Nintedanib

Structural formula
General
Non-proprietary name	Nintedanib
other names	BIBF 1120 Intedanib Methyl- (3 Z ) -3 - {[(4- {methyl [(4-methylpiperazin-1-yl) acetyl] amino} phenyl) amino] (phenyl) methylene} -2-oxo-2,3-dihydro- 1 H -indole-6-carboxylate
Molecular formula	C 31 H 33 N 5 O 4
Brief description	yellow solid
External identifiers / databases
CAS number 656247-17-5 (nintedanib, free base) 656247-18-6 (Nintedanib esilat ) EC number 809-588-0 ECHA InfoCard 100.237.441 PubChem 9809715 ChemSpider 7985471 DrugBank DB09079 Wikidata Q15149723
Drug information
Drug class	Tyrosine kinase inhibitor
properties
Molar mass	539.6 g · mol -1 (nintedanib, free base) 649.8 g · mol -1 (Nintedanibesilat)
Physical state	firmly
Melting point	253 ° C
solubility	soluble in DMSO
safety instructions
GHS labeling of hazardous substances Caution H and P phrases H: 315-319-335 P: 264-302 + 352-304 + 340-305 + 351 + 338-332 + 313-337 + 313
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Nintedanib (trade names: Vargatef , Ofev ) is a tyrosine kinase inhibitor and angiokinase inhibitor that blocks the receptors for vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF). The active ingredient inhibits the formation of new blood vessels in the supply of tumors ( tumor angiogenesis ). Nintedanib was developed by Boehringer Ingelheim and a patent was applied for in 2004.

properties

Nintedanib is effective against bronchial carcinoma and pulmonary fibrosis . The EU-wide drug approval for the treatment of advanced non-small cell lung cancer (NSCLC) in combination with docetaxel was applied for in October 2013 and for the treatment of idiopathic pulmonary fibrosis in June 2014.

The European Commission has now approved nintedanib for the treatment of interstitial lung disease in adults with systemic sclerosis (SSc-ILD). It is currently (08/2020) the only approved drug for this indication.

Furthermore, there is also approval for other chronic progressive fibrosing interstitial lung diseases (ILDs), e.g. B. Hypersensitivity pneumonitis (exogenous allergic alveolitis), autoimmune ILDs such as ILD in rheumatoid arthritis and idiopathic nonspecific interstitial pneumonia.

The ethanesulfonic acid salt of nintedanib (nintedanibesilate) is a yellow, crystalline solid with a melting point of 244 to 251 ° C , which is very poorly soluble in water and not very soluble in DMSO (25 g · l ⁻¹ ).

In the course of use in advanced non-small cell lung cancer, a dose of 200 mg nintedanib twice daily with an interval of approximately 12 hours is recommended on days 2 to 21 of a 21-day standard treatment cycle with docetaxel. The Vargatef soft capsules should be taken orally, whole, with meals and with water. The recommended maximum daily dose is 400 mg and should not be exceeded. Patients can continue nintedanib therapy after discontinuation of docetaxel as long as clinical benefit is observed or until unacceptable toxicity occurs.

When used in idiopathic pulmonary fibrosis, 150 mg Ofev capsules twice daily, whole with plenty of water, are recommended. The receipts should be made 12 hours apart and with the food.

Contraindications (contraindications)

If there is hypersensitivity to the active ingredient itself or to components of its dosage form (capsule and / or filling material), treatment should be avoided.

Drug interactions

Nintedanib causes weak inhibition of OCT-1, BCRP and P-gp, but this is of little clinical relevance. However, the plasma level of nintedanib can be used as a substrate for P-gp by simultaneous administration of strong P-gp inhibitors such as. B. ketoconazole or erythromycin , so that depending on tolerability, a dose reduction must be considered. The simultaneous administration of strong P-gp inducers such as B. rifampicin , carbamazepine , phenytoin and St. John's wort reduce the plasma concentration of nintedanib. It is advisable to carefully examine the benefits of taking it at the same time. There is no inhibition or induction of CYP enzymes by the drug or its metabolites.

