Phenoxyacetic acid derivatives, preparation method thereof and use thereof as medicament

Abstract

The present invention relates to a novel phenoxyacetic acid derivative represented by the general formula (I), preparation method thereof and use of a pharmaceutical composition containing the derivative in preparing a medicament for treating diabetes and metabolic syndrome. The phenoxyacetic acid derivatives have excellent in vivo hypoglycemic activity, which can be used for preventing or treating diabetes.

Claims

1. A compound is selected from the group consisting of 2-(4-((2-chloro-[1,1-biphenyl]-3-methylene)amino)-2-fluorophenoxy)acetic acid (I-2), 2-(4-((2-methoxy-[1,1-biphenyl]-3-methylene)amino)-2-fluorophenoxy)acetic acid (I-6), 2-(4-((2-nitrile-[1,1-biphenyl]-3-methylene)amino)-2-fluorophenoxy)acetic acid (I-7), 2-(4-((2-trifluoromethyl-[1,1-biphenyl]-3-methylene)amino)-2-fluorophenoxy)acetic acid (I-8), 2-(4-(([1,1-biphenyl]-3-methylene)amino)-2-fluorophenoxy)acetic acid (I-11), 2-(4-((2-chloro-[1,1-biphenyl]-3-methylene)amino)phenoxy)acetic acid (I-24), 2-(4-((2-trifluoromethyl-[1,1-biphenyl]-3-methylene)amino)phenoxy)acetic acid (I-28), 2-(4-((4-trifluoromethoxy-2,6-dimethyl-[1,1-biphenyl]-3-methylene)amino)phenoxy)acetic acid (I-29), 2-(4-(((4-ethoxy-2-methyl-[1,1-biphenyl]-3-yl)methylene)amino)phenoxy)acetic acid (I-31), 2-(4-((2-trifluoromethoxy-[1,1-biphenyl]-3-methylene)amino)phenoxy)acetic acid (I-32), 2-(4-((2-trifluoromethoxy-[1,1-biphenyl]-3-methylene)amino-2-fluoro)phenoxy)acetic acid (I-33), 2-(4-((4-trifluoromethoxy-2,6-dimethyl-[1,1-biphenyl]-3-methylene)amino)-2-fluorophenoxy)acetic acid (I-34), 2(4-(((4-(hexyloxy)-2,6-dimethyl-[1,1-biphenyl]-3-yl)methyl)amino)phenoxy)acetic acid (I-43), and 2(4-(((4-(cyclohexyloxy)-2,6-dimethyl-[1,1-biphenyl]-3-yl)methyl)amino)phenoxy)acetic acid (I-45).

2. A pharmaceutical composition for treating diabetes and metabolic syndrome, comprising the compound according to claim 1, and suitable carriers or excipients.

Description

DESCRIPTION OF DRAWINGS

(1) FIG. 1: d8-TCA concentration after administration of different compounds, wherein in each pair of data, the left contains Ca.sup.2+ and the right does not contain Ca.sup.2+.

EMBODIMENTS

(2) The invention is further illustrated by the following examples. It should be noted that the following examples are for illustrative purposes only and are not intended to limit the invention. Various changes made by those skilled in the art in light of the teachings of the present invention are intended to be within the scope of the appended claims.

Example 1

(4-amino-2-fluorophenoxy) ethyl acetate

(3) ##STR00004##

(4) 2-fluoro-4-nitrophenol (1 g, 6.37 mmol) was dissolved in 30 ml of acetonitrile, to which ethyl chloroacetate (0.94 g, 7.64 mmol) was added and stirred until it dissolved, and potassium carbonate (1.76 g, 12.73 mmol) was added. The mixture was heated to reflux for 3 hours, filtered under vacuum, and the filtrate was evaporated under reduced pressure to give 1.3 g of grey brown crude solid with yield of 83%.

(5) The above crude solid (0.5 g, 2.6 mmol) was dissolved in 20 ml of 80% aqueous ethanol solution, iron powder (0.34 g, 6.17 mmol), ammonium chloride (0.55 g, 10.28 mmol) were added, and heated at 80 C. for 6 h. After the reaction was completed, the reaction solution was added with sodium carbonate to adjust the pH to 8-9, filtered with celite, and the filter cake was washed. The filtrate was concentrated under reduced pressure to give 0.3 g of dark brown crude solid with yield of 68.2%.

Example 2

2-(4-((4-ethoxy-2,6-dimethyl-[1,1-biphenyl]-3-methylene)amino)-2-fluorophenoxy) acetic acid (I-1)

(6) ##STR00005##

(7) Step 1: 3,5-dimethyl-4-bromophenol (0.5 g, 2.49 mmol), m-formylbenzeneboronic acid (0.45 g, 2.98 mmol) were added to 42 ml of mixed solvent of toluene, ethanol and water (3:1:3), there mixture was stirred until it dissolved, sodium carbonate (0.5 g, 6.22 mmol), tetrakis(triphenylphosphine)palladium (0.02 g, 0.012 mmol) were added to react under N.sub.2 atmosphere for 24 h at 80 C. After the reaction was completed, ethyl acetate (30 ml4) was added as extraction agent, and the organic phases were combined and washed with saturated brine (20 ml2), dried over anhydrous sodium sulfate and filtered, then the filtrate was evaporated under reduced pressure to give a brown oil which was purified by column chromatography (petroleum ether/ethyl acetate, 90:10, v/v) to give a white solid (II-1, 0.75 g, yield: 70%).

(8) Step 2: II-1 (0.9 g, 2.21 mmol) was added to 20 ml of acetonitrile, stirred and dissolved, then ethyl bromide (0.29 g, 2.65 mmol) and potassium carbonate (0.46 g, 3.31 mmol) were added to react for 2 h at 65 C. After the reaction was completed, the filter cake obtained after vacuum filtering was washed with ethyl acetate and the filtrate was evaporated under reduced pressure to give a yellow solid (III-1, 0.45 g, yield: 80.3%).

(9) Step 3: compound III-1 (0.3 g, 1.18 mmol) was dissolved in 20 ml of methanol, and (4-amino-2-fluorophenoxy) ethyl acetate (0.25 g, 1.18 mmo) was added and stirred at room temperature for 1 h. Sodium cyanoborohydride (0.11 g, 1.77 mmol) was added to react for 6 h. After completion of the reaction, the residue was purified by column chromatography (petroleum ether/ethyl acetate, 90:10, v/v) to give 0.4 g of pale yellow oily liquid. The obtained yellow oily liquid was dissolved in 4 mL of tetrahydrofuran, 6 mL of methanol and 2 mL of water and LiOH (0.2 g, 8 mmol) was added to react at room temperature for 4 h, the mixture was adjusted to pH 2-3 with 1N of dilute hydrochloric acid, and extracted with dichloromethane (30 ml4), the organic phases were combined, washed with saturated brine (20 ml2), dried over anhydrous sodium sulfate and filtered, the filtrate was evaporated under reduced pressure to give a brown oil which was purified by column chromatography (petroleum ether/ethyl acetate, 90:10, v/v) to give a white solid 2-(4-((4-ethoxy-2,6-dimethyl-[1,1-biphenyl]-3-methylene)amino)-2-fluorophenoxy)acetic acid (0.2 g, m.p.: 102-104 C., yield: 40%).

(10) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 7.43-7.26 (m, 2H), 7.04 (s, 1H), 6.95 (d, J=7.3 Hz, 1H), 6.81 (t, J=9.3 Hz, 1H), 6.65 (s, 2H), 6.42, 6.37 (dd, J=14.1, 2.5 Hz, 1H), 6.29 (d, J=8.9 Hz, 1H), 4.51 (s, 2H), 4.26 (s, 2H), 4.01 (q, J=7.0 Hz, 2H), 1.87 (s, 6H), 1.31 (t, J=7.0 Hz, 3H).

(11) .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 170.78, 157.55, 144.89, 140.61, 140.49, 136.93, 134.27, 128.87, 128.77, 128.07, 125.92, 117.63, 113.55, 108.23, 101.25, 66.90, 63.16, 47.14, 21.17, 15.23. ESI-MS m/z: 422.2 [M-H].sup.. Anal. calcd. For C.sub.25H.sub.26FNO.sub.4: C, 70.91; H, 6.19; N, 3.31; Found: C, 70.90; H, 6.17; N, 3.28.

Example 3

2-(4-((2-chloro-[1,1-biphenyl]-3-methylene)amino)-2-fluorophenoxy)acetic acid (I-2)

(12) ##STR00006##

(13) By substituting 2-chlorobromobenzene for the 3,5-dimethyl-4-bromophenol of Example 2, Compound I-2 was prepared in a similar manner as in Example 2 to give a white solid (0.42 g, m.p.: 134-135 C., yield: 69%).

