(-)-1-[(4-Chlorophenyl)phenylmethyl]piperazine
[CAS# 300543-56-0]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Piperazine
• Name: (-)-1-[(4-Chlorophenyl)phenylmethyl]piperazine
• Synonyms: (R)-1-(p-Chlorobenzhydryl)piperazine
• Molecular Formula: C₁₇H₁₉ClN₂
• Molecular Weight: 286.80
• CAS Registry Number: 300543-56-0 (130018-88-1)
• EC Number: 608-439-5
• SMILES: C1CN(CCN1)[C@H](C2=CC=CC=C2)C3=CC=C(C=C3)Cl

Properties

• Density: 1.158

Safety Data

• Hazard Symbols: GHS07;GHS08;GHS09 Danger
• Risk Statements: H302-H315-H317-H319-H335-H373-H400-H413
• Safety Statements: P260-P261-P264-P264+P265-P270-P271-P272-P273-P280-P301+P317-P302+P352-P304+P340-P305+P351+P338-P319-P321-P330-P332+P317-P333+P317-P337+P317-P362+P364-P391-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	4	H302
Eye irritation	Eye Irrit.	2	H319
Skin irritation	Skin Irrit.	2	H315
Specific target organ toxicity - single exposure	STOT SE	3	H335
Acute hazardous to the aquatic environment	Aquatic Acute	1	H400
Chronic hazardous to the aquatic environment	Aquatic Chronic	4	H413
Specific target organ toxicity - repeated exposure	STOT RE	2	H373
Skin sensitization	Skin Sens.	1	H317

Discovery and Applications

(-)-1-[(4-Chlorophenyl)phenylmethyl]piperazine, commonly known as aripiprazole lauroxil, was discovered during the development of aripiprazole, a well-known antipsychotic. Researchers aimed to improve the drug's pharmacokinetic profile by creating a prodrug with better solubility, stability, and extended-release properties. Through structure-activity relationship (SAR) studies, the lauroxil ester derivative was synthesized by modifying the aripiprazole structure to include a lipophilic lauroxil group. This modification aimed to prolong the drug's release and enhance its efficacy. This discovery provided a new approach to administering aripiprazole, making it suitable for long-acting injectable formulations used in treating schizophrenia and other psychiatric disorders.

Aripiprazole lauroxil is primarily used in treating schizophrenia, a chronic mental disorder characterized by delusions, hallucinations, and cognitive impairment. Its long-acting formulation allows for once-monthly injections, improving adherence to medication schedules, which is crucial in managing symptoms and preventing relapse in patients with schizophrenia. The extended-release properties ensure stable blood levels of the active drug, reducing the need for daily oral administration and minimizing the risk of missed doses. Beyond schizophrenia, aripiprazole lauroxil is also used in managing bipolar disorder, particularly in controlling manic episodes. Its long-lasting effects help maintain mood stability and prevent mood swings, offering a consistent therapeutic approach for patients with bipolar disorder. This provides a convenient and effective option for long-term maintenance therapy.

The long-acting nature of aripiprazole lauroxil improves patient compliance by reducing the frequency of dosing. Patients who struggle with daily medication adherence benefit from the once-monthly injection, which ensures continuous therapeutic levels of the drug and reduces the burden of daily pill-taking. This is especially beneficial for individuals with cognitive impairments or difficulties adhering to complex medication regimens.Consistent medication adherence achieved through long-acting injections can significantly reduce the likelihood of hospitalizations due to acute exacerbations of symptoms. By maintaining stable drug levels, aripiprazole lauroxil helps prevent the recurrence of severe symptoms that often lead to hospitalization, ultimately improving patients' quality of life and reducing healthcare costs.

Aripiprazole lauroxil acts as a partial agonist at dopamine D2 receptors, meaning it activates the receptor but to a lesser extent than dopamine itself. This action helps balance dopamine activity in the brain, which is often dysregulated in conditions like schizophrenia and bipolar disorder. Its unique mechanism provides antipsychotic effects while minimizing side effects such as extrapyramidal symptoms (EPS) and prolactin elevation commonly associated with traditional antipsychotics. Additionally, aripiprazole lauroxil modulates serotonin receptors, including 5-HT1A agonism and 5-HT2A antagonism. This dual action contributes to its efficacy in managing mood disorders and psychotic symptoms, providing a broader spectrum of therapeutic benefits.

The development of aripiprazole lauroxil represents a significant advancement in drug delivery technology. It showcases the benefits of creating prodrugs that can be administered less frequently while maintaining therapeutic efficacy. This innovation is applicable to other medications where adherence and consistent drug levels are critical, offering a model for developing long-acting formulations for various therapeutic areas.The success of aripiprazole lauroxil opens the door for similar approaches in other psychiatric and chronic conditions. The concept of long-acting injectables can be extended to treatments for depression, anxiety, and other mental health disorders, providing patients with more convenient and effective treatment options.

References

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