Use during pregnancy and breastfeeding

Nintedanib is teratogenic, foetotoxic and permeable to milk, which is why it should not be used during pregnancy and breastfeeding. Women of childbearing potential should use consistent contraception during treatment with this drug or, in the event of pregnancy, consult their doctor to weigh the benefits of treatment with Ofev or Vargatef.

Special patient groups

• Children and adolescents (0-18 years):

Effectiveness and safety have not been proven (no data available).

• elderly patients (over 65 years):

The starting dose does not need to be reduced. The effectiveness and safety of the drug do not differ when compared with middle-aged patients.

• Kidney dysfunction:

Since only a very small part (less than 1%) of the drug is excreted via the kidneys, no dose adjustment is necessary for mild to moderate renal insufficiency. There are no clinical data available for the treatment of patients with severe renal insufficiency.

• Liver dysfunction:

Nintedanib is mainly excreted in the biliary / faeces, but no dose adjustment is necessary in patients with mild hepatic insufficiency (Child Pugh A), but close monitoring of liver function tests is recommended. Patients with moderate to severe hepatic insufficiency (Child Pugh B or C) should not be treated with the drug.

• Smoker:

Smoking reduces the plasma concentration of the drug by 21%. Patients should be advised to refrain from smoking cigarettes and the like during therapy. to renounce.

Adverse effects (side effects)

Very common ADRs:

• diarrhea
• Nausea, vomiting
• stomach pain
• Increase in liver enzymes
• increased chance of bleeding (due to VEGF inhibition)
• decreased appetite
• Weight loss
• a headache

Common ADRs:

• hypertension

Pharmacological properties

Mechanism of action (pharmacodynamics)

Nintedanib is a small molecule receptor tyrosine kinase inhibitor. The drug blocks the vascular endothelial growth factor receptors (VEGFR 1 to 3), the kinase activity of fibroblast growth factor receptors (FGFR 1 to 3) and the platelet-derived growth factor receptors (PDGFR. Receptor) α and ß. It is therefore also referred to as a triple targeted angiokinase inhibitor. Furthermore, nintedanib inhibits the non-receptor tyrosine kinases (nRTKs), lymphocyte-specific tyrosine protein kinase (Lck), Fms-like tyrosine protein kinase (Flt) 3 and proto-oncogenic tyrosine protein kinase (Src). The competitive binding of nintedanib to the adenosine triphosphate binding pocket of the above-mentioned receptors has a decisive influence on intracellular signal transmission and thus the proliferation and survival of endothelial cells and perivascular cells (pericytes and vascular smooth muscle cells).

Importance for treatment

• of advanced non-small cell lung cancer:

Nintedanib has a direct "antitumor" effect by inhibiting the blood supply to the tumor, but also prevents other escape mechanisms by simultaneously inhibiting several classes of receptors. In addition, by inhibiting tumor angiogenesis, normalization of the vascular structure is brought about and thus better accessibility of the tumor for other chemotherapeutic agents is ensured.

• of idiopathic pulmonary fibrosis:

Fibroblasts are responsible for the scarred remodeling of the lungs that is characteristic of IPF. By inhibiting the signal transduction of the growth factors VEGF, FGF and PDGF, the proliferation, migration and transformation of fibroblasts is influenced and further scarring of the lungs is reduced.

• Systemic sclerosis :

There is evidence that nintedanib slows the deterioration of lung function in systemic sclerosis.

Absorption and distribution in the body (pharmacokinetics)

• Absorption: max. Plasma concentration is reached after 2 to 4 hours (orally, soft gelatin capsules); Bioavailability 4.7% (healthy, 100mg Ofev); Absorption and bioavailability are reduced by transporter effects (substrate of P-gp) and first-pass metabolism.

When taken with a meal, the amount of nintedanib ingested is about 20% higher than when it was fasted.

