Hydroxamic acid derivatives and medicinal utilization thereof

5-Methyl-3(R)-[1(S)-[4-[2-[1-(4-methyl)piperazinyl]ethoxy]benzoyl]-2-phenyl]ethylcarbamoyl-2(R or S)-phthalimidomethylhexanohydroxamic Acid Dihydrochloride

(1) 1-(2-Hydroxyethyl)-4-methylpiperazine

A mixture of 1-(2-hydroxyethyl)piperazine (10.0 g, 76.8 mmol), 37% aqueous formaldehyde solution (11.5 ml, 154 mmol), 10% palladium carbon catalyst (1.0 g) and methanol (100 ml) was stirred for 13 hr at room temperature in a hydrogen atmosphere. The reaction mixture was filtrated and the filtrate was concentrated. To the obtained residue was added 2N hydrochloric acid, and the mixture was washed with diethyl ether (200 ml). Sodium hydroxide (16 g) was added to the aqueous layer to make the layer alkaline, and the mixture was extracted with chloroform (4×200 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound (9.3 g, 84%) as a pale-yellow liquid.

1 H-NMR (300 MHz, CDCl 3 ) δ 3.61 (t, J=5.4 Hz, 2H), 2.90-2.30 (m, 8H), 2.55 (t, J=5.4 Hz, 2H), 2.29 (s, 3H).

(2) O-Benzyl-4-bromophenol

To a solution of 4-bromophenol (20.0 g, 116 mmol) dissolved in DMF (100 ml) were added successively benzyl bromide (13.7 ml, 116 mmol), potassium carbonate (47.9 g, 347 mmol) and sodium iodide (1.7 g, 11.6 mmol), and the mixture was stirred for 4 hr at room temperature. Insoluble material was filtered off and water (500 ml) was added to the obtained filtrate. The precipitate was collected by filtration and the obtained precipitate was dissolved in diethyl ether (300 ml). The mixture was washed with water (100 ml) and saturated brine (100 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained residue was washed with cold hexane and dried to give the title compound (26.2 g, 86%) as a white solid.

1 H-NMR (300 MHz, CDCl 3 ) δ 7.37 (d, J=8.9 Hz, 2H), 7.50-7.30 (m, 5H), 6.84 (d, J=8.9 Hz, 2H), 5.02 (s, 2H).

(3) 1-(4-Benzyloxy)phenyl-2(S)-(tert-butoxycarbonyl)amino-3-phenyl-1-propanone

The title compound (14.69 g, 55.8 mmol) of Example 1(2) was dissolved in tetrahydrofuran (THF, 200 ml). To the solution was added dropwise n-butyllithium (1.57M hexane solution, 35.6 ml, 55.8 mmol) at −70° C. for 10 min and the mixture was stirred for 1 hr at −70° C. to −65° C. Then, a solution of N a -(tert-butoxycarbonyl)-L-phenylalanine N-methoxy-N-methylamide (5.74 g, 18.6 mmol) prepared according to the method of Jean-Alain Fehrentz et al. [Synthesis (1983) 676-678] and dissolved in THF (50 ml) was added dropwise at −70° C. over 5 min and the mixture was stirred for 30 min at −70° C. to −65° C. A saturated aqueous ammonium chloride solution (50 ml) was added to the reaction mixture under ice-cooling, and the mixture was concentrated. A saturated aqueous ammonium chloride solution (50 ml) was added to the obtained residue and the mixture was extracted with ethyl acetate (2×200 ml). The organic layer was washed with saturated brine (100 ml), dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (10:1 hexane-ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound (4.42 g, 55%) as a white solid.

1 H-NMR (300 MHz, CDCl 3 ) δ 7.92 (d, J=8.9 Hz, 2H), 7.50-6.95 (m, 10H), 7.01 (d, J=8.9 Hz, 2H), 5.55-5.35 (m, 2H), 5.14 (s, 2H), 3.22 (dd, J=13.7, 5.7 Hz, 1H), 2.96 (dd, J=13.7, 5.6 Hz, 1H), 1.42 (s, 9H).

(4) 2(S)-Amino-1-(4-benzyloxy)phenyl-3-phenyl-1-propanone Trifluoroacetate

The title compound (4.30 g, 9.97 mmol) of Example 1(3) was dissolved in methylene chloride (20 ml). Thereto was added trifluoroacetic acid (20 ml) under ice-cooling and the mixture was stirred for 30 min at the same temperature. The reaction mixture was concentrated and crystallized from diethyl ether to give the title compound (3.64 g, 82%) as a white solid.

1 H-NMR (300 MHz, CDCl 3 ) δ 7.78 (d, J=8.9 Hz, 2H), 7.50-7.05 (m, 10H), 6.95 (d, J=8.9 Hz, 2H), 5.27 (t, J=6.1 Hz, 1H), 5.10 (s, 2H), 3.32 (dd, J=14.4, 6.2 Hz, 1H), 3.25 (dd, J=14.4, 6.2 Hz, 1H).

(5) tert-Butyl 3(R)-[1(S)-(4-Benzyloxy)benzoyl-2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanoate

The title compound (3.60 g, 8.08 mmol) of Example 1(4), 4-tert-butoxy-2(R)-isobutyl-3(R or S)-phthalimidomethylsuccinic acid (3.15 g, 8.08 mmol) prepared according to the method described in JP-A-4-352757 and JP-A-7-157470, 1-hydroxybenzotriazole monohydrate (HOBt-H 2 O) (1.24 g, 8.08 mmol) and N-methylmorpholine (2.70 ml, 24.2 mmol) were dissolved in DMF (80 ml) and BOP reagent (5.36 g, 12.1 mmol) was added under ice-cooling, which was followed by stirring at room temperature for 6 hr. Water (300 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2×200 ml). The organic layer was washed successively with 1N hydrochloric acid (100 ml), water (100 ml), saturated aqueous sodium hydrogencarbonate solution (2×100 ml) and saturated brine (100 ml), dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (2:1 hexane-ethyl acetate) to give the title compound (5.35 g, 94%) as an amorphous powder.

1 H-NMR (300 MHz, CDCl 3 ) δ 7.99 (d, J=8.9 Hz, 2H), 7.90-7.80 (m, 2H), 7.78-7.65 (m, 2H), 7.48-7.30 (m, 5H), 7.23-7.10 (m, 4H), 7.10-7.03 (m, 1H), 7.01 (d, J=8.9 Hz, 2H), 6.93 (d, J=8.3 Hz, 1H), 6.00-5.90 (m, 1H), 5.14 (s, 2H), 3.49 (dd, J=14.0, 8.1 Hz, 1H), 3.38 (dd, J=14.0, 5.0 Hz, 1H), 3.28 (dd, J=14.1, 5.8 Hz, 1H), 3.02 (dd, J=14.1, 8.0 Hz, 1H), 3.00-2.88 (m, 1H), 2.68-2.55 (m, 1H), 1.75-1.60 (m, 1H), 1.50-1.30 (m, 1H), 1.26 (s, 9H), 1.12-0.98 (m, 1H), 0.80 (d, J=6.5 Hz, 3H), 0.76 (d, J=6.5 Hz, 3H).

(6) tert-Butyl 3(R)-[1(S)-(4-Hydroxy)benzoyl-2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanoate

A mixture of the title compound (5.00 g, 7.11 mmol) of Example 1(5), 10% palladium carbon catalyst (0.50 g) and ethanol (50 ml) was stirred for 28 hr at room temperature in a hydrogen atmosphere. The reaction mixture was filtrated and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (10:1 chloroform-methanol) to give the title compound (3.12 g, 72%) as an amorphous solid.

1 H-NMR (300 MHz, CDCl 3 ) δ 8.50 (s, 1H), 7.90-7.65 (m, 6H), 7.30-7.00 (m, 6H), 6.89 (d, J=8.5 Hz, 2H), 6.00-5.80 (m, 1H), 3.50 (dd, J=14.1, 8.1 Hz, 1H), 3.42-3.25 (m, 2H), 3.05-2.85 (m, 2H), 2.73-2.60 (m, 1H), 1.75-1.60 (m, 1H), 1.50-1.30 (m, 1H), 1.28 (s, 9H), 1.17-1.00 (m, 1H), 0.84 (d, J=6.3 Hz, 3H), 0.76 (d, J=6.3 Hz, 3H).

(7) tert-Butyl 5-Methyl-3(R)-[1(S)-[4-[2-[1-(4-methyl)piperazinyl]ethoxy]benzoyl]-2-phenyl]ethylcarbamoyl-2(R or S)-phthalimidomethylhexanoate

The title compound (200 mg, 0.33 mmol) of Example 1(6), the title compound (141 mg, 0.98 mmol) of Example 1(1) and triphenylphosphine (257 mg, 0.98 mmol) were dissolved in THF (5 ml). Diethyl azodicarboxylate (40% toluene solution, 426 mg, 0.98 mmol) was added to the solution under ice-cooling and the mixture was stirred for 4 hr at room temperature. The reaction mixture was concentrated and the obtained residue was purified by silica gel column chromatography (20:1 chloroform-methanol) to give the title compound (200 mg, 83%) as an amorphous solid.

1 H-NMR (300 MHz, CDCl 3 ) δ 7.97 (d, J=8.9 Hz, 2H), 7.90-7.78 (m, 2H), 7.78-7.65 (m, 2H), 7.22-7.12 (m, 4H), 7.12-7.00 (m, 1H), 7.00-6.80 (m, 1H), 6.94 (d, J=8.9 Hz, 2H), 6.00-5.90 (m, 1H), 4.17 (t, J=5.8 Hz, 2H), 3.55-3.45 (m, 1H), 3.45-3.35 (m, 1H), 3.35-3.20 (m, 1H), 3.10-2.90 (m, 2H), 2.84 (t, J=5.8 Hz, 2H), 2.75-2.35 (m, 9H), 2.30 (s, 3H), 1.73-1.60 (m, 1H), 1.35-1.26 (m, 1H), 1.26 (s, 9H), 1.12-1.00 (m, 1H), 0.81 (d, J=6.5 Hz, 3H), 0.76 (d, J=6.5 Hz, 3H).

(8) 5-Methyl-3(R)-[1(S)-[4-[2-[1-(4-methyl)piperazinyl]ethoxy]benzoyl]-2-phenyl]ethylcarbamoyl-2(R or S)-phthalimidomethylhexanoic Acid Ditrifluoroacetate

The title compound (200 mg, 0.27 mmol) of Example 1(7) was dissolved in methylene chloride (10 ml) and trifluoroacetic acid (10 ml) was added under ice-cooling. The mixture was stirred for 2 hr at room temperature. The reaction mixture was concentrated to give the title compound (217 mg, 88%) as an amorphous solid.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 8.70 (d, J=8.8 Hz, 1H), 8.03 (d, J=8.8 Hz, 2H), 7.95-7.82 (m, 4H), 7.35 (d, J=7.5 Hz, 2H), 7.12 (t, J=7.6 Hz, 2H), 7.05 (d, J=8.8 Hz, 2H), 6.85 (t, J=7.4 Hz, 1H), 5.75-5.60 (m, 1H), 4.20 (t, J=5.3 Hz, 2H), 3.20-3.00 (m, 5H), 3.00-2.85 (m, 3H), 2.85-2.60 (m, 4H), 2.78 (s, 3H), 2.60-2.40 (m, 2H), 2.40-2.25 (m, 1H), 1.50-1.35 (m, 1H), 1.10-0.95 (m, 1H), 0.90-0.75 (m, 1H), 0.68 (d, J=6.4 Hz, 3H), 0.61 (d, J=6.4 Hz, 3H).

(9) 2-Tetrahydropyranyl 5-Methyl-3(R)-[1(S)-[4-[2-[1-(4-methyl)piperazinyl]ethoxy]benzoyl]-2-phenyl]ethylcarbamoyl-2(R or S)-phthalimidomethylhexanohydroxamate

The title compound (210 mg, 0.23 mmol) of Example 1(8), O-2-tetrahydropyranylhydroxylamine (33 mg, 0.28 mmol), HOBt-H 2 O (36 mg, 0.23 mmol) and N-methylmorpholine (0.25 ml, 2.32 mmol) were dissolved in DMF (10 ml), and BOP reagent (154 mg, 0.35 mmol) was added under ice-cooling. The mixture was stirred for 13 hr at room temperature. Water (50 ml) was added and the mixture was extracted with ethyl acetate (2×50 ml). The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution (2×50 ml) and saturated brine (50 ml), dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (20:1 chloroform-methanol) to give the title compound (120 mg, 66%) as a white solid.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 10.95-10.80 (m, 1H), 8.72-8.60 (m, 1H), 8.00 (d, J=8.8 Hz, 2H), 7.95-7.75 (m, 4H), 7.35 (d, J=7.4 Hz, 2H), 7.09 (t, J=7.6 Hz, 2H), 7.02 (d, J=8.8 Hz, 2H), 6.81 (t, J=7.3 Hz, 1H), 5.70-5.55 (m, 1H), 4.55-4.30 (m, 1H), 4.11 (t, J=5.7 Hz, 2H), 3.70-3.55 (m, 1H), 3.18-3.05 (m, 1H), 3.05-2.95 (m, 1H), 2.95-2.80 (m, 1H), 2.80-2.55 (m, 1H), 2.64 (t, J=5.7 Hz, 2H), 2.55-2.20 (m, 10H), 2.20-2.05 (m, 1H), 2.14 (s, 3H), 1.60-1.20 (m, 7H), 1.05-0.90 (m, 1H), 0.80-0.70 (m, 1H), 0.64 (d, J=6.3 Hz, 3H), 0.60 (d, J=6.3 Hz, 3H).

(10) 5-Methyl-3(R)-[1(S)-[4-[2-[1-(4-methyl)piperazinyl]ethoxy]benzoyl]-2-phenyl]ethylcarbamoyl-2(R or S)-phthalimidomethylhexanohydroxamic Acid Dihydrochloride

To a solution of the title compound (110 mg, 0.14 mmol) of Example 1(9), methylene chloride (10 ml) and methanol (10 ml) was added 1.3N hydrogen chloride-methanol reagent (1 ml) under ice-cooling, and the mixture was stirred for 2 hr at room temperature. Diethyl ether was added to the reaction mixture to precipitate a solid to give the title compound (69 mg, 62%) as a white solid.

1 H-NMR (500 MHz, DMSO-d 6 ) δ 10.31 (br s, 1H), 8.63 (d, J=8.6 Hz, 1H), 8.04 (d, J=8.7 Hz, 2H), 7.90-7.80 (m, 4H), 7.35 (d, J=7.3 Hz, 2H), 7.10-7.05 (m, 4H), 6.79 (t, J=7.4 Hz, 1H), 5.70-5.60 (m, 1H), 4.50-4.20 (br, 2H), 3.65-3.15 (m, 11H), 3.11 (dd, J=14.0, 4.5 Hz, 1H), 2.86 (dd, J=14.0, 10.7 Hz, 1H), 2.81 (s, 3H), 2.50-2.40 (m, 2H), 2.25-2.15 (m, 1H), 1.41-1.32 (m, 1H), 1.08-0.97 (m, 1H), 0.82-0.75 (m, 1H), 0.68 (d, J=6.5 Hz, 3H), 0.62 (d, J=6.5 Hz, 3H).