(14) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 12.91 (s, 1H), 7.61-7.23 (m, 8H), 6.84 (t, J=9.2 Hz, 1H), 6.47 (d, J=13.9 Hz, 1H), 6.33 (d, J=8.5 Hz, 1H), 4.52 (s, 2H), 4.28 (s, 2H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 170.31, 154.21, 144.42, 140.01, 139.75, 138.60, 131.44, 131.23, 129.83, 129.13, 128.18, 127.55, 127.48, 126.63, 117.18, 107.55, 100.76, 100.47, 66.35, 46.68. ESI-MS m/z: 384.1 [M-H].sup.. Anal. calcd. For C.sub.21H.sub.17ClFNO.sub.3: C, 65.38; H, 4.44; N, 3.63; Found: C, 65.37; H, 4.45; N, 3.61.

Example 4

2-(4-((2-methyl-[1,1-biphenyl]-3-methylene)amino)-2-fluorophenoxy)acetic acid (I-3)

(15) ##STR00007##

(16) By substituting 2-methylbromobenzene for the 3,5-dimethyl-4-bromophenol of Example 2, Compound I-3 was prepared in a similar manner as in Example 2 to give a white solid, (0.51 g, m.p.: 103-104 C., yield: 85%).

(17) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 7.42-7.14 (m, 8H), 6.82 (t, J=9.3 Hz, 1H), 6.47, 6.43 (dd, J=14.1, 2.5 Hz, 1H), 6.32 (d, J=8.8 Hz, 1H), 4.50 (s, 2H), 4.27 (s, 2H), 2.17 (s, 3H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 170.80, 154.74, 151.54, 144.81, 141.71, 140.36, 136.59, 135.12, 130.79, 129.88, 128.69, 128.37, 127.70, 126.36, 126.30, 117.71, 108.04, 101.26, 66.96, 47.18, 20.54. ESI-MS m/z: 364.1 [M-H].sup.. Anal. calcd. For C.sub.22H.sub.20FNO.sub.3: C, 72.31; H, 5.52; N, 3.83; Found: C, 72.32; H, 5.54; N, 3.82.

Example 5

2-(4-((2-fluoro-[1,1-biphenyl]-3-methylene)amino)-2-fluorophenoxy)acetic acid (I-4)

(18) ##STR00008##

(19) By substituting 2-fluorobromobenzene for the 3,5-dimethyl-4-bromophenol of Example 2, Compound I-4 was prepared in a similar manner as in Example 2 to give a pale yellow solid (0.46 g, m.p.: 105-107 C., yield: 76%).

(20) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 7.53-7.28 (m, 8H), 6.83 (t, J=9.3 Hz, 1H), 6.48, 6.44 (dd, J=14.1, 2.5 Hz, 1H), 6.32 (d, J=7.0 Hz, 1H), 4.53 (s, 2H), 4.28 (s, 2H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 170.29, 160.64, 154.23, 151.04, 144.44, 140.41, 135.05, 130.75, 129.56, 128.54, 127.71, 126.76, 124.91, 117.23, 116.22, 115.92, 107.48, 100.73, 66.39, 46.74. ESI-MS m/z: 368.1 [M-H].sup.. Anal. calcd. For C.sub.21H.sub.17FNO.sub.3: C, 68.29; H, 4.64; N, 3.79; Found: C, 68.28; H, 4.66; N, 3.77.

Example 6

2-(4-((2-chloro-4-methyl-[1,1-biphenyl]-3-methylene)amino)-2-fluorophenoxy)acetic acid (I-5)

(21) ##STR00009##

(22) By substituting 2-chloro-4-methylbromobenzene for the 3,5-dimethyl-4-bromophenol of Example 2, Compound I-5 was prepared in a similar manner as in Example 2 to give a pale white solid (0.42 g, m.p.: 141-143 C., yield: 72%).

(23) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 7.50-7.17 (m, 7H), 6.96 (t, J=9.3 Hz, 1H), 6.48, 6.44 (dd, J=14.2, 2.6 Hz, 1H), 6.32 (d, J=7.1 Hz, 1H), 4.62 (s, 2H), 4.37 (s, 2H), 2.35 (s, 3H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 170.20, 154.08, 150.88, 138.97, 138.59, 136.73, 131.13, 130.06, 128.44, 128.14, 127.76, 126.69, 117.03, 108.61, 101.67, 66.29, 47.30, 20.22. ESI-MS m/z: 398.1 [M-H].sup.. Anal. calcd. For C.sub.22H.sub.19ClFNO.sub.3: C, 66.09; H, 4.79; N, 3.50; Found: C, 66.07; H, 4.76; N, 3.53.

Example 7

2-(4-((2-methoxy-[1,1-biphenyl]-3-methylene)amino)-2-fluorophenoxy)acetic acid (I-6)

(24) ##STR00010##

(25) By substituting 2-bromophenol for the 3,5-dimethyl-4-bromophenol in Example 2 and substituting methyl iodide for ethyl bromide in Example 2, Compound I-6 was prepared in the same manner as in Example 2 to give an off-white solid (0.52 g, m.p. 95-96 C., yield 82%).

(26) .sup.1H NMR (300 MHz, DMSO-ds) : 7.44 (s, 1H), 7.35-7.24 (m, 5H), 7.09 (d, J=8.1 Hz, 1H), 7.02 (t, J=7.3 Hz, 1H), 6.83 (t, J=9.3 Hz, 1H), 6.48, 6.44 (dd, J=14.1, 2.6 Hz, 1H), 6.32 (d, J=8.7 Hz, 1H), 4.52 (s, 2H), 4.24 (s, 2H), 3.72 (s, 3H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 170.82, 156.50, 151.51, 144.97, 140.09, 138.59, 136.54, 130.79, 130.24, 129.30, 128.65, 128.36, 126.25, 121.18, 117.64, 112.12, 107.97, 101.18, 66.87, 55.82, 47.29. ESI-MS m/z: 381.1 [M-H].sup.. Anal. calcd. For C.sub.22H.sub.19ClFNO.sub.3: C, 69.28; H, 5.29; N, 3.67; Found: C, 69.27; H, 5.28; N, 3.65.

Example 8

2-(4-((2-Nitrile-[1,1-biphenyl]-3-methylene)amino)-2-fluorophenoxy)acetic acid (I-7)

(27) ##STR00011##

(28) By substituting 2-carbonitrile-bromobenzene for the 3,5-dimethyl-4-bromophenol of Example 2, Compound I-7 was prepared in a similar manner as in Example 2 to give an off-white solid (0.43 g, m.p. 137-140 C., yield 76%).

(29) .sup.1H NMR (300 MHz, DMSO-ds) : 7.96 (d, J=7.3 Hz, 1H), 7.80 (t, J=7.1 Hz, 1H), 7.66-7.54 (m, 3H), 7.50-7.46 (m, 3H), 6.82 (t, J=9.3 Hz, 1H), 6.49, 6.45 (dd, J=14.0, 2.4 Hz, 1H), 6.32 (d, J=8.7 Hz, 1H), 4.52 (s, 2H), 4.30 (s, 2H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 170.32, 152.93, 144.52, 140.74, 137.80, 136.23, 133.84, 133.51, 130.05, 128.68, 128.18, 127.65, 127.53, 127.08, 118.52, 117.18, 107.42, 66.43, 46.72. ESI-MS m/z: 375.1 [M-H].sup.. Anal. calcd. For C.sub.22H.sub.17FN.sub.2O.sub.3: C, 70.20; H, 4.55; N, 7.44; Found: C, 70.21; H, 4.53; N, 7.46.

Example 9

2-(4-((2-trifluoromethyl-[1,1-biphenyl]-3-methylene)amino)-2-fluorophenoxy)acetic acid (I-8)

(30) ##STR00012##

(31) By substituting 2-trifluoromethylbromobenzene for the 3,5-dimethyl-4-bromophenol of Example 2, Compound I-8 was prepared in a similar manner as in Example 2 to give a white solid (0.34 g, m.p. 120 C., yield 61%).

(32) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 12.83 (brs, 1H), 7.83 (d, J=7.7 Hz, 1H), 7.72 (t, J=7.4 Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.45-7.36 (m, 3H), 7.29 (s, 1H), 7.21-7.17 (m, 1H), 6.82 (t, J=9.3 Hz, 1H), 6.45, 6.41 (dd, J=14.1, 2.6 Hz, 1H), 6.30 (d, J=8.9 Hz, 1H), 4.52 (s, 2H), 4.26 (s, 2H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 170.31, 154.23, 151.03, 144.44, 140.71, 139.75, 136.12, 135.97, 132.19, 127.95, 127.00, 126.55, 126.02, 125.95, 122.30, 117.19, 107.56, 100.69, 66.41, 46.69. ESI-MS m/z: 418.1 [M-H].sup.. Anal. calcd. For C.sub.22H.sub.17F.sub.4NO.sub.3: C, 63.01; H, 4.09; N, 3.34; Found: C, 63.03; H, 4.07; N, 3.36.