• Distribution: high plasma protein binding (97.8%, mainly to albumin), preferred distribution via plasma (blood-plasma ratio 0.87). The volume of distribution is very large at 1050 liters.
• Elimination: half-life 9.5 h (IPF patients), renal unchanged excretion after 48 h 0.05% (oral) or 1.4% (iv), renal clearance 20 ml / min. The total plasma clearance after intravenous administration is very high at 1390 ml / min.
• Metabolism: 25% ester cleavage (esterases) to free acid (BIBF 1202), then glucuronidation by UGT enzymes (1A1, 1A7, 1A8, 1A10); only 5% CYP-dependent (predominantly 3A4) metabolism
• Elimination: 93.4% biliary as BIBF 1202; 0.65% renal; after 4 days, over 90% of the dose has been eliminated

toxicology

Nintedanib is teratogenic, foetotoxic and permeable to milk. The acute lethal dose in rats and mice when ingested orally is more than 2000 mg / kg. After repeated exposure for 13 weeks, 3 mg / kg body weight orally is fatal in monkeys. The Ames test on Salmonella typhimurium is negative, meaning that there is no mutagenicity.

Chemical characteristics

Stereochemistry

Nintedanib has an ( E - / Z ) isomerism between C20 and C21, with the ( Z ) isomer used in the drug. There are no stereocenters in the molecule.

Acidic and basic groups

The indole nitrogen is weakly acidic. The most basic point is found on the tertiary (methylated) nitrogen of the piperazine residue.

synthesis

The synthesis of nintedanib consists of several sub-steps:

Esterification of 3-nitrobenzoic acid (e.g. with methanol in the acid) to methyl 3-nitrobenzoate , subsequent electrophilic substitution on the aromatic by methyl chloroacetate to give methyl 4-methoxycarbonyl-methyl-3-nitrobenzoate. Reductive cyclization (intramolecular amidation) yields 6-methoxycarbonyl-2-oxindole.

The 6-methoxycarbonyl-2-oxindole reacts with chloroacetic anhydride to form the "chlorimide" (methyl 1- (chloroacetyl) -2-oxoindoline-6-carboxylate):

This reaction of 6-methoxycarbonyl-2-oxindole with chloroacetic anhydride or an appropriately activated chloroacetic acid derivative (e.g. chloroacetyl chloride) should preferably be carried out in a high-boiling and aprotic solvent, e.g. toluene , xylene or butyl acetate , at a temperature of 80 ° C to about 130 ° C respectively. It is an N -alkylation ( S _N 2 reaction ). Crystallization of the product is initiated by adding a non-polar solvent (for example cyclohexane or methylcyclohexane ) at a temperature of about 80 to 100 ° C and is completed at a temperature of about −5 ° C to room temperature. The solid is collected, washed (preferably with polar solvents such as alcohols - most preferably methanol), and dried to obtain the "chlorimide" compound.

The reaction of the “chloride imide” with trimethyl orthobenzoate yields “chlorenol” (methyl 1- (chloroacetyl) -3- [methoxy (phenyl) methylene] -2-oxoindoline-6-carboxylate). This reaction takes place in a high-boiling and aprotic solvent, such as butyl acetate, N , N- dimethylformamide , xylene or, preferably, toluene, at temperatures from about 100 to about 140.degree . The reaction is mediated by "methanol scavengers" such as acetic anhydride.

The orthoester hydrolyzes to the diacylcarbenium ion, an electrophile, and methanol. An electrophilic substitution takes place on the indole in position 3, whereby an acetal is formed. This is then hydrolyzed. The crystallization of the product can be regarded as complete when it reaches room temperature to about −10 ° C. The solid is collected and washed, preferably with solvents such as toluene, xylene and / or ethyl acetate . After drying, you get the “Chlorenol” compound.

The "chlorenol" reacts with bases, so that the "enolindole" (methyl 3- [methoxy (phenyl) methylene] -2-oxoindoline-6-carboxylate) is obtained:

The base-catalyzed dechloroacetylation of methyl 1- (chloroacetyl) -3- [methoxy (phenyl) methylene] -2-oxoindoline-6-carboxylate is carried out in protic solvents such as alcohols (isopropanol or preferably methanol) at temperatures from about 70 ° C. to room temperature carried out. Inorganic bases such as alkali metal hydroxides or organic bases such as sodium methoxide are used as the catalyst. The crystallization is understood to be complete at room temperature to about −10 ° C. The solid is collected and washed, preferably with alcohols, most preferably methanol. After drying, the “enolindole” is obtained.

