Loratadine
Description
Loratadine is a second-generation, long-acting antihistamine with selective peripheral histamine H₁-receptor antagonism . It is widely used for allergic conditions such as allergic rhinitis and chronic urticaria due to its rapid onset (1–3 hours) and non-sedating properties at therapeutic doses (10 mg/day) . Unlike first-generation antihistamines, this compound minimally crosses the blood-brain barrier, reducing central nervous system side effects like sedation . Its metabolic pathway involves cytochrome P450 enzymes (CYP3A4 and CYP2D6), producing the active metabolite desthis compound, which contributes to its prolonged duration of action (up to 24 hours) .
Properties
IUPAC Name |
ethyl 4-(13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-ylidene)piperidine-1-carboxylate |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C22H23ClN2O2/c1-2-27-22(26)25-12-9-15(10-13-25)20-19-8-7-18(23)14-17(19)6-5-16-4-3-11-24-21(16)20/h3-4,7-8,11,14H,2,5-6,9-10,12-13H2,1H3 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
JCCNYMKQOSZNPW-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CCOC(=O)N1CCC(=C2C3=C(CCC4=C2N=CC=C4)C=C(C=C3)Cl)CC1 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C22H23ClN2O2 |
Source
|
| Record name | loratadine | |
| Source | Wikipedia | |
| URL | https://en.wikipedia.org/wiki/Loratadine | |
| Description | Chemical information link to Wikipedia. | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID2023224 |
Source
|
| Record name | Loratadine | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID2023224 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
382.9 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Physical Description |
Solid |
Source
|
| Record name | Loratadine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0005000 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Solubility |
<1 mg/ml at 25°C |
Source
|
| Record name | Loratadine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00455 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
Color/Form |
Crystals from acetonitrile | |
CAS No. |
79794-75-5 |
Source
|
| Record name | Loratadine | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=79794-75-5 | |
| Description | CAS Common Chemistry is an open community resource for accessing chemical information. Nearly 500,000 chemical substances from CAS REGISTRY cover areas of community interest, including common and frequently regulated chemicals, and those relevant to high school and undergraduate chemistry classes. This chemical information, curated by our expert scientists, is provided in alignment with our mission as a division of the American Chemical Society. | |
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| Record name | Loratadine [USAN:USP:INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0079794755 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
| Record name | Loratadine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00455 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | loratadine | |
| Source | DTP/NCI | |
| URL | https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=758628 | |
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| Record name | loratadine | |
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| Description | The NCI Development Therapeutics Program (DTP) provides services and resources to the academic and private-sector research communities worldwide to facilitate the discovery and development of new cancer therapeutic agents. | |
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| Record name | Loratadine | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID2023224 | |
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| Record name | ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine-1-carboxylate | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.216.235 | |
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| Record name | 1-Piperidinecarboxylic acid, 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-, ethyl ester | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.120.122 | |
| Description | The European Chemicals Agency (ECHA) is an agency of the European Union which is the driving force among regulatory authorities in implementing the EU's groundbreaking chemicals legislation for the benefit of human health and the environment as well as for innovation and competitiveness. | |
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| Record name | LORATADINE | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/7AJO3BO7QN | |
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| Record name | LORATADINE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/3578 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Loratadine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0005000 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Melting Point |
134-136 °C, 134 - 136 °C |
Source
|
| Record name | Loratadine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00455 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | LORATADINE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/3578 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Loratadine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0005000 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Preparation Methods
Historical Overview of Loratadine Synthesis Routes
Route 1: Ritter Reaction-Based Synthesis
The foundational method, documented in Proceedings of Guangdong Institute of Medicine (2005) and patents IN2008MU00804/WO2006116157, begins with 2-cyano-3-methylpyridine undergoing a Ritter reaction with tert-butanol and sulfuric acid to form an intermediate. Subsequent condensation with m-chlorobenzyl chloride, deprotection with phosphorus oxychloride (POCl₃), and Grignard reaction with 4-chloro-N-methylpiperidine yield key precursors. Cyclization using trifluoromethanesulfonic acid and final ethyl chloroformate substitution complete the synthesis. While this route achieves ~65% overall yield, its reliance on strong acids (e.g., HF, trifluoromethanesulfonic acid) raises safety and cost concerns.