Example 10

2-(4-((4-propoxy-2,6-dimethyl-[1,1-biphenyl]-3-methylene)amino)-2-fluorophenoxy) acetic acid (I-9)

(33) ##STR00013##

(34) By substituting 1-bromopropane for bromoethane of Example 2, Compound I-9 was prepared in a similar manner as in Example 2 to give a off-white solid (0.41 g, m.p. 95-96 C., yield 71%).

(35) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 12.98 (brs, 1H), 7.45-7.25 (m, 2H), 7.06 (s, 1H), 6.96 (d, J=7.3 Hz, 1H), 6.84 (t, J=9.2 Hz, 1H), 6.66 (s, 2H), 6.48 (d, J=14.6 Hz, 1H), 6.36 (d, J=8.4 Hz, 1H), 4.54 (s, 2H), 4.29 (s, 2H), 3.91 (t, J=6.5 Hz, 2H), 1.87 (s, 6H), 1.75-1.68 (m, 2H), 0.98 (t, J=7.4 Hz, 3H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 170.66, 157.74, 152.34, 140.67, 139.67, 136.94, 134.21, 129.08, 128.89, 128.29, 126.22, 117.53, 113.59, 107.56, 69.15, 66.81, 55.35, 22.58, 21.13, 10.89. ESI-MS m/z: 436.2 [M-H].sup.. Anal. calcd. For C.sub.26H.sub.28FNO.sub.4: C, 71.38; H, 6.45; N, 3.20; Found: C, 71.37; H, 6.43; N, 3.22.

Example 11

2-(2-fluoro-4-((4-(2-methoxyethoxy)-2,6-dimethyl-[1,1-biphenyl]-3-methylene)amino phenoxy)acetic acid (I-10)

(36) ##STR00014##

(37) By substituting bromoethanol for bromoethane in Example 2, Compound I-10 was prepared in the same manner as in Example 2 to give a white solid (0.52 g, m.p. 138-140 C., yield: 82%).

(38) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 12.85 (brs, 1H), 7.38-7.29 (m, 2H), 7.05 (s, 1H), 6.96 (d, J=6.9 Hz, 1H), 6.82 (t, J=9.2 Hz, 1H), 6.68 (s, 2H), 6.40 (d, J=14.1 Hz, 1H), 6.29 (d, J=8.1 Hz, 1H), 4.52 (s, 2H), 4.27 (s, 2H), 4.07 (t, J=3.4 Hz, 2H), 3.64 (t, J=3.4 Hz, 2H), 3.32 (s, 3H), 1.88 (s, 6H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 170.28, 157.01, 140.08, 139.97, 136.51, 133.98, 128.40, 128.28, 127.58, 125.48, 117.15, 113.11, 107.80, 100.84, 70.40, 66.60, 66.39, 58.11, 46.69, 20.66. ESI-MS m/z: 455.2 [M-H].sup.. Anal. calcd. For C.sub.26H.sub.28FNO.sub.5: C, 68.86; H, 6.22; N, 3.09; Found: C, 68.85; H, 6.24; N, 3.06.

Example 12

2-(4-(([1,1-biphenyl]-3-methylene)amino)-2-fluorophenoxy)acetic acid (I-11)

(39) ##STR00015##

(40) By substituting bromobenzene for the 3,5-dimethyl-4-bromophenol of Example 2, Compound I-11 was prepared in a similar manner as in Example 2 to give a white solid (0.23 g, m.p. 115-116 C., yield 41%).

(41) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 7.69-7.59 (m, 3H), 7.55-7.30 (m, 6H), 6.83 (t, J=9.3 Hz, 1H), 6.50, 6.45 (dd, J=14.1, 2.6 Hz, 1H), 6.34, 6.31 (dd, J=8.8, 1.5 Hz, 1H), 4.53 (s, 2H), 4.28 (s, 2H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 170.32, 154.24, 151.05, 144.47, 140.68, 140.18, 136.16, 128.89, 127.40, 126.65, 126.37, 125.67, 125.09, 117.21, 107.52, 100.79, 66.43, 46.86. ESI-MS m/z: 350.1 [M-H].sup.. Anal. calcd. For C.sub.2H.sub.18FNO.sub.3: C, 71.78; H, 5.16; N, 3.99; Found: C, 71.77; H, 5.14; N, 3.97.

Example 13

2-(4-(((2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)-[1,1-biphenyl]-3-methylene)amino)-2-fluorophenoxy)acetic acid (I-12)

(42) ##STR00016##

(43) By substituting 1-bromo-3-(methylsulfonyl)propane for ethyl bromide of Example 2, Compound I-12 was prepared in a similar manner as in Example 2 to give an off-white solid (0.26 g, m.p. 69-70 C., yield 38%).

(44) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 7.45-7.24 (m, 2H), 7.05 (s, 1H), 6.96 (d, J=7.2 Hz, 1H), 6.80 (t, J=9.4 Hz, 1H), 6.69 (s, 2H), 6.43, 6.38 (dd, J=14.1, 2.4 Hz, 1H), 6.29 (d, J=8.7 Hz, 1H), 4.52 (s, 2H), 4.26 (s, 2H), 4.08 (t, J=6.0 Hz, 2H), 3.27 (t, J=6.6 Hz, 2H), 3.03 (s, 3H), 2.21-2.06 (m, 2H), 1.88 (s, 6H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 170.30, 156.82, 154.19, 151.01, 144.28, 140.04, 136.57, 134.17, 128.41, 128.25, 127.54, 125.49, 117.16, 113.20, 107.76, 100.78, 66.43, 65.33, 50.51, 46.65, 22.01, 20.65. ESI-MS m/z: 514.2 [M-H].sup.. Anal. calcd. For C.sub.27H.sub.30FNO.sub.6S: C, 62.90; H, 5.87; N, 2.72; Found: C, 62.92; H, 5.85; N, 2.75.

Example 14

2-(4-(((4-ethoxy-2-methyl-[1,1-biphenyl]-3-yl)methylene)amino)-2-fluorophenoxy)acetic acid (I-13)

(45) ##STR00017##

(46) By substituting 3-methyl-4-bromophenol for 3,5-dimethyl-4-bromophenol in Example 2, Compound I-13 was prepared in a similar manner as in Example 2 to give a white solid (0.32 g, m.p. 95-96 C., yield 63%).

(47) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 12.89 (s, 1H), 7.47-7.23 (m, 3H), 7.15 (d, J=7.4 Hz, 1H), 7.08 (d, J=8.3 Hz, 1H), 6.97-6.66 (m, 3H), 6.46 (dd, J=14.0, 2.5 Hz, 1H), 6.32 (d, J=8.0 Hz, 1H), 4.52 (s, 2H), 4.26 (s, 2H), 4.04 (q, J=7.0 Hz, 2H), 2.15 (s, 3H), 1.33 (t, J=6.9 Hz, 3H). .sup.13C NMR (75 MHz, DMSO-d.sub.6): 170.32, 157.60, 144.47, 144.34, 140.92, 139.76, 136.02, 135.91, 133.60, 130.49, 128.11, 127.39, 125.43, 117.18, 114.50, 111.78, 107.55, 66.38, 62.85, 46.69, 20.35, 14.67. ESI-MS m/z: 408.2 [M-H].sup.. Anal. calcd. For C.sub.24H.sub.24FNO.sub.4: C, 70.40; H, 5.91; N, 3.42; Found: C, 70.43; H, 5.92; N, 3.43.

Example 15

2-(4-((3-(3,5-dimethylisoxazol-4-yl)benzyl)amino)-2-fluorophenoxy)acetic acid (I-14)

(48) ##STR00018##

(49) By substituting 4-bromo-3,5-dimethylisoxazole for 3,5-dimethyl-4-bromophenol in Example 2, Compound I-14 was prepared in a similar manner as in Example 2 to give a glassy light yellow solid (0.21 g, m.p. 72-73 C., yield 34%).

(50) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 12.86 (brs, 1H), 7.49-7.14 (m, 4H), 6.83 (t, J=93 Hz, 1H), 6.47 (d, J=13.8 Hz, 1H), 6.32 (d, J=8.6 Hz, 1H), 4.53 (s, 2H), 4.27 (s, 2H), 2.35 (s, 3H), 2.17 (s, 3H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 170.76, 165.48, 158.52, 144.83, 143.66, 141.13, 130.16, 129.30, 128.16, 127.64, 127.29, 126.91, 117.78, 108.16, 101.29, 63.16, 46.93, 11.68, 10.84. ESI-MS m/z: 369.1 [M-H].sup.. Anal. calcd. For C.sub.20H.sub.19FN.sub.2O.sub.4: C, 64.86; H, 5.17; N, 7.56; Found: C, 64.84; H, 5.16; N, 7.53.

