4-aminothiazole derivs, their preparation and their use as inhibitors of cyclin-dependent kinases
A technology of alkyl and alkynyl, which is applied in the field of pharmaceutical compositions of aminothiazole compounds, and can solve problems such as CDK activity imbalance
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Embodiment A
[0071] Example A(1): (4-amino-2-phenylamino-thiazol-5-yl)-(3-nitrophenyl)-methanone
[0072] Sodium (188 mg, 8.20 mmol) was carefully dissolved in methanol (9 mL) at 0 °C following the procedure described by Gewald et al., J. Prakt. Chem., Vol. 35 (1967), pp. 97-104 , and allowed to warm to room temperature. The resulting solution was added portionwise to a mixture of cyanamide (345 mg, 8.20 mmol) and phenyl isothiocyanate (0.98 mL, 8.2 mmol), with evolution of heat. 2-Bromo-3'-nitroacetophenone (2.00 g, 8.2 mmol) was added, and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with water (150 mL). The tan solid was filtered out, washed with water and a small amount of ether, dried in vacuo, and recrystallized from ethanol to obtain 2.17 g (52% yield) of the title compound as dark brown crystals with a melting point (mp) of 186-187°C. 1 H NMR (DMSO-d 6 ): δ10.95(1H, s), 8.44(1H, t, J=1.9Hz), 8.54-8.22(2H, bs), 8.34(1H, ddd, J=8.2, 1...
Embodiment B
[0100] Example B: [4-amino-2-(p-tolylamino)-thiazole-5-carbonyl]-phenyl benzoate
[0101] First, the intermediate product S-(4-benzoyloxyphenylacetyl)-N'-cyano- N"-p-tolyl-isothiourea. Sodium (6.7 mg, 0.29 mmol) was carefully dissolved in methanol (0.5 mL) and allowed to cool to room temperature. To the resulting solution was added p-toluene ester (43 mg, 0.29 mmol) and cyanamide (12 mg, 0.29 mmol). After 1 hour, 4-bromoacetophenone benzoate (92 mg, 0.29 mmol) was added and the resulting mixture was stirred at room temperature overnight The mixture was then diluted with water (10 mL). The resulting tan solid was filtered off, washed with water and a small amount of ether, dried in vacuo, and recrystallized from ethanol / chloroform to obtain 63 mg (51% yield) of S- Raw material of (4-benzoyloxyphenylacetyl)-N′-cyano-N″-p-tolyl-isothiourea (white needle-like crystals): 1 H NMR (DMSO-d 6 ): δ 8.10-8.04 (2H, m), 7.72 (1H, ddd, J = 7.5, 1.8, 1.8Hz), 7.67-7.54 (4H, m), 7.20 (2...
Embodiment C
[0103] Example C(1): 4-[4-Amino-5-(4-methoxy-benzoyl)-thiazol-2-ylamino]-benzoic acid methyl ester
[0104] To a mixture of 4-methoxycarbonylphenyl isothiocyanate (82 mg, 0.5 mmol) and cyanamide (23 mg, 0.55 mmol) in acetonitrile (5 mL) was added potassium tert-butoxide (61 mg, 0.55 mmol) in tert-butanol (5 mL). After standing at room temperature for 30 minutes, 2-bromo-4'-methoxy-acetophenone (115 mg, 0.5 mmol) was added. After standing at room temperature for 2 hours, the reaction mixture was diluted with water (50 mL). The product was collected by filtration, washed with water and ether, and dried in vacuo to obtain 172 mg (90% yield) of a yellow solid. 1 H NMR (DMSO-d 6): δ 8.00 (2H, d, J = 8.2Hz), 7.84 (2H, d, J = 8.2Hz), 7.72 (2H, d, J = 8.2Hz), 7.10 (2H, d, J = 8.2Hz) , 3.90 (6H, s).FABMS (MH+): 384. Analytical calculated value: C 19 h 17 N 3 o 4 5·0.5H 2 O: C, 57.36; H, 4.71; N, 10.56; S, 8.06. Found: C, 56.97; H, 4.74; N, 10.51; S, 8.07.
[0105] Example C...
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