Route 2: Ketone Intermediate Pathway
U.S. Pat. No. 4,550,233 utilizes 8-chloro-5,6-dihydro-11H-benzocyclohepta[1,2-b]pyridin-11-one as the starting material. Grignard reaction with methylmagnesium bromide forms a tertiary alcohol, which undergoes dehydration and ethyl chloroformate coupling. Although this method avoids Ritter reaction complexities, the high cost of the ketone precursor and low cyclization efficiency (~50%) limit its industrial feasibility.
Route 3: Wittig Reaction Approach
ES2080700 introduces a Wittig reaction between 2-cyano-3-methylpyridine derivatives and organophosphorus reagents. While innovative, this route requires toxic phosphides and multistep hydrolysis/reduction, culminating in a meager 42% yield. Environmental hazards from phosphorus waste further diminish its practicality.
Route 4: McMurry Coupling Strategy
WO9838166/US6093827 employs McMurry coupling of 8-chloro-5,6-dihydro-11H-benzocyclohepta[1,2-b]pyridin-11-one with N-ethoxycarbonylpiperidin-4-one. Despite avoiding Grignard reagents, the use of high-valent titanium catalysts complicates product purification, necessitating silica gel chromatography and reducing yields to ≤55%.
Modern Innovations in this compound Synthesis
Optimized Ritter Reaction and Cyclization System
The CN112341433A patent revolutionizes this compound synthesis by redesigning the cyclization step. Key improvements include:
- Catalyst System : Substituting trifluoromethanesulfonic acid with boric acid–sulfuric acid (1:8–10 molar ratio), reducing corrosion risks and catalyst cost by 70%.
- Deprotection Optimization : Using POCl₃ at 110°C streamlines tert-butyl group removal, achieving 98% conversion vs. 85% in prior methods.
- Grignard Reaction Efficiency : Controlled addition of 4-chloro-N-methylpiperidine at 75°C enhances intermediate V yield to 83.3% (Example 4).
Table 1: Comparative Analysis of Cyclization Catalysts
| Catalyst | Yield (%) | Cost (USD/kg) | Toxicity Profile |
|---|---|---|---|
| Trifluoromethanesulfonic Acid | 62 | 450 | High |
| Boric Acid–H₂SO₄ | 78 | 25 | Low |
| Titanium(IV) Chloride | 55 | 300 | Moderate |
Stepwise Breakdown of the Novel Method
Ritter Reaction and Intermediate II Formation
2-Cyano-3-methylpyridine reacts with tert-butanol (1:25–30 molar ratio) at 70–75°C in concentrated H₂SO₄. Post-reaction alkalization (pH 9–10) precipitates Intermediate II with 95% purity.
m-Chlorobenzyl Chloride Condensation
Intermediate II undergoes lithiation with n-butyllithium at −10°C, followed by m-chlorobenzyl chloride addition. Quenching with water extracts Intermediate III at 89% yield.
Deprotection and Grignard Reaction
POCl₃-mediated deprotection at 110°C liberates the amine group (Intermediate IV), which reacts with 4-chloro-N-methylpiperidine-derived Grignard reagent. Acidic workup (pH <2) and recrystallization yield Intermediate V (83.3%).
Environmental and Economic Implications
Waste Reduction and Solvent Recovery
The CN112341433A method recovers 90% of THF and chlorobenzene via reduced-pressure distillation, cutting solvent costs by 40% compared to prior routes.
Catalytic System Sustainability
Boric acid’s low ecotoxicity (LD₅₀ > 2,000 mg/kg) and H₂SO₄’s recyclability align with green chemistry principles, reducing hazardous waste by 65%.
Chemical Reactions Analysis
Types of Reactions: Loratadine undergoes various chemical reactions, including oxidation, reduction, and substitution. For instance, oxidation is likely to occur in the piperidine and cycloheptane rings .
Common Reagents and Conditions: Common reagents used in these reactions include hydrogen peroxide for oxidation and sodium borohydride for reduction. The conditions typically involve controlled temperatures and pH levels to ensure the desired reaction outcomes.
Major Products Formed: The major products formed from these reactions include desthis compound, which is an active metabolite of this compound and retains antihistaminic properties .
Scientific Research Applications
Clinical Applications
Loratadine is primarily indicated for:
- Allergic Rhinitis : It alleviates symptoms such as sneezing, runny nose, and itchy eyes.
- Urticaria : It reduces wheal formation and itching associated with hives.
- Other Allergic Conditions : It may be used for various dermatological allergies.
Allergic Rhinitis
A double-blind placebo-controlled study demonstrated that this compound significantly relieved nasal symptoms compared to placebo within three days of treatment. In this study involving 69 patients allergic to grass pollen, this compound showed a rapid onset of action and was well-tolerated without significant side effects.
Combination Therapy
Recent meta-analysis results indicate that combining this compound with montelukast can significantly enhance the reduction of total nasal symptom scores compared to either agent alone or placebo. This combination therapy is particularly beneficial for patients with moderate to severe allergic rhinitis.
Safety Profile
This compound has a favorable safety profile, especially in pediatric and geriatric populations. It is generally well-tolerated, with minimal side effects compared to first-generation antihistamines. However, caution is advised in elderly patients or those on higher doses due to potential cardiotoxicity risks.
Data Table: Summary of Clinical Studies on this compound
Mechanism of Action
Loratadine acts as a selective inverse agonist for peripheral histamine H1-receptors. When histamine is released during an allergic reaction, it binds to these receptors, causing symptoms such as itching and sneezing. This compound blocks this binding, effectively halting the allergic response . It has minimal effects on the central nervous system, reducing the risk of sedation .
Comparison with Similar Compounds
Efficacy in Allergic Rhinitis
Table 1: Comparative Efficacy of Antihistamines in Allergic Rhinitis
- Key Findings: this compound and fexofenadine show comparable efficacy, but levocetirizine demonstrates superior symptom reduction in meta-analyses .
Table 2: Adverse Event (AE) Comparison
- Key Findings :
Pharmacological Properties
Table 3: Pharmacokinetic and Structural Comparison
- Key Findings: this compound’s lack of H-bond donors reduces solubility compared to trichlormethiazide-like compounds . Structural studies reveal this compound’s docked pose in histamine H₁-receptor (H1R) differs from cetirizine, influencing receptor selectivity .
Biological Activity
Anti-Inflammatory Effects
Recent research has highlighted this compound's potential as an anti-inflammatory agent. A study demonstrated that this compound effectively suppresses inflammation by targeting the TAK1 signaling pathway, which subsequently inhibits the activation of the AP-1 transcription factor. This inhibition leads to a significant reduction in pro-inflammatory gene expression, including matrix metalloproteinases (MMP1, MMP3, MMP9) and cytokines (IL-6, TNF-α) in macrophage cell lines and in vivo models .
Table 1: Summary of Anti-Inflammatory Effects
Inhibition of Bacterial Virulence
This compound has also been shown to inhibit the virulence of Staphylococcus aureus, a significant pathogen responsible for various infections. In vitro studies indicated that concentrations as low as 25 μM could effectively reduce biofilm formation and virulence factor production without impacting bacterial growth. Notably, this compound reduced the expression of several virulence-related genes in clinical isolates .
Table 2: Effects on Staphylococcus aureus
| Concentration | Effect on Biofilm Formation | Impact on Virulence Factors |
|---|---|---|
| 25 μM | Inhibition observed | Reduced hemolysin and pigmentation; downregulation of agrA, splB genes |
| 50 μM | Significant inhibition | Further reduction in mRNA levels of virulence genes |
Clinical Applications
This compound's biological activity extends to various clinical applications beyond allergy treatment. A randomized controlled trial showed that this compound significantly alleviated pegfilgrastim-induced bone pain in cancer patients, suggesting its utility in managing pain associated with chemotherapy . Additionally, a meta-analysis indicated that combining this compound with montelukast significantly improved nasal symptom scores in allergic rhinitis patients compared to either drug alone .
Case Study: this compound for Bone Pain Management
In a study involving 213 cancer patients undergoing pegfilgrastim treatment:
Q & A
Basic Research Questions
Q. How can researchers design a validated HPLC method for simultaneous quantification of Loratadine and pseudoephedrine in combination formulations?
- Methodological Answer : Utilize a cation-exchange column and apply experimental design optimization (e.g., factorial design) to balance resolution, retention time, and sensitivity. Validate the method by assessing accuracy (bias < 2.0%), repeatability, intermediate precision (%RSD < 2.0%), and system suitability parameters (e.g., tailing factor, theoretical plates) . Include robustness testing under varying mobile phase compositions and flow rates.
Q. What statistical approaches are essential for analyzing pharmacokinetic data from this compound bioavailability studies?