Example 16

2-(4-(((4-propoxy-2-methyl-[1,1-biphenyl]-3-yl)methylene)amino)-2-fluorophenoxy) acetic acid (I-15)

(51) ##STR00019##

(52) By substituting 3-methyl-4-bromophenol for the 3,5-dimethyl-4-bromophenol in Example 2 and substituting 1-bromopropane for the ethyl bromide in Example 2, Compound I-15 was prepared in a similar manner as in Example 2 to give a white solid (0.25 g, m.p. 75-76 C., yield 36%).

(53) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 12.98 (brs, 1H), 7.41-7.23 (m, 3H), 7.15 (d, J=7.2 Hz, 1H), 7.08 (d, J=8.3 Hz, 1H), 6.91-6.74 (m, 3H), 6.48, 6.43 (dd, J=14.1, 2.1 Hz, 1H), 6.32 (d, J=8.6 Hz, 1H), 4.53 (s, 2H), 4.26 (s, 2H), 3.93 (t, J=6.5 Hz, 2H), 2.15 (s, 3H), 1.81-1.62 (m, 2H), 0.98 (t, J=7.4 Hz, 3H). .sup.13C NMR (75 MHz, DMSO-ds) : 170.33, 157.77, 144.49, 140.95, 139.75, 136.09, 135.94, 133.61, 130.49, 128.11, 127.39, 125.42, 117.22, 116.19, 111.79, 107.55, 100.75, 68.80, 66.44, 46.72, 22.05, 20.32, 10.37. ESI-MS m/z: 422.2 [M-H].sup.. Anal. calcd. For C.sub.25H.sub.26FNO.sub.4: C, 70.91; H, 6.19; N, 3.31; Found: C, 70.93; H, 6.17; N, 3.33.

Example 17

2-(2-fluoro-4-(((2-isopropyl-[1,1-biphenyl]-3-methylene)amino)phenoxy)acetic acid (I-16)

(54) ##STR00020##

(55) By substituting 2-isopropylbromobenzene for the 3,5-dimethyl-4-bromophenol of Example 2, Compound I-16 was prepared in a similar manner as in Example 2 to give a white solid (0.28 g, m.p. 137-140 C., yield 56%).

(56) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 7.46-7.28 (m, 4H), 7.21 (m, 2H), 7.11 (m, 2H), 6.83 (t, J=9. 137-140 C. 3 Hz, 1H), 6.45, 6.40 (dd, J=14.1, 2.3 Hz, 1H), 6.31 (d, J=8.6 Hz, 1H), 4.52 (s, 2H), 4.28 (s, 2H), 2.95-2.86 (m, 1H), 1.04 (d, J=6.8 Hz, 6H). .sup.13C NMR (75 MHz, DMSO-d6) : 170.77, 154.76, 151.57, 146.16, 144.91, 141.78, 140.96, 140.29, 136.57, 129.92, 128.68, 128.25, 127.70, 126.23, 125.93, 117.74, 108.04, 101.19, 66.98, 47.09, 29.27, 24.43. ESI-MS m/z: 392.2 [M-H].sup.. Anal. calcd. For C.sub.24H.sub.24FNO.sub.3: C, 73.26; H, 6.15; N, 3.56; Found: C, 73.25; H, 6.14; N, 3.54.

Example 18

2-(4-((4-ethoxy-2,6-dimethyl-[1,1-biphenyl]-3-methylene)amino)phenoxy)acetic acid (I-17)

(57) ##STR00021##

(58) By substituting 4-nitrophenol for the 2-fluoro-4-nitrophenol in Example 1, Compound I-17 was prepared in a similar manner as in Example 2 to give a white solid (0.31 g, m.p. 135-138 C., yield 56%).

(59) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 7.43-7.29 (m, 2H), 7.08 (s, 1H), 6.98 (d, J=6.6 Hz, 1H), 6.73 (s, 4H), 6.65 (s, 2H), 4.52 (s, 2H), 4.33 (s, 2H), 4.00 (q, J=6.9 Hz, 2H), 1.86 (s, 6H), 1.32 (t, J=13.1 Hz, 3H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 170.37, 157.10, 146.51, 142.13, 140.18, 136.48, 133.64, 129.27, 128.35, 128.14, 126.36, 115.24, 113.04, 65.06, 62.67, 20.70, 14.72. ESI-MS m/z: 404.2 [M-H].sup.. Anal. calcd. For C.sub.25H.sub.27NO.sub.4: C, 74.05; H, 6.71; N, 3.45; Found: C, 74.04; H, 6.74; N, 3.42.

Example 19

2-(4-((4-methoxy-2,6-dimethyl-[1,1-biphenyl]-3-methylene)amino)phenoxy)acetic acid (I-18)

(60) ##STR00022##

(61) By substituting 4-nitrophenol for the 2-fluoro-4-nitrophenol in Example 1 and substituting methyl iodide for the ethyl bromide in Example 2, Compound I-18 was prepared in a similar manner as in Example 2 to give a white solid (0.46 g, m.p. 131-134 C., yield 53%).

(62) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 7.43-7.29 (m, 2H), 7.08 (s, 1H), 6.98 (d, J=6.6 Hz, 1H), 6.73 (s, 4H), 6.65 (s, 2H), 4.57 (s, 2H), 4.32 (s, 2H), 3.89 (s, 3H), 1.86 (s, 6H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 170.37, 157.10, 146.51, 142.13, 140.18, 136.48, 133.64, 129.27, 128.35, 128.14, 126.36, 115.24, 113.04, 65.06, 55.9, 20.70. ESI-MS m/z: 391.18 [M-H].sup.. Anal. calcd. For C.sub.24H.sub.25NO.sub.4: C, 73.64; H, 6.44; N, 3.58; Found: C, 73.65; H, 6.46; N, 3.57.

Example 20

2-(4-(((4-methoxy-2-methyl-[1,1-biphenyl]-3-yl)methylene)amino)-2-fluorophenoxy) acetic acid (I-19)

(63) ##STR00023##

(64) By substituting 3-methyl-4-bromophenol for the 3,5-dimethyl-4-bromophenol in Example 2 and substituting methyl iodide for the ethyl bromide in Example 2, Compound I-19 was prepared in a similar manner as in Example 2 to give a white solid (0.26 g, m.p. 129-132 C., yield of 63%).

(65) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 7.43-7.29 (m, 3H), 7.08 (s, 1H), 6.98 (d, J=6.6 Hz, 1H), 6.73 (s, 4H), 6.65 (s, 2H), 4.57 (s, 2H), 4.32 (s, 2H), 3.70 (s, 3H), 2.27 (s, 3H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 169.9, 159.4, 152.9, 142.1, 141.5, 137.9, 136.3, 133.6, 128.8, 125.9, 116.7, 113.6, 111.6, 103.0, 67.5, 55.8, 48.3, 19.0. ESI-MS m/z: 395.16 [M-H].sup.. Anal. calcd. For C.sub.23H.sub.22NO.sub.4: C, 69.86; H, 5.61; N, 3.54; Found: C, 69.87; H, 5.62; N, 3.53.

Example 21

2-(4-((4-methoxy-2,6-dimethyl-[1,1-biphenyl]-3-methylene)amino)-2-fluorophenoxy)acetic acid (I-20)

(66) ##STR00024##

(67) By substituting methyl iodide for the ethyl bromide in Example 2, Compound I-20 was prepared in a similar manner as in Example 2 to give a white solid (0.36 g, m.p. 133-136 C., yield 64%).

(68) .sup.1H NMR (300 MHz, DMSO-ds) : 7.57-7.41 (m, 4H), 6.94 (d, J=6.6 Hz, 2H), 6.77 (s, 1H), 6.54 (s, 2H), 4.66 (s, 2H), 4.32 (s, 2H), 3.81 (s, 3H), 2.57 (s, 6H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 169.9, 159.3, 152.9, 142.1, 141.5, 138.2, 137.9, 136.3, 130.9, 129.0, 128.7, 125.8, 116.7, 111.4, 110.6, 103.0, 67.5, 55.8, 48.3, 19.3. ESI-MS m/z: 409.17 [M-H].sup.. Anal. calcd. For C.sub.24H.sub.24NO.sub.4: C, 70.40; H, 5.91; N, 3.42; Found: C, 70.41; H, 5.92; N, 3.42.

Example 22

2-(4-(((4-methoxy-2-methyl-[1,1-biphenyl]-3-yl)methylene)amino)phenoxy)acetic acid (I-21)

(69) ##STR00025##

(70) By substituting 4-nitrophenol for the 2-fluoro-4-nitrophenol in Example 1, substituting 3-methyl-4-bromophenol for the 3,5-dimethyl-4-bromophenol in Example 2, and substituting methyl iodide for the ethyl bromide in Example 2, Compound I-21 was prepared in a similar manner as in Example 2 to give a white solid (0.41 g, m.p. 121-124 C., yield 51%).

