Nintedanib Esylate
[CAS# 656247-18-6]

Identification

• Classification: Organic raw materials >> Amino compound >> Sulfonic acid amino compound
• Name: Nintedanib Esylate
• Synonyms: (3Z)-2,3-Dihydro-3-[[[4-[methyl[2-(4-methyl-1-piperazinyl)acetyl]amino]phenyl]amino]phenylmethylene]-2-oxo-1H-indole-6-carboxylic acid methyl ester ethanesulfonate
• Molecular Formula: C₃₁H₃₃N₅O₄.C₂H₆O₃S
• Molecular Weight: 649.76
• CAS Registry Number: 656247-18-6
• EC Number: 620-104-5
• SMILES: CCS(=O)(=O)O.COC(=O)c1ccc2c(c1)NC(=O)/C2=C(Nc1ccc(N(C)C(=O)CN2CCN(C)CC2)cc1)c1ccccc1

Properties

• Solubility: DMSO > 47 mg/mL (Expl.)

Safety Data

• Hazard Symbols: GHS08 Danger
• Risk Statements: H360-H372-H373
• Safety Statements: P203-P260-P264-P270-P280-P318-P319-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Reproductive toxicity	Repr.	1B	H360
Specific target organ toxicity - repeated exposure	STOT RE	2	H373
Chronic hazardous to the aquatic environment	Aquatic Chronic	2	H411
Specific target organ toxicity - repeated exposure	STOT RE	1	H372

Discovery and Applications

Nintedanib esylate is the esylate salt form of nintedanib, a small-molecule tyrosine kinase inhibitor used primarily in the treatment of idiopathic pulmonary fibrosis (IPF) and certain cancers, including non-small cell lung cancer (NSCLC). The esylate form enhances the stability, solubility, and bioavailability of nintedanib, making it suitable for pharmaceutical formulation and oral administration. Chemically, nintedanib esylate consists of the nintedanib cation paired with a 2-hydroxyethylsulfonate (esylate) anion, which helps improve its physicochemical properties compared to the free base.

The development of nintedanib esylate followed the initial discovery of nintedanib, which was designed to inhibit multiple receptor tyrosine kinases (RTKs) involved in angiogenesis and fibrosis. These include vascular endothelial growth factor receptors (VEGFR 1–3), platelet-derived growth factor receptors (PDGFR α and β), and fibroblast growth factor receptors (FGFR 1–3). By targeting these signaling pathways, nintedanib esylate can reduce fibroblast proliferation and extracellular matrix deposition in fibrotic tissues, and inhibit tumor angiogenesis in cancer. The esylate salt form was developed to optimize the oral pharmacokinetics and facilitate clinical use while maintaining the pharmacodynamic profile of the parent compound.

Pharmacologically, nintedanib esylate exhibits the same multitargeted kinase inhibition as nintedanib. In idiopathic pulmonary fibrosis, it slows the progression of lung fibrosis by limiting fibroblast activation and extracellular matrix accumulation. In oncology applications, the inhibition of VEGFR-mediated signaling reduces tumor vascularization and growth. The compound is metabolized primarily through esterases and cytochrome P450 enzymes, particularly CYP3A4, and is excreted via feces and urine. Its formulation as the esylate salt enhances oral absorption, making it suitable for twice-daily dosing in clinical practice.

Clinically, nintedanib esylate is used in the management of IPF and systemic sclerosis-associated interstitial lung disease, where it significantly slows the decline in forced vital capacity. It is also incorporated into combination regimens for certain cancers to target angiogenesis-driven tumor progression. The esylate form allows for consistent dosing and improved handling in pharmaceutical preparations. Common adverse effects include gastrointestinal disturbances and elevated liver enzymes, which are generally manageable with monitoring and supportive care.

The synthesis of nintedanib esylate involves first producing nintedanib through a sequence of condensation, acylation, and cyclization reactions to build the bisindolinone scaffold. Subsequently, the esylate salt is formed by reacting nintedanib with 2-hydroxyethanesulfonic acid under controlled conditions, yielding a crystalline salt with enhanced solubility and stability. The crystalline form ensures uniformity in dosage and facilitates incorporation into oral capsules or tablets.

Nintedanib esylate represents an important advancement in the development of kinase inhibitors, demonstrating how salt formation can optimize the pharmacokinetic and pharmaceutical properties of a bioactive compound. Its applications in fibrotic lung diseases and oncology illustrate the potential of multitargeted inhibitors to address complex pathological processes, while ongoing research continues to explore additional therapeutic indications and combination therapies.