- Methodological Answer : Apply a two-way ANOVA to evaluate carryover effects and inter-product variability. Use natural log (Ln) transformation for plasma concentration data to stabilize variance. Calculate 90% confidence intervals (80–125%) for AUC0-t, AUC0-inf, and Cmax to establish bioequivalence. Ensure compliance with regulatory guidelines for parametric analysis of Ln-transformed metrics .
Q. How can researchers ensure reproducibility in quantifying this compound and its metabolite desthis compound in plasma?
- Methodological Answer : Employ LC-MS/MS with MRM transitions (e.g., 383.0 → 337.0 for this compound). Validate the method using matrix-matched calibration curves and quality controls. Address matrix effects via post-column infusion studies and internal standardization. Include stability tests for freeze-thaw cycles and long-term storage .
Advanced Research Questions
Q. What experimental strategies resolve contradictions in this compound’s metabolic pathway contributions across CYP enzymes?
- Methodological Answer : Conduct in vitro inhibition and correlation studies using human liver microsomes to quantify CYP3A4, CYP2D6, and CYP2C19 contributions. Apply siRNA knockdown of specific CYP isoforms (e.g., NRF2 in chondrocytes) to isolate metabolic pathways. Pair clinical pharmacokinetic data with genotyping (e.g., CYP2D6 polymorphisms) to explain inter-subject variability .
Q. How can researchers validate this compound’s anticancer mechanisms observed in retrospective cohort studies?
- Methodological Answer : Use RNA-seq to identify apoptosis- and pyroptosis-related genes modulated by this compound in lung cancer cell lines (e.g., A549). Validate findings with in vivo xenograft models, measuring tumor volume and caspase-3 activation. Cross-reference clinical survival data with histamine receptor expression levels in tumor biopsies .
Q. What methodologies address the environmental impact of this compound in freshwater ecosystems?
- Methodological Answer : Perform ecotoxicological assays (e.g., Daphnia magna acute toxicity tests) to determine EC50 values. Model environmental fate using hydrophobicity (log Kow = 5.20) and photolysis susceptibility. Prioritize analysis of WWTP sludge samples via SPE-LC-MS/MS to quantify sorption behavior .
Q. How can response surface methodology optimize this compound’s buccoadhesive wafer formulation?
- Methodological Answer : Apply a 3<sup>2</sup> factorial design to evaluate sodium alginate and lactose monohydrate effects on bioadhesive force and drug release. Use Design-Expert software to generate contour plots and desirability functions. Validate optimized formulations via DSC, FTIR, and in vivo retention studies .
Q. Data Analysis & Contradiction Resolution
Q. How should researchers reconcile discrepancies in this compound’s anti-inflammatory effects across different cell models?
- Methodological Answer : Standardize experimental conditions (e.g., AGEs concentration in SW1353 chondrocytes vs. macrophage models). Use multiplex ELISA to quantify NLRP3 inflammasome components (e.g., IL-1β, caspase-1) and Western blotting for NOX4 expression. Perform meta-analysis of RNA-seq datasets to identify context-dependent signaling pathways .
Q. What statistical frameworks address variability in this compound’s steady-state plasma concentrations?
Q. Experimental Design & Validation
Q. How to design a study evaluating this compound’s drug-drug interactions with CYP3A4 inhibitors (e.g., omeprazole)?
- Methodological Answer : Conduct a crossover pharmacokinetic study in beagles, comparing this compound exposure with/without omeprazole co-administration. Use LC-MS/MS for plasma quantification and non-compartmental analysis for AUC comparisons. Include in vitro CYP3A4 inhibition assays to confirm mechanistic overlap .
Retrosynthesis Analysis
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Strategy Settings
| Precursor scoring | Relevance Heuristic |
|---|---|
| Min. plausibility | 0.01 |
| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
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Please be aware that all articles and product information presented on BenchChem are intended solely for informational purposes. The products available for purchase on BenchChem are specifically designed for in-vitro studies, which are conducted outside of living organisms. In-vitro studies, derived from the Latin term "in glass," involve experiments performed in controlled laboratory settings using cells or tissues. It is important to note that these products are not categorized as medicines or drugs, and they have not received approval from the FDA for the prevention, treatment, or cure of any medical condition, ailment, or disease. We must emphasize that any form of bodily introduction of these products into humans or animals is strictly prohibited by law. It is essential to adhere to these guidelines to ensure compliance with legal and ethical standards in research and experimentation.