3(R)-[1(S)-[4-(2-Dimethylaminoethoxy)benzoyl]-2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamic Acid Hydrochloride

(1) N,N-Dimethyl-2-(4-bromophenoxy)ethylamine

4-Bromophenol (10.0 g, 57.8 mmol) and 2-dimethylaminoethyl chloride hydrochloride (8.33 g, 57.8 mmol) were dissolved in DMF (200 ml), and potassium carbonate (24.0 g, 173 mmol) and sodium iodide (0.87 g, 5.78 mmol) were added under ice-cooling. The mixture was stirred for 13 hr at room temperature and at 70° C. for 3 hr. Water (400 ml) was added to the reaction mixture and the mixture was extracted with chloroform (2×200 ml). The organic layer was washed successively with water (2×200 ml) and saturated brine (200 ml), dried over anhydrous magnesium sulfate and concentrated. The obtained residue was dissolved in 1N hydrochloric acid (100 ml) and washed with ethyl acetate (2×200 ml). Sodium hydroxide (4 g) was added to the aqueous layer to make the layer alkaline, and the mixture was extracted with chloroform (2×200 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated. Hexane was added to the obtained residue and insoluble matter was filtered off. The mother liquor was concentrated to give the title compound (5.25 g, 37%) as a transparent oil.

1 H-NMR (300 MHz, CDCl 3 ) δ 7.36 (d, J=8.9 Hz, 2H), 6.80 (d, J=8.9 Hz, 2H), 4.02 (t, J=5.7 Hz, 2H), 2.71 (t, J=5.7 Hz, 2H), 2.33 (s, 6H).

(2) 2(S)-(tert-Butoxycarbonyl)amino-1-[4-(2-dimethylaminoethoxy)phenyl]-3-phenyl-1-propanone

According to the method of Example 1(3), the title compound of Example 2(1) and N α -(tert-butoxycarbonyl)-L-phenylalanine N-methoxy-N-methylamide were reacted and the resulting product was purified by silica gel column chromatography (100:1 chloroform-methanol), followed by recrystallization from hexane, to give the title compound (yield 15%) as a white solid.

1 H-NMR (300 MHz, CDCl 3 ) δ 7.91 (d, J=8.8 Hz, 2H), 7.30-7.12 (m, 3H), 7.02 (d, J=7.4 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 5.55-5.35 (m, 2H), 4.14 (t, J=5.7 Hz, 2H), 3.22 (dd, J=13.7, 5.7 Hz, 1H), 2.92 (dd, J=13.7, 5.5 Hz, 1H), 2.76 (t, J=5.7 Hz, 2H), 2.35 (s, 6H), 1.42 (s, 9H).

(3) 2(S)-Amino-1-[4-(2-dimethylaminoethoxy)phenyl]-3-phenyl-1-propanone Ditrifluoroacetate

The title compound of Example 2(2) was treated in the same manner as in Example 1(4) to give the title compound quantitatively as a yellow viscous oil.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 10.20-9.80 (br, 1H), 8.50-8.20 (br, 3H), 8.01 (d, J=8.9 Hz, 2H), 7.30-7.20 (m, 3H), 7.20-7.15 (m, 2H), 7.11 (d, J=8.9 Hz, 2H), 5.45-5.30 (m, 1H), 4.50-4.40 (m, 2H), 3.60-3.50 (m, 2H), 3.20-3.00 (m, 2H), 2.88 (s, 6H).

(4) tert-Butyl 3(R)-[1(S)-[4-(2-Dimethylaminoethoxy)benzoyl]-2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanoate

In the same manner as in Example 1(5), 4-tert-butoxy-2(R)-isobutyl-3(R or S)-phthalimidomethylsuccinic acid and the title compound of Example 2(3) were reacted and the resulting product was purified by silica gel column chromatography (50:1 chloroform-methanol) to give the title compound as an amorphous solid.

1 H-NMR (300 MHz, CDCl 3 ) δ 7.98 (d, J=8.9 Hz, 2H), 7.90-7.78 (m, 2H), 7.78-7.65 (m, 2H), 7.20-7.10 (m, 4H), 7.10-7.00 (m, 1H), 6.96 (d, J=8.9 Hz, 2H), 6.95-6.85 (m, 1H), 6.00-5.90 (m, 1H), 4.15 (t, J=5.6 Hz, 2H), 3.49 (dd, J=14.0, 8.1 Hz, 1H), 3.38 (dd, J=14.0, 5.0 Hz, 1H), 3.27 (dd, J=14.1, 5.8 Hz, 1H), 3.02 (dd, J=14.1, 7.9 Hz, 1H), 2.95-2.85 (m, 1H), 2.79 (t, J=5.6 Hz, 2H), 2.65-2.53 (m, 1H), 2.37 (s, 6H), 1.75-1.60 (m, 1H), 1.50-1.25 (m, 1H), 1.26 (s, 9H), 1.10-0.95 (m, 1H), 0.81 (d, J=6.6 Hz, 3H), 0.76 (d, J=6.6 Hz, 3H).

(5) 3(R)-[1(S)-[4-(2-Dimethylaminoethoxy)benzoyl]-2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanoic Acid Trifluoroacetate

The title compound of Example 2(4) was treated in the same manner as in Example 1(8) and the resulting product was crystallized from diethyl ether to give the title compound as a white solid at an overall yield from the title compound of Example 2(2) (3 steps) of 84%.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 12.80-12.00 (br, 1H), 9.80-9.40 (br, 1H), 8.71 (d, J=8.7 Hz, 1H), 8.07 (d, J=8.9 Hz, 2H), 7.95-7.80 (m, 4H), 7.36 (d, J=7.2 Hz, 2H), 7.20-7.00 (m, 4H), 6.84 (t, J=7.4 Hz, 1H), 5.75-5.65 (m, 1H), 4.40 (t, J=4.8 Hz, 2H), 3.52 (t, J=4.8 Hz, 2H), 3.45-3.30 (m, 1H), 3.11 (dd, J=13.9, 4.3 Hz, 1H), 2.90-2.80 (m, 1H), 2.86 (s, 6H), 2.70-2.60 (m, 1H), 2.55-2.45 (m, 1H), 2.35 (dd, J=13.6, 5.1 Hz, 1H), 1.50-1.35 (m, 1H), 1.10-0.90 (m, 1H), 0.90-0.75 (m, 1H), 0.69 (d, J=6.5 Hz, 3H), 0.62 (d, J=6.5 Hz, 3H).

(6) 2-Tetrahydropyranyl 3(R)-[1(S)-[4-(2-Dimethylaminoethoxy)benzoyl]-2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamate

In the same manner as in Example 1(9), the title compound of Example 2(5) and O-2-tetrahydropyranylhydroxylamine were reacted, and the product was purified by silica gel column chromatography (20:1 chloroform-methanol) and recrystallized from diethyl ether-hexane to give the title compound (yield 78%) as a white solid.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 11.00-10.80 (m, 1H), 8.75-8.60 (m, 1H), 8.00 (d, J=8.8 Hz, 2H), 7.90-7.85 (m, 4H), 7.36 (d, J=7.4 Hz, 2H), 7.09 (t, J=7.5 Hz, 2H), 7.02 (d, J=8.8 Hz, 2H), 6.81 (t, J=7.3 Hz, 1H), 5.70-5.55 (m, 1H), 4.55-4.30 (m, 1H), 4.09 (t, J=5.5 Hz, 2H), 3.70-3.60 (m, 1H), 3.50-3.25 (m, 2H), 3.13 (dd, J=14.0, 4.1 Hz, 1H), 3.05-2.65 (m, 1H), 2.87 (dd, J=14.0, 10.8 Hz, 1H), 2.58 (t, J=5.5 Hz, 2H), 2.55-2.47 (m, 1H), 2.47-2.40 (m, 1H), 2.19 (s, 6H), 2.09 (dd, J=13.5, 4.1 Hz, 1H), 1.60-1.20 (m, 7H), 1.10-0.90 (m, 1H), 0.82-0.70 (m, 1H), 0.64 (d, J=6.6 Hz, 3H), 0.60 (d, J=6.6 Hz, 3H).

(7) 3(R)-[1(S)-[4-(2-Dimethylaminoethoxy)benzoyl]-2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamic Acid Hydrochloride

The title compound of Example 2(6) was treated in the same manner as in Example 1(10) and the product was crystallized from diethyl ether to give the title compound (yield 86%) as a white solid.

1 H-NMR (500 MHz, DMSO-d 6 ) δ 10.33 (br s, 1H), 10.20-10.00 (br, 1H), 8.64 (d, J=8.6 Hz, 1H), 8.61 (br s, 1H), 8.07 (d, J=9.0 Hz, 2H), 8.00-7.82 (m, 4H), 7.36 (d, J=7.4 Hz, 2H), 7.11 (d, J=9.0 Hz, 2H), 7.08 (t, J=7.7 Hz, 2H), 6.78 (t, J=7.4 Hz, 1H), 5.71-5.63 (m, 1H), 4.45-4.35 (br t, 2H), 3.55-3.48 (br t, 2H), 3.48-3.40 (m, 1H), 3.09 (dd, J=14.0, 4.4 Hz, 1H), 2.90-2.85 (m, 1H), 2.84 (s, 6H), 2.49-2.42 (m, 2H), 2.20-2.13 (m, 1H), 1.40-1.30 (m, 1H), 1.08-0.95 (m, 1H), 0.81-0.73 (m, 1H), 0.67 (d, J=6.5 Hz, 3H), 0.62 (d, J=6.5 Hz, 3H).

3(R)-[1(S)-(2-Furyl)carbonyl-2-(4-guanidinophenyl)]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamic Acid Hydrochloride

(1) N a -(tert-Butoxycarbonyl)-L-(4-nitro)phenylalanine N-Methoxy-N-methylamide

According to the method of Jean-Alain Fehrentz et al. [Synthesis (1983) 676-678], N-(tert-butoxycarbonyl)-L-(4-nitro)phenylalanine and N,O-dimethylhydroxylamine hydrochloride were reacted and the resulting product was purified by silica gel column chromatography (2:1 hexane-ethyl acetate) to give the title compound (yield 96%) as a yellow viscous liquid.

1 H-NMR (300 MHz, CDCl 3 ) δ 8.15 (d, J=8.6 Hz, 2H), 7.34 (d, J=8.6 Hz, 2H), 5.25 (br d, J=8.7 Hz, 1H), 5.05-4.85 (m, 1H), 3.73 (s, 3H), 3.25-3.10 (m, 1H), 3.19 (s, 3H), 2.97 (dd, J=13.5, 7.2 Hz, 1H), 1.38 (s, 9H).

(2) 2(S)-(tert-Butoxycarbonyl)amino-1-(2-furyl)-3-(4-nitro)phenyl-1-propanone

According to the method of Example 1(3), furan and the title compound of Example 3(1) were reacted and the resulting product was recrystallized from ethyl acetate-hexane to give the title compound (yield 59%) as a pale-yellow solid.

1 H-NMR (300 MHz, CDCl 3 ) δ 8.12 (d, J=8.6 Hz, 2H), 7.64 (d, J=1.6 Hz, 1H), 7.45-7.25 (m, 3H), 6.59 (dd, J=3.6, 1.6 Hz, 1H), 5.45-5.25 (m, 2H), 3.45-3.20 (m, 1H), 3.20-3.00 (m, 1H), 1.40 (s, 9H).

(3) 3-(4-Amino)phenyl-2(S)-(tert-butoxycarbonyl)amino-1-(2-furyl)-1-propanone

A mixture of the title compound (1.00 g, 2.78 mmol) of Example 3(2), 10% palladium carbon catalyst (0.10 g), ethanol (20 ml) and ethyl acetate (20.ml) was stirred for 3 hr at room temperature in a hydrogen atmosphere. The reaction mixture was filtrated and the filtrate was concentrated to give the title compound (0.92 g, quantitatively) as an amorphous solid.

1 H-NMR (300 MHz, CDCl 3 ) δ 7.61 (d, J=1.2 Hz, 1H), 7.22 (d, J=3.5 Hz, 1H), 6.86 (d, J=8.1 Hz, 2H), 6.70-6.45 (m, 3H), 5.35-5.10 (m, 2H), 3.58 (br s, 2H), 3.10 (dd, J=13.9, 5.7 Hz, 1H), 2.93 (dd, J=13.9, 5.6 Hz, 1H), 1.41 (s, 9H).

(4) 2(S)-(tert-Butoxycarbonyl)amino-3-[4-(2,3-dibenzyloxycarbonylguanidino)phenyl]-1-(2-furyl)-1-propanone

The title compound (0.92 g, 2.78 mmol) of Example 3(3) was dissolved in methylene chloride (30 ml). 1H-Pyrazole-1-(N,N′-dibenzyloxycarbonyl)carboxamidine (1.58 g, 4.16 mmol) was added under ice-cooling and the mixture was stirred for 65 hr at room temperature. The reaction mixture was concentrated and recrystallized from ethyl acetate-hexane to give the title compound (1.56 g, 88%) as a white solid.

1 H-NMR (300 MHz, CDCl 3 ) δ 11.88 (br s, 1H), 10.20 (br s, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.55-7.25 (m, 10H), 7.46 (d, J=8.3 Hz, 2H), 7.24 (d, J=3.6 Hz, 1H), 7.05 (d, J=8.3 Hz, 2H), 6.53 (dd, J=3.6, 1.6 Hz, 1H), 5.35-5.20 (m, 2H), 5.23 (s, 2H), 5.14 (s, 2H), 3.30-3.10 (m, 1H), 3.10-2.95 (m, 1H), 1.41 (s, 9H).

(5) 2(S)-Amino-3-[4-(2,3-dibenzyloxycarbonylguanidino)phenyl]-1-(2-furyl)-1-propanone Trifluoroacetate

The title compound of Example 3(4) was treated in the same manner as in Example 1(4) and the product was crystallized from diethyl ether to give the title compound (yield 89%) as a white solid.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 11.40-11.20 (br, 1H), 9.95 (s, 1H), 8.50-8.10 (br, 3H), 8.08 (d, J=1.7 Hz, 1H), 7.65 (d, J=3.7 Hz, 1H), 7.55-7.25 (m, 10H), 7.48 (d, J=8.5 Hz, 2H), 7.16 (d, J=8.5 Hz, 2H), 6.75 (dd, J=3.7, 1.7 Hz, 1H), 5.25 (s, 2H), 5.04 (s, 2H), 4.96 (t, J=6.7 Hz, 1H), 3.20-3.00 (m, 2H).