The reaction of N -methyl-4-nitroaniline with chloroacetic anhydride provides the "chloroacetyl" ( N - (4-nitroaniline) - N -methyl-2-chloro-acetamide):

The chloroacetylation of N- methyl-4-nitroaniline takes place in aprotic solvents, such as toluene, or esters, preferably ethyl acetate, at temperatures not lower than 60.degree. Activated derivatives of chloroacetic acid such as chloroacetic acid chloride, or preferably chloroacetic acid anhydride, can be used as alkylating agents. Crystallization is initiated by adding non-polar solvents, preferably cyclohexane or methylcyclohexane, at temperatures from about 60 ° C to about 80 ° C and completed at room temperature to about −10 ° C. The solid is collected and washed, preferably with non-polar solvents such as methylcyclohexane. After drying, the “chloroacetyl” compound is obtained.

By reacting the “chloroacetyl” with 1-methylpiperazine, the “nitroaniline” ( N - (4-nitrophenyl) - N -methyl-2- (4-methylpiperazin-1-yl) acetamide) is obtained and the “aniline” is obtained through subsequent hydrogenation "( N - (4-aminophenyl) - N -methyl-2- (4-methylpiperazin-1-yl) acetamide):

The initial reaction of N - (4-nitroanilino) - N -methyl-2-chloroacetamide with 1-methylpiperazine takes place in aprotic solvents such as esters (e.g. butyl acetate), ketones (e.g. methyl isobutyl ketone ) or aromatic solvents , preferably toluene, at temperatures from about 30 ° C to about 60 ° C. The organic salts are then removed by extraction with water or diluted with aqueous solutions of inorganic salts, for example common salt solution. The remaining reaction mixture is diluted with an alcohol, preferably isopropanol, and hydrogenated at temperatures from about 20 ° C. to about 90 ° C., at hydrogen pressures from about 1 bar to 10 bar, using heterogeneous hydrogenation catalysts such as palladium on charcoal. After the catalyst has been removed, the majority of the solvents are distilled off at reduced pressure and at temperatures from about 40.degree. C. to about 80.degree. The residue is dissolved in toluene or in a mixture of toluene and an ester, preferably ethyl acetate, at about 70 to 90 ° C and then crystallized out by lowering the temperature to about 10 ° C to −10 ° C. The crystals are separated and washed with a non-polar solvent, preferably toluene, and dried to obtain the “aniline” compound.

The reaction of the “aniline” with the “enolindole” produces the “anilino” compound (3-Z- [1- (4- ( N - ((4-methyl-piperazin-1-yl) -methylcarbonyl) - N - methyl-amino) anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone). This reaction is stereospecific with respect to the Z and E isomers and yields the Z isoform:

The reaction of methyl 3- [methoxy (phenyl) methylene] -2-oxoindoline-6-carboxylate and N - (4-aminophenyl) - N -methyl-2- (4-methylpiperazin-1-yl) acetamide is protic Solvents such as alcohols, for example ethanol or preferably methanol, or aromatic solvents such as toluene, or in mixtures of these solvents with strongly polar solvents such as N , N -dimethylacetamide or, preferably, N , N -dimethylformamide, at a temperature of not less than 50 ° C carried out under reflux conditions. When the conversion is complete (approx. 8 h), crystallization is initiated at a temperature of at least ambient temperature. The solid is collected and then washed with a protic solvent such as ethanol or, preferably, methanol, or with aromatic solvents such as toluene. After drying, the “anilino” compound, called nintedanib, is isolated in the form of yellow crystals.