(71) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 7.43-7.29 (m, 3H), 7.08 (s, 1H), 6.98 (d, J=6.6 Hz, 1H), 6.73 (s, 4H), 6.65 (s, 2H), 4.57 (s, 2H), 4.32 (s, 2H), 3.70 (s, 3H), 2.27 (s, 3H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 169.9, 159.4, 146.5, 142.1, 141.6, 136.3, 133.6, 129.0, 128.8, 128.14, 125.8, 115.1, 113.6, 64.7, 55.8, 19.70. ESI-MS m/z: 377.16 [M-H].sup.. Anal. calcd. For C.sub.23H.sub.23NO.sub.4: C, 73.19; H, 6.14; N, 3.71; Found: C, 73.18; H, 6.14; N, 3.72.

Example 23

2-(4-(((4-isopropoxy-2-methyl-[1,1-biphenyl]-3-yl)methylene)amino)-2-fluorophenoxy)acetic acid (I-22)

(72) ##STR00026##

(73) By substituting 3-methyl-4-bromophenol for the 3,5-dimethyl-4-bromophenol in Example 2, and substituting 2-bromopropane for the ethyl bromide in Example 2 Compound I-22 was prepared in a similar manner as in Example 2_to give a white solid (0.35 g, m.p. 134-137 C., yield 43%).

(74) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 7.90-7.57 (m, 3H), 7.41 (d, J=6.8 Hz, 2H), 7.04 (s, 1H), 6.80 (d, J=6.8 Hz, 2H), 6.54 (s, 2H). 4.69 (m, J=8.9 Hz, 1H), 4.66 (s, 2H), 4.32 (s, 2H), 2.57 (s, 3H), 1.29 (d, J=8.9 Hz, 6H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 169.9, 156.2, 152.9, 142.1, 141.5, 137.9, 136.3, 133.2, 128.7, 125.8, 125.2, 116.7, 113.7, 111.9, 111.4, 103.0, 75.8, 67.5, 48.3, 22.0, 19.0. ESI-MS m/z: 423.48 [M-H].sup.. Anal. calcd. For C.sub.25H.sub.26FNO.sub.4: C, 70.91; H, 6.19; N, 3.31; Found: C, 70.90; H, 6.18; N, 3.32.

Example 24

2-(4-((4-isopropoxy-2-methyl-[1,1-biphenyl]-3-yl)methylene)amino)phenoxy)acetic acid (I-23)

(75) ##STR00027##

(76) By substituting 4-nitrophenol for the 2-fluoro-4-nitrophenol in Example 1, substituting 3-methyl-4-bromophenol for the 3,5-dimethyl-4-bromophenol in Example 2_and substituting 2-bromopropane for the ethyl bromide of Example 2, Compound I-23 was prepared in a similar manner as in Example 2 to give a white solid (0.42 g, m.p. 132-135 C., yield 45%).

(77) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 7.90-7.57 (m, 3H), 7.45 (s, 2H), 7.04 (s, 1H), 6.93 (s, 1H), 6.75 (s, 4H), 4.69 (m, J=8.9 Hz, 1H), 4.57 (s, 2H), 4.32 (s, 2H), 2.57 (s, 3H), 1.29 (d, J=8.9 Hz, 6H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 169.9, 156.2, 146.5, 142.1, 141.6, 136.3, 133.3, 129.0, 128.7, 125.2, 115.1, 113.3, 111.9, 75.8, 64.7, 48.3, 22.0, 19.0. ESI-MS m/z: 405.19 [M-H].sup.. Anal. calcd. For C.sub.25H.sub.27NO.sub.4: C, 74.05; H, 6.71; N, 3.45; Found: C, 74.04; H, 6.70; N, 3.46.

Example 25

2-(4-((2-chloro-[1,1-biphenyl]-3-methylene)amino)phenoxy)acetic acid (I-24)

(78) ##STR00028##

(79) By substituting 4-nitrophenol for the 2-fluoro-4-nitrophenol in Example 1, and substituting 2-chlorobromobenzene for the 3,5-dimethyl-4-bromophenol in Example 2, Compound I-24 was prepared in a similar manner as in Example 2 to give a white solid (0.49 g, m.p. 124-126 C., yield 51%).

(80) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 12.91 (s, 1H), 7.71-7.41 (m, 5H), 7.38 (s, 2H), 6.77 (s, 2H), 6.73 (s, 2H), 6.54 (s, 1H), 4.57 (s, 2H), 4.32 (s, 2H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 169.9, 146.5, 142.1, 141.6, 139.4, 136.3, 132.6, 128.7, 129.3, 129.0, 127.3, 125.8, 115.1, 113.3, 64.7, 48.3. ESI-MS m/z: 367.1 [M-H].sup.. Anal. calcd. For C.sub.21H.sub.18ClNO.sub.3: C, 68.57; H, 4.93; N, 3.81; Found: C, 68.56; H, 4.94; N, 3.81.

Example 26

2-(4-((2-methyl-[1,1-biphenyl]-3-methylene)amino)phenoxy)acetic acid (I-25)

(81) ##STR00029##

(82) By substituting 4-nitrophenol for the 2-fluoro-4-nitrophenol in Example 1, and substituting 2-methylbromobenzene for the 3,5-dimethyl-4-bromophenol in Example 2, Compound I-25 was prepared in a similar manner as in Example 2 to give a white solid (0.32 g, m.p. 101-104 C., yield 44%).

(83) .sup.1H NMR (300 MHz, DMSO-ds) :12.91 (s, 1H), 7.90-7.57 (m, 5H), 7.35 (s, 2H), 6.77 (s, 2H), 6.73 (s, 2H), 6.54 (s, 1H), 4.57 (s, 2H), 4.32 (s, 2H), 2.23 (s, 3H). .sup.13C NMR (75 MHz, DMSO-d6) :169.9, 146.5, 142.1, 141.6, 136.3, 135.9, 133.6, 129.5, 129.0, 128.7, 127.5, 126.2, 125.6, 115.1, 113.3, 64.7, 48.3, 18.3. ESI-MS m/z: 347.15 [M-H].sup.. Anal. calcd. For C.sub.22H.sub.21NO.sub.3: C, 76.06; H, 6.09; N, 4.03; Found: C, 76.07; H, 6.08; N, 4.05.

Example 27

2-(4-((2-fluoro-[1,1-biphenyl]-3-methylene)amino)phenoxy)acetic acid (I-26)

(84) ##STR00030##

(85) By substituting 4-nitrophenol for the 2-fluoro-4-nitrophenol in Example 1, and substituting 2-fluorobromobenzene for the 3,5-dimethyl-4-bromophenol in Example 2, Compound I-26 was prepared in a similar manner as in Example 2 to give a white solid (0.46 g, m.p. 111-112 C., yield 53%).

(86) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 12.91 (s, 1H), 7.90-7.57 (m, 5H), 7.41 (s, 2H), 6.73 (s, 2H), 6.53 (s, 2H), 6.44 (s, 1H), 4.57 (s, 2H), 4.32 (s, 2H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) :169.9, 158.7, 146.5, 142.1, 141.6, 136.3, 129.0, 125.9, 129.0, 124.8, 115.1, 114.7, 113.3, 64.7, 48.3. ESI-MS m/z: 347.15 [M-H].sup.. Anal. calcd. For C.sub.21H.sub.18FNO.sub.3: C, 71.78; H, 5.16; N, 3.99; Found: C, 71.79; H, 5.15; N, 4.00.

Example 28

2-(4-((2-chloro-4-methyl-[1,1-biphenyl]-3-methylene)amino)phenoxy)acetic acid (I-27)

(87) ##STR00031##

(88) By substituting 4-nitrophenol for the 2-fluoro-4-nitrophenol in Example 1, and substituting 2-chloro-4-methylbromobenzene for the 3,5-dimethyl-4-bromo in Example 2. Compound I-27 was prepared in a similar manner as in Example 2 to give a white solid (0.38 g, m.p. 111-114 C., yield 46%).

(89) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 12.91 (s, 1H), 7.90-7.57 (m, 4H), 7.41 (s, 2H), 7.14 (s, 2H), 6.73 (s, 2H), 6.64 (s, 1H), 4.57 (s, 2H), 4.32 (s, 2H), 2.36 (s, 3H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) :172.9, 138.7, 136.4, 136.9, 132.5, 130.4, 129.7, 126.8, 127.6, 126.2, 129.0, 68.6, 67.5, 54.8, 45.4, 20.8 ESI-MS m/z: 381.11 [M-H].sup.. Anal. calcd. For C.sub.22H.sub.20ClNO.sub.3: C, 69.20; H, 5.28; N, 3.67; Found: C, 69.19; H, 5.27; N, 3.68.

Example 29

2-(4-((2-trifluoromethyl-[1,1-biphenyl]-3-methylene)amino)phenoxy)acetic acid (I-28)

(90) ##STR00032##

(91) By substituting 4-nitrophenol for the 2-fluoro-4-nitrophenol in Example 1, and substituting 2-trifluoromethylbromobenzene for the 3,5-dimethyl-4-bromophenol in Example 2, Compound I-28 was prepared in a similar manner as in Example 2 to give a white solid (0.39 g, m.p. 115-117 C., yield 63%).

