Mocetinostat

Mocetinostat (MGCD0103) is a potent, orally active and isotype-selective HDAC (Class I/IV) inhibitor with IC50s of 0.15, 0.29, 1.66 and 0.59 μM for HDAC1, HDAC2, HDAC3 and HDAC11, respectively. Mocetinostat shows no inhibition on HDAC4, HDAC5, HDAC6, HDAC7, or HDAC8.

N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide is a member of benzamides.|Mocetinostat has been used in trials studying the treatment of Lymphoma, Urothelial Carcinoma, Relapsed and Refractory, Myelodysplastic Syndrome, and Metastatic Leiomyosarcoma, among others.|Mocetinostat is a rationally designed, orally available, Class 1-selective, small molecule, 2-aminobenzamide HDAC inhibitor with potential antineoplastic activity. Mocetinostat binds to and inhibits Class 1 isoforms of HDAC, specifically HDAC 1, 2 and 3, which may result in epigenetic changes in tumor cells and so tumor cell death; although the exact mechanism has yet to be defined, tumor cell death may occur through the induction of apoptosis, differentiation, cell cycle arrest, inhibition of DNA repair, upregulation of tumor suppressors, down regulation of growth factors, oxidative stress, and autophagy, among others. Overexpression of Class I HDACs 1, 2 and 3 has been found in many tumors and has been correlated with a poor prognosis.

