Gimeracil

Off-White Solid

Gimeracil is an organic molecular entity.|Gimeracil is an adjunct to antineoplastic therapy, used to increase the concentration and effect of the main active componets within chemotherapy regimens. Approved by the European Medicines Agency (EMA) in March 2011, Gimeracil is available in combination with [DB03209] and [DB09256] within the commercially available product "Teysuno". The main active ingredient in Teysuno is [DB09256], a pro-drug of [DB00544] (5-FU), which is a cytotoxic anti-metabolite drug that acts on rapidly dividing cancer cells. By mimicking a class of compounds called "pyrimidines" that are essential components of RNA and DNA, 5-FU is able to insert itself into strands of DNA and RNA, thereby halting the replication process necessary for continued cancer growth. Gimeracil's main role within Teysuno is to prevent the breakdown of [DB00544] (5-FU), which helps to maintin high enough concentrations for sustained effect against cancer cells. It functions by reversibly and selectively blocking the enzyme dihydropyrimidine dehydrogenase (DPD), which is involved in the degradation of 5-FU. This allows higher concentrations of 5-FU to be achieved with a lower dose of tegafur, thereby also reducing toxic side effects.|Gimeracil is a pyridine derivative with antitumor activity. Gimeracil enhances the antitumor activity of fluoropyrimidines by competitively and reversibly inhibiting the enzyme dihydropyrimidine dehydrogenase causing decreased degradation of the fluoropyrimidines.

