[4-(1,3,3-trimethyl-2-oxo-3,4-dihydro-1H-quinoxalin-7-yl)phenoxy]ethyloxy compound or salt thereof

Abstract

The present invention relates to a novel [4-(1,3,3-trimethyl-2-oxo-3,4-dihydro-1H-quinoxalin-7-yl)phenoxy]ethyloxy compound or a salt thereof. The compound or a salt thereof of the present invention has a glucocorticoid receptor agonist activity, and is useful as a medicine, in particular as a prophylactic or therapeutic agent for the glucocorticoid receptor related disease.

Claims

1. A compound of general formula (1): ##STR00068## wherein R.sup.1 represents a hydrogen atom, a lower alkyl group which may have a substituent(s), a carboxyl group, an ester of a carboxyl group, an amide of a carboxyl group or a cyano group; and R.sup.2 represents a hydrogen atom, a lower alkylcarbonyl group which may have a substituent(s), a lower cycloalkylcarbonyl group which may have a substituent(s), an arylcarbonyl group which may have a substituent(s), a heterocyclic carbonyl group which may have a substituent(s), an ester of a carboxyl group, an amide of a carboxyl group, a phosphate group or an ester of a phosphate group, or a salt thereof.

2. The compound or a salt thereof according to claim 1, wherein, in the general formula (1), R.sup.1 represents a hydrogen atom, a lower alkyl group, a carboxyl group, an ester of a carboxyl group, an amide of a carboxyl group or a cyano group; in the case where R.sup.1 is a lower alkyl group, the lower alkyl group may have one or a plurality of groups selected from a halogen atom, a lower cycloalkyl group, an aryl group, a heterocyclic group, a hydroxyl group, an ester of a hydroxyl group, a lower alkoxyl group, a lower alkoxyl group substituted by a halogen atom(s), a lower cycloalkyloxy group, an aryloxy group, a heterocyclicoxy group, an amino group, a lower alkylamino group, a lower cycloalkylamino group, an arylamino group, a heterocyclic amino group, an amide of an amino group, an amide of a lower alkylamino group, an amide of a lower cycloalkylamino group, an amide of an arylamino group, an amide of a heterocyclic amino group, a lower alkylcarbonyl group, a lower cycloalkyl-carbonyl group, an arylcarbonyl group, a heterocyclic carbonyl group, a carboxyl group, an ester of a carboxyl group, an amide of a carboxyl group and a cyano group as a substituent(s); R.sup.2 represents a hydrogen atom, a lower alkylcarbonyl group, a lower cycloalkylcarbonyl group, an arylcarbonyl group, a heterocyclic carbonyl group, a carboxyl group, an ester of a carboxyl group, an amide of a carboxyl group, a phosphate group or an ester of a phosphate group; and in the case where R.sup.2 is a lower alkylcarbonyl group, a lower cycloalkyl-carbonyl group, an arylcarbonyl group or a heterocyclic carbonyl group, the lower alkylcarbonyl group, the lower cycloalkylcarbonyl group, the arylcarbonyl group or the heterocyclic carbonyl group may have one or a plurality of groups selected from a halogen atom, a lower cycloalkyl group, an aryl group, a heterocyclic group, a hydroxyl group, an ester of a hydroxyl group, a lower alkoxyl group, a lower alkoxyl group substituted by a halogen atom(s), a lower cycloalkyloxy group, an aryloxy group, a heterocyclicoxy group, an amino group, a lower alkylamino group, a lower cycloalkyl-amino group, an arylamino group, a heterocyclic amino group, an amide of an amino group, an amide of a lower alkylamino group, an amide of a lower cycloalkylamino group, an amide of an arylamino group, an amide of a heterocyclic amino group, a lower alkylcarbonyl group, a lower cycloalkylcarbonyl group, an arylcarbonyl group, a heterocyclic carbonyl group, a carboxyl group, an ester of a carboxyl group, an amide of a carboxyl group and a cyano group as a substituent(s).

3. The compound or a salt thereof according to claim 1, wherein, in the general formula (1), R.sup.1 represents a hydrogen atom, a lower alkyl group, a carboxyl group or an ester of a carboxyl group; in the case where R.sup.1 is a lower alkyl group, the lower alkyl group may have one or a plurality of groups selected from a halogen atom, a hydroxyl group, a lower alkoxyl group, a lower alkylcarbonyl group, a carboxyl group, an ester of a carboxyl group, an amide of a carboxyl group and a cyano group as a substituent(s); R.sup.2 represents a hydrogen atom, a lower alkylcarbonyl group, a heterocyclic carbonyl group, a phosphate group or an ester of a phosphate group; and in the case where R.sup.2 is a lower alkylcarbonyl group, the lower alkylcarbonyl group may have one or a plurality of groups selected from a halogen atom, a hydroxyl group, an ester of a hydroxyl group, a lower alkoxyl group, a lower alkoxyl group substituted by a halogen atom(s), an amino group, a lower alkylamino group, a lower alkylcarbonyl group, a carboxyl group, an ester of a carboxyl group, an amide of a carboxyl group and a cyano group as a substituent(s).

4. The compound or a salt thereof according to claim 1, wherein in the general formula (1), R.sup.1 represents a hydrogen atom, a lower alkyl group or an ester of a carboxyl group; in the case where R.sup.1 is a lower alkyl group, the lower alkyl group may have one or a plurality of groups selected from a halogen atom, a hydroxyl group, a carboxyl group, an ester of a carboxyl group, an amide of a carboxyl group and a cyano group as a substituent(s); R.sup.2 represents a hydrogen atom, a lower alkylcarbonyl group, heterocyclic carbonyl group or a phosphate group; and in the case where R.sup.2 is a lower alkylcarbonyl group, the lower alkylcarbonyl group may have one or a plurality of groups selected from a hydroxyl group, an amino group, a lower alkylamino group and a carboxyl group as a substituent(s).

5. The compound or a salt thereof according to claim 1, wherein in the general formula (1), R.sup.1 represents a lower alkyl group; the lower alkyl group may have one or a plurality of hydroxyl groups as a substituent(s); R.sup.2 represents a hydrogen atom or a lower alkylcarbonyl group; and in the case where R.sup.2 is a lower alkylcarbonyl group, the lower alkylcarbonyl group may have one or a plurality of lower alkylamino groups as a substituent(s).

6. The compound or a salt thereof according to claim 1, wherein in the general formula (1), R.sup.1 represents methyl or 1-hydroxyethyl; and R.sup.2 represents a hydrogen atom or dimethylaminomethylcarbonyl.

7. A compound selected from the group consisting of (S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxypropyl)oxy-2-methoxy-phenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, 8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxy-3,3,3-trifluoropropyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, (R)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxypropyl)oxy-2-methoxy-phenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, (R)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxybutyl)oxy-2-methoxy-phenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, (S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxybutyl)oxy-2-methoxy-phenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, (R)-7-[4-(2-ethoxycarbonyl-2-hydroxyethyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, (S)-7-[4-(2,4-dihydroxybutyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxy-methyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, (R)-7-[4-(2,4-dihydroxybutyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxy-methyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, (S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxyacetoxypropyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, 8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxyethyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, 7-[4-(2,3-dihydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxy-methyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, (S)-7-[4-(2,3-dihydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, (R)-7-[4-(2,3-dihydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, (R)-7-[4-(3-cyano-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, (S)-7-[4-(3-cyano-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, 7-[4-(3-fluoro-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, 7-[4-(3-ethoxycarbonyl-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, 7-[4-(3-t-butoxycarbonyl-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, 7-[4-(3,3-dimethyl-2-hydroxybutyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, 7-[4-(3-carboxy-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, 8-(5-fluoro-2-methylphenoxymethyl)-7-[4-[3-(N-pyrrolidylcarbonyl)-2-hydroxy-propyl]oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, 8-(5-fluoro-2-methylphenoxymethyl)-7-[4-[3-(N-morpholino)carbonyl-2-hydroxy-propyl]oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, 8-(5-fluoro-2-methylphenoxymethyl)-7-[4-[3-(N-piperidino)carbonyl-2-hydroxy-propyl]oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, (S)-7-[4-[2-(N,N-dimethylaminoacetoxy)propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, 8-(5-fluoro-2-methylphenoxymethyl)-7-[4-[(2S)-[(2S)-pyrrolidylcarbonyloxy]propyl]oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, (R)-7-[4-[2-(N,N-dimethylaminoacetoxy)propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, (S)-7-[4-(2-aminoacetoxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, 7-[4-[(2S)-[(2S)-amino-3-methylbutanoyloxy]propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, (S)-7-[4-[2-(3-carboxypropanoyloxy)propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, (S)-7-[4-[2-(2,3-dihydroxypropanoyl)oxypropyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, 7-[4-[(2S)-[(2S)-amino-3-hydroxypropanoyloxy]propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, (S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-phosphonohydroxypropyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, (S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-phosphonohydroxybutyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one and, (S)-7-[4-(3-cyano-2-phosphonohydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, or a salt thereof.

8. A pharmaceutical composition comprising the compound or a salt thereof according to claim 1.

9. A glucocorticoid receptor agonist comprising the compound or a salt thereof according to claim 1 as an active ingredient.

10. A glucocorticoid receptor activator comprising the compound or a salt thereof according to claim 1 as an active ingredient.

11. A prophylactic or therapeutic agent for a glucocorticoid receptor related disease, which comprises the compound or a salt thereof according to claim 1 as an active ingredient.

12. The prophylactic or therapeutic agent according to claim 11, wherein the glucocorticoid receptor related disease is at least one selected from the group consisting of endocrine diseases, collagen diseases, kidney diseases, heart diseases, allergic diseases, blood diseases, digestive system diseases, liver diseases, pulmonary diseases, severe infectious diseases, tuberculosis disease, nervous disease, malignant tumor, digestive organ symptoms accompanied by administration of an anti-malignant tumor agent, surgery related diseases, obstetrics and gynecology related diseases, urology related diseases, skin diseases, otolaryngology related diseases, oral surgery related diseases, glaucoma, rheumatic diseases and inflammatory diseases.

13. The prophylactic or therapeutic agent according to claim 12, wherein the inflammatory disease is at least one selected from the group consisting of inflammatory bone or joint disease, ocular inflammatory diseases, asthma, bronchitis, rhinitis, dermatitis and inflammatory bowel disease.

14. The prophylactic or therapeutic agent according to claim 13, wherein the inflammatory bone or joint disease is at least one selected from the group consisting of rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, osteoporosis and spondylarthritis.

15. The prophylactic or therapeutic agent according to claim 13, wherein the ocular inflammatory disease is an anterior eye inflammatory disease.

16. The prophylactic or therapeutic agent according to claim 13, wherein the ocular inflammatory disease is a posterior eye inflammatory disease.

17. The prophylactic or therapeutic agent according to claim 15, wherein the anterior eye inflammatory disease is at least one selected from the group consisting of keratitis, keratoconjunctivitis, conjunctivitis, blepharitis, dry eye syndrome, allergic conjunctivitis, uveitis, inflammation after anterior eye surgery and inflammation due to rejection of ocular tissue transplantation.

