a 1967 study by Segal et al., which examined its effects on rodent behavior. The research demonstrated that cyclazodone produced stimulatory effects in rats, particularly enhancing performance in continuous avoidance tasks, with actions comparable to d-amphetamine and pemoline. These findings highlighted its potential to counteract fatigue by increasing locomotor activity and behavioral responsiveness without the acute toxicity seen in higher doses of amphetamines.^[3]^[13] Pre-clinical evaluations further assessed cyclazodone for anorectic and anti-fatigue properties, showing appetite suppression and sustained performance enhancement in animal models, akin to established stimulants like pemoline. However, concerns over its safety profile, including potential hepatotoxicity similar to related compounds, and the advent of safer alternatives such as methylphenidate in the late 1960s, contributed to its limited advancement beyond early testing stages.^[9]

Patents and Commercial Interest

Cyclazodone's development in the mid-20th century was marked by several key patents filed by pharmaceutical companies interested in its potential as a central nervous system stimulant. The British patent GB 1,005,738, issued in 1965 to Les Laboratoires Dausse in Paris, France, described 5-phenyl-2-cyclopropylamino-4-oxazolinone and its non-toxic acid addition salts as a central nervous system stimulant and anorexic agent, suitable for oral administration in pharmaceutical formulations.^[11] Similarly, U.S. patent US 3,609,159, granted in 1971 and also assigned to Les Laboratoires Dausse, detailed improved synthesis methods for the compound, emphasizing its enhanced potency as a psychotonic and antifatigue agent compared to earlier oxazolinones, with low toxicity profiles in animal models (e.g., LD50 of 0.081 g/kg intraperitoneally in mice). Les Laboratoires Dausse pursued cyclazodone in the 1960s as a non-amphetamine alternative stimulant for medical applications, such as fatigue reduction and appetite suppression, amid growing interest in safer CNS agents following the success of related compounds like pemoline. The company's efforts reflected broader industry trends toward developing oxazolidinone-based stimulants with reduced abuse potential and peripheral side effects, positioning cyclazodone for potential markets in psychiatry and obesity treatment. Les Laboratoires Dausse's patents further underscored this commercial intent, proposing daily oral doses of 1-60 mg for therapeutic use.^[11] Interest in cyclazodone waned by the 1970s, with no evidence of commercialization or regulatory approval for medical use. This decline aligned with heightened scrutiny of stimulant drugs, exemplified by the market withdrawal of the related anorectic aminorex due to its association with primary pulmonary hypertension, a severe adverse effect observed in approximately 2 per 1,000 users.^[14] Emerging safety concerns, coupled with the availability of alternative stimulants like methylphenidate, likely contributed to the shift away from further development, leaving cyclazodone unmarketed despite initial promise. A later reference to cyclazodone appeared in international patent WO 2006/079999 A2, filed in 2006 by inventor Frederik H. Barth and published by the World Intellectual Property Organization. This patent proposed combinations of cyclazodone with 5-HT2A agonists and NMDA antagonists to induce novel mental states (termed "eudynoia") for therapeutic applications in conditions like Alzheimer's disease and schizophrenia, describing cyclazodone as a mild, non-addictive psychostimulant to counter sedation without neurotoxicity.^[12] This filing indicates sporadic renewed interest in its pharmacological synergies, though no subsequent commercialization ensued.

Legal and Societal Aspects

Legal Status

Cyclazodone is not a controlled substance under the United Nations 1971 Convention on Psychotropic Substances or other international treaties administered by the United Nations Office on Drugs and Crime. In the United States, cyclazodone is unscheduled at the federal level and not approved by the Food and Drug Administration for any medical use. However, its structural similarity to pemoline, a Schedule IV controlled substance, means it may be treated as an analogue under the Federal Analogue Act (21 U.S.C. § 813) if distributed or possessed with intent for human consumption.^[15]^[10] In Germany, cyclazodone is uncontrolled and not listed under the Betäubungsmittelgesetz (BtMG, Narcotics Act) or the Neue-psychoaktive-Stoffe-Gesetz (NpSG, New Psychoactive Substances Act).^[15] In Switzerland, it is similarly not controlled under the Betäubungsmittelgesetz (BtmG, Narcotics Act).^[15] Across the European Union, cyclazodone occupies a legal gray area, with no specific scheduling at the EU level, though it may be subject to monitoring as a novel psychoactive substance (NPS) by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA).^[10] Cyclazodone has been prohibited by the World Anti-Doping Agency (WADA) since 2006 as a specified stimulant under section S6 of the Prohibited List, due to its potential to enhance athletic performance, imposing restrictions on its use by athletes in competitive sports worldwide.^[9]^[16] Import and distribution controls for cyclazodone as a research chemical vary by jurisdiction, often requiring compliance with general chemical regulations rather than specific drug prohibitions.^[15]

Non-medical Use and Availability

Cyclazodone emerged as a research chemical on the online market in 2017, primarily marketed as a nootropic powder for cognitive enhancement and study aid purposes, with no prior documented history of recreational human use.^[10] It is typically sold by vendors such as Umbrella Labs in powder or liquid form, explicitly labeled for laboratory research use only and not for human consumption.^[17] Common non-medical administration involves oral doses ranging from 15-25 mg, with onset in 20-45 minutes and effects lasting 5-7 hours; higher doses above 25 mg are reported to increase risks such as elevated blood pressure.^[10] User reports describe mild stimulation, enhanced focus, and stamina, often positioning it as a legal alternative to prescription stimulants like Adderall due to its amphetamine-like effects but with reduced euphoria.^[10]^[18] In market trends, cyclazodone continues to be available as a research chemical despite regulatory warnings, with vendors emphasizing non-human use to navigate legal gray areas.^[17] A related variant, N-methyl-cyclazodone, has been noted in toxicity cases since its appearance around 2017, including a 2022 report of a 38-year-old man experiencing uncontrollable movements, palpitations, restlessness, and elevated liver enzymes after self-medicating for ADHD.^[19] Harm reduction for non-medical use highlights the untested purity of online-sourced products and the complete lack of human clinical trials, underscoring unknown long-term risks including potential hepatotoxicity similar to related compounds like pemoline.^[10]^[20] Users are advised to start with low doses and employ standard practices to mitigate adverse effects from impurities or overdose.^[10]