A mixture of compound 6 (8.0 g, 44 mmol), acetonitrile (100 mL), acetic acid (3 mL)and sodium iodide (13.2 g, 88 mmol) was heated for 8 h at 60 °C. Then the mixture was cooled to room temperature and poured into 10percent sodium thiosulfate solution (200 mL) to precipitate a colourless solid, which was recrystallised from water to give pure compound 2: Yield 5.6 g (86percent); m.p.272–273 °C (lit.7 273–274 °C); 1H NMR (400 MHz, DMSO-d6): δ 5.70(s, 1H), 7.51 (s, 1H), 11.29 (br, 2H) ; 13C NMR (100 MHz, DMSO-d6): δ163.5, 163.2, 134.6, 105.6, 98.7; LRMS (ESI) m/z (percent): 146 (100) [M (35Cl+ 1]+, 148 (30) [M (37Cl) + 1]+; HRMS (ESI) m/z calcd for C5H535ClNO2:[M + H]+: 146.0003; found: 146.0012; calcd for C5H537ClNO2: [M + H]+:147.9975; found: 147.9975.Xylene (40 mL) was added to 2, 2-cyclohexyl-5-chloro-1, 3-dioxin-4-one (4.25 g, 0.021 mol), produced in Referential Example 2, and ketene diethyl ether (2.91 g, 0.025 mol), and the mixture was stirred under heating at 128 to 130°C (internal temperature) for 40 minutes. The reaction mixture was cooled to room temperature, and concentrated. The residue was dissolved in ethanol (60 mL), and at room temperature, acetyl chloride (0.17 g, 0.0022 mol) was added to the solution, followed by stirring for one hour. To the reaction mixture, concentrated ammonia (28percent) (4.2 mL) was added, followed by stirring at room temperature for four hours. A 30percent aqueous solution of sodium hydroxide (3 g, 0.0225 mol) was added to the reaction mixture, followed by stirring at room temperature for 12 hours. The precipitated crystals were collected through filtration, washed with ethanol (10 mL, two times), and dried under reduced pressure at room temperature for five hours, to thereby yield 3.04 g of a product as crystals. The thus-obtained crystals were dissolved in water (30 mL) under heating, and the solution was cooled to room temperature. 6N Aqueous hydrochloric acid (4.5 g) was added to the solution, followed by stirring at room temperature for five hours. The precipitated crystals were collected through filtration, washed with water, and dried under reduced pressure at 40 to 45°C for 18 hours, to thereby yield 2.21 g of the title compound (yield with respect to 2, 2-cyclohexyl-5-chloro-1, 3-dioxin-4-one: 72.4percent).The compound (0.23 g, 0.001 mol) was dissolved in ethanol (5 mL), and acetyl chloride (0.1 mL) was added to the solution at room temperature, followed by stirring for one hour. The reaction mixture was concentrated, and the residue was dissolved in ethanol (5 mL). Concentrated aqueous ammonia (28percent) (1 mL) was added to the solution, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated, and water (1.4 mL) and acetic acid (0.14 mL) were added to the residue, followed by stirring at room temperature for two hours. The precipitated crystals were collected through filtration, washed with water, and dried under reduced pressure at 40 to 45°C for 18 hours, to thereby yield 0.05 g of the title compound (yield with respect to 5-chloro-2, 2-diethoxy-2, 3-dihydropyran-4-one: 33.0percent, yield with respect to 5-chloro-2, 2-dimethyl-1, 3-dioxin-4-one: 29.4percent).Reference Example 8 Alternative synthesis of 3-{3-[4-hydroxy-5-chloro-2-pyridyloxycarbonyl]benzoyl}-1-ethoxymethyl-5-fluorouracil (Compound 8a) 1-Ethoxymethyl-3-m-hydroxycarbonylbenzoyl-5-fluorouracil (3.46 g) was dissolved in methylene chloride (50 mL). Thionyl chloride (0.9 mL) and dimethylformamide (0.04 mL) were then added thereto. The resulting reaction product was refluxed for 2.5 hours, and the solvents were then evaporated. The residue was dissolved in dimethylacetamide (12 mL) to obtain a dimethylacetamide solution of acid chloride. The dimethylacetamide solution of acid chloride was added dropwise under ice cooling to a solution of 2, 4-dihydroxy-5-chloropyridine (1.5 g), triethylamine (1.57 mL), and dimethylacetamide (15 mL). The resulting reaction product was stirred at room temperature for 8 hours. Water was added thereto, and the mixture was separated by a mixed solvent of ethyl acetate and n-hexane (1:1). The organic layer was dried with sodium sulfate, and the solvent was then evaporated. The residue was purified by silica gel column chromatography (eluted with ethyl acetate/n-hexane (1:1)) to obtain Compound 8a (668 mg). Yield: 14percentReference Example 4 Synthesis of 4-{2, 6-dibenzyloxyisonicotinoyloxy}-5-chloro-2-hydroxypyridine (Compound 5a), 2-{2, 6-dibenzyloxyisonicotinoyloxy}-5-chloro-4-hydroxypyridine (Compound 5b), and 2, 4-di{2, 6-dibenzyloxyisonicotinoyloxy}-5-chloropyridine (Compound 5c). Thionyl chloride (98.5 mL) and dimethylformamide (1.7 mL) were added dropwise to a solution of 2, 6-dibenzyloxyisonicotinic acid (Compound 2a) (75.45 g) obtained in Reference and toluene (800 mL), and the mixture was stirred at 80°C for 4.5 hours. After being cooled, the solvents were evaporated. Without purification, the residual acid chloride was dissolved in dimethylacetamide (100 mL) to obtain a dimethylacetamide solution of acid chloride to be used in the following reaction. The dimethylacetamide solution of acid chloride was added dropwise under ice cooling to a solution of 2, 4-dihydroxy-5-chloropyridine (31.9 g), triethylamine (31.19 mL) and dimethylacetamide (1.6 L). The resulting mixture was stirred at room temperature for 1 hour, and water (1.7 L) was then added thereto. The mixture was separated by a mixed solvent (1 L) of ethyl acetate and n-hexane (3:1). After the solution was dried with sodium sulfate, the solvent was evaporated. The precipitate was filtered and dried to obtain Compound 5a. Yield: 44.8g (45percent) Meanwhile, the filtrate was concentrated and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate/n-hexane (1:1)) to obtain Compound 5b (18.94 g) and Compound 5c (4.74 g). Compound 5a 1H-NMR (DMSOd6, deltaPPM): 12.09 (1H, brs), 7.91 (1H, s), 7.50-7.30 (10H, m), 6.99 (2H, s), 6.58 (1H, s), 5.42 (4H, s)Melting point: 149-150°C12.09 (1H, brs), 7.91 (1H, s), 7.50-7.30 (10H, m), 6.99 (2H, s), 6.58 (1H, s), 5.42 (4H, s)Compound 5b1H-NMR (DMSOd6, deltaPPM): 12.26 (1H, brs), 8.27 (1H, s), 7.50-7.30 (10H, m), 6.98 (2H, s), 6.86 (1H, s), 5.42 (4H, s)Melting point: 136-138°C (decomposition temperature)12.26 (1H, brs), 8.27 (1H, s), 7.50-7.30 (10H, m), 6.98 (2H, s), 6.86 (1H, s), 5.42 (4H, s)Compound 5c1H-NMR (DMSOd6, deltaPPM): 8.75 (1H, s), 7.79 (1H, s), 7.50-7.30 (20H, m), 7.05 (2H, s), 7.02 (2H, s), 5.42 (8H, s)8.75 (1H, s), 7.79 (1H, s), 7.50-7.30 (20H, m), 7.05 (2H, s), 7.02 (2H, s), 5.42 (8H, s)

1. Gimeracil is an inhibitor of dihydropyrimidine dehydrogenase, which inhibits the early step in homologous recombination for double strand breaks repair.
2. Gimeracil is an antitumor agent. Gimeracil is a potent inhibitor of dihydropyrimidine dehydrogenase (DPD).
3. Antitumor agent. A potent inhibitor of dihydropyrimidine dehydrogenase (DPD)

Molecular Weight:145.54
XLogP3:-0.1
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:2
Exact Mass:144.9930561
Monoisotopic Mass:144.9930561
Topological Polar Surface Area:49.3
Heavy Atom Count:9
Complexity:207
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes