Masitinib; 790299-79-5; Masivet; AB1010; AB-1010;
Regulatory and Commercial Status
Masitinib is a tyrosine-kinase inhibitor used in the treatment of mast cell tumors in animals, specifically dogs. Since its introduction in November 2008 it has been distributed under the commercial name Masivet. It has been available in Europe since the second part of 2009. In the USA it is distributed under the name Kinavet and has been available for veterinaries since 2011.
Mechanism of action
Masitinib inhibits the receptor tyrosine kinase c-Kit which is displayed by various types of tumour. It also inhibits the platelet derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR).
In a preferred embodiment of the above-depicted treatment, the active ingredient masitinib is administered in the form of masitinib mesilate; which is the orally bioavailable mesylate salt of masitinib – CAS 1048007-93-7 (MsOH); C28H30N6OS.CH3SO3H; MW 594.76:
003 : 4-(4-Methyl-piperazin-l-ylmethyl)-N-[3-(4-pyridin-3-yl-thiazol-2-ylamino)- phenyl] -benzamide
4-(4-Methyl-piperazin-l-yl)-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylmethyl)- phenyl] -benzamide
beige brown powder mp : 128-130°C
1H RMN (DMSO-d6) δ = 2.15 (s, 3H) ; 2.18 (s, 3H) ; 2.35-2.41 (m, 4H) ; 3.18-3.3.24 (m, 4H) ; 6.94 (d, J = 8.9 Hz, 2H) ; 7.09 (d, J = 8.4 Hz, IH) ; 7.28-7.38 (m, 3H) ; 7.81 (d, J = 8.9 Hz, 2H) ; 8.20-8.25 (m, IH) ; 8.40 (dd, J = 1.6 Hz, J = 4.7 , IH) ; 8.48 (d, J = 1.9 Hz, IH) ; 9.07 (d, J = 1.5 Hz, IH) ; 9.35 (s, IH) ; 9.84 (s, IH)
EXAMPLE 4 N- [4-Methyl-3 -(4-pyridin-3 -yl-thiazol-2-ylamino)-phenyl] -benzamide derivatives
Method A In a reactor and under low nitrogen pressure, add 4-Methyl-N3-(4-pyridin-3-yl-thiazol- 2-yl)-benzene-l,3-diamine (95 g, 336.45 mmol), dichloromethane (2 L). To this suspension cooled to temperature of 5°C was added dropwise 2M/n-hexane solution of trimethylaluminium (588 mL). The reaction mixture was brought progressively to 15°C, and maintained for 2 h under stirring. 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid methyl ester (100 g, 402.71 mmol) in dichloromethane (200 mL) was added for 10 minutes. After 1 h stirring at room temperature, the reaction mixture was heated to reflux for 20 h and cooled to room temperature. This solution was transferred dropwise via a cannula to a reactor containing 2N NaOH (2.1 L) cooled to 5°C. After stirring for 3 h at room temperature, the precipitate was filtered through Celite. The solution was extracted with dichloromethane and the organic layer was washed with water and saturated sodium chloride solution, dried over MgSO4 and concentrated under vacuum. The brown solid obtained was recrystallized from /-Pr2O to give 130.7 g (78%) of a beige powder.
Method B Preparation of the acid chloride
To a mixture of 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid dihydrochloride (1.0 eq), dichloromethane (7 vol) and triethylamine (2.15 eq), thionyl chloride (1.2 eq) was added at 18-28°C . The reaction mixture was stirred at 28-32°C for 1 hour. Coupling of acid chloride with amino thiazole To a chilled (0-50C) suspension of 4-Methyl-N3-(4-pyridin-3-yl-thiazol-2-yl)-benzene- 1,3-diamine (0.8 eq) and thiethylamine (2.2 eq) in dichloromethane (3 vol), the acid chloride solution (prepared above) was maintaining the temperature below 5°C. The reaction mixture was warmed to 25-300C and stirred at the same temperature for 1O h. Methanol (2 vol) and water (5 vol) were added to the reaction mixture and stirred. After separating the layers, methanol (2 vol), dihloromethane (5 vol) and sodium hydroxide solution (aqueous, 10%, till pH was 9.5-10.0) were added to the aqueous layer and stirred for 10 minutes. The layers were separated. The organic layer was a washed with water and saturated sodium chloride solution. The organic layer was concentrated and ethanol (2 vol) was added and stirred. The mixture was concentrated. Ethanol was added to the residue and stirred. The product was filtered and dried at 50-550C in a vaccum tray drier. Yield = 65-75%.
To a solution of 4-methyl-N3-(4-pyridin-3-yl-thiazol-2-yl)-benzene-l,3-diamine (1.0 eq) in DMF (20 vol) were added successively triethylamine (5 eq), 2-chloro-l- methylpyridinium iodide (2 eq) and 4-(4-methyl-piperazin-l-ylmethyl)-benzoic acid (2 eq). The reaction mixture was stirred for 7 h at room temperature. Then, the mixture was diluted in diethyl ether and washed with water and saturated aqueous NaHCO3, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography using an elution of 100% EtOAc to give a yellow solid.
Yield = 51%.
1H NMR (CDCl3) : δ = 9.09 (IH, s, NH); 8.52 (IH, br s); 8.27 (IH, s); 8.13 (IH, s);
8.03 (IH, s); 7.85 (2H, d, J= 8.3Hz); 7.45 (2H, m); 7.21-7.38 (4H, m); 6.89 (IH, s);
3.56 (2H, s); 2.50 (8H, br s); 2.31 (6H, br s).
MS (CI) m/z = 499 (M+H)+.
An additional aspect of the present invention relates to a particular polymorph of the methanesulfonic acid salt of N-[4-Methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]- benzamide of formula (IX).
Hereinafter is described the polymorph form of (IX) which has the most advantageous properties concerning processability, storage and formulation. For example, this form remains, dry at 80% relative humidity and thermodynamically stable at temperatures below 2000C.
The polymorph of this form is characterized by an X-ray diffraction pattern illustrated in FIG.I, comprising characteristic peaks approximately 7.269, 9.120, 11.038, 13.704, 14.481, 15.483, 15.870, 16.718, 17.087, 17.473, 18.224, 19.248, 19.441, 19.940, 20.441, 21.469, 21.750, 22.111, 23.319, 23.763, 24.120, 24.681, 25.754, 26.777, 28.975, 29.609, 30.073 degrees θ, and is also characterized by differential scanning calorimetry (DSC) illustrated in FIG.II, which exhibit a single maximum value at approximately 237.49 ± 0.3 0C. X-ray diffraction pattern is measured using a Bruker AXS (D8 advance). Differential scanning calorimetry (DSC) is measured using a Perking Elmer Precisely (Diamond DSC).
This polymorph form can be obtained by treatement of 4-(4-Methyl-piperazin-l- ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-benzamide with 1.0 to 1.2 equivalent of methanesulfonic acid, at a suitable temperature, preferably between 20-800C.
The reaction is performed in a suitable solvent especially polar solvent such as methanol or ethanol, or ketone such as acetone, or ether such as diethylether or dioxane, or a mixture therof. This invention is explained in example given below which is provided by way of illustration only and therefore should not be construed to limit the scope of the invention. Preparation of the above-mentioned polymorph form of 4-(4-Methyl-piperazin-l- ylmethyl)-N- [4-methyl-3 -(4-pyridin-3 -yl-thiazol-2-ylamino)-phenyl] -benzamide methanesulfonate .
4-(4-Methyl-piperazin- 1 -ylmethyl)-N- [4-methyl-3 -(4-pyridin-3 -yl-thiazol-2-ylamino) phenyl] -benzamide (1.0 eq) was dissolved in ethanol (4.5 vol) at 65-700C. Methanesulfonic acid (1.0 eq) was added slowly at the same temperature. The mixture was cooled to 25-300C and maintained for 6 h. The product was filtered and dried in a vacuum tray drier at 55-600C. Yield = 85-90%. Starting melting point Smp = 236°C.
- Hahn, K.A.; Oglivie, G.; Rusk, T.; Devauchelle, P.; Leblanc, A.; Legendre, A.; Powers, B.; Leventhal, P.S.; Kinet, J.-P.; Palmerini, F.; Dubreuil, P.; Moussy, A.; Hermine, O. (2008). “Masitinib is Safe and Effective for the Treatment of Canine Mast Cell Tumors”. Journal of Veterinary Internal Medicine 22 (6): 1301–1309. doi:10.1111/j.1939-1676.2008.0190.x. ISSN 0891-6640.
- Information about Masivet at the European pharmacy agency website
- Orphan designation for Masitinib at the European pharmacy agency website
|WO2004014903A1||Jul 31, 2003||Feb 19, 2004||Ab Science||2-(3-aminoaryl)amino-4-aryl-thiazoles and their use as c-kit inhibitors|
|WO2008098949A2||Feb 13, 2008||Aug 21, 2008||Ab Science||Process for the synthesis of 2-aminothiazole compounds as kinase inhibitors|
|EP1525200B1||Jul 31, 2003||Oct 10, 2007||AB Science||2-(3-aminoaryl)amino-4-aryl-thiazoles and their use as c-kit inhibitors|
|US7423055||Aug 1, 2003||Sep 9, 2008||Ab Science||2-(3-Aminoaryl)amino-4-aryl-thiazoles for the treatment of diseases|
|US20080207572 *||Jul 13, 2006||Aug 28, 2008||Ab Science||Use of Dual C-Kit/Fgfr3 Inhibitors for Treating Multiple Myeloma|
|Systematic (IUPAC) name|
|Trade names||Masivet, Kinavet|
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