A 2L, three-neck round bottom flask equipped with a thermometer, nitrogen inlet, a mechanical stirrer and a dropping funnel was charged with 4-((4-(pyridin-3-yl)pyrirnidin-2- ylarnino)rnethyl)benzoic acid (3, 40 g, 0.131 mol), 1, 2-phenylenediamine (59.3 g, 0.548 mol), 1- hydroxybenzotriazole hydrate (HOBT) (21.7 g, 0.156 mol) and DMSO (240 rnL) at roomtemperature. To this stirred mixture Et3N (43.7 mL, 0.313 mol) was added. The reaction mixture was stirred for 10 mm then was charged with a suspension of 1-(3-dimethylarninopropyl)-3- ethylcarbodiirnide hydrochloride (EDC x HC1) (30.04 g, 0.156 mol)) in DMSO (240 rnL) at the same temperature. The addition occurred in three equal portions over 30 mm.[0275] The reaction mixture was then stirred for 20 hours (the progress of the reaction was monitored by NMR or HPLC for the disappearance of the acid 3). Upon completion of the reaction 30percent IPA in water (800 mL) was added to the reaction mixture in three portions over 30 mm. After complete addition the reaction mixture turned into a suspension which was cooled to 0-5°C over 45 mm and then stirred at the same temperature for another hour. The solid material was collected by a suction filtration, washed with 30percent IPA (400 rnL) and air-dried to afford crude title compound 4 (43.04 g, 83percent yield).II. Preparation of MGCD0103 Amide Derivatives. (0122) To a solution of the acid in DMF (10 mL) were added HBTU, and DIEA. After 30 min, MGCD0103 was added to the reaction solution. The reaction mixture was stirred overnight at room temperature, then poured into 50 mL water and filtered. The solid obtained was purified by flash C18 chromatography using proper ACN in water for 15 min to obtain the amide product. The reactions were summarized in Table 4.A 250 ml three-neck round bottom flask equipped with a mechanical stirrer, thermometer and nitrogen inlet was charged with 10.0 g of N-(2-aminophenyl)-4-[(4-pyridin-3- yl-pyrimidin-2-ylamino)-methyl]-benzarnide (4) and EtOH (150 ml). The temperature was adjusted to 0-5 C and hydrobromic acid (48% w/w, 6.2 ml, 2.2 eq.) was added while keeping the temperature below 10 C. The reaction mixture was stirred at 0-5 C for 3 hours, the precipitate formed was collected by filtration and rinsed with EtOH (2x 20 ml) and heptanes (2x20 ml). The filter cake was re-suspended in heptanes (10 ml) and the mixture was stirred for 1 hour at 20-25C. Filtration of the suspension afforded a solid material that was rinsed with heptanes (2x20 ml), dried in a high vacuum oven at 20-25 C for 24 hours at which time the temperature was increased to 40-45 C. The heating continued until constant weight was reached. Yields: 8.45- 9.86 g (60-70 %).A 2L, three-neck round bottom flask equipped with a thermometer, nitrogen inlet, a mechanical stirrer and a dropping funnel was charged with 4-((4-(pyridin-3-yl)pyrirnidin-2- ylarnino)rnethyl)benzoic acid (3, 40 g, 0.131 mol), 1, 2-phenylenediamine (59.3 g, 0.548 mol), 1- hydroxybenzotriazole hydrate (HOBT) (21.7 g, 0.156 mol) and DMSO (240 rnL) at roomtemperature. To this stirred mixture Et3N (43.7 mL, 0.313 mol) was added. The reaction mixture was stirred for 10 mm then was charged with a suspension of 1-(3-dimethylarninopropyl)-3- ethylcarbodiirnide hydrochloride (EDC x HC1) (30.04 g, 0.156 mol)) in DMSO (240 rnL) at the same temperature. The addition occurred in three equal portions over 30 mm.[0275] The reaction mixture was then stirred for 20 hours (the progress of the reaction was monitored by NMR or HPLC for the disappearance of the acid 3). Upon completion of the reaction 30% IPA in water (800 mL) was added to the reaction mixture in three portions over 30 mm. After complete addition the reaction mixture turned into a suspension which was cooled to 0-5C over 45 mm and then stirred at the same temperature for another hour. The solid material was collected by a suction filtration, washed with 30% IPA (400 rnL) and air-dried to afford crude title compound 4 (43.04 g, 83% yield).Step 4 Synthesis of N-(2-Amino-phenyl)-4-[(4-pyridin-3-yl-pyrimidin-2-ylamino)-methyl]-benzamide Intermediate 3 (3.68 g, 11.5 mmol) was mixed with THF (23 mL), MeOH (23 mL) and H2O (11.5 mL) at rt. LiOH (1.06 g, 25.3 mmol) was added to reaction mixture. The resulting reaction mixture was warmed up to 40 C. overnight. HCl solution (12.8 mL, 2N) was added to adjust pH=3 when the mixture was cooled down to rt. The mixture was evaporated to dryness and then the solid was washed with minimum quantity of H2O upon filtration. The filter cake was dried over freeze dryer to give 3.44 g acid of the title compound (95%, M+1: 307 on MS). Acid (3.39 g, 11.1 mmol) of the title compound, BOP (5.679 g, 12.84 mmol) and o-Ph(NH2)2 (2.314 g, 21.4 mmol) were dissolved in the mixture of DMF (107 mL) and Et3N (2.98 mL, 21.4 mmol). The reaction mixture was stirred at rt for 5 h and then evaporated to dryness. The residue was purified by flash column (pure EtOAc to 5% MeOH/EtOAc) and then interested fractions were concentrated. The final product was triturated with EtOAc to give 2.80 g of title product (66%, MS+1: 397 on MS). 1H NMR (400 MHz, DMSO-D6) delta (ppm): 9.57 (s, 1H), 9.22 (s, 1H), 8.66 (d, J=3.5 Hz, 1H), 8.39 (d, J=5.1 Hz, 2H), 8.00 (t, J=6.5 Hz, 1H), 7.90 (d, J=8.2 Hz, 2H), 7.50 (m, 3H), 7.25 (d, J=5.1 Hz, 1H), 7.12 (d, J=7.4 Hz, 1H), 6.94 (dd, J=7.0, 7.8 Hz, 1H), 6.75 (d, J=8.2 Hz, 1H), 6.57 (dd, J=7.0, 7.8 Hz, 1H), 4.86 (s, 2H), 4.64 (d, J=5.9 Hz, 2H).Step 4: Synthesis of N-(2-Amino-phenyl)-4-[(4-pyridin-3-yl-pyrimidin-2-ylamino)-methyl]-benzamide Intermediate 3 (3.68 g, 11.5 mmol) was mixed with THF (23 mL), MeOH (23 mL) and H2O (11.5 mL) at rt. LiOH (1.06 g, 25.3 mmol) was added to reaction mixture. The resulting reaction mixture was warmed up to 40 C. overnight. HCl solution (12.8 mL, 2N) was added to adjust pH=3 when the mixture was cooled down to rt. The mixture was evaporated to dryness and then the solid was washed with minimum quantity of H2O upon filtration. The filter cake was dried over freeze dryer to give 3.44 g acid of the title compound (95%, M+1: 307 on MS). Acid (3.39 g, 11.1 mmol) of the title compound, BOP (5.679 g, 12.84 mmol) and o-Ph(NH2)2 (2.314 g, 21.4 mmol) were dissolved in the mixture of DMF (107 mL) and Et3N (2.98 mL, 21.4 mmol). The reaction mixture was stirred at rt for 5h and then evaporated to dryness. The residue was purified by flash column (pure EtOAc to 5% MeOH/EtOAc) and then interested fractions were concentrated. The final product was triturated with EtOAc to give 2.80 g of title product (66%, MS+1: 397 on MS). 1H NMR (400 MHz, DMSO-D6) delta (ppm): 9.57 (s, 1H), 9.22 (s, 1H), 8.66 (d, J=3.5 Hz, 1H), 8.39 (d, J=5.1 Hz, 2H), 8.00 (t, J=6.5 Hz, 1H), 7.90 (d, J=8.2 Hz, 2H), 7.50 (m, 3H), 7.25 (d, J=5.1 Hz, 1H), 7.12 (d, J=7.4 Hz, 1H), 6.94 (dd, J=7.0, 7.8 Hz, 1H), 6.75 (d, J=8.2 Hz, 1H), 6.57 (dd, J=7.0, 7.8 Hz, 1H), 4.86 (s, 2H), 4.64 (d, J=5.9 Hz, 2H).

Mocetinostat is a multi-targeted histone deacetylase inhibitor used in cancer therapy. Mocetinostat is undergoing clinical trials for the treatment of various cancers including follicular lymphoma, Hodgkin~"s lymphoma and acute myelogenous leukemia.

Molecular Weight:396.4
XLogP3:2.8
Hydrogen Bond Donor Count:3
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:6
Exact Mass:396.16985928
Monoisotopic Mass:396.16985928
Topological Polar Surface Area:106
Heavy Atom Count:30
Complexity:538
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes