Nintedanib esylate

Nintedanib esylate is a potent, oral triple angiokinase inhibitor developed by Boehringer Ingelheim that targets proangiogenic and pro-fibrotic pathways mediated by the vascular endothelial growth factor receptor, fibroblast growth factor receptor and plateletderived growth factor receptor families, as well as Src and Flt-3 kinases. It was approved for the treatment of idiopathic pulmonary fibrosis (IPF), a condition in which the lungs become progressively scarred over time, by the US FDA in October 2014 and by the EMA in January 2015. The FDA granted nintedanib esylate fast-track, priority review, orphan product, and breakthrough designations. The drug was also approved by the EMA in November 2014 for treatment of non-small cell lung cancer in combination with docetaxel after first-line chemotherapy.

Nintedanib esilate is a bright yellow powder. The octanol-water partition coefficient (log Pow) for the nintedanib esilate-free base was determined to be 3.6, demonstrating the molecule's lipophilic character. Due to the ionisable groups in nintedanib esilate, the lipophilicity profile is strongly pH-dependent. At physiological pH (pH = 7.4), the apparent partition coefficient (log D) was calculated to be 3.0. The molecule is less lipophilic in the acidic pH range (log D ≤ 1 for pH < 5). Nintedanib esilate is soluble in water. A saturated solution in water was found to have a concentration of 2.8 mg/mL and exhibited an intrinsic pH of 5.7. The solubility of nintedanib esilate is strongly pH dependent, with an increased solubility at acidic pH, particularly for pH < 3. The highest solubility of nintedanib esilate in organic solvents is observed in methanol and N-methylpyrrolidone. The best solubility in pharmaceutically relevant co-solvents is observed in propylene glycol. OFEV are soft gelatin capsules containing 100 mg or 150 mg nintedanib (as nintedanib esilate) for oral administration. Excipients: Each OFEV capsule contains medium-chain triglycerides, hard fat and lecithin.

Nintedanib Esylate is the salt form of Nintedanib, which is angiokinase inhibitor and is used in the treatment of idiopathic pulmonary fibrosis. Also inhibits the process blood vessel formation which may be used to assist in cancer therapy.

ChEBI: An organosulfonate salt obtained by combining nintedanib with one molar equivalent of ethanesulfonic acid. A kinase inhibitor used for the treatment of idiopathic pulmonary fibrosis and cancer.

The synthesis of indolinone 197 commenced with commercial 4-chloro-3-nitro-benzoic acid (194)aesterification of which preceded displacement of the chloride by dimethyl malonate (195) in the presence of base to generate nitrobenzene 196. Hydrogenation of 196 under acidic conditions furnished 6-methyoxycarbonyl- substituted oxindole 197 by decarboxylative cyclization in 87% yield. Acylation of indolinone 197 with chloroacetic anhydride in refluxing toluene and subsequent condensation with trimethyl orthobenzoate resulted in indolone 198, which was isolated in 86% yield over the two-step sequence. While these two steps could reportedly be combined into a one-pot protocol using acetic anhydride as the solvent, the stepwise procedure was found to be more amenable for large-scale synthesis due to fewer complications with undesired side products. Subjection of 198 to methanolic potassium hydroxide followed by condensation with aniline fragment 199 in refluxing methanol and then exposure to aqueous ethanesulfonic acid in methanol provided nintedanib esylate (XXIII) in 82% over the three-step sequence.
Aniline fragment 199 was prepared in three steps and 82% overall yield via initial acylation of N-methyl-4-nitroaniline 200 with chloro acetylchloride followed by displacement of the a-amidochloride with N-methylpiperazine and hydrogenative reduction of the nitro group gave the desired aniline.183,184

Nintedanib esylate (NE) is used in the treatment of idiopathic pulmonary fibrosis (IPF) and in diverse cancers, including nonsmall cell lung cancer (NSCLC). NE has a pH-dependent solubility profile with low aqueous solubility under neutral pH and increased solubility at acidic pH. The oral bioavailability of NE is 4.7% because it is a P-gp substrate and also undergoes first-pass metabolism in the liver by esterases. However, the administration of NE along with food increases the area under the curve (AUC) and maximum concentration (Cmax) when the drug is taken with food; hence, it has a positive food effect[1].

[1] Priyanshi Patel, Mitali Patel. “Enhanced oral bioavailability of nintedanib esylate with nanostructured lipid carriers by lymphatic targeting: In vitro, cell line and in vivo evaluation.” European Journal of Pharmaceutical Sciences 159 (2021): Article 105715.
[2] Veerareddy Arava, Surendrareddy Gogireddy. “An improved process for the synthesis of nintedanib esylate.” Synthetic Communications 47 10 (2017): Pages 975-981.
[3] Esylate, Nintedanib. “Nintedanib Esylate.” Definitions 10 1 (2020).
[4] Shabari Girinath Kala, Santhivardhan Chinni. “Bioavailability enhancement of vitamin E TPGS liposomes of nintedanib esylate: formulation optimization, cytotoxicity and pharmacokinetic studies.” Drug Delivery and Translational Research 12 11 (2022): 2856–2864.