Tilmacoxib

5-ethoxymethyl-7-fluoro-3-oxo-1,2,3,5-tetrahydrobenzo(4,5)imidazo(1,2a)pyridine-4-N–(2-fluorophenyl)carboxamide

Japan Tobacco (JT) (Originator)

Tilmacoxib or JTE-522 is a COX-2 inhibitor and is an effective chemopreventive agent against rat experimental liver fibrosis.^[1]

A member of the class of 1,3-oxazoles that is that is 1,3-oxazole which is substituted at positions 2, 4 and 5 by methyl, cyclohexyl, and 3-fluoro-4-sulfamoylphenyl groups, respectively.

………..

4-(4-Cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamides as selective cyclooxygenase-2 inhibitors: Enhancement of the selectivity by introduction of a fluorine atom and identification of a potent, highly selective, and orally active COX-2 inhibitor JTE-522
J Med Chem 2002, 45(7): 1511

http://pubs.acs.org/doi/abs/10.1021/jm010484p

A series of 4-(4-cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamide derivatives were synthesized and evaluated for their abilities to inhibit cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) enzymes. In this series, substituent effects at the ortho position to the sulfonamide group on the phenyl ring were examined. Most substituents reduced or lost both COX-2 and COX-1 activities. In contrast, introduction of a fluorine atom preserved COX-2 potency and notably increased COX1/COX-2 selectivity. This work led to the identification of a potent, highly selective, and orally active COX-2 inhibitor JTE-522 [9d, 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide], which is currently in phase II clinical trials for the treatment of rheumatoid arthritis, osteoarthritis, and acute pain.

9d as a white solid:  mp 166−167 °C; ¹H NMR (CDCl₃) δ 1.3−1.5 (m, 3H), 1.6−1.9 (m, 7H), 2.51 (s, 3H), 2.79 (tt, J = 3.7, 11.3 Hz, 1H), 5.11 (s, 2H), 7.36−44 (m, 2H), 7.94 (t, J = 7.9 Hz, 1H). Anal. (C₁₆H₁₉FN₂O₃S) C, H, N.

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WO 1996019463 OR http://www.google.com/patents/EP0745596A1?cl=en

Example 2

• [0080]
  Synthesis of 5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole (formula (I); R=cyclohexyl, R₁=4-aminosulfonyl-3-fluorophenyl, R₂=methyl, Z=oxygen atom)
  Step 10) Cyclohexyl 3-fluorobenzyl ketone (formula (IV’); R’=cyclohexyl, R₁‘=3-fluorophenyl)

  
• [0081]
  To a solution of tetrakis(triphenylphosphine)palladium (2.00 g) and zinc powder (17.98 g) in 1,2-dimethoxyethane (50 ml) was added a solution of cyclohexanecarbonyl chloride (20.00 g) in 1,2-dimethoxyethane (50 ml) at room temperature under a nitrogen atmosphere. A solution of 3-fluorobenzyl bromide (26.00 g) in 1,2-dimethoxyethane (100 ml) was gradually added dropwise to the mixture with stirring under ice-cooling. The mixture was stirred under ice-cooling for 30 minutes, and at room temperature for 2 hours. The insoluble matter was removed by filtration and the filtrate was concentrated under reduced pressure. Then, ethyl acetate (200 ml) was added to the residue, and the mixture was washed with 1N hydrochloric acid, and then with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give 29.20 g of an oily crude product.
  Step 16) 2-Cyclohexyl-1-(3-fluorophenyl)-2-oxoethyl acetate (formula (V”); R’=cyclohexyl, R₁‘=3-fluorophenyl, R₂‘=methyl, Z=oxygen atom)

  
• [0082]
  Lead tetraacetate (75.00 g) was added to a solution of the compound (29.20 g) obtained in the above Step 10) in acetic acid (300 ml). The mixture was refluxed under heating for 1.5 hours, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=9:1) to give 18.30 g of the title compound as an oil (yield 50%).
  Step 17) 4-Cyclohexyl-5-(3-fluorophenyl)-2-methyloxazole (formula (XIII); R’=cyclohexyl, R₁‘=3-fluorophenyl, R₂=methyl, Z=oxygen atom)

  
• [0083]
  A solution of the compound (18.00 g) obtained in the above Step 16) and ammonium acetate (15.00 g) in acetic acid (100 ml) was refluxed under heating for 5 hours, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 17.20 g of an oily crude product. Step 15) 5-(4-Aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole (formula (I); R=cyclohexyl, R₁=4-aminosulfonyl-3-fluorophenyl, R₂=methyl, Z=oxygen atom)

  
• [0084]
  To a solution of the compound (17.00 g) obtained in the above Step 17) in chloroform (80 ml) was added dropwise chlorosulfonic acid (27 ml) with stirring under ice-cooling, and the mixture was heated at 100°C for 3 hours. The reaction mixture was cooled to room temperature, and dropwise added to ice-water (300 ml) with stirring. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 20.31 g of a crude product.
• [0085]
  Aqueous ammonia (28%) was added to a solution of the obtained compound (10.00 g) in tetrahydrofuran (40 ml) with stirring at room temperature, and the mixture was stirred at room temperature for one hour. The solvent was evaporated under reduced pressure and ethyl acetate was added to the residue. The mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was separated and purified by silica gel column chromatography (developing solvent; dichloromethane:ethyl acetate=6:1) to give 5.74 g of the title compound (yield 61%).

Example 2′

• [0086]
  The compound of Example 2 (formula (I); R=cyclohexyl, R₁=4-aminosulfonyl-3-fluorophenyl, R₂=methyl, Z=oxygen atom) was synthesized according to another synthetic method.
  Step 11) Cyclohexyl 3-fluorobenzyl ketone oxime (formula (XI); R’= cyclohexyl, R₁‘=3-fluorophenyl)

  
• [0087]
  To a solution of the compound (353 g) obtained according to a method similar to that of the above Example 2, Step 10) in ethanol (1300 ml) were added hydroxylamine hydrochloride (123 g) and sodium acetate (158 g). The mixture was refluxed under heating for 2 hours, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product was recrystallized from n-heptane to give 160 g of the title compound (yield 42%).
  Step 14) 4-Cyclohexyl-5-(3-fluorophenyl)-2-methyloxazole (formula (XIII); R’=cyclohexyl, R₁‘=3-fluorophenyl, R₂=methyl, Z=oxygen atom)

  
• [0088]
  Acetic anhydride (95 ml) was dropwise added to a solution of the compound (158 g) obtained in the above Step 11) in acetic acid (900 ml) with stirring at room temperature, and the mixture was refluxed under heating for 7 hours. The solvent was evaporated under reduced pressure and n-heptane was added to the residue. The mixture was washed with water, saturated aqueous sodium hydrogencarbonate solution, saturated brine and acetonitrile. The solvent was evaporated under reduced pressure to give 119 g of the title compound as an oil.
• [0089]
  Then, the obtained compound (119 g) was reacted in the same manner as in the above Example 2, Step 15) to give a compound of Example 2 (formula (I); R=cyclohexyl, R₁=4-aminosulfonyl-3-fluorophenyl, R₂=methyl, Z=oxygen atom).

Example 3

• [0090]
  Synthesis of 4-cyclohexyl-5-(3-fluoro-4-methylsulfonylphenyl)-2-methyloxazole (formula (I); R=cyclohexyl, R₁=3-fluoro-4-methylsulfonylphenyl, R₂=methyl, Z=oxygen atom)
  Step 15) 4-Cyclohexyl-5-(3-fluoro-4-methylsulfonylphenyl)-2-methyloxazole (formula (I); R=cyclohexyl, R₁=3-fluoro-4-methylsulfonylphenyl, R₂=methyl, Z=oxygen atom)

  
• [0091]
  To a solution of the compound (17.00 g) obtained in the above Example 2, Step 17) in chloroform (80 ml) was dropwise added chlorosulfonic acid (27 ml) with stirring under ice-cooling. The mixture was heated at 100°C for 3 hours. The reaction mixture was cooled to room temperature and dropwise added to ice-water (300 ml) with stirring. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 20.31 g of a crude product.
• [0092]
  Water (25 ml) was added to the obtained compound (3.66 g). To the mixture were added sodium sulfite (1.42 g) and sodium hydrogencarbonate (1.89 g) successively with stirring at room temperature. The mixture was heated at 70°C for 2 hours. Ethanol (25 ml) and methyl iodide (2.20 g) were added to the mixture, and the mixture was heated at 100°C for 2 hours. The mixture was cooled to room temperature and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate.
• [0093]
  The solvent was evaporated under reduced pressure, and the residue was saparated and purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=2:1) to give 0.82 g of the title compound (yield 24%).

References