Analytics

Instrument-based analytics

• ¹ H-NMR (500 MHz, DMSO -d ⁶ , ppm)

δ: 11.00 (s, 1H, 23-H); 12.23 (s, 19-H); 7.61 (t, J = 7.1 Hz, 1H, 33-H); 7.57 (t, J = 7.5Hz, 2H, 32-H + 34-H); 7.50 (d, J = 7.7 Hz, 2H, 31-H + 35-H); 7.43 (d, J = 1.6 Hz, 1H, 29-H); 7.20 (dd, J = 8.3; 1.6 Hz, 1H, 27-H); 7.13 (d, J = 8.3 Hz, 2H, 14-H + 18-H); 6.89 (d, 8.3 Hz, 2H, 15-H + 17-H); 5.84 (d, J = 8.3 Hz, 1H, 26-H); 3.77 (s, 3H, 40-H3); 3.06 (m, 3H, 12-H3); 2.70 (m, 2H, 8-H2); 2.19 (m, 8H, 2-H2, 3-H2, 5-H2, 6-H2); 2.11 (s, 3H, 7-H3)

• ¹³ C-NMR (126 MHz, DMSO-d ⁶ )

δ: 54.5 (C-2 + C-6); 52.2 (C-3 + C-5); 45.6 (C-7); 59.1 (C-8); 168.5 (C-9); 36.6 (C-12); 140.1 (C-13); 127.6 (C-14 + C-18); 123.8 (C-17 + C-15); 137.0 (C-16); 158.3 (C-20); 97.5 (C-21); 170.1 (C-22); 136.2 (C-24); 128.9 (C-25); 117.2 (C-26); 121.4 (C-27); 124.0 (C-28); 109.4 (C-29); 131.9 (C-30); 128.4 (C-31 + C-35); 129.4 (C-32 + C-34); 130.4 (C-33); 166.3 (C-37); 51.7 (C-40)

• IR

1610 cm ⁻¹ (indolinone), 1655 cm ⁻¹ (amide), 1711 cm ⁻¹ (ester)

• MS ( ESI-MS )

Molecular peak at m / z = 540 [M + H] ⁺

Organic reactivity analysis

The drug nintedanib can be identified wet-chemically by various detection reactions, e.g. B. by hydroxamic acid reaction with hydroxylamine and iron (III) chloride reagent for the detection of the carboxylic acid ester or by the detection of tertiary amines by adding citric acid and acetaldehyde, so that a red-blue dye is formed, the structure of which has not yet been fully clarified.

literature

• Package insert "Ofev - 150mg capsules" Boehringer Ingelheim Prescribing Information about Ofev .
• European Commission “Health and Consumers”: Summary of Product Characteristics Vargatef . , Appendix 1 to the implementation decision of the European Commission "Health and Consumers" on the granting of an authorization for the human medicinal product "Vargatef - Nintedanib" according to Regulation (EC) No. 726/2004 of the European Parliament and of the Council of November 21, 2014.

Individual evidence

1. ↑ ^{a b} BIBF1120 (Vargatef, Nintedanib) - VEGFR / PDGFR / FGFR inhibitor , accessed December 27, 2019.
2. ↑ Patent application EP1473043 A1 Pharmaceutical combination for the treatment of diseases involving cell proliferation, migration or apotosis of myeloma cells, or angiogenesis. Registered on April 29, 2003, published on November 3, 2004, applicant: Boehringer Ingelheim Pharma GmbH & Co. KG, inventor: Dr. Martin Stefanic, Dr. Gerd Munzert, Dr. Frank Hilberg
3. ↑ ^{a b} fluorochem: Safety Data Sheet , accessed December 27, 2019.
4. ↑ Boehringer-Ingelheim Annual Report 2006, p. 132 ( Memento of the original dated November 22, 2012 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. (PDF; 7.4 MB). 
5. ^ F. Hilberg, GJ Roth, M. Krssak, S. Kautschitsch, W. Sommergruber, U. Tontsch-Grunt, P. Garin-Chesa, G. Bader, A. Zoephel, J. Quant, A. Heckel, WJ Rettig : BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy . In: Cancer Res . 68, No. 12, 2008, pp. 4774-4782. doi : 10.1158 / 0008-5472.CAN-07-6307 . PMID 18559524 .
6. ↑ Patent application EP1473043 A1 Pharmaceutical combination for the treatment of diseases involving cell proliferation, migration or apotosis of myeloma cells, or angiogenesis. Registered on April 29, 2003, published on November 3, 2004, applicant: Boehringer Ingelheim Pharma GmbH & Co. KG, inventor: Dr. Martin Stefanic, Dr. Gerd Munzert, Dr. Frank Hilberg
7. ↑ Boehringer Ingelheim submits nintedanib *, a novel oncology compound, for European approval. Press release from October 14, 2013.
8. ↑ EMA accepts marketing authorization application for nintedanib in IPF. Press release from June 5, 2014.
9. ↑ EMA: Ofev product information. Retrieved August 5, 2020 . 
10. ↑ Boehringer Ingelheim: Package leaflet: Information for the patient Ofev® 150 mg soft capsules nintedanib .
11. ^ German safety data sheet ( Memento of November 13, 2013 in the Internet Archive ) at LC Laboratories.
12. ↑ European Commission "Health and Consumers": Summary of the product characteristics Vargatef, p. 2.
13. ↑ Package insert, p. 2.
14. ↑ European Commission "Health and Consumers": Summary of the product characteristics Vargatef, p. 5.
15. ↑ European Commission “Health and Consumers”: Summary of the product characteristics Vargatef, pp. 7–8.
16. ↑ ^{a b} package insert, p. 6.
17. ↑ European Commission “Health and Consumers”: Summary of the product characteristics Vargatef, pp. 8–9.
18. ↑ Package insert, p. 7.
19. ↑ European Commission "Health and Consumers": Summary of the product characteristics Vargatef, p. 23.
20. ↑ Package insert, p. 4.
21. ↑ Advanced non-small cell lung carcinoma - nintedanib *: angiokinase inhibitor with extended mechanism of action in advanced clinical development PharmaForum in Onkologie 36, October 2013, S. Karger Verlag für Medizin und Naturwissenschaften GmbH.
22. ↑ European Commission "Health and Consumers": Summary of the product characteristics Vargatef, p. 11.
23. ^ Deutsches Ärzteblatt Idiopathic Lung Fibrosis: Nintedanib and Pirfenidone Curb Disease Progression Article from May 19, 2014, Ärzte-Verlag GmbH.
24. ↑ https://www.aerzteblatt.de/nachrichten/103274/Systemische-Sklerose-Nintedanib-verlangsamt-Verschlechtung-der-Lungenfunktion?rt=677d4218b2f333a120d562938b62b910
25. ↑ Package insert, p. 9.
26. ↑ Boehringer Ingelheim MSDS: Ofev ( Memento of the original from March 4, 2016 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. 
27. ↑ Patent application WO 2009/071523 A1 PROCESS FOR THE MANUFACTURE OF AN INDOLINONE DERIVATIVE. Registered on December 2, 2008, published on June 11, 2009, applicant: Boehringer Ingelheim International GmbH, inventor: Jörn Merten.
28. ↑ ^{a b} patent application WO2009071524 (A2) INDOLINONE DERIVATIVES AND PROCESS FOR THEIR MANUFACTURE. Registered on December 2, 2008, published on June 11, 2009, applicant: Boehringer Ingelheim International GmbH, inventor: Jörn Merten.
29. ↑ Patent application EP1473043 A1 Pharmaceutical combination for the treatment of diseases involving cell proliferation, migration or apotosis of myeloma cells, or angiogenesis. Registered on April 29, 2003, published on November 3, 2004, applicant: Boehringer Ingelheim Pharma GmbH & Co. KG, inventor: Dr. Martin Stefanic.
30. ↑ Patent application WO2004013099 (A1) 3-Z- [1- (4- (N - ((4-METHYL-PIPERAZIN-1-YL) -METHYLCARBONYL) -N-METHYL-AMINO) -ANILINO) -1-PHENYL-METHYLENE -6-METHOXYCARBONYL-2-INDOLINONE-MONOETHANESULPHONATE AND THE USE THEREOF AS A PHARMACEUTICAL COMPOSITION. ] Registered on July 18, 2003, published on February 12, 2004, applicant: Boehringer Ingelheim Pharma GmbH & Co. KG, inventor: Gerald Jürgen Roth.

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