(92) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 12.91 (s, 1H), 7.90-7.66 (m, 5H), 7.33 (s, 2H), 7.14 (s, 2H), 6.77 (s, 2H), 6.64 (s, 1H), 4.57 (s, 2H), 4.32 (s, 2H), 2.36 (s, 3H). .sup.13C NMR (75 MHz, DMSO-ds) : 169.9, 146.5, 142.1, 141.6, 136.3, 132.5, 129.7, 128.7, 127.9, 126.0, 125.6, 123.9, 115.1, 113.3, 64.7, 48.3. ESI-MS m/z: 401.12 [M-H].sup.. Anal. calcd. For C.sub.22H.sub.18F.sub.3NO.sub.3: C, 65.83; H, 4.52; N, 3.49; Found: C, 65.83; H, 4.56; N, 3.48.

Example 30

2-(4-((4-trifluoromethoxy-2,6-dimethyl-[1,1-biphenyl]-3-methylene)amino)phenoxy)acetic acid (I-29)

(93) ##STR00033##

(94) By substituting 4-nitrophenol for the 2-fluoro-4-nitrophenol in Example 1, and substituting 2,6-dimethyl-4-trifluoromethoxybromobenzene for 3,5-dimethyl-4-bromophenol in Example 2, Compound I-29 was prepared in a similar manner as in Example 2 to give a white solid (0.27 g, m.p. 117-120 C., yield 56%).

(95) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 12.80 (s, 1H), 7.90 (s, 1H), 7.57-7.35 (m, 4H), 6.94 (s, 2H), 6.77 (s, 2H), 6.64 (s, 1H), 4.57 (s, 2H), 4.32 (s, 2H), 2.57 (s, 6H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 169.9, 159.3, 146.5, 142.1, 141.6, 138.2, 136.3, 130.9, 129.7, 128.7, 125.8, 115.1, 113.3, 110.6, 64.7, 48.3, 19.3. ESI-MS m/z: 445.15 [M-H].sup.. Anal. calcd. For C.sub.24H.sub.22F.sub.3NO.sub.4: C, 64.71; H, 4.98; N, 3.14; Found: C, 64.72; H, 4.97; N, 3.14.

Example 31

2-(4-((4-trifluoromethoxy-2-methyl-[1,1-biphenyl]-3-methylene)amino)phenoxy)acetic acid (I-30))

(96) ##STR00034##

(97) By substituting 4-nitrophenol for the 2-fluoro-4-nitrophenol in Example 1, and substituting 2-methyl-4-trifluoromethoxybromobenzene for the 3,5-dimethyl-4-bromophenol in Example 2, Compound I-30 was prepared in a similar manner as in Example 2 to give a white solid (0.33 g, m.p. 118-120 C., yield 43%).

(98) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 12.80 (s, 1H), 7.90 (s, 1H), 7.72-7.35 (m, 4H), 7.04 (d, J=6.8 Hz, 2H), 6.93 (d, J=6.8 Hz, 1H), 6.77 (s, 2H), 6.64 (s, 1H), 4.57 (s, 2H), 4.32 (s, 2H), 2.57 (s, 3H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 169.9, 159.4, 146.5, 142.1, 141.6, 136.3, 133.6, 129.7, 128.7, 125.9, 115.1, 113.1, 111.8, 64.7, 48.3, 19.0. ESI-MS m/z: 431.13 [M-H].sup.. Anal. calcd. For C.sub.23H.sub.20F.sub.3NO.sub.4: C, 64.03; H, 4.67; N, 3.25; Found: C, 64.02; H, 4.67; N, 3.24.

Example 32

2-(4-(((4-ethoxy-2-methyl-[1,1-biphenyl]-3-yl)methylene)amino)phenoxy)acetic acid (I-31)

(99) ##STR00035##

(100) By substituting 4-nitrophenol for the 2-fluoro-4-nitrophenol in Example 1, and substituting 3-methyl-4-bromophenol for the 3,5-dimethyl-4-bromophenol in Example 2, Compound I-31 was prepared in a similar manner as in Example 2 to give a white solid (0.47 g, m.p. 121-124 C., yield 44%).

(101) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 12.80 (s, 1H), 7.90 (s, 1H), 7.72-7.35 (m, 4H), 7.04 (d, J=6.8 Hz, 1H), 6.93 (d, J=6.8 Hz, 1H), 6.77 (s, 2H), 6.73 (s, 2H), 4.57 (s, 2H), 4.06 (q, J=8.9 Hz, 2H), 4.32 (s, 2H), 2.57 (s, 3H), 1.34 (t, J=8.9 Hz, 3H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 169.9, 156.2, 146.5, 142.1, 141.6, 136.3, 133.2, 129.0, 128.7, 125.9, 125.3, 115.1, 113.3, 111.9, 64.7, 48.3, 19.0, 14.8. ESI-MS m/z: 391.47 [M-H].sup.. Anal. calcd. For C.sub.24H.sub.24NO.sub.4: C, 73.64; H, 6.44; N, 3.58; Found: C, 73.62; H, 6.45; N, 3.58.

Example 33

2-(4-((2-trifluoromethoxy-[1,1-biphenyl]-3-methylene)amino)phenoxy)acetic acid (I-32)

(102) ##STR00036##

(103) By substituting 4-nitrophenol for the 2-fluoro-4-nitrophenol in Example 1, and substituting 2-trifluoromethoxybromobenzene for the 3,5-dimethyl-4-bromophenol in Example 2, Compound i-32 was prepared in a similar manner as in Example 2 to give a white solid (0.34 g, m.p. 107-110 C., yield 45%).

(104) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 12.80 (s, 1H), 7.99 (d, J=6.9 Hz, 1H), 7.90 (s, 1H), 7.57-7.41 (m, 4H), 7.14 (d, J=6.8 Hz, 2H), 6.77 (s, 2H), 6.73 (s, 2H), 4.57 (s, 2H), 4.32 (s, 2H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 169.9, 157.7, 146.5, 142.1, 141.6, 136.3, 131.9, 130.8, 130.0, 128.7, 125.8, 121.5, 116.6, 115.1, 113.3, 64.6, 48.3. ESI-MS m/z: 417.12 [M-H].sup.. Anal. calcd. For. C.sub.22H.sub.18F.sub.3NO.sub.4: C, 63.31; H, 4.35; N, 3.36; Found: C, 63.32; H, 4.35; N, 3.38.

Example 34

2-(4-((2-trifluoromethoxy-[1,1-biphenyl]-3-methylene)amino-2-fluorophenoxy)acetic acid (I-33)

(105) ##STR00037##

(106) By substituting 2-trifluoromethoxybromobenzene for the 3,5-dimethyl-4-bromophenol of Example 2, Compound I-33 was prepared in a similar manner as in Example 2 to give a white solid (0.48 g, m.p. 111-113 C., yield 48%).

(107) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 12.80 (s, 1H), 7.99 (d, J=6.9 Hz, 1H), 7.90 (s, 1H), 7.57-7.41 (m, 4H), 7.14 (d, J=6.8 Hz, 2H), 6.82 (s, 2H), 6.54 (s, 1H), 4.66 (s, 2H), 4.32 (s, 2H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 169.9, 157.7, 152.9, 142.1, 141.5, 137.9, 136.3, 131.9, 130.8, 130.0, 129.0, 128.7, 125.8, 121.5, 116.7, 111.4, 103.0, 67.5, 48.3. ESI-MS m/z: 435.11 [M-H].sup.. Anal. calcd. For C.sub.22H.sub.17F.sub.4NO.sub.4: C, 60.69; H, 3.94; N, 3.22; Found: C, 60.68; H, 3.95; N, 3.21.

Example 35

2-(4-((4-trifluoromethoxy-2,6-dimethyl-[1,1-biphenyl]-3-methylene)amino)-2-fluorophenoxy)acetic acid (I-34)

(108) ##STR00038##

(109) By substituting 2,6-dimethyl-4-trifluoromethoxybromobenzene for 3,5-dimethyl-4-bromophenol, Compound I-34 was prepared in a similar manner as in Example 2 to give a white solid (0.28 g, m.p. 127-130 C., yield 53%).

(110) .sup.1H NMR (300 MHz, DMSO-d.sub.6) :12.80 (s, 1H), 7.90 (s, 1H), 7.57-7.41 (m, 3H), 6.94 (d, J=7.2 Hz, 2H), 6.84 (d, J=7.2 Hz, 1H), 6.77 (s, 1H), 6.54 (s, 1H), 4.66 (s, 2H), 4.32 (s, 2H), 2.57 (s, 6H). .sup.13C NMR (75 MHz, DMSO-ds) : 169.9, 159.3, 152.9, 142.1, 141.5, 138.2, 137.9, 136.3, 130.9, 129.7, 128.7, 125.8, 116.7, 111.4, 110.6, 103.0, 67.5, 48.3, 19.3. ESI-MS m/z: 463.14 [M-H].sup.. Anal. calcd. For C.sub.24H.sub.21F.sub.4NO.sub.4: C, 62.20; H, 4.57; N, 3.02; Found: C, 62.22; H, 4.56; N, 3.01.

Example 36

2-(4-((4-trifluoromethoxy-2-methyl-[1,1-biphenyl]-3-methylene)amino)2-fluorophenoxy)acetic acid (I-35)

(111) ##STR00039##

(112) By substituting 2-methyl-4-trifluoromethoxybromobenzene for 2,5-dimethyl-4-bromophenol in Example 2, Compound I-35 was prepared in a similar manner as in Example 2 to give a white solid (0.41 g, m.p. 123-125 C., yield 43%).

(113) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 12.80 (s, 1H), 7.90 (s, 1H), 7.72-7.41 (m, 5H), 7.04 (s, 1H), 6.93 (d, J=7.2 Hz, 1H), 6.84 (d, J=7.2 Hz, 1H), 6.77 (s, 1H), 6.54 (s, 1H), 4.66 (s, 2H), 4.32 (s, 2H), 2.57 (s, 3H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 169.9, 159.4, 152.9, 142.1, 141.5, 137.9, 136.3, 133.6, 129.7, 128.7, 125.9, 116.7, 113.6, 111.8, 103.0, 67.5, 48.3, 19.0. ESI-MS m/z: 449.13 [M-H].sup.. Anal. calcd. For C.sub.23H.sub.19F.sub.4NO.sub.4: C, 61.47; H, 4.26; N, 3.12; Found: C, 61.45; H, 4.26; N, 3.11.

Example 37

2-(2-fluoro-4-((4-(2-ethoxyethoxy)-2,6-dimethyl-[1,1-biphenyl]-3-methylene)amino)phenoxy)acetic acid (I-36)

(114) ##STR00040##

(115) By substituting bromoethanol for the bromoethane in Example 2, compound I-36 was prepared in a similar manner as in Example 2 to give a white solid (0.49 g, m.p. 137-139 C., yield 45%).

(116) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 12.80 (s, 1H), 7.90 (s, 1H), 7.38-7.29 (m, 2H), 7.04 (s, 1H), 6.96 (d, J=7.2 Hz, 1H), 6.82 (d, J=7.2 Hz, 1H), 6.68 (s, 2H), 6.29 (s, 1H), 4.52 (s, 2H), 4.31 (t, J=3.4 Hz, 2H), 4.27 (s, 2H), 3.77 (t, J=3.4 Hz, 2H), 3.46 (q, J=4.5 Hz, 2H), 2.57 (s, 6H), 1.03 (t, J=4.5 Hz, 3H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 169.9, 156.1, 152.9, 142.1, 141.5, 137.9, 136.3, 130.2, 128.7, 125.8, 116.7, 111.4, 110.7, 103.0, 69.3, 67.5, 66.6, 48.3, 19.3, 15.2. ESI-MS m/z: 467.21 [M-H].sup.. Anal. calcd. For C.sub.27H.sub.30FNO.sub.5: C, 69.36; H, 6.47; N, 3.00; Found: C, 69.35; H, 6.46; N, 3.01.

Example 38

2-(4-((4-(2-ethoxyethoxy)-2,6-dimethyl-[1,1-biphenyl]-3-methylene)amino)phenoxy)acetic acid (I-37)

(117) ##STR00041##

(118) By substituting 4-nitrophenol for the 2-fluoro-4-nitrophenol in Example 1 with, and substituting bromoethanol for the ethyl bromide in Example 2, Compound I-37 was prepared in a similar manner as in Example 2 to give a white solid (0.29 g, m.p. 133-136 C., yield 46%).

(119) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 12.80 (s, 1H), 7.90 (s, 1H), 7.57-7.41 (m, 3H), 6.94 (d, J=7.2 Hz, 2H), 6.77 (s, 2H), 6.73 (d, J=7.2 Hz, 2H), 4.52 (s, 2H), 4.31 (t, J=3.4 Hz, 2H), 4.27 (s, 2H), 3.77 (t, J=3.4 Hz, 2H), 3.46 (q, J=4.5 Hz, 2H), 2.57 (s, 6H), 1.05 (t, J=4.5 Hz, 3H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 169.9, 156.1, 146.5, 142.1, 141.6, 137.8, 136.3, 130.2, 128.7, 125.8, 115.1, 113.3, 110.7, 69.3, 64.7, 66.6, 48.3, 19.3, 15.2. ESI-MS m/z: 449.22 [M-H].sup.. Anal. calcd. For C.sub.27H.sub.31NO.sub.5: C, 72.14; H, 6.95; N, 3.12; Found: C, 72.15; H, 6.96; N, 3.11.

Example 39

2-(2-fluoro-4-((4-(2-methoxymethoxy)-2,6-dimethyl-[1,1-biphenyl]-3-methylene) amino)phenoxy)acetic acid (I-38)

(120) ##STR00042##

(121) By substituting bromoethanol for the bromoethane in Example 2, Compound I-38 was prepared in a similar manner as in Example 2 to give a white solid (0.32 g, m.p. 136-138 C., yield 51%)

(122) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 12.80 (s, 1H), 7.90 (s, 1H), 7.57-7.41 (m, 3H), 6.96 (d, J=7.2 Hz, 2H), 6.94 (d, J=7.2 Hz, 1H), 6.84 (s, 1H), 6.54 (s, 1H), 6.02 (s, 2H), 4.66 (s, 2H), 4.32 (s, 2H), 3.30 (s, 3H), 2.57 (s, 6H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 169.9, 159.3, 152.9, 142.1, 141.5, 138.2, 137.9, 136.3, 130.9, 128.7, 125.8, 116.7, 111.4, 110.6, 103.0, 94.9, 67.5, 55.6, 48.3, 19.3. ESI-MS m/z: 439.18 [M-H].sup.. Anal. calcd. For C.sub.25H.sub.26FNO.sub.5: C, 68.32; H, 5.96; N, 3.19; Found: C, 68.31; H, 5.96; N, 3.18.

Example 40

2-(4-((4-(2-methoxymethoxy)-2,6-dimethyl-[1,1-biphenyl]-3-methylene)amino)phenoxy)acetic acid (I-39)

(123) ##STR00043##

(124) By substituting 4-nitrophenol for the 2-fluoro-4-nitrophenol in Example 1, and substituting bromoethanol for the ethyl bromide in Example 2, Compound I-39 was prepared in a similar manner as in Example 2 to give a white solid (0.42 g, m.p. 132-134 C., yield 57%).

(125) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 12.80 (s, 1H), 7.90 (s, 1H), 0.57-7.41 (m, 3H), 6.94 (d, J=7.2 Hz, 2H), 6.77 (s, 2H), 6.73 (d, J=7.2 Hz, 2H), 6.02 (s, 2H), 4.66 (s, 2H), 4.32 (s, 2H), 3.30 (s, 3H), 2.57 (s, 6H). .sup.13C NMR (75 MHz, DMSO-ds) : 169.9, 159.3, 146.5, 142.1, 141.6, 138.2, 136.3, 130.9, 128.7, 125.8, 115.1, 113.3, 110.6, 94.9, 64.7, 55.6, 48.3, 19.3. ESI-MS m/z: 421.19 [M-H].sup.. Anal. calcd. For C.sub.25H.sub.27NO.sub.5: C, 71.24; H, 6.46; N, 3.32; Found: C, 71.25; H, 6.46; N, 3.31.

Example 41

2-(2-fluoro-4-((4-(2-ethoxymethoxy)-2,6-dimethyl-[1,1-biphenyl]-3-methylene)amino)phenoxy)acetic acid (I-40)

(126) ##STR00044##

(127) By substituting bromoethanol for bromoethane of Example 2, and Compound I-40 was prepared in a similar manner as in Example 2 to give a white solid (0.40 g, m.p. 136-139 C., yield 47%).

(128) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 12.80 (s, 1H), 7.90 (s, 1H), 7.57-7.41 (m, 3H), 6.96 (d, J=7.2 Hz, 2H), 6.94 (d, J=7.2 Hz, 1H), 6.84 (s, 1H), 6.54 (s, 1H), 6.02 (s, 2H), 4.66 (s, 2H), 4.32 (s, 2H), 3.53 (q, J=5.6 Hz, 2H), 2.57 (s, 6H), 1.18 (t, J=5.6 Hz, 3H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 169.9, 159.3, 152.9, 142.1, 141.5, 138.2, 137.9, 136.3, 130.9, 128.7, 125.8, 116.7, 111.4, 110.6, 103.0, 92.4, 67.5, 63.9, 48.3, 19.3, 15.2. ESI-MS m/z: 453.20 [M-H].sup.. Anal. calcd. For C.sub.26H.sub.28FNO.sub.5: C, 68.86; H, 6.22; N, 3.09; Found: C, 68.87; H, 6.23; N, 3.08.

Example 42

2-(4-((4-(2-ethoxymethoxy)-2,6-dimethyl-[1,1-biphenyl]-3-methylene)amino)phenoxy)acetic acid (I-41)

(129) ##STR00045##

(130) By substituting 4-nitrophenol for the 2-fluoro-4-nitrophenol in Example 1, and substituting bromoethanol for the ethyl bromide in Example 2, Compound I-41 was prepared in a similar manner as in Example 2 to give a white solid (0.40 g, m.p. 128-131 C., yield 54%).

(131) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 12.80 (s, 1H), 7.90 (s, 1H), 7.57-7.41 (m, 3H), 6.94 (d, J=7.2 Hz, 2H), 6.77 (d, J=7.2 Hz, 2H), 6.73 (s, 2H), 6.02 (s, 2H), 4.66 (s, 2H), 4.32 (s, 2H), 3.53 (q, J=5.6 Hz, 2H), 2.57 (s, 6H), 1.18 (t, J=5.6 Hz, 3H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) : 169.9, 159.3, 146.5, 142.1, 141.6, 138.2, 136.3, 130.9, 128.7, 125.8, 115.1, 113.3, 110.6, 92.4, 64.7, 63.9, 48.3, 19.3, 15.2. ESI-MS m/z: 435.20 [M-H].sup.. Anal. calcd. For C.sub.26H.sub.29NO.sub.5: C, 71.70; H, 6.71; N, 3.22; Found: C, 71.69; H, 6.72; N, 3.22.

Example 43

2(2-fluoro-4-(((4-(hexyloxy)-2,6-dimethyl-[1,1-biphenyl]-3-yl)methyl)amino)phenoxy)acetic acid (I-42)

(132) ##STR00046##

(133) By substituting 1-bromohexane for the ethyl bromide in Example 2, Compound I-42 was prepared in a similar manner as in Example 2 to give a white solid (0.60 g, m.p. 132-135 C. and yield 45%).

(134) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 12.80 (s, 1H), 7.90 (s, 1H), 7.57-7.41 (m, 3H), 6.94 (d, J=7.2 Hz, 2H), 6.77 (d, J=7.2 Hz, 1H), 6.73 (s, 2H), 4.66 (s, 2H), 4.32 (s, 2H), 4.06 (t, J=5.6 Hz, 2H), 2.57 (s, 6H), 1.80 (m, 2H), 1.47 (m, 2H), 1.37 (m, 4H), 0.88 (t, t, J=5.2 Hz, 3H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) :169.9, 156.1, 152.9, 142.1, 141.5, 137.9, 136.3, 130.2, 128.7, 125.8, 116.7, 111.4, 110.7, 103.0, 68.7, 67.5, 48.3, 31.8, 29.6, 25.6, 22.7, 19.3, 14.1. ESI-MS m/z: 479.25 [M-H].sup.. Anal. calcd. For C.sub.29H.sub.34FNO.sub.4: C, 72.63; H, 7.15; N, 2.92; Found: C, 72.62; H, 7.14; N, 2.92.

Example 44

2(4-(((4-(hexyloxy)-2,6-dimethyl-[1,1-biphenyl]-3-yl)methyl)amino)phenoxy)acetic acid (I-43)

(135) ##STR00047##

(136) By substituting 1-bromohexane for the ethyl bromide in Example 2, and substituting 4-nitrophenol for the 2-fluoro-4-nitrophenol in Example 1, Compound I-43 was prepared in a similar manner as in Example 2 to give a white solid (0.64 g, m.p. 130-132 C., yield 49%).

(137) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 12.80 (s, 1H), 7.90 (s, 1H), 7.57-7.41 (m, 3H), 6.94 (d, J=7.2 Hz, 2H), 6.77 (d, J=7.2 Hz, 2H), 6.73 (s, 2H), 4.66 (s, 2H), 4.32 (s, 2H), 4.06 (t, J=5.6 Hz, 2H), 2.57 (s, 6H), 1.80 (m, 2H), 1.47 (m, 2H), 1.37 (m, 4H), 0.88 (t, t, J=5.2 Hz, 3H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) :169.9, 156.1, 152.9, 142.1, 141.5, 137.9, 136.3, 130.2, 128.7, 125.8, 116.7, 113.1, 111.4, 110.7, 103.0, 68.7, 64.7, 48.3, 31.8, 29.6, 25.6, 22.7, 19.3, 14.1. ESI-MS m/z: 461.26 [M-H].sup.. Anal. calcd. For C.sub.29H.sub.35NO.sub.4: C, 75.46; H, 7.64; N, 3.03; Found: C, 75.45; H, 7.64; N, 3.02.

Example 45

2(2-fluoro-4-(((4-(cyclohexyloxy)-2,6-dimethyl-[1,1-biphenyl]-3-yl)methyl)amino)phenoxy)acetic acid (I-44)

(138) ##STR00048##

(139) By substituting 1-bromocyclohexane for the bromoethane of Example 2, Compound I-44 was prepared in a similar manner as in Example 2 to give a white solid (0.52 g, m.p. 136-138 C. and yield 49%).

(140) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 12.80 (s, 1H), 7.90 (s, 1H), 7.57-7.35 (m, 3H), 6.94 (d, J=7.2 Hz, 2H), 6.77 (d, J=7.2 Hz, 1H), 6.73 (s, 2H), 4.66 (s, 2H), 4.32 (s, 2H), 3.64 (m, 1H), 2.57 (s, 6H), 1.95, 1.70 (dd, J=5.8 Hz, 2H), 1.53, 1.43 (dd, J=5.5 Hz, 2H), 1.46, 1.44 (dd, J=5.1 Hz, 2H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) :169.9, 156.1, 152.9, 142.1, 141.5, 137.9, 136.3, 130.2, 128.7, 125.8, 116.7, 111.4, 110.7, 103.0, 78.0, 67.5, 48.3, 33.9, 26.0, 24.2, 19.3. ESI-MS m/z: 477.23 [M-H].sup.. Anal. calcd. For C.sub.29H.sub.32FNO.sub.4: C, 72.93; H, 6.75; N, 2.93; Found: C, 72.94; H, 6.74; N, 2.92.

Example 46

2(4-((4-(cyclohexyloxy)-2,6-dimethyl-[1,1-biphenyl]-3-yl)methyl)amino)phenoxy)acetic acid (I-45)

(141) ##STR00049##

(142) By substituting 1-bromocyclohexane for the ethyl bromide in Example 2, and substituting 4-nitrophenol for the 2-fluoro-4-nitrophenol in Example 1, Compound I-45 was prepared in a similar manner as in Example 2 to give a white solid (0.52 g, m.p. 136-138, yield 49%).

(143) .sup.1H NMR (300 MHz, DMSO-d.sub.6) : 12.80 (s, 1H), 7.90 (s, 1H), 7.57-7.35 (m, 3H), 6.94 (d, J=7.2 Hz, 2H), 6.77 (d, J=7.2 Hz, 2H), 6.73 (s, 2H), 4.66 (s, 2H), 4.32 (s, 2H), 3.64 (m, 1H), 2.57 (s, 6H), 1.95, 1.70 (dd, J=5.8 Hz, 2H), 1.53, 1.43 (dd, J=5.5 Hz, 2H), 1.46, 1.44 (dd, J=5.1 Hz, 2H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) :169.9, 156.1, 152.9, 146.5, 142.1, 141.6, 137.8, 136.3, 130.2, 128.7, 125.8, 115.1, 113.3, 110.7, 78.0, 64.7, 48.3, 33.9, 26.0, 24.2, 19.3. ESI-MS m/z: 459.24 [M-H].sup.. Anal. calcd. For C.sub.29H.sub.33FNO.sub.4: C, 75.79; H, 7.24; N, 3.05; Found: C, 75.78; H, 7.24; N, 3.04.

Example 47

(144) Tablets containing any of the compounds of the invention:

(145) TABLE-US-00004 Each tablet contains (mg) any of the compounds of the invention (Examples 2-46) 15 mg microcrystalline cellulose 80 mg pregelatinized starch 40 mg polyvinylpyrrolidone 8 mg sodium carboxymethyl starch 6 mg magnesium stearate 1.5 mg talc powder 2.5 mg ethanol appropriate amount

(146) The active ingredient, pregelatinized starch and microcrystalline cellulose were sieved, thoroughly mixed. A solution of polyvinylpyrrolidone was added and mixed to make the mixture into soft materials. After sieving, wet granules were prepared, dried at 50-60 C., and sodium carboxymethyl starch, magnesium stearate and talc powder were sieved and added to the above granules for tableting.

(147) The above composition has also been confirmed to have excellent in vivo hypoglycemic activity.