(6) tert-Butyl 3(R)-[2-[4-(2,3-Dibenzyloxycarbonylguanidino)phenyl]-1(S)-(2-furyl)carbonyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanoate

In the same manner as in Example 1(5), 4-tert-butoxy-2(R)-isobutyl-3(R or S)-phthalimidomethylsuccinic acid and the title compound of Example 3(5) were reacted and the product was purified by silica gel column chromatography (1:1 hexane-ethyl acetate) to give the title compound (yield 82%) as an amorphous solid.

1 H-NMR (300 MHz, CDCl 3 ) δ 11.60 (s, 1H), 10.07 (s, 1H), 7.75-7.65 (m, 2H), 7.63 (d, J=1.7 Hz, 1H), 7.59-7.51 (m, 2H), 7.48 (d, J=8.5 Hz, 2H), 7.45-7.25 (m, 11H), 7.21 (d, J=8.5 Hz, 2H), 6.71 (d, J=8.7 Hz, 1H), 6.55 (dd, J=3.6, 1.7 Hz, 1H), 5.82-5.70 (m, 1H), 5.19 (s, 2H), 5.10 (s, 2H), 3.45 (dd, J=13.9, 8.8 Hz, 1H), 3.29 (dd, J=14.1, 5.7 Hz, 1H), 3.14 (dd, J=13.9, 4.8 Hz, 1H), 2.96 (dd, J=14.1, 9.0 Hz, 1H), 2.95-2.83 (m, 1H), 2.55 (ddd, J=10.2, 10.2, 2.9 Hz, 1H), 1.75-1.60 (m, 1H), 1.50-1.30 (m, 1H), 1.24 (s, 9H), 1.10-0.95 (m, 1H), 0.84 (d, J=6.5 Hz, 3H), 0.78 (d, J=6.5 Hz, 3H).

(7) 3(R)-[2-[4-(2,3-Dibenzyloxycarbonylguanidino)phenyl]-1(S)-(2-furyl)carbonyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanoic Acid

The title compound of Example 3(6) was treated in the same manner as in Example 1(8) and the product was crystallized from diethyl ether to give the title compound (yield 79%) as a white solid.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 12.40-12.10 (br, 1H), 10.95 (s, 1H), 9.81 (s, 1H), 8.68 (d, J=8.9 Hz, 1H), 8.08 (d, J=1.7 Hz, 1H), 7.79 (d, J=3.6 Hz, 1H), 7.66-7.58 (m, 2H), 7.57-7.30 (m, 16H), 6.77 (dd, J=3.6, 1.7 Hz, 1H), 5.63-5.50 (m, 1H), 5.21 (s, 2H), 5.04 (s, 2H), 3.50-3.25 (m, 1H), 3.20-3.05 (m, 1H), 2.88-2.70 (m, 1H), 2.60-2.40 (m, 2H), 1.90-1.78 (m, 1H), 1.50-1.35 (m, 1H), 1.20-1.05 (m, 1H), 0.87-0.75 (m, 1H), 0.75 (d, J=6.5 Hz, 3H), 0.66 (d, J=6.5 Hz, 3H).

(8) 2-Tetrahydropyranyl 3(R)-[2-[4-(2,3-Dibenzyloxycarbonylguanidino)phenyl]-1(S)-(2-furyl)carbonyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamate

In the same manner as in Example 1(9), the title compound of Example 3(7) and O-2-tetrahydropyranylhydroxylamine were reacted, and water (50 ml)-diethyl ether (50 ml) was added to the reaction mixture under ice-cooling. The precipitated solid was collected by filtration, washed successively with water, saturated aqueous sodium hydrogencarbonate solution, water and diethyl ether, and dried to give the title compound (yield 75%) as a white solid.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 11.00-10.75 (m, 2H), 9.90-9.65 (br, 1H), 8.64 (d, J=8.6 Hz, 1H), 8.10-8.00 (m, 1H), 7.90-7.20 (m, 19H), 6.80-6.70 (m, 1H), 5.60-5.40 (m, 1H), 5.30-4.85 (m, 4H), 4.55-4.30 (m, 1H), 3.70-2.90 (m, 3H), 2.90-2.70 (m, 1H), 2.70-2.25 (m, 3H), 1.90-1.60 (m, 1H), 1.60-1.18 (m, 7H), 1.18-1.00 (m, 1H), 0.90-0.75 (m, 1H), 0.73 (d, J=6.3 Hz, 3H), 0.65 (d, J=6.3 Hz, 3H).

(9) 2-Tetrahydropyranyl 3(R)-[1(S)-(2-Furyl)carbonyl-2-(4-guanidino)phenyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamate Acetate

A mixture of the title compound (395 mg, 0.41 mmol) of Example 3(8), 10% palladium carbon catalyst (40 mg), methanol (20 ml), methylene chloride (20 ml) and acetic acid (1 ml) was stirred for 26 hr at room temperature in a hydrogen atmosphere. The reaction mixture was filtrated and the filtrate was concentrated. The obtained residue was recrystallized from ethyl acetate-diethyl ether to give the title compound (294 mg, 95%) as a white solid.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 11.10-10.90 (br, 1H), 8.78 (d, J=8.3 Hz, 1H), 8.02 (d, J=1.6 Hz, 1H), 7.90-7.80 (m, 4H), 7.56 (d, J=3.6 Hz, 1H), 7.50-7.10 (br, 4H), 7.34 (d, J=8.3 Hz, 2H), 6.96 (d, J=8.3 Hz, 2H), 6.73 (dd, J=3.6, 1.6 Hz, 1H), 5.40-5.23 (m, 1H), 4.60-4.35 (m, 1H), 3.80-2.45 (m, 8H), 1.74 (s, 3H), 1.60-1.10 (m, 8H), 0.93-0.80 (m, 1H), 0.76 (d, J=6.3 Hz, 3H), 0.68 (d, J=6.3 Hz, 3H).

(10) 3(R)-[1(S)-(2-Furyl)carbonyl-2-(4-guanidinophenyl)]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamic Acid Hydrochloride

The title compound of Example 3(9) was treated in the same manner as in Example 1(10) and the product was crystallized from diethyl ether to give the title compound (yield 90%) as a white solid.

1 H-NMR (500 MHz, DMSO-d 6 ) δ 10.42 (br s, 1H), 9.38 (br s, 1H), 8.78 (d, J=8.1 Hz, 1H), 8.75-8.60 (br, 1H), 8.01 (d, J=1.7 Hz, 1H), 7.90-7.80 (m, 4H), 7.55 (d, J=3.6 Hz, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.09 (br s, 4H), 7.03 (d, J=8.4 Hz, 2H), 6.73 (dd, J=3.6, 1.7 Hz, 1H), 5.35-5.28 (m, 1H), 3.90-3.60 (m, 1H), 3.12 (dd, J=14.0, 5.4 Hz, 1H), 2.93 (dd, J=14.0, 9.4 Hz, 1H), 2.75 (dd, J=13.5, 3.8 Hz, 1H), 2.62-2.55 (m, 1H), 1.47-1.32 (m, 1H), 1.25-1.12 (m, 1H), 0.92-0.83 (m, 1H), 0.76 (d, J=6.5 Hz, 3H), 0.69 (d, J=6.5 Hz, 3H).

3(R)-[1(S)-[2-[5-(2-Dimethylaminoethoxy)methyl]furyl]-carbonyl-2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamic Acid Hydrochloride

(1) 2-[(2-Dimethylaminoethoxy)methyl]furan

Furfuryl alcohol (10.0 g, 102 mmol) was dissolved in DMF (200 ml) and sodium hydride (60% dispersion in oil, 9.00 g, 225 mmol) was added under ice-cooling. The mixture was stirred for 15 min at the same temperature. Then, 2-dimethylaminoethyl chloride hydrochloride (15.4 g, 107 mmol) was added under ice-cooling and the mixture was stirred at the same temperature for 30 min and at room temperature for 3.5 hr. Water (200 ml) was added to the reaction mixture under ice-cooling and the mixture was extracted with diethyl ether (2×500 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (20:1 chloroform-methanol) to give the title compound (4.19 g, 24%) as a red-brown liquid.

1 H-NMR (300 MHz, CDCl 3 ) δ 7.45-7.35 (m, 1H), 6.40-6.30 (m, 2H), 4.48 (s, 2H), 3.56 (t, J=5.8 Hz, 2H), 2.51 (t, J=5.8 Hz, 2H), 2.25 (s, 6H).

(2) 2(S)-(tert-Butoxycarbonyl)amino-1-[2-[5-(2-dimethylaminoethoxy)methyl]furyl]-3-phenyl-1-propanone

Diisopropylamine (3.65 ml, 26.1 mmol) was dissolved in THF (50 ml) and n-butyllithium (1.57M hexane solution, 16.6 ml, 26.1 mmol) was added dropwise under ice-cooling. The mixture was stirred for 30 min at the same temperature. Then, a solution of the title compound (4.19 g, 24.8 mmol) of Example 4(1) dissolved in THF (25 ml) was added dropwise at −78° C. and the mixture was stirred for 40 min at the same temperature. A solution of N α -(tert-butoxycarbonyl)-L-phenylalanine N-methoxy-N-methylamide (2.55 g, 8.27 mmol) dissolved in THF (25 ml) was added dropwise at −78° C. and the mixture was stirred for 3 hr at the same temperature. A 5% aqueous citric acid solution (50 ml) was added and THF was evaporated under reduced pressure. The obtained residue was extracted with ethyl acetate (3×100 ml). The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution (2×100 ml) and saturated brine (100 ml), dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (20:1 chloroform-methanol) to give the title compound (280 mg, 8%) as a red-brown liquid.

1 H-NMR (300 MHz, CDCl 3 ) δ 7.35-7.05 (m, 6H), 6.45 (d, J=3.5 Hz, 1H), 5.40-5.20 (m, 2H), 4.52 (s, 2H), 3.70-3.50 (m, 2H), 3.18 (dd, J=13.2, 5.9 Hz, 1H), 3.02 (dd, J=13.2, 5.7 Hz, 1H), 2.60-2.45 (m, 2H), 2.25 (s, 6H), 1.41 (s, 9H).

(3) 2(S)-Amino-1-[2-[5-(2-dimethylaminoethoxy)methyl]furyl]-3-phenyl-1-propanone Ditrifluoroacetate

The title compound of Example 4(2) was treated in the same manner as in Example 1(4) to give the title compound quantitatively as a red oil.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 9.45-9.10 (br, 3H), 8.60-8.40 (br, 1H), 7.59 (d, J=3.7 Hz, 1H), 7.35-7.15 (m, 5H), 6.72 (d, J=3.7 Hz, 1H), 5.10-4.90 (m, 1H), 4.58 (s, 2H), 3.80-3.65 (m, 2H), 3.20-3.10 (m, 4H), 2.78 (s, 6H).

(4) tert-Butyl 3(R)-[1(S)-[2-[5-(2-Dimethylaminoethoxy)methyl]furyl]carbonyl-2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanoate

In the same manner as in Example 1(5), 4-tert-butoxy-2(R)-isobutyl-3(R or S)-phthalimidomethylsuccinic acid and the title compound of Example 4(3) were reacted and the resulting product was purified by silica gel column chromatography (10:1 chloroform-methanol) to give the title compound as an amorphous solid at an overall yield (2 steps) of 20% from the title compound of Example 4(2).

1 H-NMR (300 MHz, DMSO-d 6 ) δ 8.77 (d, J=8.5 Hz, 1H), 7.98-7.80 (m, 4H), 7.61 (d, J=3.5 Hz, 1H), 7.35 (d, J=7.0 Hz, 2H), 7.12 (t, J=7.6 Hz, 2H), 6.86 (t, J=7.3 Hz, 1H), 6.67 (d, J=3.5 Hz, 1H), 5.50-5.35 (m, 1H), 4.52 (s, 2H), 3.60-3.40 (m, 1H), 3.52 (t, J=5.9 Hz, 2H), 3.10 (dd, J=13.9, 4.4 Hz, 1H), 2.87 (dd, J=13.9, 10.7 Hz, 1H), 2.78-2.45 (m, 2H), 2.45-2.30 (m, 1H), 2.40 (t, J=5.9 Hz, 2H), 2.13 (s, 6H), 1.55-1.30 (m, 1H), 1.30-1.05 (m, 1H), 1.09 (s, 9H), 0.90-0.70 (m, 1H), 0.79 (d, J=6.4 Hz, 3H), 0.68 (d, J=6.4 Hz, 3H).

(5) 3(R)-[1(S)-[2-[5-(2-Dimethylaminoethoxy)methyl]furyl]carbonyl-2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanoic Acid Trifluoroacetate

The title compound of Example 4(4) was treated in the same manner as in Example 1(8) to give the title compound (yield 98%) as an amorphous solid.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 12.60-12.30 (br, 1H), 9.50-9.25 (br, 1H), 8.75 (d, J=8.2 Hz, 1H), 7.95-7.75 (m, 4H), 7.63 (d, J=3.5 Hz, 1H), 7.35 (d, J=7.3 Hz, 2H), 7.13 (t, J=7.6 Hz, 2H), 6.87 (t, J=7.4 Hz, 1H), 6.75 (d, J=3.5 Hz, 1H), 5.48-5.32 (m, 1H), 4.63 (s, 2H), 3.82-3.70 (m, 2H), 3.45 (dd, J=13.4, 11.1 Hz, 1H), 3.10 (dd, J=13.9, 4.5 Hz, 1H), 2.86 (dd, J=13.9, 10.9 Hz, 1H), 2.85-2.40 (m, 5H), 1.55-1.30 (m, 1H), 1.30-1.10 (m, 1H), 0.95-0.75 (m, 1H), 0.80 (d, J=6.5 Hz, 3H), 0.70 (d, J=6.5 Hz, 3H).

(6) 2-Tetrahydropyranyl 3(R)-[1(S)-[2-[5-(2-Dimethylaminoethoxy)methyl]furyl]carbonyl-2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamate

In the same manner as in Example 1(9), the title compound of Example 4(5) and O-2-tetrahydropyranylhydroxylamine were reacted and the resulting product was purified by silica gel column chromatography (10:1 chloroform-methanol) to give the title compound (yield 47%) as an amorphous solid.

1 H-NMR (500 MHz, DMSO-d 6 ) δ 11.00-10.85 (m, 1H), 8.72-8.65 (m, 1H), 7.88-7.78 (m, 4H), 7.64-7.58 (m, 1H), 7.35 (d, J=7.1 Hz, 2H), 7.08 (t, J=7.6 Hz, 2H), 6.73-6.68 (m, 1H), 6.67 (d, J=3.5 Hz, 1H), 5.42-5.32 (m, 1H), 4.52 (s, 2H), 4.57-4.35 (m, 1H), 3.72-3.30 (m, 2H), 3.53 (t, J=5.9 Hz, 2H), 3.13-3.00 (m, 1H), 2.92-2.78 (m, 1H), 2.78-2.20 (m, 4H), 2.41 (t, J=5.9 Hz, 2H), 2.13 (s, 6H), 1.60-1.10 (m, 8H), 0.95-0.75 (m, 1H), 0.76 (d, J=6.5 Hz, 3H), 0.67 (d, J=6.5 Hz, 3H).

(7) 3(R)-[1(S)-[2-[5-(2-Dimethylaminoethoxy)methyl]furyl]carbonyl2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamic Acid Hydrochloride

The title compound of Example 4(6) was treated in the same manner as in Example 1(10) and the resulting product was crystallized from diethyl ether to give the title compound (yield 63%) as a white solid.

1 H-NMR (500 MHz, DMSO-d 6 ) δ 10.33 (br s, 1H), 8.68 (d, J=8.1 Hz, 1H), 8.60 (br s, 1H), 7.90-7.80 (m, 4H), 7.62 (d, J=3.5 Hz, 1H), 7.35 (d, J=7.1 Hz, 2H), 7.09 (t, J=7.7 Hz, 2H), 6.81 (t, J=7.4 Hz, 1H), 6.74 (d, J=3.5 Hz, 1H), 5.40-5.32 (m, 1H), 4.63 (s, 2H), 3.79 (t, J=5.1 Hz, 2H), 3.48 (dd, J=13.4, 11.3 Hz, 1H), 3.09 (dd, J=13.8, 4.4 Hz, 1H), 2.86 (dd, J=13.8, 10.7 Hz, 1H), 2.80-2.72 (m, 2H), 2.78 (s, 6H), 2.67-2.40 (m, 2H), 2.30 (dd, J=13.4, 4.4 Hz, 1H), 1.45-1.35 (m, 1H), 1.27-1.15 (m, 1H), 0.90-0.75 (m, 1H), 0.78 (d, J=6.6 Hz, 3H), 0.69 (d, J=6.6 Hz, 3H).

3(R)-[2-[4-(2-Dimethylaminoethoxy)phenyl]-1(S)-(2-furyl)carbonyl]ethylcarbamoyl-5-methyl-2(R or S)-(2,5-dioxo-3,4,4-trimethyl-1-imidazolidinyl)methylhexanohydroxamic Acid Hydrochloride

(1) N α -(tert-Butoxycarbonyl)-L-(O-benzyl)tyrosine N-Methoxy-N-methylamide

According to the method of Jean-Alain Fehrentz et al. [Synthesis (1983) 676-678], N-(tert-butoxycarbonyl)-L-(O-benzyl)tyrosine and N,O-dimethylhydroxylamine hydrochloride were reacted, and the resulting product was purified by silica gel column chromatography (2:1 hexane-ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound (yield 89%) as a white solid.

1 H-NMR (300 MHz, CDCl 3 ) δ 7.50-7.20 (m, 5H), 7.08 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.5 Hz, 2H), 5.22-5.08 (m, 1H), 5.03 (s, 2H), 4.98-4.80 (m, 1H), 3.65 (br s, 3H), 3.16 (br s, 3H), 3.07-2.90 (m, 1H), 2.90-2.75 (m, 1H), 1.39 (s, 9H).

(2) 3-(4-Benzyloxy)phenyl-2(S)-(tert-butoxycarbonyl)amino-1-(2-furyl)-1-propanone

According to the method of Example 1(3), furan and the title compound of Example 5(1) were reacted, and the product was purified by silica gel column chromatography (1:1 hexane-ethyl acetate) and crystallized from hexane to give the title compound (yield 83%) as a yellow solid.

1 H-NMR (300 MHz, CDCl 3 ) δ 7.65-7.55 (m, 1H), 7.48-7.25 (m, 5H), 7.23 (d, J=3.6 Hz, 1H), 7.00 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 6.60-6.45 (m, 1H), 5.38-5.15 (m, 2H), 5.02 (br s, 2H), 3.16 (dd, J=13.6, 4.9 Hz, 1H), 2.98 (dd, J=13.6, 5.3 Hz, 1H), 1.41 (s, 9H).

(3) 2(S)-Amino-3-(4-benzyloxy)phenyl-1-(2-furyl)-1-propanone Trifluoroacetate

The title compound of Example 5(2) was treated in the same manner as in Example 1(4) and the product was crystallized from diethyl ether-hexane to give the title compound quantitatively as a brown solid.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 8.60-8.20 (br, 3H), 8.08 (d, J=1.6 Hz, 1H), 7.63 (d, J=3.6 Hz, 1H), 7.50-7.25 (m, 5H), 7.09 (d, J=8.6 Hz, 2H), 6.92 (d, J=8.6 Hz, 2H), 6.75 (dd, J=3.6, 1.6 Hz, 1H), 5.06 (s, 2H), 4.95 (t, J=6.7 Hz, 1H), 3.07 (d, J=6.7 Hz, 2H).

(4) tert-Butyl 3(R)-[2-(4-Benzyloxy)phenyl-1(S)-(2-furyl)carbonyl]ethylcarbamoyl-5-methyl-2(R or S)-(2,5-dioxo-3,4,4-trimethyl-1-imidazolidinyl)methylhexanoate

In the same manner as in Example 1(5), 4-tert-butoxy-2(R)-isobutyl-3(R or S)-(2,5-dioxo-3,4,4-trimethyl-1-imidazolidinyl)methylsuccinic acid prepared according to the method described in JP-A-6-65196 and the title compound, of Example 5(3) were reacted and the product was purified by silica gel column chromatography (1:1 hexane-ethyl acetate) to give the title compound (yield 68%) as an amorphous solid.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 8.69 (d, J=8.5 Hz, 1H), 8.04 (d, J=1.6 Hz, 1H), 7.65 (d, J=3.6 Hz, 1H), 7.45-7.25 (m, 5H), 7.26 (d, J=8.5 Hz, 2H), 6.79 (d, J=8.5 Hz, 2H), 6.74 (dd, J=3.6, 1.6 Hz, 1H), 5.42-5.30 (m, 1H), 4.94 (s, 2H), 3.40-3.18 (m, 1H), 3.02 (dd, J=13.8, 4.3 Hz, 1H), 2.90-2.70 (m, 1H), 2.65 (s, 3H), 2.70-2.40 (m, 2H), 2.19 (dd, J=13.4, 4.4 Hz, 1H), 1.37-1.00 (m, 1H), 1.29 (s, 9H), 1.26 (s, 6H), 0.90-0.70 (m, 1H), 0.79 (d, J=6.5 Hz, 3H), 0.68 (d, J=6.5 Hz, 3H).

(5) tert-Butyl 3(R)-[1(S)-(2-Furyl)carbonyl-2-(4-hydroxy)phenyl]ethylcarbamoyl-5-methyl-2(R or S)-(2,5-dioxo-3,4,4-trimethyl-1-imidazolidinyl)methylhexanoate

In the same manner as in Example 1(6), the title compound of Example 5(4) was subjected to catalytic hydrogenation and the resulting product was purified by silica gel column chromatography (50:1 chloroform-methanol) to give the title compound (yield 49%) as an amorphous solid.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 9.04 (br s, 1H), 8.66 (d, J=8.4 Hz, 1H), 8.03 (d, J=1.6 Hz, 1H), 7.61 (d, J=3.6 Hz, 1H), 7.10 (d, J=8.0 Hz, 2H), 6.73 (dd, J=3.6, 1.6 Hz, 1H), 6.52 (d, J=8.0 Hz, 2H), 5.38-5.25 (m, 1H), 2.96 (dd, J=13.8, 4.5 Hz, 1H), 2.88-2.65 (m, 1H), 2.76 (s, 3H), 2.65-2.40 (m, 2H), 2.21 (dd, J=13.6, 4.6 Hz, 1H), 1.55-1.38 (m, 1H), 1.30 (s, 9H), 1.26 (s, 6H), 1.25-1.05 (m, 1H), 0.85-0.70 (m, 1H), 0.78 (d, J=6.5 Hz, 3H), 0.68 (d, J=6.5 Hz, 3H).

(6) tert-Butyl 3(R)-[2-[4-(2-Dimethylaminoethoxy)phenyl]-1(s)-(2-furyl)carbonyl]ethylcarbamoyl-5-methyl-2(R or S)-(2,5-dioxo-3,4,4-trimethyl-1-imidazolidinyl)methylhexanoate

In the same manner as in Example 1(7), the title compound of Example 5(5) and 2-dimethylaminoethanol were reacted and the product was purified by silica gel column chromatography (20:1 chloroform-methanol) to give the title compound as an amorphous solid.

1 H-NMR (300 MHz, CDCl 3 ) δ 7.60 (d, J=1.7 Hz, 1H), 7.28 (d, J=3.6 Hz, 1H), 7.18 (d, J=8.5 Hz, 1H), 7.10 (d, J=8.5 Hz, 2H), 6.75 (d, J=8.5 Hz, 2H), 6.52 (dd, J=3.6, 1.7 Hz, 1H), 5.70-5.58 (m, 1H), 3.98 (t, J=5.8 Hz, 2H), 3.43 (dd, J=14.3, 4.9 Hz, 1H), 3.25 (dd, J=14.3, 6.2 Hz, 1H), 3.20 (dd, J=14.6, 6.1 Hz, 1H), 2.99 (dd, J=14.6, 8.2 Hz, 1H), 2.85-2.75 (m, 1H), 2.70-2.55 (m, 1H), 2.67 (t, J=5.8 Hz, 2H), 2.31 (s, 6H), 1.70-1.55 (m, 1H), 1.45-1.20 (m, 1H), 1.39 (s, 9H), 1.37 (s, 6H), 1.05-0.95 (m, 1H), 0.80 (d, J=6.5 Hz, 3H), 0.76 (d, J=6.5 Hz, 3H).

(7) 3(R)-[2-[4-(2-Dimethylaminoethoxy)phenyl]-1(S)-(2-furyl)carbonyl]ethylcarbamoyl-5-methyl-2(R or S)-(2,5-dioxo-3,4,4-trimethyl-1-imidazolidinyl)methylhexanoic Acid Trifluoroacetate

The title compound of Example 5(6) was treated in the same manner as in Example 1(8) to give the title compound as an amorphous solid.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 8.69 (d, J=8.3 Hz, 1H), 8.02 (d, J=1.7 Hz, 1H), 7.59 (d, J=3.5 Hz, 1H), 7.27 (d, J=8.6 Hz, 2H), 6.81 (d, J=8.6 Hz, 2H), 6.72 (dd, J=3.5, 1.7 Hz, 1H), 5.40-5.28 (m, 1H), 4.20-4.00 (m, 2H), 3.40-3.28 (m, 1H), 3.28-3.15 (m, 2H), 3.04 (dd, J=13.8, 5.6 Hz, 1H), 2.82 (s, 6H), 2.90-2.70 (m, 1H), 2.70-2.40 (m, 3H), 1.50-1.35 (m, 1H), 1.30-1.10 (m, 1H), 1.25 (s, 6H), 0.90-0.75 (m, 1H), 0.75 (d, J=6.5 Hz, 3H), 0.67 (d, J=6.5 Hz, 3H).

(8) 2-Tetrahydropyranyl 3(R)-[2-[4-(2-Dimethylaminoethoxy)phenyl]-1(S)-(2-furyl)carbonyl]ethylcarbamoyl-5-methyl-2(R or S)-(2,5-dioxo-3,4,4-trimethyl-1-imidazolidinyl)methylhexanohydroxamate

In the same manner as in Example 1(9), the title compound of Example 5(7) and O-2-tetrahydropyranylhydroxylamine were reacted, and the resulting product was purified by silica gel column chromatography (20:1 chloroform-methanol) and crystallized from hexane to give the title compound as a pale-yellow solid at an overall yield (3 steps) of 42% from the title compound of Example 5(5).

1 H-NMR (300 MHz, DMSO-d 6 ) δ 11.10-10.90 (m, 1H), 8.65-8.50 (m, 1H), 8.08-8.00 (m, 1H), 7.70-7.62 (m, 1H), 7.25 (d, J=8.4 Hz, 2H), 6.88-6.63 (m, 3H), 5.38-5.20 (m, 1H), 4.12-3.95 (m, 2H), 3.95-3.70 (m, 1H), 33-3.10 (m, 1H), 3.08-2.95 (m, 1H), 2.85-2.05 (m, 10H), 2.20 (s, 6H), 1.70-1.05 (m, 14H), 0.90-0.70 (m, 1H), 0.76 (d, J=6.5 Hz, 3H), 0.67 (d, J=6.5 Hz, 3H).

(9) 3(R)-[2-[4-(2-Dimethylaminoethoxy)phenyl]-1(S)-(2-furyl)carbonyl]ethylcarbamoyl-5-methyl-2(R or S)-(2,5-dioxo-3,4,4-trimethyl-1-imidazolidinyl)methylhexanohydroxamic Acid Hydrochloride

The title compound of Example 5(8) was treated in the same manner as in Example 1(10) and diethyl ether was added to the reaction mixture. The precipitated solid was collected by filtration. The obtained solid was purified by reversed phase column chromatography (Chromatorex ODS DM-1020T, Fuji Silysia Chemical Ltd.; 17-33% acetonitrile-0.1% aqueous trifluoroacetic acid solution) and lyophilized. 0.1N Hydrochloric acid (20 ml) was added to the obtained residue and the mixture was again lyophilized to give the title compound (164 mg, 45%) as an amorphous solid.

1 H-NMR (500 MHz, DMSO-d 6 ) δ 10.37 (br s, 1H), 9.95-9.75 (br, 1H), 8.72-8.62 (br, 1H), 8.61 (d, J=8.0 Hz, 1H), 8.01 (d, J=1.7 Hz, 1H), 7.58 (d, J=3.6 Hz, 1H), 7.27 (d, J=8.6 Hz, 2H), 6.80 (d, J=8.6 Hz, 2H), 6.72 (dd, J=3.6, 1.7 Hz, 1H), 5.32-5.25 (m, 1H), 4.22-4.10 (m, 2H), 3.45-3.20 (m, 3H), 3.03 (dd, J=13.9, 5.3 Hz, 1H), 2.88-2.80 (m, 1H), 2.81 (s, 6H), 2.76 (s, 3H), 2.57-2.45 (m, 2H), 2.40-2.30 (m, 1H), 1.43-1.35 (m, 1H), 1.25 (s, 3H), 1.23 (s, 3H), 1.20-1.10 (m, 1H), 0.85-0.75 (m, 1H), 0.74 (d, J=6.6 Hz, 3H), 0.67 (d, J=6.6 Hz, 3H).

Sodium Salt of 3(R)-[1(S)-(2-furyl)carbonyl-2-[4-(hydroxysulfonyloxy)phenyl]]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamic Acid

(1) tert-Butyl 3(R)-[2-(4-Benzyloxy)phenyl-1(S)-(2-furyl)carbonyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanoate

In the same manner as in Example 1(5), 4-tert-butoxy-2(R)-isobutyl-3(R or S)-phthalimidomethylsuccinic acid and the title compound of Example 5(3) were reacted, and the resulting product was purified by silica gel column chromatography (2:1 hexane-ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound (yield 56%) as a white solid.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 8.73 (d, J=8.8 Hz, 1H), 8.07 (d, J=1.3 Hz, 1H), 7.90-7.73 (m, 4H), 7.73 (d, J=3.4 Hz, 1H), 7.31 (d, J=8.6 Hz, 2H), 7.25-7.10 (m, 3H), 6.98-6.85 (m, 2H), 6.80-6.70 (m, 3H), 5.55-5.40 (m, 1H), 4.57 (s, 2H), 3.45-3.25 (m, 1H), 3.06 (dd, J 13.8, 4.0 Hz, 1H), 2.79 (dd, J=13.8, 11.8 Hz, 1H), 2.64 (ddd, J=11.2, 11.1, 5.0 Hz, 1H), 2.58-2.45 (m, 1H), 2.10 (dd, J=13.7, 5.1 Hz, 1H), 1.55-1.38 (m, 1H), 1.25-0.95 (m, 1H), 1.07 (s, 9H), 0.90-0.60 (m, 1H), 0.78 (d, J=6.5 Hz, 3H), 0.68 (d, J=6.5 Hz, 3H).

(2) tert-Butyl 3(R)-[1(S)-(2-Furyl)carbonyl-2-(4-hydroxy)phenyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanoate

In the same manner as in Example 1(6), the title compound of Example 6(1) was subjected to catalytic hydrogenation, and the product was purified by silica gel column chromatography (1:1 hexane-ethyl acetate) to give the title compound (yield 62%) as an amorphous solid.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 8.82 (br s, 1H), 8.69 (d, J=8.6 Hz, 1H), 8.05 (d, J=1.7 Hz, 1H), 7.92-7.80 (m, 4H), 7.65 (d, J=3.6 Hz, 1H), 7.11 (d, J=8.4 Hz, 2H), 6.74 (dd, J=3.6, 1.7 Hz, 1H), 6.48 (d, J=8.4 Hz, 2H), 5.45-5.30 (m, 1H), 3.50-3.30 (m, 1H), 2.99 (dd, J=13.8, 4.5 Hz, 1H), 2.75-2.60 (m, 1H), 2.73 (dd, J=13.8, 11.1 Hz, 1H), 2.60-2.45 (m, 1H), 2.28 (dd, J=13.7, 5.2 Hz, 1H), 1.55-1.38 (m, 1H), 1.32-1.05 (m, 1H), 1.09 (s, 9H), 0.90-0.70 (m, 1H), 0.78 (d, J=6.5 Hz, 3H), 0.68 (d, J=6.5 Hz, 3H).

(3) 3(R)-[1(S)-(2-Furyl)carbonyl-2-(4-hydroxy)phenyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanoic Acid

The title compound of Example 6(2) was treated in the same manner as in Example 1(8) and the product was recrystallized from diethyl ether to give the title compound (yield 87%) as a white solid.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 12.70-12.00 (br, 1H), 9.00-8.70 (br, 1H), 8.66 (d, J=8.6 Hz, 1H), 8.05 (d, J=1.6 Hz, 1H), 7.90-7.75 (m, 4H), 7.64 (d, J=3.6 Hz, 1H), 7.11 (d, J=8.4 Hz, 2H), 6.74 (dd, J=3.6, 1.6 Hz, 1H), 6.48 (d, J=8.4 Hz, 2H), 5.42-5.30 (m,1H), 3.42 (dd, J=13.7, 11.3 Hz, 1H), 2.99 (dd, J=13.8, 4.5 Hz, 1H), 2.75-2.45 (m, 2H), 2.73 (dd, J=13.8, 11.2 Hz, 1H), 2.38 (dd, J=13.7, 4.8 Hz, 1H), 1.55-1.38 (m, 1H), 1.28-1.05 (m, 1H), 0.92-0.75 (m, 1H), 0.77 (d, J=6.5 Hz, 3H), 0.68 (d, J=6.5 Hz, 3H).

(4) 2-Tetrahydropyranyl 3(R)-[1(S)-(2-Furyl)carbonyl-2-(4-hydroxy)phenyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamate

In the same manner as in Example 1(9), the title compound of Example 6(3) and O-2-tetrahydropyranylhydroxylamine were reacted and the resulting product was purified by silica gel column chromatography (20:1 chloroform-methanol) to give the title compound (yield 75%) as a white solid.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 11.00-10.85 (m, 1H), 8.77 (br s, 1H), 8.70-8.55 (m, 1H), 8.10-8.00 (m, 1H), 7.90-7.75 (m, 4H), 7.68-7.60 (m, 1H), 7.11 (d, J=8.3 Hz, 2H), 6.74 (dd, J=3.6, 1.6 Hz, 1H), 6.46 (d, J=8.3 Hz, 2H), 5.40-5.25 (m, 1H), 4.60-4.30 (m, 1H), 3.75-3.35 (m, 2H), 3.10-2.65 (m, 1H), 2.98 (dd, J=13.9, 4.5 Hz, 1H), 2.73 (dd, J=13.9, 11.0 Hz, 1H), 2.65-2.38 (m, 2H), 2.38-2.20 (m, 1H), 1.65-1.05 (m, 8H), 0.90-0.70 (m, 1H), 0.76 (d, J=6.4 Hz, 3H), 0.67 (d, J=6.4 Hz, 3H).

(5) Sodium Salt of 2-Tetrahydropyranyl 3(R)-[1(S)-(2-Furyl)carbonyl-2-[4-(hydroxysulfonyloxy)phenyl]]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamate

The title compound (500 mg, 0.77 mmol) of Example 6(4) was dissolved in DMF (3 ml) and a pyridine-sulfur trioxide complex (370 mg, 2.32 mmol) was added to the solution under ice-cooling. The mixture was stirred for 2 hr at room temperature. A 1N aqueous sodium hydrogencarbonate solution (20 ml) was added to the reaction mixture and the mixture was stirred for 30 min at room temperature. The reaction mixture was purified by reversed phase column chromatography (Chromatorex ODS DM-1020T, Fuji Silysia Chemical Ltd.; 0-50% aqueous methanol solution) and lyophilized to give the title compound (528 mg, 91%) as an amorphous solid.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 11.30-10.60 (br, 1H), 8.80-8.70 (m, 1H), 8.05-7.97 (m, 1H), 7.85-7.75 (m, 4H), 7.60-7.50 (m, 1H), 7.18 (d, J=8.4 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 6.70 (dd, J=3.6, 1.8 Hz, 1H), 5.32-5.20 (m, 1H), 4.60-4.35 (m, 1H), 3.80-3.20 (m, 3H), 3.10-2.95 (m, 1H), 2.93-2.70 (m, 2H), 2.70-2.50 (m, 2H), 1.60-1.10 (m, 8H), 0.90-0.75 (m, 1H), 0.77 (d, J=6.4 Hz, 3H), 0.68 (d, J=6.4 Hz, 3H).

(6) Sodium Salt of 3(R)-[1(S)-(2-Furyl)carbonyl-2-[4-(hydroxysulfonyloxy)phenyl]]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamic Acid

To a solution of the title compound (200 mg, 0.27 mmol) of Example 6(5), water (1.5 ml) and methanol (3 ml) was added 1N hydrochloric acid (1.5 ml) and the mixture was stirred for 1.5 hr at room temperature. Then, 1N aqueous sodium hydrogencarbonate solution (1.5 ml) was added and the mixture was stirred for 30 min at room temperature. The reaction mixture was concentrated, and the obtained residue was purified by reversed phase column chromatography (Chromatorex ODS DM-1020T, Fuji Silysia Chemical Ltd.; 0-17% aqueous methanol solution) and lyophilized to give the title compound (94 mg, 53%) as an amorphous solid.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 10.38 (br s, 1H), 8.72 (d, J=8.0 Hz, 1H), 8.63 (br s, 1H), 8.03-7.95 (m, 1H), 7.87-7.75 (m, 4H), 7.52 (d, J=3.5 Hz, 1H), 7.17 (d, J=8.4 Hz, 2H), 6.93 (t, J=8.4 Hz, 2H), 6.69 (dd, J=3.5, 1.5 Hz, 1H), 5.30-5.18 (m, 1H), 3.80-3.60 (m, 1H), 3.02 (dd, J=13.9, 5.5 Hz, 1H), 2.90-2.74 (m, 1H), 2.87 (dd, J=13.9, 9.0 Hz, 1H), 2.70-2.50 (m, 2H), 1.52-1.32 (m, 1H), 1.30-1.10 (m, 1H), 0.92-0.75 (m, 1H), 0.77 (d, J=6.4 Hz, 3H), 0.69 (d, J=6.4 Hz, 3H).

Sodium Salt of 3(R)-[1(S)-(2-Furyl)carbonyl-2-(4-sulfophenyl)ethylcarbamoyl]-5-methyl-2(R or S)-(2-naphthylmethyl)hexanohydroxamic Acid

(1) N-Benzyloxycarbonyl-L-4′-sulfophenylalanine

To a suspension of L-4′-sulfophenylalanine (368 g, 1.50 mol) in water (2 L) was added sodium hydrogencarbonate (508 g, 6.05 mol) over 20 min under ice-cooling. Then, benzyl chloroformate (300 ml, 2.00 mol) was added dropwise over 20 min under ice-cooling, and the mixture was stirred for 4 hr at room temperature. The reaction mixture was washed with ethyl acetate (3×1 L) and filtrated. 6N Hydrochloric acid (1020 ml, 6.12 mol) was added to the filtrate under ice-cooling, and the obtained acidic aqueous solution was saturated with sodium chloride and extracted with THF (4×1 L). The THF solution was washed with saturated brine (2 L), dried over anhydrous magnesium sulfate and concentrated to give the title compound (509 g, 89%) as a white solid.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 7.66 (d, J=8.4 Hz, 1H), 7.52 (d, J=8.1 Hz, 2H), 7.43-7.25 (m, 5H), 7.21 (d, J=8.1 Hz, 2H), 4.98 (s, 2H), 4.27-4.13 (m, 1H), 3.07 (dd, J=13.6, 4.4 Hz, 1H), 2.84 (dd, J=13.6, 10.5Hz, 1H).

(2) N a -Benzyloxycarbonyl-L-4′-sulfophenylalanine N-Methoxy-N-methylamide

According to the method of Jean-Alain Fehrentz et al. [Synthesis (1983) 676-678], to a solution of the title compound (57.4 g, 151 mmol) of Example 7(1) dissolved in DMF (180 ml) were added N,O-dimethylhydroxylamine (17.7 g, 182 mmol) and BOP reagent (86.7 g, 196 mmol). Triethylamine (84 ml, 604 mmol) was added dropwise under ice-cooling and the mixture was stirred under ice-cooling for 30 min, and at room temperature for 5 hr. THF (1.5 L) was added to the reaction mixture, and the mixture was washed successively with a 2:1 mixed solution (1.2 L) of saturated aqueous sodium hydrogencarbonate solution and saturated brine and saturated brine (0.6 L), dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (10:1 chloroform-methanol) to give the title compound (37.1 g, 55%) as a white solid.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 7.73 (d, J=8.6 Hz, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.40-7.21 (m, 5H), 7.20 (d, J=8.0 Hz, 2H), 4.95 (s, 2H), 4.70-4.50 (m, 1H), 3.74 (s, 3H), 3.11 (s, 3H), 2.89 (dd, J=13.6, 4.3 Hz, 1H), 2.73 (dd, J=13.6, 9.9 Hz, 1H).

(3) 2(S)-(N-Benzyloxycarbonylamino)-1-(2-furyl)-3-(4-sulfophenyl)-1-propanone

To a solution of furan (10 ml, 137 mmol) dissolved in THF (90 ml) was added dropwise n-butyllithium (1.54M hexane solution, 65 ml, 100 mmol) at −70° C. over 10 min and the mixture was stirred for 2 hr at −30° C. Then a solution of the title compound (7.42 g, 16.7 mmol) of Example 7(2) dissolved in THF (110 ml) was added dropwise at −70° C. over 20 min and the mixture was stirred for 2 hr at −40° C. The reaction mixture was added to 1N hydrochloric acid (140 ml) saturated with sodium chloride to separate the organic layer from the aqueous layer. The aqueous layer was extracted with THF (2×200 ml). The organic layer and THF layer were combined, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (10:1 chloroform-methanol) to give the title compound (6.65 g, 93%) as a brown oil.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 8.10-8.00 (m, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.65-7.55 (m, 1H), 7.51 (d, J=8.0 Hz, 2H), 7.40-7.18 (m, 7H), 6.78-6.67 (m, 1H), 5.05-4.95 (m, 3H), 3.05 (dd, J=13.5, 4.4 Hz, 1H), 2.82 (dd, J=13.5, 10.4 Hz, 1H).

(4) 2(S)-Amino-1-(2-furyl)-3-(4-sulfophenyl)-1-propanone Trifluoroacetate

A mixture of the title compound (7.63 g, 17.8 mmol) of Example 7(3), thioanisole (3.2 ml, 27.3 mmol) and trifluoroacetic acid (26 ml) was stirred for 3 hr at room temperature. Thioanisole (3.2 ml, 27.3 mmol) was added and the mixture was stirred for 1.5 hr at room temperature. Then, thioanisole (2.2 ml, 18.7 mmol) was added, and the mixture was stirred at room temperature for 1 hr. Diethyl ether (360 ml) was added to the reaction mixture and the precipitate was collected by filtration, and washed with diethyl ether. The obtained precipitate was reprecipitated from methanol-ethyl acetate to give the title compound (4.29 g, 59%) as a purple powder.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 8.34 (br s, 3H), 8.13 (d, J=1.2 Hz, 1H), 7.73 (d, J=3.7 Hz, 1H), 7.53 (d, J=8.0 Hz, 2H), 7.16 (d, J=8.1 Hz, 2H), 6.80 (dd, J=3.6, 1.6 Hz, 1H), 5.06-4.96 (m, 1H), 3.19 (dd, J=14.2, 5.8Hz, 1H), 3.08 (dd, J=14.2, 7.4Hz, 1H).

(5) Sodium Salt of tert-Butyl 3(R)-[1(S)-(2-furylcarbonyl)-2-(4-sulfophenyl)ethylcarbamoyl]-5-methyl-2(R or S)-(2-naphthylmethyl)hexanoic Acid

In the same manner as in Example 1(5), 4-tert-butoxy-2(R)-isobutyl-3(R or S)-(2-naphthylmethyl)succinic acid prepared according to the method described in JP-A-4-352757 and the title compound of Example 7(4) were reacted. After the completion of the reaction, ethyl acetate was added to the reaction mixture, and the mixture was washed successively with 1N hydrochloric acid saturated with sodium chloride, a 2:1 mixed solution of saturated aqueous sodium hydrogencarbonate solution and saturated brine and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (10:1 chloroform-methanol) to give the title compound (yield 96%) as a pale-yellow foam.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 8.78 (d, J=7.5 Hz, 1H), 8.00 (d, J=1.4 Hz, 1H), 7.89-7.78 (m, 3H), 7.57 (d, J=3.6 Hz, 1H), 7.55 (s, 1H), 7.49 (d, J=8.2 Hz, 2H), 7.48-7.43 (m, 2H), 7.27 (d, J=8.2 Hz, 2H), 7.23 (dd, J=8.5, 1.5 Hz, 1H), 6.70 (dd, J=3.6, 1.7 Hz, 1H), 5.39-5.26 (m, 1H), 3.13 (dd, J=14.1, 5.2 Hz, 1H), 2.98 (dd, J=14.2, 9.0 Hz, 1H), 2.78-2.65 (m, 3H), 2.65-2.54 (m, 1H), 1.64-1.49(m, 1H), 1.29-1.18 (m, 1H), 1.14 (s, 9H), 0.97-0.84 (m, 1H), 0.78 (d, J=6.4 Hz, 3H), 0.72 (d, J=6.5 Hz, 3H).

(6) 3(R)-[1(S)-(2-Furylcarbonyl)-2-(4-sulfophenyl)ethylcarbamoyl]-5-methyl-2(R or S)-(2-naphthylmethyl)hexanoic Acid

In the same manner as in Example 1(8), the title compound of Example 7(5) was dissolved in trifluoroacetic acid and the mixture was stirred for 1.5 hr at room temperature. The reaction mixture was concentrated, and diethyl ether was added to the residue to give the title compound (quantitatively) as a pale-green powder.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 13.20-11.60 (br), 8.77 (d, J=7.5 Hz, 1H), 8.00 (d, J=1.4 Hz, 1H), 7.89-7.78 (m, 3H), 7.60-7.52 (m, 2H), 7.52-7.41 (m, 4H), 7.26 (d, J=8.1 Hz, 2H), 7.22 (dd, J=8.5, 1.5 Hz, 1H), 6.70 (dd, J=3.6, 1.6 Hz, 1H), 5.38-5.26 (m, 1H), 3.12 (dd, J=14.0, 5.4 Hz, 1H), 2.98 (dd, J=14.2, 9.0 Hz, 1H), 2.80-2.66 (m, 3H), 2.66-2.55 (m, 1H), 1.63-1.50 (m, 1H), 1.31-1.16 (m, 1H), 1.01-0.89 (m, 1H), 0.78 (d, J=6.4 Hz) and 0.72 (d, J=6.5 Hz) (6H total).

(7) Sodium Salt of 2-Tetrahydropyranyl 3(R)-[1(S)-(2-Furyl)carbonyl-2-(4-sulfophenyl)ethylcarbamoyl]-5-methyl-2(R or S)-(2-naphthylmethyl)hexanohydroxamate

In the same manner as in Example 1(9), the title compound of Example 7(6) and O-2-tetrahydropyranylhydroxylamine were reacted. After the completion of the reaction, the reaction mixture was diluted with THF, washed successively with a 2:1 mixed solution of saturated aqueous sodium hydrogencarbonate solution and saturated brine and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was triturated with diethyl ether to give the title compound (quantitatively) as a pale-yellow powder.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 10.93 (s) and 10.90 (s) (1H total), 8.87-8.73 (m, 1H), 8.06-7.09 (m, 13H), 6.73-6.66 (m, 1H), 5.38-5.20 (m, 1H), 4.70 (s) and 4.24 (s) (1H total), 3.71-2.37 (m, 8H), 1.68-1.17 (m, 8H), 1.03-0.91 (m, 1H), 0.83-0.66 (m, 6H).

(8) Sodium Salt of 3(R)-[1(S)-(2-Furyl)carbonyl-2-(4-sulfophenyl)ethylcarbamoyl]-5-methyl-2(R or S)-(2-naphthylmethyl)hexanohydroxamic Acid

The title compound of Example 7(7) was treated in the same manner as in Example 6(6) and the product was purified by reversed phase column chromatography (Chromatorex ODS DM-1020T, Fuji Silysia Chemical Ltd.; 0-25% aqueous methanol solution). The resulting product was concentrated and triturated with diethyl ether to give the title compound (yield 16%) as a white powder.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 10.27 (br s, 1H), 8.77 (d, J=7.4Hz, 1H), 8.63 (br s, 1H), 7.99 (d, J=1.1 Hz, 1H), 7.88-7.81 (m, 2H), 7.77 (d, J=8.4 Hz, 1H), 7.53 (d, J=3.6 Hz, 1H), 7.52-7.38 (m, 5H), 7.25 (d, J=8.1 Hz, 2H), 7.14 (dd, J=8.4, 1.0 Hz, 1H), 6.69 (dd, J=3.5, 1.6 Hz, 1H), 5.38-5.22 (m, 1H), 3.12 (dd, J=14.3, 5.7 Hz, 1H), 2.97 (dd, J=14.3, 8.6 Hz, 1H), 2.90-2.76 (m, 1H), 2.70-2.58 (m, 1H), 2.58-2.37 (m, 2H), 1.52-1.38 (m, 1H), 1.35-1.16 (m, 1H), 1.00-0.88 (m, 1H), 0.78 (d, J=6.4 Hz) and 0.71 (d, J=6.5 Hz) (6H total).

Sodium Salt of 3(R)-[1(S)-(2-Furyl)carbonyl-2-(4-sulfophenyl)ethylcarbamoyl]-5-methyl-2(R or S)-(1-naphthylmethyl)hexanohydroxamic Acid

In the same manner as in Example 7(5)-(8), the title compound was obtained as a white amorphous solid from 4-tert-butoxy-2(R)-isobutyl-3(R or S)-(1-naphthylmethyl)succinic acid prepared according to the method described in JP-A-4-352757 and the title compound of Example 7(4), at an overall yield (4 steps) of 9%.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 10.12 (s, 1H), 8.93 (d, J=7.2 Hz, 1H), 8.55 (s, 1H), 8.02-7.92 (m, 2H), 7.88 (d, J=7.6 Hz, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.59-7.46 (m, 3H), 7.41 (d, J=8.1 Hz, 2H), 7.38-7.32 (m, 1H), 7.21 (d, J=8.1 Hz, 2H), 7.17 (d, J=7.0 Hz, 1H), 6.66 (dd, J=3.6, 1.6 Hz, 1H), 5.46-5.34 (m, 1H), 3.25-3.13 (m, 1H), 3.13-2.97 (m, 3H), 2.79-2.66 (m, 1H), 2.61-2.47 (m, 1H), 1.53-1.39 (m, 1H), 1.37-1.21 (m, 1H), 1.01-0.87 (m, 1H), 0.78 (d, J=6.4 Hz) and 0.72 (d, J=6.5 Hz) (6H total).

Sodium Salt of 2(R or S)-Benzyl-3(R)-[1(S)-(2-furyl)carbonyl-2-(4-sulfophenyl)ethylcarbamoyl]-5-methylhexanohydroxamic Acid

In the same manner as in Example 7(5)-(8), the title compound was obtained as a white amorphous solid from 3(R or S)-benzyl-4-tert-butoxy-2(R)-isobutylsuccinic acid prepared according to the method described in JP-A-4-352757 and JP-A-7-157470 and the title compound of Example 7(4), at an overall yield (4 steps) of 16%.

1 H-NMR(300 MHz, DMSO-d 6 ) δ 10.28 (br s, 1H), 8.77 (d, J=9.9 Hz, 1H), 8.66 (br s, 1H), 7.99 (d, J=1.4Hz, 1H), 7.53 (d, J=3.6 Hz, 1H), 7.46 (d, J=8.0 Hz, 2H), 7.32-7.17 (m, 4H), 7.17-7.08 (m, 1H), 6.95 (d, J=7.1 Hz, 2H), 6.69 (dd, J=3.6, 1.6Hz, 1H), 5.34-5.23 (m, 1H), 3.10 (dd, J=14.4, 5.5 Hz, 1H), 2.94 (dd, J=14.4, 8.7 Hz, 1H), 2.75-2.54 (m, 2H), 2.40-2.26 (m, 2H), 1.48-1.36 (m, 1H), 1.33-1.13 (m, 1H), 0.97-0.83 (m, 1H), 0.77 (d, J=6.4 Hz) and 0.70 (d, J=6.5 Hz) (6H total).

Sodium Salt of 3(R)-[1(S)-(2-Furyl)carbonyl-2-(4-sulfophenyl)ethylcarbamoyl]-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamic Acid

In the same manner as in Example 7(5)-(8), the title compound was obtained as a white powder from 4-tert-butoxy-2(R)-isobutyl-3(R or S)-phthalimidomethylsuccinic acid prepared according to the method described in JP-A-4-352757 and JP-A-7-157470 and the title compound of Example 7(4), at an overall yield (4 steps) of 24%.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 10.38 (s, 1H), 8.73 (d, J=7.7 Hz, 1H), 8.61 (s, 1H), 7.98 (d, J=1.4 Hz, 1H), 7.79 (s, 4H), 7.50 (d, J=3.3 Hz, 1H), 7.39 (d, J=8.0 Hz, 2H), 7.21 (d, J=8.0 Hz, 2H), 6.68 (dd, J=3.5, 1.65 Hz, 1H), 5.25 (q, J=6.4Hz, 1H), 3.70 (dd, J=13.4, 10.20 Hz, 1H), 3.07 (dd, J=13.9, 6.18 Hz, 1H), 2.94-2.82 (m, 2H), 2.62-2.54 (m, 2H), 1.40 (m, 1H), 1.18 (m, 1H), 0.85 (t, J=12.5 Hz, 1H), 0.76 (d, J=6.5Hz, 3H), 0.68 (d, J=6.5 Hz, 3H).

Sodium Salt of 3(R)-[1(S)-(2-Furyl)carbonyl-2-(4-sulfophenyl)ethylcarbamoyl]-5-methyl-2(R or S)-(1-oxoisoindolin-2-ylmethyl)hexanohydroxamic Acid

(1) Benzyl 4-tert-Butoxy-2(R)-isobutyl-3(R or S)-phthalimidomethylsuccinate

To a solution of 4-tert-butoxy-2(R)-isobutyl-3(R or S)-phthalimidomethylsuccinic acid (10.7 g, 27.4 mmol) prepared according to the method described in JP-A-4-352757 and JP-A-7-157470, benzyl alcohol (3.26 g, 30.1 mmol), methylene chloride (20 ml) and DMF (20 ml) were added successively HOBt-H 2 O (4.19 g, 27.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.83 g, 35.6 mmol), N-methylmorpholine (9.02 ml, 82.8 mmol) and 4-dimethylaminopyridine (1.67 g, 13.7 mmol), and the mixture was stirred for 69 hr at room temperature. Ethyl acetate and diethyl ether were added to the reaction mixture and the mixture was washed successively with dilute hydrochloric acid, dilute aqueous sodium hydrogencarbonate solution and water, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (10:1 hexane-ethyl acetate) to give the title compound (12.6 g, 96%) as a transparent liquid.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 7.97-7.80 (m, 4H), 7.42-7.27 (m, 5H), 5.18-5.02 (m, 2H), 3.94 (dd, J=13.8, 9.8 Hz, 1H), 3.59 (dd, J=13.8, 5.7 Hz, 1H), 3.20-3.01 (m, 1H), 2.80-2.67 (m, 1H), 1.70-1.40 (m, 2H), 1.30-1.10 (m, 10H), 0.92-0.70 (m, 6H).

(2) Benzyl 4-tert-Butoxy-2(R)-isobutyl-3(R or S)-thiophthalimidomethylsuccinate

A mixture of the title compound (12.2 g, 25.4 mmol) of Example 11(1), Lawesson's reagent (3.00 g, 7.41 mmol) and toluene (100 ml) was stirred for 2.5 hr under reflux with heating. Lawesson's reagent (2.66 g, 6.58 mmol) was added and the mixture was stirred for 1.5 hr under reflux with heating. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography (25:1 hexane-ethyl acetate) to give the title compound (6.17 g, 49%) as a red-brown liquid.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 8.00-7.80 (m, 4H), 7.45-7.28 (m, 5H), 5.20-5.05 (m, 2H), 4.34 (dd, J=13.7, 9.9 Hz, 1H), 3.95 (dd, J=13.7, 5.8 Hz, 1H), 3.35-3.20 (m, 1H), 2.83-2.62 (m, 1H), 1.70-1.40 (m, 2H), 1.28-1.13 (m, 10H), 0.92-0.77 (m, 6H).

(3) 4-tert-Butoxy-2(R)-isobutyl-3(R or S)-(1-oxoisoindolin-2-ylmethyl)succinic Acid

To a solution of the title compound (6.03 g, 12.2 mmol) of Example 11(2) dissolved in ethanol (100 ml) was added Raney nickel (112 g) and the mixture was stirred for 2.5 hr under reflux with heating. Raney nickel (112 g) was added and the mixture was stirred for 2.5 hr under reflux with heating. The reaction mixture was filtrated and the filtrate was concentrated. The residue was dissolved in chloroform, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (1:0-5:1 chloroform-methanol) and precipitated from ethyl acetate-hexane to give the title compound (1.31 g, 29%) as a pale-yellow solid.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 7.70-7.40 (m, 4H), 4.51-4.30 (m, 2H), 3.84 (dd, J=13.6, 10.1 Hz, 1H), 3.51 (dd, J=13.6, 5.3 Hz, 1H), 2.94-2.80 (m, 1H), 2.60-2.50 (m, 1H), 1.70-1.42 (m, 2H), 1.25 (s, 9H), 1.20-1.03 (m, 1H), 0.95-0.80 (m, 6H).

(4) Sodium Salt of 3(R)-[1(S)-(2-Furyl)carbonyl-2-(4-sulfophenyl)yl]-5-methyl-2(R or S)-(1-oxoisoindolin-2-ylmethyl)hexanohydroxamic Acid

In the same manner as in Example 7(5)-(8), the title compound was obtained as a white powder from the title compound of Example 11(3) and the title compound of Example 7(4), at an over all yield (4 steps) of 23%.

1 H-NMR (300 MHz, DMSO-d 6 ) δ 10.52-10.41 (m, 1H), 8.80-8.69 (m, 2H), 8.00-7.90 (m, 1H), 7.70-7.38 (m, 7H), 7.19 (d, J=8.0 Hz, 2H), 6.70-6.60 (m, 1H), 5.30-5.17 (m, 1H), 4.40-4.12 (m, 2H), 3.57-3.40 (m, 1H), 3.30-3.16 (m, 1H), 3.15-3.05 (m, 1H), 3.00-2.88 (m, 1H), 2.75-2.48 (m, 2H), 1.50-1.35 (m, 1H), 1.30-1.11 (m, 1H), 1.00-0.82 (m, 1H), 0.78-0.61 (m, 6H).

The compounds of the above Examples are shown in the following Table 1.

In the same manner as in Examples 1-11, the compounds of Examples 12-323 were synthesized.

Me:methyl, iBu:isobutyl, tBu:tert-butyl, Bn:benzyl, Ph:phenyl, THP:2-tetrahydropyranyl, PhtNCH 2 :phthalimidomethyl, HydCH 2 :(2,5-dioxo-3,4,4-trimethyl-1-imidazolidinyl)methyl, 1-NaphCH 2 :1-naphthylmethyl, 2-NaphCH 2 :2-naphthylmethyl, IndoCH 2 :1-oxoisoindolin-2-ylmethyl, PhSCH 2 :phenylthiomethyl, 3-Ph(CH 2 ) 3: 3-phenylpropyl, CH 2 ═CHCH 2 :2-propenyl, 4-NH 2 Bn HCl:4-aminobenzyl hydrochloride, 4-ABn HCl:4-(2-dimethylaminoethoxy)benzyl hydrochloride, 4-ABn:4-(2-dimethylaminoethoxy)benzyl, 4-BBn HCl:4-guanidinobenzyl hydrochloride, 4-NBn Na:4-(hydroxysulfonyloxy)benzyl sodium salt, 4-QBn Na:4-sulfobenzyl sodium salt, 2-PyCH 2 HCl:2-pyridylmethyl hydrochloride, 3-PyCH 2 HCl:3-pyridylmethyl hydrochloride, 3-BnOPh:3-benzyloxyphenyl, 3-APh HCl:3-(2-dimethylaminoethoxy)phenyl hydrochloride, 4-BnOPh:4-benzyloxyphenyl, 4-MeOPh:4-methoxyphenyl, 4-Me 2 NPh:4-dimethylaminophenyl, 4-APh HCl:4-(2-dimethylaminoethoxy)phenyl hydrochloride, 4-APh:4-(2-dimethylaminoethoxy)phenyl, 4-CPh 2HCl:4-[2-[1-(4-methyl)piperazinyl]ethoxy]phenyl dihydrochloride, 4-DPh HCl:4-(2-morpholinoethoxy)phenyl hydrochloride, 4-EPh HCl:4-[2-(2-pyridyl)ethoxy]phenyl hydrochloride, 4-FPh HCl:4-(3-dimethylaminopropoxy)phenyl hydrochloride, 4-GPh HCl:4-[2-(1-pyrrolidinyl)ethoxy]phenyl hydrochloride, 4-HPh HCl:4-(2-piperidinoethoxy)phenyl hydrochloride, 4-HPh:4-(2-piperidinoethoxy)phenyl, 4-IPh 2HCl:4-[2-[2-[1-(4-methyl)piperazinyl]ethoxy]ethoxy]phenyl dihydrochloride, 2-Fu:2-furyl, 5-J-2-Fu HCl:2-(5-dimethylaminomethyl)furyl hydrochloride, 5-K-2-Fu:2-(5-benzyloxymethyl)furyl, 5-L-2-Fu:2-(5-hydroxymethyl)furyl, 5-M-2-Fu HCl:2-[5-(2-dimethylaminoethoxy)methyl]furyl hydrochloride, 3-Fu:3-furyl, 2-Thio:2-thienyl, 2-Pyrr:2-pyrrolyl, 2-Thia:2-thiazolyl, 3-Py:3-pyridyl, 4-UPh Na:4-[2-(hydroxysulfonyloxy)ethoxy]phenyl sodium salt, 4-VPh Na:4-(2-sulfoethoxy)phenyl sodium salt, 4-WPh Na:4-(carboxymethoxy)phenyl sodium salt, 5-X-2-Fu Na:2-[5-[2-(hydroxysulfonyloxy)ethoxy]methyl]furyl sodium salt, 5-Y-2-Fu Na:2-[5-(2-sulfoethoxy)methyl]furyl sodium salt, 5-Z-2-Fu Na:2-(5-carboxymethoxy)furyl sodium salt, 4-UBn Na:4-[2-(hydroxysulfonyloxy)ethoxy]benzyl sodium salt, 4-VBn Na:4-(2-sulfoethoxy)benzyl sodium salt.

Of these compounds, the 1 H-NMR spectrum data of the representative compounds are shown in the following.

3(R)-[2-(4-Aminophenyl)-1(S)-(2-furyl)carbonyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamic Acid Hydrochloride

1 H-NMR (300 MHz, DMSO-d 6 ) δ 10.39 (br s, 1H), 8.74 (d, J=8.0 Hz, 1H), 8.05-7.95 (m, 1H), 7.90-7.75 (m, 4H), 7.55 (d, J=3.6 Hz, 1H), 7.37 (d, J=8.0 Hz, 2H), 7.07 (d, J=8.0 Hz, 2H), 6.75-6.68 (m, 1H), 5.35-5.22 (m, 1H), 3.75-3.60 (m, 1H), 3.09 (dd, J=13.9, 5.3 Hz, 1H), 2.92 (dd, J=13.9, 9.4 Hz, 1H), 2.86-2.75 (m, 1H), 2.68-2.50 (m, 2H), 1.47-1.32 (m, 1H), 1.25-1.10 (m, 1H), 0.90-0.75 (m, 1H), 0.77 (d, J=6.4 Hz, 3H), 0.68 (d, J=6.4 Hz, 3H).

2-Tetrahydropyranyl 5-Methyl-3(R)-[2-phenyl-1(S)-[4-(2-piperidinoethoxy)benzoyl]]ethylcarbamoyl-2(R or S)-phthalimidomethylhexanohydroxamate

1 H-NMR (300 MHz, DMSO-d 6 ) δ 11.00-10.80 (m, 1H), 8.70-8.60 (m, 1H), 7.99 (dd, J=8.7, 2.0 Hz, 2H), 7.90-7.78 (m, 4H), 7.35 (d, J=7.5 Hz, 2H), 7.09 (t, J=7.6 Hz, 2H), 7.01 (d, J=8.7 Hz, 2H), 6.81 (t, J=7.4 Hz, 1H), 5.70-5.55 (m, 1H), 4.55-4.30 (m, 1H), 4.10 (t, J=5.3 Hz, 2H), 3.75-3.25 (m, 2H), 3.12 (dd, J=14.0, 4.5 Hz, 1H), 3.08-2.65 (m, 1H), 2.87 (dd, J=14.0, 10.7 Hz, 1H), 2.65-2.30 (m, 8H), 2.20-2.05 (m, 1H), 1.60-1.20 (m, 13H), 1.10-0.90 (m, 1H), 0.85-0.70 (m, 1H), 0.63 (d, J=6.4 Hz, 3H), 0.60 (d, J=6.4 Hz, 3H).

5-Methyl-3(R)-[2-phenyl-1(S)-[4-(2-piperidinoethoxy)benzoyl]]-ethylcarbamoyl-2(R or S)-phthalimidomethylhexanohydroxamic Acid Hydrochloride

1 H-NMR (300 MHz, DMSO-d 6 ) δ 10.33 (br s, 1H), 10.10-9.90 (br, 1H), 8.70-8.50 (br, 1H), 8.64 (d, J=8.6 Hz, 1H), 8.06 (d, J=8.9 Hz, 2H), 7.95-7.80 (m, 4H), 7.36 (d, J=7.4 Hz, 2H), 7.10 (d, J=8.9 Hz, 2H), 7.08 (t, J=7.6 Hz, 2H), 6.78 (t, J=7.2 Hz, 1H), 5.75-5.60 (m, 1H), 4.55-4.40 (m, 2H), 3.60-3.25 (m, 5H), 3.11 (dd, J=14.2, 4.4 Hz, 1H), 3.10-2.90 (m, 2H), 2.86 (dd, J=14.2, 10.4 Hz, 1H), 2.60-2.40 (m, 2H), 2.25-2.12 (m, 1H), 1.90-1.63 (m, 5H), 1.50-1.25 (m, 2H), 1.10-0.90 (m, 1H), 0.85-0.70 (m, 1H), 0.68 (d, J=6.4 Hz, 3H), 0.62 (d, J=6.4 Hz, 3H).

3(R)-[1(S)-[2-(5-Dimethylaminomethyl)furyl]carbonyl-2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamic Acid Hydrochloride

1 H-NMR (300 MHz, DMSO-d 6 ) δ 10.65-10.40 (br, 1H), 10.34 (br s, 1H), 8.70 (d, J=8.7 Hz, 1H), 8.70-8.50 (br, 1H), 7.90-7.80 (m, 4H), 7.68 (d, J=3.6 Hz, 1H), 7.37 (d, J=7.2 Hz, 2H), 7.09 (t, J=7.7 Hz, 2H), 6.95 (d, J=3.6 Hz, 1H), 6.79 (t, J=7.4 Hz, 1H), 5.48-5.35 (m, 1H), 4.50 (s, 2H), 3.55-3.25 (m, 1H), 3.14 (dd, J=13.5, 4.2 Hz, 1H), 2.87 (dd, J=13.5, 11.1 Hz, 1H), 2.76 (s, 6H), 2.65-2.40 (m, 2H), 2.25 (dd, J=13.2, 3.9 Hz, 1H), 1.46-1.32 (m, 1H), 1.25-1.10 (m, 1H), 0.90-0.75 (m, 1H), 0.78 (d, J=6.5 Hz, 3H), 0.69 (d, J=6.5 Hz, 3H).

2-Tetrahydropyranyl 3(R)-[2-[4-(2-Dimethylaminoethoxy)phenyl]-1(S)-(2-furyl)carbonyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamate

1 H-NMR (300 MHz, DMSO-d 6 ) δ 10.91-10.78 (m, 1H), 8.70-8.50 (m, 1H), 8.10-8.00 (m, 1H), 7.90-7.80 (m, 4H), 7.80-7.65 (m, 1H), 7.32-7.18 (m, 2H), 6.80-6.70 (m, 1H), 6.63-6.50 (m, 2H), 5.50-5.33 (m, 1H), 4.60-4.30 (m, 1H), 3.74-3.40 (m, 4H), 3.10-2.94 (m, 1H), 2.80-2.20 (m, 4H), 1.93 (s, 6H), 1.83 (t, J=6.1 Hz, 2H), 1.60-1.00 (m, 8H), 0.85-0.60 (m, 7H).

3(R)-[2-[4-(2-Dimethylaminoethoxy)phenyl]-1(S)-(2-furyl)carbonyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamic Acid Hydrochloride

1 H-NMR (300 MHz, DMSO-d 6 ) δ 10.38-10.26 (m, 1H), 10.05 (br s, 1H), 8.90-8.37 (m, 2H), 8.10-8.02 (m, 1H), 7.92-7.80 (m, 4H), 7.70-7.60 (m, 1H), 7.30 (d, J=8.6 Hz, 2H), 6.74 (dd, J=3.6, 1.6 Hz, 1H), 6.71 (d, J=8.6 Hz, 2H), 5.45-5.30 (m, 1H), 3.86 (t, J=5.1 Hz, 2H), 3.50-3.40 (m, 1H), 3.05 (dd, J=13.9, 4.7 Hz, 1H), 2.95-2.39 (m, 11H), 2.25-2.11 (m, 1H), 1.48-1.30 (m, 1H), 1.22-1.02 (m, 1H), 0.88-0.59 (m, 7H).

3(R)-[1(S)-[2-(5-Hydroxymethyl)furyl]carbonyl-2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamic Acid

1 H-NMR (300 MHz, DMSO-d 6 ) δ 10.33 (br s, 1H), 8.65 (d, J=8.3 Hz, 1H), 8.61 (br s, 1H), 7.90-7.80 (m, 4H), 7.60 (d, J=3.5 Hz, 1H), 7.36 (d, J=7.4 Hz, 2H), 7.08 (t, J=7.6 Hz, 2H), 6.78 (t, J=7.4 Hz, 1H), 6.54 (t, J=3.5 Hz, 1H), 5.54 (t, J=5.8 Hz, 1H), 5.42-5.30 (m, 1H), 4.50 (d, J=5.8 Hz, 2H), 3.47 (dd, J=13.2, 10.9 Hz, 1H), 3.09 (dd, J=13.8, 4.4 Hz, 1H), 2.85 (dd, J=13.8, 10.5 Hz, 1H), 2.60-2.40 (m, 2H), 2.25 (dd, J=13.2, 3.9 Hz, 1H), 1.48-1.35 (m, 1H), 1.30-1.10 (m, 1H), 0.90-0.75 (m, 1H), 0.78 (d, J=6.5 Hz, 3H), 0.69 (d, J=6.5 Hz, 3H).

2(R or S),5-Dimethyl-3(R)-[1(S)-[4-(2-dimethylaminoethoxy)benzoyl]-2-phenyl]ethylcarbamoylhexanohydroxamic Acid Hydrochloride

1 H-NMR (300 MHz, DMSO-d 6 ) δ 10.40-10.30 (m, 1H), 10.02 (br s, 1H), 8.52 (d, J=8.3 Hz, 1H), 8.03 (d, J=8.8 Hz, 2H), 7.39-7.13 (m, 5H), 7.11 (d, J=8.8 Hz, 2H), 5.65-5.48 (m, 1H), 4.50-4.35 (m, 2H), 3.60-3.48 (m, 2H), 3.12-3.02 (m, 1H), 2.92-2.78 (m, 7H), 2.42-2.23 (m, 1H), 2.05-1.90 (m 1H), 1.36-1.20 (m, 1H), 1.07-0.92 (m, 1H), 0.80-0.40 (m, 10H).

2-Tetrahydropyranyl 3(R)-[1(S)-[4-(2-Dimethylaminoethoxy)benzoyl]-2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-(3-phenylpropyl)hexanohydroxamate

1 H-NMR (300 MHz, DMSO-d 6 ) δ 11.10-11.00 (m, 1H), 8.60-8.50 (m, 1H), 8.02-7.90 (m, 2H), 7.40-6.98 (m, 12H), 5.65-5.50 (m, 1H), 4.85-4.70 (m, 1H), 4.20-4.07 (m, 2H), 4.00-3.80 (m, 1H), 3.50-3.32 (m, 1H), 3.17-3.00 (m, 1H), 2.90-2.76 (m, 1H), 2.70-2.58 (m, 2H), 2.43-1.94 (m, 10H), 1.70-1.39 (m, 6H), 1.39-1.08 (m, 5H), 1.08-0.90 (m, 1H), 0.88-0.72 (m, 1H), 0.70-0.50 (m, 6H).

3(R)-[1(S)-[4-(2-Dimethylaminoethoxy)benzoyl]-2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-(3-phenylpropyl)hexanohydroxamic Acid Hydrochloride

1 H-NMR (300 MHz, DMSO-d 6 ) δ 10.46-10.38 (m, 1H), 10.15-9.98 (m, 1H), 8.54 (d, J=8.3 Hz, 1H), 8.04 (d, J=8.8 Hz, 2H), 7.40-7.00 (m, 12H), 5.65-5.50 (m, 1H), 4.50-4.31 (t, J=4.9 Hz, 2H), 3.60-3.47 (m, 2H), 3.10-2.98 (m, 1H), 2.90-2.73 (m, 7H), 2.40-1.85 (m, 4H), 1.36-0.90 (m, 6H), 0.83-0.55 (m, 7H).

2-Tetrahydropyranyl 3(R)-[1(S)-[4-(2-Dimethylaminoethoxy)benzoyl]-2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-(2,5-dioxo-3,4,4-trimethyl-1-imidazolidinyl)methylhexanohydroxamate

1 H-NMR (300 MHz, DMSO-d 6 ) δ 11.00-10.80 (m, 1H), 8.65-8.50 (m, 1H), 8.08-7.95 (m, 2H), 7.40-6.90 (m, 7H), 5.70-5.45 (m, 1H), 4.80-4.55 (m, 1H), 4.20-4.05 (m, 2H), 3.95-3.70 (m, 1H), 3.50-3.20 (m, 2H), 3.10 (dd, J=13.9, 4.2 Hz, 1H), 2.92-2.78 (m, 1H), 2.86 (s, 3H), 2.69-2.60 (m, 2H), 2.55-2.30 (m, 2H), 2.21 (s, 6H), 2.08-1.90 (m, 1H), 1.70-1.15 (m, 7H), 1.24 (s, 6H), 1.07-0.89 (m, 1H), 0.80-0.65 (m, 1H), 0.63 (d, J=6.5 Hz, 3H), 0.60 (d, J=6.5 Hz, 3H).

3(R)-[1(S)-[4-(2-Dimethylaminoethoxy)benzoyl]-2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-(2,5-dioxo-3,4,4-trimethyl-1-imidazolidinyl)methylhexanohydroxamic Acid Hydrochloride

1 H-NMR (500 MHz, DMSO-d 6 ) δ 10.31 (br s, 1H), 10.00-9.90 (br, 1H), 8.64 (br s, 1H), 8.57 (d, J=8.6 Hz, 1H), 8.06 (d, J=8.9 Hz, 2H), 7.35 (d, J=7.2 Hz, 2H), 7.13 (t, J=7.5 Hz, 2H), 7.11 (d, J=8.9 Hz, 2H), 6.98 (t, J=7.4 Hz, 1H), 5.70-5.60 (m, 1H), 4.50-4.35 (m, 2H), 3.60-3.45 (m, 2H), 3.35-3.20 (m, 1H), 3.29 (s, 6H), 2.90-2.80 (m, 1H), 2.76 (s, 3H), 2.55-2.40 (m, 2H), 1.99 (dd, J=13.4, 3.6 Hz, 1H), 1.40-1.30 (m, 1H), 1.24 (s, 3H), 1.23 (s, 3H), 1.05-0.95 (m, 1H), 0.80-0.70 (m, 1H), 0.66 (d, J=6.5 Hz, 3H), 0.61 (d, J=6.5 Hz, 3H).

2-Tetrahydropyranyl 3(R)-[2,2-Dimethyl-1(S)-[4-(2-dimethylaminoethoxy)benzoyl]]propylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamate

1 H-NMR (300 MHz, DMSO-d 6 ) δ 11.10-10.93 (m, 1H), 8.41-8.30 (m, 1H), 8.00-7.90 (m, 2H), 7.90-7.75 (m, 4H), 7.10-7.00 (m, 2H), 5.35-5.20 (m, 1H), 4.65-4.40 (m, 1H), 4.20-4.05 (m, 2H), 4.05-2.57 (m, 8H), 2.30-2.17 (m, 6H), 1.66-1.23 (m, 7H), 1.23-1.00 (m, 1H), 1.00-0.57 (m, 16H).

3(R)-[2,2-Dimethyl-1(S)-[4-(2-dimethylaminoethoxy)benzoyl]]propylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamic Acid Hydrochloride

1 H-NMR (300 MHz, DMSO-d 6 ) δ 10.50-10.37 (m, 1H), 9.60 (br s, 1H), 8.72-8.60 (m, 1H), 8.40-8.27 (m, 1H), 7.97 (d, J=8.8 Hz, 2H), 7.87-7.75 (m, 4H), 7.09 (d, J=8.8 Hz, 2H), 5.30-5.20 (m, 1H), 4.50-4.31 (m, 2H), 4.10-3.95 (m, 1H), 3.60-3.45 (m, 2H), 3.40-3.36 (m, 1H), 3.00-2.60 (m, 8H), 1.50-1.30 (m, 1H), 1.23-0.55 (m, 17H).

3(R)-[1(S)-[4-(2-Dimethylaminoethoxy)benzoyl]-2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-(2-propenyl)hexanohydroxamic Acid Hydrochloride

1 H-NMR (500 MHz, DMSO-d 6 ) δ 10.36 (br s, 1H), 9.90-9.70 (br, 1H), 8.75-8.65 (br, 1H), 8.52 (d, J=8.4 Hz, 1H), 8.04 (d, J=8.9 Hz, 2H), 7.35 (d, J=7.3 Hz, 2H), 7.24 (t, J=7.6 Hz, 2H), 7.15 (t, J=7.6 Hz, 1H), 7.11 (d, J=8.9 Hz, 2H), 5.62-5.55 (m, 1H), 5.42-5.30 (m, 1H), 4.81 (d, J=10.3 Hz, 1H), 4.71 (dd, J=17.1, 1.8 Hz, 1H), 4.48-4.35 (m, 2H), 3.60-3.50 (m, 2H), 3.08 (dd, J=14.0, 4.2 Hz, 1H), 2.90-2.80 (m, 1H), 2.86 (s, 6H), 2.36 (ddd, J=10.4, 10.4, 3.1 Hz, 1H), 1.92 (ddd, J=10.8, 10.7, 2.8 Hz, 1H), 1.88-1.75 (m, 1H), 1.32-1.20 (m, 2H), 1.08-0.95 (m, 1H), 0.85-0.75 (m, 1H), 0.67 (d, J=6.5 Hz, 3H), 0.60 (d, J=6.5 Hz, 3H).

Sodium Salt of 2-Tetrahydropyranyl 3(R)-[1(S)-(2-Furyl)carbonyl-2-[4-(hydroxysulfonyloxy)phenyl]]ethylcarbamoyl-5-methyl-2(R or S)-(2,5-dioxo-3,4,4-trimethyl-1-imidazolidinyl)methylhexanohydroxamic Acid

1 H-NMR (300 MHz, DMSO-d 6 ) δ 10.96 (br s, 1H), 8.70-8.55 (m, 1H), 8.07-7.98 (m, 1H), 7.65-7.55 (m, 1H), 7.20 (d, J=8.3 Hz, 2H), 6.98-6.88 (m, 2H), 6.75-6.70 (m, 1H), 5.35-5.10 (m, 1H), 4.80-4.50 (m, 1H), 4.00-3.25 (m, 3H), 3.02 (dd, J=14.3, 4.8 Hz, 1H), 2.92-2.68 (m, 4H), 2.62-2.30 (m, 2H), 1.70-1.05 (m, 8H), 1.26 (s, 3H), 1.25 (s, 3H), 0.90-0.70 (m, 1H), 0.75 (d, J=6.3 Hz, 3H), 0.67 (d, J=6.3 Hz, 3H).

Sodium Salt of 3(R)-[1(S)-(2-Furyl)carbonyl-2-[4-(hydroxysulfonyloxy)phenyl]]ethylcarbamoyl-5-methyl-2(R or S)-(2,5-dioxo-3,4,4-trimethyl-1-imidazolidinyl)methylhexanohydroxamic Acid

1 H-NMR (300 MHz, DMSO-d 6 ) δ 10.37 (br s, 1H), 8.67 (br s, 1H), 8.63 (d, J=8.1 Hz, 1H), 8.02 (d, J=1.7 Hz, 1H), 7.60 (d, J=3.6 Hz, 1H), 7.20 (d, J=8.5 Hz, 2H), 6.93 (d, J=8.5 Hz, 2H), 6.72 (dd, J=3.6, 1.7 Hz, 1H), 5.35-5.20 (m, 1H), 3.50-3.20 (m, 1H), 3.01 (dd, J=13.8, 4.9 Hz, 1H), 2.82 (dd, J=13.8, 10.2 Hz, 1H), 2.74 (s, 3H), 2.65-2.40 (m, 2H), 2.35-2.20 (m, 1H), 1.50-1.30 (m, 1H), 1.30-1.05 (m, 1H), 1.25 (s, 3H), 1.24 (s, 3H), 0.90-0.70 (m, 1H), 0.75 (d, J=6.5 Hz, 3H), 0.67 (d, J=6.5 Hz, 3H).

3(R)-[2,2-Dimethyl-1(S)-[4-(2-dimethylaminoethoxy)benzoyl]]propylcarbamoyl-5-methyl-2(R or S)-(2,5-dioxo-3,4,4-trimethyl-1-imidazolidinyl)methylhexanohydroxamic Acid Hydrochloride

1 H-NMR (300 MHz, DMSO-d 6 ) δ 10.72 (br s, 1H), 10.47 (s, 1H), 8.72 (br s, 1H), 8.30 (d, J=7.6 Hz, 1H), 8.01 (d, J=8.6 Hz, 2H), 7.11 (d, J=8.7 Hz, 2H), 5.29 (d, J=7.6 Hz, 1H), 4.47 (br s, 2H), 3.86 (dd, J=12.3, 12.1 Hz, 1H), 3.53 (br s, 2H), 3.10 (dd, J=12.8, 4.2 Hz, 1H), 2.93-2.79 (m, 1H), 2.84 (s, 6H), 2.76 (s, 3H), 2.65 (ddd, J=10.7, 10.7, 4.2 Hz, 1H), 1.44-1.31 (m, 1H), 1.25 (s, 6H), 1.18-1.05 (m, 1H), 0.93 (s, 9H), 0.89-0.79 (m, 1H), 0.76 (d, J=6.3 Hz, 3H), 0.64 (d, J=6.5 Hz, 3H).

3(R)-[1(S)-[2-(5-Hydroxymethyl)furyl]carbonyl-2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-(2,5-dioxo-3,4,4-trimethyl-1-imidazolidinyl)methylhexanohydroxamic Acid

1 H-NMR (300 MHz, DMSO-d 6 ) δ 10.35 (br s, 1H), 8.75-8.60 (br, 1H), 8.60 (d, J=8.4 Hz, 1H), 7.59 (d, J=3.6 Hz, 1H), 7.36 (d, J=7.3 Hz, 2H), 7.13 (t, J=7.6 Hz, 2H), 6.99 (t, J=7.4 Hz, 1H), 6.54 (d, J=3.6 Hz, 1H), 5.70-5.40 (br, 1H), 5.40-5.28 (m, 1H), 4.49 (s, 2H), 3.40-3.20 (m, 1H), 3.07 (dd, J=13.7, 4.5 Hz, 1H), 2.83 (dd, J=13.7, 10.8 Hz, 1H), 2.75 (s, 3H), 2.60-2.35 (m, 2H), 2.03 (dd, J=13.3, 3.8 Hz, 1H), 1.45-1.30 (m, 1H), 1.30-1.10 (m, 1H), 1.24 (s, 3H), 1.22 (s, 3H), 0.85-0.70 (m, 1H), 0.76 (d, J=6.5 Hz, 3H), 0.68 (d, J=6.5 Hz, 3H).

Experimental Example 1

Inhibitory Activity of TNF α Release

The inhibitory effect of each compound (compounds of Examples 1, 2, 3, 6, 35, 39 and 44) on the release of TNF α from THP-1 cells which are monocyte cultured cells [see Nature 370, 218-220 (1994)] was investigated.

The THP-1 cells were suspended to a concentration of 1×10 6 cells/ml in RPMI1640 medium supplemented with 10% fetal calf serum (FCS) and dispensed by 100 μl. A 2 μg/ml LPS was prepared with RPMI1640 medium supplemented with 10% FCS. Each compound (dissolved in dimethyl sulfoxide) was diluted 500-fold with the LPS solution.

The diluted solutions of these compounds were added to the dispensed cell suspensions by 100 μl and allowed for 3 hr to react under the conditions of 37° C., 5% CO 2 . After the completion of the reaction, the reaction mixture was centrifuged and the culture supernatant was collected. The TNF α amount was quantitatively measured by ELISA (enzyme-linked immunosorbent assay). The TNF α release inhibitory effect by each compound was calculated from the proportion of released TNF α amount of the compound addition group relative to that of the compound non-addition group.

Experimental Example 2

Inhibitory Activity of TNF α Release

The inhibitory effect of each compound (compounds of Examples 2, 6, 7, 10, 11, 37, 147, 231 and 245) on the release of TNF α from LPS treated human whole blood [see: Lymphokine Res 8, 141-146 (1989)] was investigated.

Human whole blood was diluted 4-fold with RPMI1640 medium supplemented with 10% FCS. The diluted blood was dispensed to a 96 multi-well plate by 100 μl and equilibrated under the conditions of 37° C., 5% CO 2 . LPS (2 μg/ml) was prepared with RPMI1640 medium supplemented with 10% FCS and a culture broth prepared by dissolving each compound (dissolved in dimethyl sulfoxide) in the LPS solution was added by 100 μl/well (final concentrated of dimethyl sulfoxide 0.1%), which was followed by incubation for 24 hr (37° C., 5% CO 2 ). After the incubation, the reaction mixture was centrifuged (1,500 rpm, 5 min). The culture supernatant (40 μl/well) was collected, and TNF α amount in the supernatant was quantitatively measured by ELISA. The TNF α release inhibitory effect by each compound was calculated from the proportion of release TNF α amount of the compound addition group relitive to that of the compound non-addition group.

It is evident from the above experimental results that the hydroxamic acid derivative of the present invention inhibits the production of TNF α.

Experimental Example 3

Solubility

The solubility of the Example compounds of the present invention in saline (0.9% aqueous sodium chloride solution) at 25° C. was measured. The results are shown in Table 13.

Formulation Example 1

Tablets having the following composition were produced by a conventioal method.

Formulation Example 2

Capsules having the following composition were produced by a conventional method.

Formulation Example 3

Ointment having the following composition was produced by a conventional method.

Formulation Example 4

Injections having the following composition were produced by a conventional method.

Formulation Example 5

Eye drops having the following composition were produced by a conventional method.