18. The prophylactic or therapeutic agent according to claim 16, wherein the posterior eye inflammatory disease is at least one selected from the group consisting of age-related macular degeneration, diabetic retinopathy, diabetic macular edema, neovascular maculopathy, proliferative vitreoretinopathy, central retinal vein occlusion, central retinal artery occlusion, branch retinal vein occlusion, branch retinal artery occlusion, inflammation or degeneration of posterior eye caused by external injury, retinitis, uveitis, scleritis and optic neuritis.

19. A method for the prophylaxis or treatment of a glucocorticoid receptor related disease, which comprises administering an effective amount of the compound or a salt thereof according to claim 1.

20. The method for the prophylaxis or treatment according to claim 19, wherein the glucocorticoid receptor related disease is at least one selected from the group consisting of endocrine diseases, collagen diseases, kidney diseases, heart diseases, allergic diseases, blood diseases, digestive system diseases, liver diseases, pulmonary diseases, severe infectious diseases, tuberculosis disease, nervous disease, malignant tumor, digestive organ symptoms accompanied by administration of an anti-malignant tumor agent, surgery related diseases, obstetrics and gynecology related diseases, urology related diseases, skin diseases, otolaryngology related diseases, oral surgery related diseases, glaucoma, rheumatic diseases and inflammatory diseases.

21. The method for the prophylaxis or treatment according to claim 20, wherein the inflammatory disease is at least one selected from the group consisting of inflammatory bone or joint disease, ocular inflammatory disease, asthma, bronchitis, rhinitis, dermatitis and inflammatory bowel disease.

22. The method for the prophylaxis or treatment according to claim 21, wherein the inflammatory bone or joint disease is at least one selected from the group consisting of rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, osteoporosis and spondylarthritis.

23. The method for the prophylaxis or treatment according to claim 21, wherein the ocular inflammatory disease is an anterior eye inflammatory disease.

24. The method for the prophylaxis or treatment according to claim 21, wherein the ocular inflammatory disease is a posterior eye inflammatory disease.

25. The method for the prophylaxis or treatment according to claim 23, wherein the anterior eye inflammatory disease is at least one selected from the group consisting of keratitis, keratoconjunctivitis, conjunctivitis, blepharitis, dry eye syndrome, allergic conjunctivitis, uveitis, inflammation after anterior eye surgery and inflammation due to rejection of ocular tissue transplantation.

26. The method for the prophylaxis or treatment according to claim 24, wherein the posterior eye inflammatory disease is at least one selected from the group consisting of age-related macular degeneration, diabetic retinopathy, diabetic macular edema, neovascular maculopathy, proliferative vitreoretinopathy, central retinal vein occlusion, central retinal artery occlusion, branch retinal vein occlusion, branch retinal artery occlusion, inflammation or degeneration of posterior eye caused by external injury, retinitis, uveitis, scleritis and optic neuritis.

Description

PRODUCTION EXAMPLES

Reference Example 1

(S)-4-benzyloxy-2-hydroxybutyl Methanesulfonate (the Reference Compound 1-1)

(1) A methylene chloride (50 mL) solution of methanesulfonyl chloride (4.1 mL, 53.0 mmol) was added dropwise to a methylene chloride (200 mL) solution of (S)-4-benzyloxy-1,2-butanediol (10.0 g, 51.0 mmol) and 2,6-lutidine (59 mL, 507 mmol) at 20 C. over 30 minutes, and the mixture was stirred at room temperature for 24 hours.

(2) Further, a methylene chloride (30 mL) solution of methanesulfonyl chloride (1.3 mL, 16.8 mmol) was added dropwise to the above mixture at room temperature over 30 minutes, and the mixture was stirred for 1.5 hours. The mixture was washed with 0.5N hydrochloric acid (200 mL4), a saturated aqueous sodium hydrogen carbonate solution (100 mL3), and a saturated saline solution (100 mL). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the titled reference compound (12.3 g) (Yield: 88%).

(3) TABLE-US-00001 TABLE 1 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.39-7.28 (5H, m), 4.53 (2H, s), 4.30-4.07 (3H, m), 3.80-3.62 (2H, m), 3.20 (1H, d, J = 2.9 Hz), 3.05 (3H, s), 1.93-1.76 (2H, m)

Reference Example 2

(S)-4-benzyloxy-1,2-epoxybutane (the Reference Compound 2-1)

(4) A mixture of (S)-4-benzyloxy-2-hydroxybutyl methanesulfonate (the reference compound 1-1, 12.3 g, 44.8 mmol), potassium carbonate (12.3 g, 89.0 mmol) and methanol (100 mL) was stirred at room temperature for 75 minutes. After removing the solvent under reduced pressure, 0.5N sodium hydroxide (450 mL) and ethyl acetate (200 mL) were added to the residue. The mixture was distributed, and the aqueous layer was extracted with ethyl acetate (100 mL2). The organic layers were combined, and washed with a saturated saline solution (100 mL). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the titled reference compound (8.0 g) (quantitative).

(5) TABLE-US-00002 TABLE 2 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.41-7.27 (5H, m), 4.53 (2H, s), 3.69-3.58 (2H, m), 3.12- 3.04 (1H, m), 2.79 (1H, dd, J = 5.1, 4.0 Hz), 2.53 (1H, dd, J = 5.1, 2.7 Hz), 1.98-1.86 (1H, m), 1.84-1.72 (1H, m)

(R)-4-benzyloxy-1,2-epoxybutane (the Reference Compound 2-2)

(6) Under ice-cooling, p-toluenesulfonyl chloride (1.45 g, 7.6 mmol) was added to a pyridine (25 mL) solution of (R)-4-benzyloxy-1,2-butanediol (1.24 g, 6.3 mmol) and after stirring for 5 hours, the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (100 mL), and washed with 1N hydrochloric acid (50 mL, 30 mL) and a saturated saline solution (50 mL). The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (60 mL), sodium hydride (0.38 g, 9.5 mmol) was added thereto at room temperature, and the resulting mixture was stirred at 50 C. overnight. After allowing to cool at room temperature, water (200 mL) was added to the mixture and the mixture was extracted with ethyl acetate (200 mL), and the organic layer was washed with a saturated saline solution (100 mL). The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the titled reference compound (0.99 g) (Yield: 89%).

(7) TABLE-US-00003 TABLE 3 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.38-7.27 (5H, m), 4.53 (2H, s), 3.69-3.57 (2H, m), 3.12- 3.03 (1H, m), 2.79 (1H, dd, J = 4.9, 4.0 Hz), 2.53 (1H, dd, J = 4.9, 2.7 Hz), 1.98-1.87 (1H, m), 1.84-1.73 (1H, m)

Reference Example 3

(S)-7-[4-(4-benzyloxy-2-hydroxybutyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Reference Compound 3-1)

(8) A mixture of 8-(5-fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the compound A (produced with reference to the above-mentioned Patent Document 2, hereinafter the same), 500 mg, 1.11 mmol), (S)-4-benzyloxy-1,2-epoxybutane (the reference compound 2-1, 500 mg, 2.81 mmol), potassium carbonate (600 mg, 4.34 mmol) and ethanol (5 mL) was stirred at 60 C. for 7 hours. To the mixture was added water (30 mL), and the mixture was extracted with ethyl acetate (30 mL2). The organic layer was washed with a saturated saline solution (30 mL), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the titled reference compound (420 mg) as white amorphous (Yield: 60%).

(9) TABLE-US-00004 TABLE 4 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.39-7.28 (5H, m), 7.21 (1H, dd, J = 6.6, 2.2 Hz), 6.92-6.84 (2H, m), 6.70 (1H, d, J = 7.8 Hz), 6.61-6.54 (2H, m), 6.38 (1H, td, J = 8.3, 2.4 Hz), 6.04 (1H, dd, J = 11.2, 2.4 Hz), 5.21 (1H, d, J = 13.7 Hz), 4.84 (1H, d, J = 13.7 Hz), 4.56 (2H, s), 4.30-4.21 (1H, m), 4.04-3.95 (2H, m), 3.79 (3H, s), 3.79-3.66 (2H, m), 3.46 (3H, s), 3.08 (1H, t, J = 3.0 Hz), 2.01 (3H, s), 1.99-1.92 (2H, m), 1.54-1.50 (1H, m), 1.28 (3H, s), 0.90 (3H, s)

Reference Example 4

8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-tetrahydropyran-2-yloxyethyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Reference Compound 4-1)

(10) A tetrahydrofuran (5 mL) suspension of 8-(5-fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the compound A, 100 mg, 0.22 mmol), 2-(tetrahydropyran-2-yloxy)ethanol (65 L, 0.48 mmol), tri-n-butylphosphine (115 L, 0.48 mmol) and 1,1-(azodicarbonyl)dipiperidine (115 mg, 0.46 mmol) was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (30 mL), and the organic layer was washed with a saturated saline solution (30 mL2). The organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the titled reference compound (150 mg) as a yellow oily product (quantitative).

(11) TABLE-US-00005 TABLE 5 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.22 (1H, d, J = 8.8 Hz), 6.88 (2H, d, J = 8.0 Hz), 6.70 (1H, d, J = 8.0 Hz), 6.64-6.59 (2H, m), 6.38 (1H, td, J = 8.4, 2.4 Hz), 6.04 (1H, dd, J = 11.2, 2.4 Hz), 5.22 (1H, d, J = 13.9 Hz), 4.85 (1H, d, J = 13.9 Hz), 4.26-4.18 (2H, m), 4.14- 4.05 (1H, m), 3.98-3.82 (2H, m), 3.80 (3H, s), 3.79-3.63 (2H, m), 3.47 (3H, s), 2.84-2.79 (1H, m), 2.01 (3H, s), 1.91-1.48 (6H, m), 1.28 (3H, s), 0.89 (3H, s)

Reference Example 5

7-[4-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Reference Compound 5-1)

(12) A mixture of 8-(5-fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the compound A, 600 mg, 1.3 mmol), p-toluenesulfonic acid (2,2-dimethyl-1,3-dioxolan-4-yl)methyl ester (572 mg, 2.0 mmol), cesium carbonate (868 mg, 2.7 mmol) and N,N-dimethylformamide (5.0 mL) was stirred at 80 C. overnight. After allowing to cool at room temperature, water (150 mL) was added to the mixture and the mixture was extracted with ethyl acetate (150 mL). The organic layer was washed with a saturated saline solution (150 mL), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the titled reference compound (710 mg) as white amorphous (Yield: 95%).

(13) TABLE-US-00006 TABLE 6 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.22 (1H, d, J = 8.5 Hz), 6.93-6.84 (2H, m), 6.70 (1H, d, J = 8.0 Hz), 6.63-6.55 (2H, m), 6.38 (1H, td, J = 8.3, 2.4 Hz), 6.04 (1H, dd, J = 11.3, 2.4 Hz), 5.21 (1H, d, J = 13.7 Hz), 4.84 (1H, d, J = 13.7 Hz), 4.57-4.47 (1H, m), 4.20 (1H, dd, J = 8.5, 6.3 Hz), 4.11 (1H, dd, J = 9.5, 5.6 Hz), 4.01 (1H, dd, J = 9.5, 5.9 Hz), 3.93 (1H, dd, J = 8.5, 5.9 Hz), 3.80 (3H, s), 3.68 (1H, s), 3.46 (3H, s), 2.01 (3H, s), 1.49 (3H, s), 1.42 (3H, s), 1.28 (3H, s), 0.91 (3H, s)

(14) Reference compounds 5-2 to 5-6 were obtained by using the compound A and a commercially available compound in accordance with the production process of Reference compound 5-1.

(R)-7-[4-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Reference Compound 5-2)

(15) TABLE-US-00007 TABLE 7 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.22 (1H, d, J = 8.3 Hz), 6.92-6.84 (2H, m), 6.70 (1H, d, J = 8.0 Hz), 6.63-6.56 (2H, m), 6.38 (1H, td, J = 8.3, 2.3 Hz), 6.04 (1H, dd, J = 11.3, 2.3 Hz), 5.21 (1H, d, J = 13.4 Hz), 4.84 (1H, d, J = 13.4 Hz), 4.57-4.47 (1H, m), 4.20 (1H, dd, J = 8.7, 6.5 Hz), 4.11 (1H, dd, J = 9.4, 5.7 Hz), 4.01 (1H, dd, J = 9.4, 5.7 Hz), 3.93 (1H, dd, J = 8.4, 5.7 Hz), 3.80 (3H, s), 3.68 (1H, s), 3.46 (3H, s), 2.01 (3H, s), 1.49 (3H, s), 1.42 (3H, s), 1.28 (3H, s), 0.91 (3H, s)

(S)-7-[4-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Reference Compound 5-3)

(16) TABLE-US-00008 TABLE 8 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.22 (1H, d, J = 8.5 Hz), 6.93-6.85 (2H, m), 6.70 (1H, d, J = 8.1 Hz), 6.63-6.55 (2H, m), 6.38 (1H, td, J = 8.3, 2.4 Hz), 6.04 (1H, dd, J = 11.2, 2.4 Hz), 5.21 (1H, d, J = 13.7 Hz), 4.84 (1H, d, J = 13.7 Hz), 4.57-4.47 (1H, m), 4.20 (1H, dd, J = 8.5, 6.3 Hz), 4.13-4.09 (1H, m), 4.01 (1H, dd, J = 9.4, 5.7 Hz), 3.93 (1H, dd, J = 8.4, 5.7 Hz), 3.80 (3H, s), 3.68 (1H, s), 3.46 (3H, s), 2.01 (3H, s), 1.49 (3H, s), 1.42 (3H, s), 1.28 (3H, s), 0.91 (3H, s)

(R)-7-[4-(2,3-epoxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Reference Compound 5-4)

(17) TABLE-US-00009 TABLE 9 0 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.22 (1H, d, J = 8.0 Hz), 6.93-6.84 (2H, m), 6.70 (1H, d, J = 8.0 Hz), 6.65-6.56 (2H, m), 6.38 (1H, td, J = 8.3, 2.4 Hz), 6.04 (1H, dd, J = 11.2, 2.4 Hz), 5.21 (1H, d, J = 13.7 Hz), 4.84 (1H, d, J = 13.7 Hz), 4.30 (1H, dd, J = 11.1, 3.0 Hz), 4.06-3.97 (1H, m), 3.81 (3H, s), 3.68 (1H, s), 3.46 (3H, s), 3.42-3.36 (1H, m), 2.94 (1H, t, J = 4.5 Hz), 2.83-2.76 (1H, m), 2.01 (3H, s), 1.28 (3H, s), 0.91 (3H, s)

(S)-7-[4-(2,3-epoxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Reference Compound 5-5)

(18) TABLE-US-00010 TABLE 10 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.22 (1H, d, J = 8.3 Hz), 6.93-6.84 (2H, m), 6.70 (1H, d, J = 8.0 Hz), 6.64-6.56 (2H, m), 6.38 (1H, td, J = 8.3, 2.4 Hz), 6.04 (1H, dd, J = 11.3, 2.4 Hz), 5.21 (1H, d, J = 13.7 Hz), 4.84 (1H, d, J = 13.7 Hz), 4.30 (1H, dd, J = 11.1, 3.0 Hz), 4.07-3.96 (1H, m), 3.81 (3H, s), 3.68 (1H, s), 3.46 (3H, s), 3.43-3.35 (1H, m), 2.94 (1H, t, J = 4.5 Hz), 2.84-2.76 (1H, m), 2.01 (3H, s), 1.28 (3H, s), 0.91 (3H, s)

7-[4-(3,3-dimethyl-2-oxobutyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxy-methyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Reference Compound 5-6)

(19) TABLE-US-00011 TABLE 11 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.20 (1H, d, J = 8.3 Hz), 6.93-6.83 (2H, m), 6.70 (1H, d, J = 8.0 Hz), 6.64 (1H, d, J = 2.4 Hz), 6.47 (1H, dd, J = 8.3, 2.4 Hz), 6.38 (1H, td, J = 8.3, 2.4 Hz), 6.03 (1H, dd, J = 11.5, 2.4 Hz), 5.21 (1H, d, J = 13.7 Hz), 4.93 (2H, s), 4.84 (1H, d, J = 13.7 Hz), 3.80 (3H, s), 3.69 (1H, s), 3.46 (3H, s), 2.01 (3H, s), 1.28 (12H, s), 0.89 (3H, s)

Reference Example 6

8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(methoxycarbonylmethyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Reference Compound 6-1)

(20) A mixture of 8-(5-fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxy-phenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the compound A, 2.0 g, 4.4 mmol), methyl bromoacetate (0.64 mL, 6.8 mmol), potassium carbonate (0.95 g, 6.9 mmol) and dehydrated acetonitrile (45 mL) was refluxed at 100 C. overnight. After allowing to cool at room temperature, water (100 mL) was added to the mixture and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with a saturated saline solution (100 mL) and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the titled reference compound (2.4 g) as pale orange amorphous (quantitative).

(21) TABLE-US-00012 TABLE 12 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) 7.17 (1H, d, J = 8.3 Hz), 6.99 (1H, t, J = 7.6 Hz), 6.78 (2H, s), 6.71 (1H, d, J = 2.4 Hz), 6.61 (1H, dd, J = 8.3, 2.4 Hz), 6.48 (1H, td, J = 8.3, 2.4 Hz), 6.12-6.03 (2H, m), 5.22 (1H, d, J = 14.1 Hz), 4.86 (2H, s), 4.82 (1H, d, J = 14.1 Hz), 3.79 (3H, s), 3.72 (3H, s), 3.32 (3H, s), 1.92 (3H, s), 1.07 (3H, s), 0.75 (3H, s)

Reference Example 7

2,2-dimethyl-1,3-dioxolane-4-carboxylic Acid (the Reference Compound 7-1)

(22) Under ice-cooling, an aqueous (30 mL) solution of potassium permanganate (1.8 g, 11.3 mmol) was added dropwise to an aqueous (50 mL) solution of 2,2-dimethyl-1,3-dioxolane-4-methanol (1.0 g, 7.6 mmol) and potassium hydroxide (1.0 g, 15 mmol), and the mixture was stirred for 2 hours. The mixture was filtered on celite, and the filtrate was concentrated under reduced pressure. A saturated aqueous potassium hydrogen sulfate solution was added to the resulting filtrate until a pH thereof became 4. The mixture was extracted with ethyl acetate (200 mL2), and the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the titled reference compound (0.33 g) as a colorless oily product (Yield: 30%).

(23) TABLE-US-00013 TABLE 13 .sup.1H-NMR (500 MHz, CDCl.sub.3) 4.62 (1H, dd, J = 7.6, 4.8 Hz), 4.31 (1H, dd, J = 8.9, 7.6 Hz), 4.20 (1H, dd, J = 8.9, 4.8 Hz), 1.54 (3H, s), 1.42 (3H, s)

(24) The reference compound 7-2 was obtained by using a commercially available compound in accordance with the production process of the reference compound 7-1.

(S)-()-N-t-butylcarbonyl-2,2-dimethyl-1,3-dioxazolidine-4-carboxylic Acid (the Reference Compound 7-2)

(25) TABLE-US-00014 TABLE 14 .sup.1H-NMR (400 MHz, CDCl.sub.3) 4.54-4.04 (3H, m), 1.52 (12H, s), 1.43 (3H, s)

Reference Example 8

(S)-7-[4-(2-benzyloxyacetoxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Reference Compound 8-1)

(26) A mixture of (S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxypropyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the compound 1-1, 60 mg, 0.12 mmol), benzyloxyacetic acid (4 mg, 0.24 mmol), 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (45 mg, 0.24 mmol), 4-dimethylamino-pyridine (2.9 mg, 0.024 mmol) and anhydrous methylene chloride (3.0 mL) was stirred at room temperature overnight. Water (10 mL) was added to the mixture and the resulting mixture was extracted with ethyl acetate (10 mL2). The organic layer was washed with a saturated saline solution (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the titled reference compound (62 mg) as a white solid (Yield: 81%).

(27) TABLE-US-00015 TABLE 15 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.41-7.27 (5H, m), 7.22 (1H, d, J = 8.8 Hz), 6.93-6.82 (2H, m), 6.70 (1H, d, J = 8.1 Hz), 6.60-6.53 (2H, m), 6.38 (1H, td, J = 8.4, 2.5 Hz), 6.03 (1H, dd, J = 11.2, 2.4 Hz), 5.47-5.37 (1H, m), 5.21 (1H, d, J = 13.7 Hz), 4.83 (1H, d, J = 13.7 Hz), 4.65 (2H, s), 4.17-4.01 (4H, m), 3.79 (3H, s), 3.46 (3H, s), 2.01 (3H, s), 1.43 (3H, d, J = 6.3 Hz), 1.28 (3H, s), 0.90 (3H, s)

(28) The reference compounds 8-2 and 8-3 were obtained by using the compound 1-1, and the reference compounds 7-1 and 7-2 in accordance with the producing process of the reference compound 8-1.

(S)-7-[4-[2-(2,2-dimethyl-1,3-dioxolan-4-ylcarbonyloxy)propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Reference Compound 8-2)

(29) TABLE-US-00016 TABLE 16 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.22 (1H, dd, J = 8.8, 1.5 Hz), 6.93-6.84 (2H, m), 6.70 (1H, d, J = 7.8 Hz), 6.60-6.52 (2H, m), 6.38 (1H, td, J = 8.4, 2.4 Hz), 6.04 (1H, d, J = 11.2 Hz), 5.44-5.35 (1H, m), 5.21 (1H, d, J = 13.9 Hz), 4.84 (1H, d, J = 13.9 Hz), 4.65-4.57 (1H, m), 4.30-4.20 (1H, m), 4.17-4.03 (3H, m), 3.81 (3H, s), 3.68 (1H, s), 3.46 (3H, s), 2.01 (3H, s), 1.52 (3H, d, J = 11.2 Hz), 1.43 (3H, d, J = 6.6 Hz), 1.40 (3H, s), 1.28 (3H, s), 0.90 (3H, s)

(S)-7-[4-[2-(N-t-butoxycarbonyl-2,2-dimethyl-1,3-dioxazolidin-4-ylcarbonyloxy)-propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Reference Compound 8-3)

(30) TABLE-US-00017 TABLE 17 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) 7.17 (1H, d, J = 8.1 Hz), 6.99 (1H, t, J = 7.7 Hz), 6.78 (2H, s), 6.70-6.59 (2H, m), 6.48 (1H, td, J = 8.5, 2.1 Hz), 6.12-6.02 (2H, m), 5.30-5.16 (2H, m), 4.82 (1H, d, J = 12.8 Hz), 4.44-4.37 (1H, m), 4.22-4.06 (3H, m), 3.97-3.89 (1H, m), 3.78 (3H, s), 3.33 (3H, s), 1.92 (3H, s), 1.56 (3H, s), 1.44-1.27 (15H, m), 1.07 (3H, s), 0.75 (3H, s)

Example 1

(S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxypropyl)oxy-2-methoxy-phenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 1-1)

(31) In two pressure resistant reaction tubes with a volume of 200 mL were charged 8-(5-fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the compound A, 7.5 g, 16.7 mmol), dehydrated ethanol (113 mL), potassium carbonate (11.5 g, 83.2 mmol) and (S)-()-propylene oxide (5.8 mL, 82.9 mmol), respectively, and sealed, and stirred at 100 C. overnight. After allowing to cool, two reaction mixtures were combined and concentrated under reduced pressure. Ethyl acetate (150 mL) was added to the residue, and the mixture was washed with water (150 mL2 times) and a saturated saline solution (150 mL). The organic layer was dried over magnesium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, 2-propanol (90 mL) was added to the residue and the resulting mixture was stirred at room temperature overnight. The precipitated solid was collected by filtration, and washed with 2-propanol (7.5 mL). The solid was dried at 60 C. under reduced pressure to give the title compound (11.5 g) as a white solid (Yield: 68%).

(32) TABLE-US-00018 TABLE 18 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.23 (1H, d, J = 8.8 Hz), 6.93-6.84 (2H, m), 6.71 (1H, d, J = 7.7 Hz), 6.62-6.56 (2H, m), 6.38 (1H, td, J = 8.3, 2.2 Hz), 6.04 (1H, dd, J = 11.4, 2.2 Hz), 5.22 (1H, d, J = 13.6 Hz), 4.84 (1H, d, J = 13.6 Hz), 4.29-4.19 (1H, m), 4.05-3.97 (1H, m), 3.91-3.83 (1H, m), 3.81 (3H, s), 3.69 (1H, s), 3.47 (3H, s), 2.31 (1H, d, J = 3.3 Hz), 2.02 (3H, s), 1.32 (3H, d, J = 6.6 Hz), 1.28 (3H, s), 0.91 (3H, s)

8-(5-Fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxy-3,3,3-trifluoro-propyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 1-2)

(33) A mixture of 8-(5-fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the compound A, 100 mg, 0.22 mmol), 3-bromo-1,1,1-trifluoromethyl-2-propanol (46.0 L, 0.44 mmol), cesium carbonate (145 mg, 0.44 mmol) and N,N-dimethylformamide (1.5 mL) was stirred at 50 C. overnight. After allowing to cool at room temperature, water (50 mL) was added to the mixture and the resulting mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with a saturated saline solution (50 mL2), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (114 mg) as a white solid (Yield: 91%).

(34) TABLE-US-00019 TABLE 19 0 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.29-7.21 (1H, m), 6.94-6.84 (2H, m), 6.71 (1H, d, J = 8.0 Hz), 6.63-6.58 (2H, m), 6.39 (1H, td, J = 8.3, 2.4 Hz), 6.04 (1H, dd, J = 11.2, 2.4 Hz), 5.20 (1H, d, J = 13.7 Hz), 4.82 (1H, d, J = 13.7 Hz), 4.45-4.36 (1H, m), 4.32 (1H, dd, J = 9.9, 3.3 Hz), 4.23 (1H, dd, J = 9.9, 6.2 Hz), 3.82 (3H, s), 3.70 (1H, s), 3.46 (3H, s), 2.84 (1H, d, J = 6.6 Hz), 2.02 (3H, s), 1.28 (3H, s), 0.93 (3H, s)

(35) The compounds 1-3 to 1-6 were obtained by using the compound A and a commercially available compound in accordance with the production process of the compound 1-1 or 1-2.

(R)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxypropyl)oxy-2-methoxy-phenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 1-3)

(36) TABLE-US-00020 TABLE 20 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.22 (1H, d, J = 9.0 Hz), 6.94-6.84 (2H, m), 6.70 (1H, d, J = 7.8 Hz), 6.63-6.55 (2H, m), 6.38 (1H, td, J = 8.4, 2.4 Hz), 6.05 (1H, dd, J = 11.2, 2.4 Hz), 5.21 (1H, d, J = 13.7 Hz), 4.84 (1H, d, J = 13.7 Hz), 4.30-4.17 (1H, m), 4.04-3.98 (1H, m), 3.91-3.83 (1H, m), 3.81 (3H, s), 3.77-3.64 (1H, m), 3.46 (3H, s), 2.31 (1H, d, J = 3.4 Hz), 2.01 (3H, s), 1.32 (3H, d, J = 6.3 Hz), 1.28 (3H, s), 0.91 (3H, s)

(R)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxybutyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 1-4)

(37) TABLE-US-00021 TABLE 21 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.22 (1H, d, J = 9.0 Hz), 6.93-6.85 (2H, m), 6.70 (1H, d, J = 8.0 Hz), 6.62-6.57 (2H, m), 6.38 (1H, td, J = 8.3, 2.5 Hz), 6.04 (1H, dd, J = 11.3, 2.5 Hz), 5.21 (1H, d, J = 13.7 Hz), 4.85 (1H, d, J = 13.7 Hz), 4.05 (1H, dd, J = 8.5, 2.7 Hz), 4.01-3.87 (2H, m), 3.81 (3H, s), 3.68 (1H, s), 3.47 (3H, s), 2.25 (1H, d, J = 2.7 Hz), 2.01 (3H, s), 1.72-1.60 (2H, m), 1.28 (3H, s), 1.06 (3H, t, J = 7.4 Hz), 0.91 (3H, s)

(S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxybutyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 1-5)

(38) TABLE-US-00022 TABLE 22 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.22 (1H, d, J = 8.8 Hz), 6.93-6.84 (2H, m), 6.70 (1H, d, J = 8.0 Hz), 6.62-6.56 (2H, m), 6.38 (1H, td, J = 8.4, 2.6 Hz), 6.04 (1H, dd, J = 11.5, 2.6 Hz), 5.21 (1H, d, J = 13.6 Hz), 4.84 (1H, d, J = 13.6 Hz), 4.05 (1H, dd, J = 9.0, 2.7 Hz), 4.02-3.87 (2H, m), 3.81 (3H, s), 3.68 (1H, s), 3.47 (3H, s), 2.25 (1H, d, J = 2.7 Hz), 2.01 (3H, s), 1.71-1.60 (2H, m), 1.28 (3H, s), 1.06 (3H, t, J = 7.4 Hz), 0.91 (3H, s)

(R)-7-[4-(2-ethoxycarbonyl-2-hydroxyethyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 1-6)

(39) TABLE-US-00023 TABLE 23 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.22 (1H, d, J = 8.8 Hz), 6.93-6.83 (2H, m), 6.70 (1H, d, J = 8.0 Hz), 6.62-6.55 (2H, m), 6.38 (1H, td, J = 8.3, 2.4 Hz), 6.03 (1H, dd, J = 11.2, 2.4 Hz), 5.21 (1H, d, J = 13.9 Hz), 4.83 (1H, d, J = 13.9 Hz), 4.58-4.48 (1H, m), 4.38-4.26 (4H, m), 3.80 (3H, s), 3.69 (s, 1H), 3.46 (3H, s), 3.20 (1H, d, J = 6.6 Hz), 2.01 (3H, s), 1.28 (3H, s), 1.21 (3H, t, J = 7.0 Hz), 0.90 (3H, s)

Example 2

(S)-7-[4-(2,4-dihydroxybutyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 2-1)

(40) Palladium on carbon (50 mg) was added to a methanol (6 mL) solution of (S)-7-[4-(4-benzyloxy-2-hydroxybutyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the reference compound 3-1, 254 mg, 0.405 mmol), and the mixture was stirred under hydrogen atmosphere at room temperature overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (213 mg) as white amorphous (Yield: 98%).

(41) TABLE-US-00024 TABLE 24 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.23 (1H, d, J = 8.8 Hz), 6.93-6.84 (2H, m), 6.70 (1H, d, J = 7.8 Hz), 6.63-6.56 (2H, m), 6.38 (1H, td, J = 8.3, 2.4 Hz), 6.04 (1H, dd, J = 11.2, 2.4 Hz), 5.21 (1H, d, J = 13.7 Hz), 4.84 (1H, d, J = 13.7 Hz), 4.37-4.25 (1H, m), 4.08-3.90 (4H, m), 3.81 (3H, s), 3.69 (1H, s), 3.46 (3H, s), 2.88 (1H, s), 2.23 (1H, t, J = 5.2 Hz), 2.01 (3H, s), 1.93-1.81 (2H, m), 1.28 (3H, s), 0.91 (3H, s)

(R)-7-[4-(2,4-dihydroxybutyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 2-2)

(42) A mixture of 8-(5-fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the compound A, 451 mg, 1.0 mmol), (R)-4-benzyloxy-1,2-epoxybutane (the reference compound 2-2, 267 mg, 1.5 mmol), cesium carbonate (828 mg, 2.5 mmol) and N,N-dimethylformamide (4.5 mL) was stirred at 70 C. overnight. After allowing to cool at room temperature, water (100 mL) was added to the mixture and the resulting mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with an aqueous saturated ammonium chloride solution (100 mL) and a saturated saline solution (100 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate). The obtained intermediate ((R)-7-[4-(4-benzyloxy-2-hydroxybutyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxy-methyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one) was dissolved in methanol (5.0 mL), palladium on carbon (30 mg) was added to the solution and the resulting mixture was stirred under hydrogen atmosphere at room temperature overnight. The mixture was filtered with methanol (30 mL) on celite. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (341 mg) as white amorphous (Yield: 63%).

(43) TABLE-US-00025 TABLE 25 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.23 (1H, d, J = 8.8 Hz), 6.93-6.84 (2H, m), 6.70 (1H, d, J = 8.1 Hz), 6.62-6.56 (2H, m), 6.38 (1H, td, J = 8.3, 2.4 Hz), 6.04 (1H, dd, J = 11.4, 2.4 Hz), 5.21 (1H, d, J = 13.7 Hz), 4.84 (1H, d, J = 13.7 Hz), 4.36-4.26 (1H, m), 4.08-3.90 (4H, m), 3.81 (3H, s), 3.69 (1H, s), 3.47 (3H, s), 2.89 (1H, s), 2.24 (1H, t, J = 4.9 Hz), 2.01 (3H, s), 1.94-1.84 (2H, m), 1.28 (3H, s), 0.91 (3H, s)

(44) The compound 2-3 was obtained by using the reference compound 8-1 in accordance with the producing process of the compound 2-1.

(S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxyacetoxypropyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 2-3)

(45) TABLE-US-00026 TABLE 26 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.22 (1H, d, J = 8.8 Hz), 6.93-6.84 (2H, m), 6.71 (1H, d, J = 7.7 Hz), 6.59-6.54 (2H, m), 6.39 (1H, td, J = 8.3, 2.4 Hz), 6.04 (1H, dd, J = 11.4, 2.4 Hz), 5.48-5.38 (1H, m), 5.21 (1H, d, J = 13.6 Hz), 4.83 (1H, d, J = 13.6 Hz), 4.20 (2H, s), 4.14-4.04 (2H, m), 3.81 (3H, s), 3.46 (3H, s), 2.38 (1H, s), 2.01 (3H, s), 1.44 (3H, d, J = 6.6 Hz), 1.29 (3H, s), 0.91 (3H, s)

Example 3

8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxyethyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 3-1)

(46) 1N hydrochloric acid (2.0 mL) was added to a tetrahydrofuran-methanol mixed solution (1:1, 4.0 mL) of 8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-tetrahydropyran-2-yloxyethyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the reference compound 4-1, 130 mg, 0.22 mmol), and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20 mL), and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution (20 mL) and a saturated saline solution (20 mL). The organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromato-graphy (hexane/ethyl acetate) to give the title compound (72 mg) as a colorless oily product (Yield: 65%).

(47) TABLE-US-00027 TABLE 27 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.23 (1H, d, J = 8.8 Hz), 6.93-6.84 (2H, m), 6.71 (1H, d, J = 8.0 Hz), 6.64-6.57 (2H, m), 6.38 (1H, td, J = 8.4, 2.4 Hz), 6.04 (1H, dd, J = 11.2, 2.4 Hz), 5.22 (1H, d, J = 13.7 Hz), 4.85 (1H, d, J = 13.7 Hz), 4.21-4.12 (2H, m), 4.05-3.97 (2H, m), 3.81 (3H, s), 3.69 (1H, s), 3.47 (3H, s), 2.02 (3H, s), 1.28 (3H, s), 0.91 (3H, s)

Example 4

7-[4-(2,3-dihydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 4-1)

(48) Under ice-cooling, trifluoroacetic acid (4.0 mL) was added to a methylene chloride (20 mL) solution of 7-[4-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the reference compound 5-1, 685 mg, 1.2 mmol) and the resulting mixture was stirred at room temperature for 3 hours. Water (1.0 mL) was added to the mixture, and the resulting mixture was further stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate (150 mL). The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution (100 mL) and a saturated saline solution (100 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (556 mg) as white amorphous (Yield: 88%).

(49) TABLE-US-00028 TABLE 28 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.23 (1H, d, J = 8.5 Hz), 6.93-6.83 (2H, m), 6.71 (1H, d, J = 8.0 Hz), 6.63-6.57 (2H, m), 6.39 (1H, td, J = 8.3, 2.4 Hz), 6.04 (1H, dd, J = 11.2, 2.4 Hz), 5.20 (1H, d, J = 13.4 Hz), 4.83 (1H, d, J = 13.4 Hz), 4.20-4.08 (3H, m), 3.93-3.75 (2H, m), 3.81 (3H, s), 3.69 (1H, s), 3.46 (3H, s), 2.58 (1H, d, J = 4.1 Hz), 2.02 (3H, s), 1.98 (1H, t, J = 6.3 Hz), 1.28 (3H, s), 0.92 (3H, s)

(50) The compounds 4-2 and 4-3 were obtained by using the reference compounds 5-1 and 5-2 in accordance with the producing process of the compound 4-1.

(S)-7-[4-(2,3-dihydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxy-methyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 4-2)

(51) TABLE-US-00029 TABLE 29 0 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.23 (1H, d, J = 8.5 Hz), 6.94-6.84 (2H, m), 6.71 (1H, d, J = 8.0 Hz), 6.64-6.56 (2H, m), 6.39 (1H, td, J = 8.2, 2.4 Hz), 6.04 (1H, dd, J = 11.0, 2.4 Hz), 5.21 (1H, d, J = 13.7 Hz), 4.83 (1H, d, J = 13.7 Hz), 4.20-4.06 (3H, m), 3.93-3.74 (2H, m), 3.81 (3H, s), 3.69 (1H, s), 3.46 (3H, s), 2.56 (1H, d, J = 4.4 Hz), 2.02 (3H, s), 1.96 (1H, t, J = 5.9 Hz), 1.28 (3H, s), 0.92 (3H, s)

(R)-7-[4-(2,3-dihydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxy-methyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 4-3)

(52) TABLE-US-00030 TABLE 30 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.23 (1H, d, J = 8.1 Hz), 6.94-6.86 (2H, m), 6.73-6.55 (3H, m), 6.39 (1H, td, J = 8.4, 2.2 Hz), 6.03 (1H, dd, J = 11.0, 2.2 Hz), 5.20 (1H, d, J = 13.4 Hz), 4.83 (1H, d, J = 13.4 Hz), 4.20-4.08 (3H, m), 3.92-3.76 (2H, m), 3.81 (3H, s), 3.47 (3H, s), 2.01 (3H, s), 1.28 (3H, s), 0.96 (3H, s)

Example 5

(R)-7-[4-(3-cyano-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 5-1)

(53) A mixture of (R)-7-[4-(2,3-epoxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the reference compound 5-4, 235 mg, 0.46 mmol), potassium cyanide (66 mg, 1.0 mmol), water (0.90 mL) and N,N-dimethylformamide (5.0 mL) was stirred at room temperature overnight. To the mixture was added a saturated saline solution (30 mL), and the resulting mixture was extracted with ethyl acetate (30 mL3). The organic layer was washed with a saturated saline solution (40 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (208 mg) as white amorphous (Yield: 87%).

(54) TABLE-US-00031 TABLE 31 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.24 (1H, d, J = 9.0 Hz), 6.90 (1H, t, J = 7.7 Hz), 6.87 (1H, d, J = 8.0 Hz), 6.71 (1H, d, J = 8.0 Hz), 6.62-6.56 (2H, m), 6.39 (1H, td, J = 8.3, 2.4 Hz), 6.04 (1H, dd, J = 11.2, 2.4 Hz), 5.20 (1H, d, J = 13.4 Hz), 4.82 (1H, d, J = 13.4 Hz), 4.43-4.34 (1H, m), 4.19-4.08 (2H, m), 3.81 (3H, s), 3.70 (1H, s), 3.46 (3H, s), 2.87-2.71 (2H, m), 2.64 (1H, d, J = 5.4 Hz), 2.02 (3H, s), 1.28 (3H, s), 0.93 (3H, s)

(55) The compound 5-2 was obtained by using the reference compound 5-5 and a commercially available compound in accordance with the producing process of the compound 5-1.

(S)-7-[4-(3-cyano-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 5-2)

(56) TABLE-US-00032 TABLE 32 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.24 (1H, d, J = 9.0 Hz), 6.90 (1H, t, J = 7.7 Hz), 6.87 (1H, d, J = 8.0 Hz), 6.71 (1H, d, J = 8.0 Hz), 6.61 6.56 (2H, m), 6.39 (1H, td, J = 8.3, 2.4 Hz), 6.04 (1H, dd, J = 11.2, 2.4 Hz), 5.20 (1H, d, J = 13.4 Hz), 4.83 (1H, d, J = 13.4 Hz), 4.43-4.31 (1H, m), 4.20-4.07 (2H, m), 3.81 (3H, s), 3.71 (1H, s), 3.46 (3H, s), 2.86-2.72 (2H, m), 2.70 (1H, d, J = 5.4 Hz), 2.02 (3H, s), 1.28 (3H, s), 0.93 (3H, s)

Example 6

7-[4-(3-fluoro-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxy-methyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 6-1)

(57) Under ice-cooling, N,N-diethylaminosulfur trifluoride (76 L, 0.58 mmol) was added to a methylene chloride (4.0 mL) solution of 7-[4-(2,3-dihydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the compound 4-1, 200 mg, 0.38 mmol) and the resulting mixture was stirred for 3 hours. The mixture was filtered using silica gel and the filtrate was washed with ethyl acetate (20 mL3). The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (22 mg) as white amorphous (Yield: 11%).

(58) TABLE-US-00033 TABLE 33 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.23 (1H, d, J = 8.5 Hz), 6.94-6.84 (2H, m), 6.71 (1H, d, J = 7.8 Hz), 6.63-6.56 (2H, m), 6.39 (1H, td, J = 8.3, 2.4 Hz), 6.04 (1H, dd, J = 11.3, 2.4 Hz), 5.20 (1H, d, J = 13.7 Hz), 4.83 (1H, d, J = 13.7 Hz), 4.74-4.63 (1H, m), 4.62-4.51 (1H, m), 4.36-4.23 (1H, m), 4.19-4.09 (2H, m), 3.81 (3H, s), 3.69 (1H, s), 3.46 (3H, s), 2.41 (1H, d, J = 5.6 Hz), 2.02 (3H, s), 1.28 (3H, s), 0.92 (3H, s)

Example 7

7-[4-(3-ethoxycarbonyl-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 7-1)

(59) Under argon gas atmosphere, an n-butyllithium 1.6M hexane solution (4.2 mL, 6.7 mmol) was added to a mixed solution of anhydrous tetrahydrofuran (8.0 mL) and N,N-diisopropylamine (0.95 mL, 6.8 mmol) under ice-cooling and the resulting mixture was stirred for 30 minutes. The mixture was cooled to 78 C., and ethyl acetate (0.66 mL, 6.8 mmol) was added thereto and the resulting mixture was stirred for 1 hour. To the mixture was added dropwise an anhydrous tetrahydrofuran (8 mL) solution of 8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(methoxycarbonylmethyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the reference compound 6-1, 2.4 g, 4.6 mmol) over 5 minutes. The mixture was stirred accompanying with raising of the temperature for 2.5 hours, and 1N hydrochloric acid (15 mL) was added at 16 C. Water (50 mL) was added to the mixture and the resulting mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with an aqueous saturated ammonium chloride solution (50 mL) and a saturated saline solution (50 mL). The organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained intermediate (7-[4-(3-ethoxycarbonyl-2-oxopropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxy-methyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one) was dissolved in tetrahydrofuran (25 mL). Under ice-cooling, to the solution was added sodium borohydride (0.35 g, 9.3 mmol) and the mixture was stirred for 15 minutes. To the mixture were added water (50 mL) and 1N hydrochloric acid (15 mL), and the resulting mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with an aqueous saturated ammonium chloride solution (50 mL) and a saturated saline solution (50 mL). The organic layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.4 g) as white amorphous (Yield: 54%).

(60) TABLE-US-00034 TABLE 34 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.23 (1H, d, J = 8.8 Hz), 6.93-6.84 (2H, m), 6.70 (1H, d, J = 8.0 Hz), 6.62-6.56 (2H, m), 6.38 (1H, td, J = 8.3, 2.4 Hz), 6.04 (1H, dd, J = 11.2, 2.4 Hz), 5.21 (1H, d, J = 13.7 Hz), 4.84 (1H, d, J = 13.7 Hz), 4.52-4.40 (1H, m), 4.22 (2H, q, J = 7.2 Hz), 4.07 (2H, d, J = 5.4 Hz), 3.81 (3H, s), 3.69 (1H, s), 3.46 (3H, s), 3.16 (1H, d, J = 4.4 Hz), 2.74-2.68 (2H, m), 2.01 (3H, s), 1.33-1.23 (6H, m), 0.91 (3H, s)

(61) The compound 7-2 was obtained by using the reference compound 6-1 and a commercially available compound in accordance with the producing process of the compound 7-1

7-[4-(3-t-butoxycarbonyl-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 7-2)

(62) TABLE-US-00035 TABLE 35 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.22 (1H, d, J = 8.5 Hz), 6.93-6.84 (2H, m), 6.70 (1H, d, J = 7.8 Hz), 6.62-6.56 (2H, m), 6.38 (1H, td, J = 8.4, 2.4 Hz), 6.04 (1H, dd, J = 11.2, 2.4 Hz), 5.21 (1H, d, J = 13.7 Hz), 4.84 (1H, d, J = 13.7 Hz), 4.47-4.36 (1H, m), 4.09-4.00 (2H, m), 3.80 (3H, s), 3.68 (1H, s), 3.46 (3H, s), 3.26 (1H, d, J = 4.4 Hz), 2.70-2.56 (2H, m), 2.01 (3H, s), 1.49 (9H, s), 1.28 (3H, s), 0.91 (3H, s)

Example 8

7-[4-(3,3-dimethyl-2-hydroxybutyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 8-1)

(63) Under ice-cooling, sodium borohydride (9.0 mg, 0.24 mmol) was added to a methanol (1.0 mL) solution of 7-[4-(3,3-dimethyl-2-oxobutyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the reference compound 5-6, 55 mg, 0.10 mmol), and the resulting mixture was stirred for 1 hour. To the mixture was added 1N hydrochloric acid (20 mL), and the resulting mixture was extracted with ethyl acetate (15 mL2). The organic layers were combined and washed with a saturated aqueous sodium hydrogen carbonate solution (20 mL) and a saturated saline solution (20 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (51 mg) as pink amorphous (Yield: 92%).

(64) TABLE-US-00036 TABLE 36 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.23 (1H, d, J = 8.5 Hz), 6.93-6.84 (2H, m), 6.70 (1H, d, J = 8.0 Hz), 6.63-6.56 (2H, m), 6.38 (1H, td, J = 8.3, 2.4 Hz), 6.05 (1H, dd, J = 11.2, 2.4 Hz), 5.22 (1H, d, J = 13.7 Hz), 4.85 (1H, d, J = 13.7 Hz), 4.22-4.14 (1H, m), 3.93 (1H, t, J = 9.0 Hz), 3.81 (3H, s), 3.77-3.64 (2H, m), 3.47 (3H, s), 2.37 (1H, d, J = 2.9 Hz), 2.02 (3H, s), 1.28 (3H, s), 1.04 (9H, s), 0.91 (3H, s)

Example 9

7-[4-(3-Carboxy-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 9-1)

(65) A mixture of 7-[4-(3-ethoxycarbonyl-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the compound 7-1, 1.9 g, 3.3 mmol), 4N aqueous sodium hydroxide solution (10 mL) and methanol (15 mL) was stirred at 50 C. overnight. After allowing to cool at room temperature, 1N hydrochloric acid (45 mL) was added to the mixture. The precipitated solid was collected by filtration, and washed with water (50 mL). The obtained solid was dried under reduced pressure at 40 C. for 4 hours to give the title compound (1.6 g) as reddish brown solid (Yield: 88%).

(66) TABLE-US-00037 TABLE 37 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) 12.19 (1H, s), 7.16 (1H, d, J = 8.4 Hz), 6.98 (1H, t, J = 7.7 Hz), 6.81-6.73 (2H, m), 6.68 (1H, d, J = 2.3 Hz), 6.64 (1H, dd, J = 8.3, 2.3 Hz), 6.48 (1H, td, J = 8.3, 2.3 Hz), 6.12-6.00 (2H, m), 5.31-5.13 (2H, m), 4.83 (1H, d, J = 13.9 Hz), 4.27-4.16 (1H, m), 3.97 (2H, d, J = 5.1 Hz), 3.79 (3H, s), 3.32 (3H, s), 2.62-2.34 (2H, m), 1.92 (3H, s), 1.07 (3H, s), 0.74 (3H, s)

Example 10

8-(5-fluoro-2-methylphenoxymethyl)-7-[4-[3-(N-pyrrolidylcarbonyl)-2-hydroxypropyl]oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 10-1)

(67) A mixture of 7-[4-(3-carboxy-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the compound 9-1, 110 mg, 0.20 mmol), 1-hydroxybenzotriazole (48 mg, 0.31 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (59 mg, 0.31 mmol), pyrrolidine (33 L, 0.40 mmol), N-methylmorpholine (88 L, 0.80 mmol) and N,N-dimethylformamide (2.0 mL) was stirred at room temperature overnight. A saturated saline solution (10 mL) was added to the mixture, and the resulting mixture was extracted with ethyl acetate (10 mL2). The organic layer was washed with a saturated saline solution (20 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (24 mg) as pale brown amorphous (Yield: 20%).

(68) TABLE-US-00038 TABLE 38 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.22 (1H, d, J = 8.8 Hz), 6.94-6.83 (2H, m), 6.70 (1H, d, J = 8.1 Hz), 6.64-6.57 (2H, m), 6.38 (1H, td, J = 8.3, 2.4 Hz), 6.04 (1H, dd, J = 11.2, 2.4 Hz), 5.21 (1H, d, J = 13.7 Hz), 4.84 (1H, d, J = 13.7 Hz), 4.66 (1H, d, J = 3.7 Hz), 4.52-4.40 (1H, m), 4.17-4.01 (2H, m), 3.80 (3H, s), 3.68 (1H, s), 3.55-3.41 (7H, m), 2.75-2.54 (2H, m), 2.06-1.81 (7H, m), 1.28 (3H, s), 0.91 (3H, s)

(69) The compounds 10-2 and 10-3 were obtained by using the compound 9-1 and a commercially available compound in accordance with the producing process of the compound 10-1.

8-(5-fluoro-2-methylphenoxymethyl)-7-[4-[3-(N-morpholino)carbonyl-2-hydroxypropyl]oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 10-2)

(70) TABLE-US-00039 TABLE 39 0 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.22 (1H, d, J = 8.4 Hz), 6.94-6.84 (2H, m), 6.70 (1H, d, J = 8.1 Hz), 6.64-6.56 (2H, m), 6.39 (1H, td, J = 8.2, 2.4 Hz), 6.04 (1H, dd, J = 11.2, 2.4 Hz), 5.21 (1H, d, J = 13.7 Hz), 4.84 (1H, d, J = 13.7 Hz), 4.55-4.42 (1H, m), 4.20 (1H, d, J = 4.0 Hz), 4.18-4.01 (2H, m), 3.80 (3H, s), 3.75-3.59 (7H, m), 3.55-3.48 (2H, m), 3.46 (3H, s), 2.79-2.59 (2H, m), 2.02 (3H, s), 1.28 (3H, s), 0.91 (3H, s)

8-(5-fluoro-2-methylphenoxymethyl)-7-[4-[3-(N-piperidino)carbonyl-2-hydroxy-propyl]oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the compound 10-3)

(71) TABLE-US-00040 TABLE 40 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.22 (1H, d, J = 8.4 Hz), 6.94-6.83 (2H, m), 6.70 (1H, d, J = 8.1 Hz), 6.65-6.57 (2H, m), 6.38 (1H, td, J = 8.2, 2.4 Hz), 6.04 (1H, dd, J = 11.2, 2.4 Hz), 5.21 (1H, d, J = 13.6 Hz), 4.84 (1H, d, J = 13.6 Hz), 4.54 (1H, d, J = 3.7 Hz), 4.51-4.39 (1H, m), 4.18-4.00 (2H, m), 3.80 (3H, s), 3.72-3.50 (3H, m), 3.49-3.38 (5H, m), 2.80-2.56 (2H, m), 2.01 (3H, s), 1.73-1.47 (6H, m), 1.28 (3H, s), 0.91 (3H, s)

Example 11

(S)-7-[4-[2-(N,N-dimethylaminoacetoxy)propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 11-1)

(72) To N,N-dimethylformamide-methylene chloride mixed solution (1:1, 12 mL) were added (S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxypropyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the compound 1-1, 509 mg, 1.00 mmol), N,N-dimethylglycine (207 mg, 2.01 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 4-dimethylaminopyridine (10.6 mg, 0.087 mmol), and the mixture was stirred at 50 C. for 6 hours. After allowing to cool, the mixture was diluted with ethyl acetate (100 mL), and washed with a saturated aqueous sodium hydrogen carbonate solution (50 mL), an aqueous saturated ammonium chloride solution (50 mL) and a saturated saline solution (50 mL). The organic layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (205 mg) as white amorphous (Yield: 35%).

(73) TABLE-US-00041 TABLE 41 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) 7.17 (1H, d, J = 8.3 Hz), 6.99 (1H, t, J = 7.7 Hz), 6.78 (2H, s), 6.71-6.62 (2H, m), 6.48 (1H, td, J = 8.4, 2.4 Hz), 6.08 (2H, m), 5.31-5.16 (2H, m), 4.83 (1H, d, J = 13.7 Hz), 4.15-4.10 (2H, m), 3.79 (3H, s), 3.32 (3H, s), 3.16 (2H, s), 2.23 (6H, s), 1.92 (3H, s), 1.31 (3H, d, J = 6.3 Hz), 1.07 (3H, s), 0.75 (3H, s)

8-(5-Fluoro-2-methylphenoxymethyl)-7-[4-[(2S)-[(2S)-pyrrolidylcarbonyloxy]-propyl]oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one hydrochloride (the Compound 11-2)

(74) A mixture of (S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxy-propyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the compound 1-1, 306 mg, 0.60 mmol), N-t-butoxycarbonyl-L-proline (258 mg, 1.2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (234 mg, 1.2 mmol), 4-dimethylaminopyridine (9.9 mg, 0.081 mmol) and methylene chloride (6.0 mL) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the obtained residue was diluted by ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate). A 4N hydrochloric acid-1,4-dioxane solution (8.0 mL) was added to the obtained intermediate (7-[4-[(2S)-[(S)N-(t-butoxycarbonyl)pyrrolidin-2-ylcarbonyloxy]propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one), and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and diethyl ether (10 mL) and ethyl acetate (10 mL) were added to the obtained residue. The precipitated solid was collected by filtration, and washed with ethyl acetate (10 mL). The obtained solid was dried under reduced pressure at 40 C. for 3.5 hours to give the title compound (284 mg) as a white solid (Yield: 74%).

(75) TABLE-US-00042 TABLE 42 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) 9.92 (1H, s), 8.96 (1H, s), 7.18 (1H, d, J = 8.4 Hz), 6.99 (1H, t, J = 7.5 Hz), 6.78 (2H, s), 6.70-6.63 (2H, m), 6.49 (1H, td, J = 8.4, 2.4 Hz), 6.19-6.00 (2H, m), 5.40-5.29 (1H, m), 5.23 (1H, d, J = 13.6 Hz), 4.82 (1H, d, J = 13.6 Hz), 4.48-4.10 (5H, m), 3.79 (3H, s), 3.32 (3H, s), 3.29-3.12 (2H, m), 2.01-1.82 (5H, m), 1.38 (3H, d, J = 6.6 Hz), 1.07 (3H, s), 0.74 (3H, s)

(76) The compounds 11-3 to 11-5 were obtained by using the compound 1-1 and a commercially available compound in accordance with the producing process of the compound 11-1 or 11-2.

(R)-7-[4-[2-(N,N-dimethylaminoacetoxy)propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 11-3)

(77) TABLE-US-00043 TABLE 43 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) 7.17 (1H, d, J = 8.3 Hz), 6.99 (1H, t, J = 7.7 Hz), 6.77 (2H, s), 6.71-6.61 (2H, m), 6.48 (1H, td, J = 8.4, 2.4 Hz), 6.12-6.03 (2H, m), 5.28-5.17 (2H, m), 4.83 (1H, d, J = 14.2 Hz), 4.18-4.08 (2H, m), 3.79 (3H, s), 3.32 (3H, s), 3.15 (2H, s), 2.23 (6H, s), 1.92 (3H, s), 1.31 (3H, d, J = 6.3 Hz), 1.07 (3H, s), 0.75 (3H, s)

(S)-7-[4-(2-aminoacetoxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxy-methyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one hydrochloride (the Compound 11-4)

(78) TABLE-US-00044 TABLE 44 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) 8.33 (3H, s), 7.18 (1H, d, J = 8.3 Hz), 6.99 (1H, t, J = 7.7 Hz), 6.78 (2H, s), 6.71-6.63 (2H, m), 6.49 (1H, td, J = 8.4, 2.4 Hz), 6.17-6.01 (2H, m), 5.36-5.27 (1H, m), 5.22 (1H, d, J = 14.3 Hz), 4.81 (1H, d, J = 14.3 Hz), 4.22-4.11 (2H, m), 3.91-3.82 (2H, m), 3.80 (3H, s), 3.33 (3H, s), 1.92 (3H, s), 1.37 (3H, d, J = 6.3 Hz), 1.07 (3H, s), 0.75 (3H, s)

7-[4-[(2S)-[(2S)-amino-3-methylbutanoyloxy]propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one hydrochloride (the Compound 11-5)

(79) TABLE-US-00045 TABLE 45 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) 8.46 (3H, s), 7.18 (1H, d, J = 9.0 Hz), 6.99 (1H, t, J = 7.7 Hz), 6.78 (2H, s), 6.68-6.59 (2H, m), 6.49 (1H, td, J = 8.5, 2.3 Hz), 6.18-6.01 (2H, m), 5.42-5.31 (1H, m), 5.22 (1H, d, J = 14.1 Hz), 4.81 (1H, d, J = 14.1 Hz), 4.29-4.20 (1H, m), 4.19-4.09 (1H, m), 3.98-3.89 (1H, m), 3.78 (3H, s), 3.32 (3H, s), 2.23-2.10 (1H, m), 1.92 (3H, s), 1.36 (3H, d, J = 6.6 Hz), 1.07 (3H, s), 1.02-0.92 (6H, m), 0.75 (3H, s)

Example 12

(S)-7-[4-[2-(3-carboxypropanoyloxy)propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 12-1)

(80) A mixture of (S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxy-propyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the compound 1-1, 52 mg, 0.10 mmol), succinic anhydride (16 mg, 0.16 mmol), 4-dimethylaminopyridine (catalytic amount) and pyridine (0.5 mL) was stirred at room temperature overnight. Succinic anhydride (65 mg, 0.65 mmol) was additionally added and the mixture was further stirred overnight. The mixture was diluted with ethyl acetate (10 mL), and the organic layer was washed with 1N hydrochloric acid (15 mL2) and a saturated saline solution (5 mL). The organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (58 mg) as white amorphous (quantitative).

(81) TABLE-US-00046 TABLE 46 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.22 (1H, d, J = 8.4 Hz), 6.92-6.84 (2H, m), 6.70 (1H, d, J = 8.1 Hz), 6.61-6.55 (2H, m), 6.38 (1H, td, J = 8.3, 2.4 Hz), 6.04 (1H, dd, J = 11.2, 2.4 Hz), 5.37-5.29 (1H, m), 5.21 (1H, d, J = 13.7 Hz), 4.84 (1H, d, J = 13.7 Hz), 4.16-3.99 (2H, m), 3.81 (3H, s), 3.46 (3H, s), 2.76-2.61 (4H, m), 2.01 (3H, s), 1.40 (3H, d, J = 6.6 Hz), 1.28 (3H, s), 0.90 (3H, s)

Example 13

(S)-7-[4-[2-(2,3-dihydroxypropanoyl)oxypropyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 13-1)

(82) A mixture of (S)-7-[4-[2-(2,2-dimethyl-1,3-dioxolan-4-ylcarbonyloxy)propyl]-oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the reference compound 8-2, 70 mg, 0.11 mmol), 2N hydrochloric acid (1.0 mL) and methanol (4.0 mL) was stirred at 50 C. for 1 hour. After allowing to cool at room temperature, the mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (35 mg) as a white solid (Yield: 54%)

(83) TABLE-US-00047 TABLE 47 .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.23 (1H, d, J = 8.8 Hz), 6.93-6.83 (2H, m), 6.70 (1H, d, J = 8.1 Hz), 6.61-6.53 (2H, m), 6.38 (1H, td, J = 8.3, 2.4 Hz), 6.08-6.00 (1H, m), 5.50-5.38 (1H, m), 5.21 (1H, d, J = 13.9 Hz), 4.83 (1H, d, J = 13.9 Hz), 4.34-4.27 (1H, m), 4.15-4.06 (2H, m), 3.94-3.84 (2H, m), 3.81 (3H, d, J = 2.7 Hz), 3.69 (1H, s), 3.46 (3H, s), 3.10 (1H, dd, J = 11.5, 4.9 Hz), 2.01 (3H, s), 1.45 (3H, dd, J = 6.5, 1.6 Hz), 1.28 (3H, s), 1.21 (1H, t, J = 7.1 Hz), 0.91 (3H, s)

(84) The compound 13-2 was obtained by using the reference compound 8-3 in accordance with the producing process of the compound 13-1.

7-[4-[(2S)-[(2S)-amino-3-hydroxypropanoyloxy]propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 13-2)

(85) TABLE-US-00048 TABLE 48 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) 7.17 (1H, d, J = 8.1 Hz), 6.98 (1H, t, J = 7.7 Hz), 6.77 (2H, s), 6.71-6.62 (2H, m), 6.48 (1H, td, J = 8.4, 2.6 Hz), 6.12-6.04 (2H, m), 5.27-5.12 (2H, m), 4.88-4.74 (2H, m), 4.11 (2H, d, J = 5.5 Hz), 3.79 (3H, s), 3.56-3.49 (2H, m), 3.30 (3H, s), 1.92 (3H, s), 1.75 (2H, s), 1.32 (3H, d, J = 6.2 Hz), 1.06 (3H, s), 0.74 (3H, s)

Example 14

(S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-phosphonohydroxypropyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 14-1)

(86) Under ice-cooling, a methylene chloride (3.0 mL) solution of m-chloro-perbenzoic acid (41 mg, 0.24 mmol) was added dropwise to an N,N-dimethylformamide (3.0 mL) solution of (S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxypropyl)-oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the compound 1-1, 100 mg, 0.20 mmol), 1H-tetrazole (62 mg, 0.89 mmol) and di-t-butoxy(diisopropylamino)phosphine (0.19 mL, 0.60 mmol), and the mixture was stirred for 1 hour. To the mixture were added a saturated aqueous sodium hydrogen carbonate solution (5 mL) and water (50 mL), and the resulting mixture was extracted with ethyl acetate (50 mL2). The organic layers were combined, washed with a saturated saline solution (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate). The obtained intermediate ((S)-7-[4-[2-(di-t-butylphosphonohydroxy)propyl]oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one) was dissolved in anhydrous methylene chloride (1 mL). Under ice-cooling, trifluoroacetic acid (1 mL) was added to the solution, and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and hexane-diethyl ether (1:1, 2 mL) was added to the obtained residue. The precipitated solid was collected by filtration, and washed with hexane-diethyl ether (1:1, 5 mL). The obtained solid was dried to give the title compound (49 mg) as a white solid (Yield: 42%).

(87) TABLE-US-00049 TABLE 49 0 .sup.1H-NMR (500 MHz, DMSO-d.sub.6) 7.17 (1H, d, J = 8.2 Hz), 6.99 (1H, t, J = 7.6 Hz), 6.77 (2H, dd, J = 10.2, 8.2 Hz), 6.70 (1H, s), 6.65 (1H, d, J = 8.2 Hz), 6.48 (1H, td, J = 8.2, 2.4 Hz), 6.11-6.04 (2H, m), 5.22 (1H, d, J = 13.7 Hz), 4.83 (1H, d, J = 13.7 Hz), 4.61-4.51 (1H, m), 4.13-4.02 (2H, m), 3.80 (3H, s), 3.33 (3H, s), 1.92 (3H, s), 1.36 (3H, d, J = 6.4 Hz), 1.07 (3H, s), 0.74 (3H, s)

(88) The compounds 14-2 and 14-3 were obtained by using the compounds 1-5, 5-2 and a commercially available compound in accordance with the producing process of the compound 14-1.

(S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-phosphonohydroxybutyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 14-2)

(89) TABLE-US-00050 TABLE 50 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) 7.17 (1H, d, J = 8.2 Hz), 6.98 (1H, t, J = 7.7 Hz), 6.77 (2H, dd, J = 9.2, 8.3 Hz), 6.71 (1H, s), 6.66 (1H, d, J = 8.3 Hz), 6.48 (1H, td, J = 8.3, 2.4 Hz), 6.12-6.03 (2H, m), 5.23 (1H, d, J = 14.2 Hz), 4.84 (1H, d, J = 14.2 Hz), 4.42-4.30 (1H, m), 4.19-4.07 (2H, m), 3.80 (3H, s), 3.33 (3H, s), 1.92 (3H, s), 1.84-1.65 (2H, m), 1.07 (3H, s), 0.96 (3H, t, J = 7.4 Hz), 0.74 (3H, s)

(S)-7-[4-(3-cyano-2-phosphonohydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (the Compound 14-3)

(90) TABLE-US-00051 TABLE 51 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) 7.22-7.12 (1H, m), 7.02-6.93 (1H, m), 6.81-6.65 (4H, m), 6.48 (1H, td, J = 8.2, 2.1 Hz), 6.13-6.03 (2H, m), 5.22 (1H, d, J = 13.4 Hz), 4.91-4.59 (2H, m), 4.29-4.17 (2H, m), 3.80 (3H, s), 3.33 (3H, s), 3.08-3.03 (2H, m), 1.92 (3H, s), 1.07 (3H, s), 0.75 (3H, s)
[Pharmacological Test]

(91) For carrying out Pharmacological Test, the control compound B, the control compound C, the control compound D, the control compound E and the control compound F were prepared in accordance with the above-mentioned Patent Document 2 (JP 2008-74829A) for comparison with the effect of the present compound, and used in the test.

(92) The control compound B is 8-(5-fluoro-2-methylphenoxymethyl)-7-(5-hydroxymethyl-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one having the following structure:

(93) ##STR00063##

(94) The control compound C is 8-(5-fluoro-2-methylphenoxymethyl)-7-(5-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one having the following structure:

(95) ##STR00064##

(96) The control compound D is 7-(4-butyryloxy-2-methoxyphenyl)-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one having the following structure:

(97) ##STR00065##

(98) The control compound E is 7-(2,4-dimethoxyphenyl)-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one having the following structure:

(99) ##STR00066##

(100) The control compound F is 8-(5-fluoro-2-methylphenoxymethyl)-7-(2-methoxy-4-methoxymethoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one having the following structure:

(101) ##STR00067##
[Pharmacological Test]
1. GR Binding Activity Evaluation Test

(102) In order to evaluate a binding activity of the present compound to GR, a GR receptor competitor assay was carried out by a fluorescence polarization method. In the assay, a GR competitive binding assay kit (manufactured by Invitrogen, cat No. P2816) was used for the assay, and a procedure was carried out according to the protocol attached to the kit. Hereinafter, the specific method will be described.

(103) (Preparation of Reagents)

(104) GR screening buffer: A buffer containing 10 mM of potassium phosphate (pH 7.4), 20 mM of sodium molybdate (Na.sub.2MoO.sub.4), 0.1 mM of ethylene diamine tetraacetic acid (EDTA), 5 mM of dithiothreitol (DTT), 0.1 mM of stabilizing peptide and 2% of dimethylsulfoxide was prepared.

(105) 4GS1 solution: Fluormone GS1, which is a fluorescent glucocorticoid ligand, was diluted with GR screening buffer, whereby a 4 nM solution was prepared.

(106) 4GR solution: Recombinant human GR was diluted with GR screening buffer, whereby a 16 nM solution was prepared.

(107) (Preparation of Test Compound Solution and Dexamethasone (hereinafter also referred to as DEX.) Solution)

(108) After a test compound was dissolved in dimethylsulfoxide, the resulting solution was diluted with GR screening buffer, whereby a 20 M test compound solution was prepared. In addition, DEX was similarly dissolved, whereby a DEX solution with a 200 M concentration was prepared, and the solution was diluted with GR screening buffer, whereby a 2 mM DEX solution was prepared. DEX was used as positive control.

(109) (Test Method and Measurement Method)

(110) 1) The test compound solution was added in an amount of 10 L into each well of a 384-well plate. 2) 4GS1 solution and 4GR solution were added in an amount of 5 L into each well, respectively. 3) GR screening buffer was added in an amount of 10 L/well into each well in place of the test compound solution, which was made a negative control. 4) A 2 mM of DEX was added in an amount of 10 L/well into each well in place of the test compound solution, which was made a positive control. 5) The plate was incubated in a dark place at room temperature for 2 hours, and fluorescence polarization of each well was measured.
(Calculation Equation of GR Binding Ratio)

(111) A GR binding ratio (%) was calculated from the following equation.
GR binding ratio (%)=100{1(fluorescence polarization of test compound solutionaverage value of fluorescence polarization of positive control solution)/(average value of fluorescence polarization of negative control solutionaverage value of fluorescence polarization of positive control solution)}

(112) (Test Results and Discussion)

(113) The GR binding rates (%) when the compound 1-1, the compound 1-3, the compound 1-4, the compound 1-6, the compound 2-1, the compound 2-2, the compound 3-1, the compound 4-1, the compound 4-2, the compound 4-3, the compound 5-1, the compound 5-2, the compound 7-1, the compound 7-2, the compound 9-1, the compound 10-1, the compound 10-2, the compound 10-3, the compound 11-1, the compound 11-5, the compound 14-1, the control compound B, the control compound C, the control compound D, the control compound E and the control compound F were used as the test compound are shown in Table I.

(114) As a result of the GR binding activity evaluation test, the present compounds showed an excellent GR binding activity.

(115) TABLE-US-00052 TABLE I Table 52 Test compound GR binding rate (%) Compound 1-1 >99 Compound 1-3 95 Compound 1-4 >99 Compound 1-6 87 Compound 2-1 >99 Compound 2-2 91 Compound 3-1 >99 Compound 4-1 >99 Compound 4-2 >99 Compound 4-3 88 Compound 5-1 88 Compound 5-2 >99 Compound 7-1 >99 Compound 7-2 >99 Compound 9-1 >99 Compound 10-1 94 Compound 10-2 >99 Compound 10-3 >99 Compound 11-1 99 Compound 11-5 >99 Compound 14-1 >99 Control compound B >99 Control compound C >99 Control compound D 98 Control compound E 98 Control compound F 94
2. IL-6 Production Inhibitory Action Evaluation Test

(116) To evaluate the action of the present compounds as a GR agonist, IL-6 production inhibitory action in human corneal epithelial cell line after LPS stimulation was examined The IL-6 production was measured by using the HTRF method (Cat No. 62IL6PEB manufactured by Cisbio Bioassays, Inc.) according to the attached protocol. The specific method is described below.

(117) (Preparation of Reagent)

(118) LPS solution: After dissolving LPS in PBS(), the resulting solution was diluted with a culture solution, whereby an LPS solution with a 1 g/mL concentration was prepared.

(119) (Preparation of Test Compound Solution and DEX Solution)

(120) After dissolving the test compound in dimethylsulfoxide, the solution was diluted with a 10% FBS-DMEM/Ham's F12 medium, whereby a 100 M of the test compound solution was prepared. When the IC.sub.50 value is to be calculated, the 100 M solution was diluted with a 1% dimethylsulfoxide-containing 10% FBS-DMEM/Ham's F12 medium, whereby 10 M, 3 M, 1 M, 0.3 M, 0.1 M and 0.01 M of the test compound solutions were prepared, respectively. In addition, DEX was similarly dissolved, whereby a 100 M concentration of the DEX solution was prepared, and an IL-6 production inhibitory ratio of DEX was measured, and used for calculation of Efficacy (% DEX).

(121) (Used Cells and Culturing Method)

(122) Used cells: human corneal epithelium cell line (HCE-T) (RIKEN, Institute of Physical and Chemical Research)

(123) Culturing Method

(124) 1) HCE-T proliferated to a subconfluent state was washed with PBS(), and the cells were detached by the trypsin-EDTA treatment. 2) SHEM medium (supplemented hormone epithelial medium: 15% FBS, 5 g/mL of insulin, 10 ng/mL of human EGF, and 40 g/mL of gentamicin-containing DMEM/Ham's F12) was added and trypsin was inactivated. 3) The above suspension was recovered, and centrifuged by 1,000 rpm for 5 minutes to give a cell sediment. 4) The cell sediment was suspended by an SHEM medium, seeded in a culture flask, and cultured in a CO.sub.2 incubator (temperature: 37 C., CO.sub.2 concentration: 5%). The cells continued to subculture according to this method were used for the test.
(Test Method and Measurement Method) 1) The subcultured HCE-T was recovered and the cells were seeded at 2.010.sup.4 cells/0.1 mL/well in a 96-well flat bottom culture plate. 2) After culturing overnight, medium the medium was removed and each 80 L/well of 10%

(125) FBS-DMEM/Ham's F12 medium was added. 3) Test compound solution was added with each 10 L/well. 4) LPS solution was added with each 10 L/well. 5) The sample to which 1% dimethylsulfoxide-containing 10% FBS-DMEM/Ham's F12 medium was added with each 10 L/well in place of each test compound solution, and 10% FBS-DMEM/Ham's F12 medium was added in place of the LPS solution was made a negative control. 6) The sample in which 1% dimethylsulfoxide-containing 10% FBS-DMEM/Ham's F12 medium was added with each 10 L/well in place of each test compound solution was made a positive control. 7) After completion of 4 hours cultivation, the supernatant was recovered and the amount of IL-6 released in the supernatant was measured by using an HTRF human IL-6 Kit. 8) The IL-6 production inhibitory ratio was calculated according to the following calculation formula.
(Calculation of IL-6 Production Inhibitory Ratio)

(126) The IL-6 production inhibitory ratio (%) was calculated by the following formula.
IL-6 production inhibitory ratio (%)=100{1(IL-6 produced amount of each test compound solutionaverage value of IL-6 produced amount of negative control group)/(average value of IL-6 produced amount of positive control groupaverage value of IL-6 produced amount of negative control group)}(%)

(127) Further, the IL-6 production inhibitory ratio (Efficacy (% DEX)) when the DEX treated group was made 100 was calculated.
Efficacy (% DEX)=100{(average value of IL-6 production inhibitory ratio of each test compound solution)/(average value of IL-6 production inhibitory ratio of DEX treated group)}(%)

(128) In addition, IC.sub.50 was calculated according to a conventional method. IDBS XLfit4 was used for the calculation.

(129) (Test Result and Consideration)

(130) The IL-6 production inhibitory ratio (% DEX) and IC.sub.50 (M) when the compound 1-1, the compound 1-4, the compound 1-6, the compound 2-1, the compound 5-1, the compound 5-2, the compound 7-2, the compound 11-4, the compound 11-5, the control compound B, the control compound C, the control compound D, the control compound E and the control compound F were used as the test compounds are shown in Table II.

(131) As a result of the IL-6 production inhibitory action evaluation test, the present compounds showed an excellent IL-6 production inhibitory action.

(132) TABLE-US-00053 TABLE II Table 53 IL-6 production inhibitory ratio Test compound (% DEX) IC.sub.50 (M) Compound 1-1 86 0.033 Compound 1-4 92 0.034 Compound 1-6 89 <0.001 Compound 2-1 82 0.015 Compound 5-1 98 0.014 Compound 5-2 >99 0.013 Compound 7-2 >99 0.083 Compound 11-4 94 Not measured Compound 11-5 94 Not measured Control compound B 62 0.123 Control compound C 71 0.093 Control compound D 69 Not measured Control compound E 10 Not measured Control compound F 62 Not measured
3. TNF Production Inhibitory Action Evaluation Test

(133) In order to evaluate an action of the present compound as a GR agonist, a TNF production inhibitory action in rat whole blood after LPS stimulation ex vivo was investigated. For the measurement of the TNF production amount, the ELISA method (manufactured by R&D Systems, Cat No. RTA00) was used, and a procedure was carried out according to the protocol attached thereto. Hereinafter, the specific method will be described.

(134) (Preparation of Reagent)

(135) LPS solution: LPS was dissolved in PBS() and diluted with RPMI 1640 to prepare an LPS solution with a concentration of 2 g/mL.

(136) (Preparation of Test Compound Solution and DEX Solution)

(137) After the test compound was dissolved in dimethylsulfoxide, the solution was diluted with PBS() to prepare 200 M of a test compound solution. In addition, DEX was similarly dissolved to prepare 200 M of a DEX solution, and a TNF production inhibitory ratio of DEX was measured, and used for calculation of Efficacy (% DEX).

(138) (Test Method and Measurement Method)

(139) 1) Blood was collected from 3 to 5 rats using an injection syringe treated with heparin from the abdominal aorta under isoflurane anesthesia. The rats confirmed death after lething the whole blood. 2) The blood of 3 to 5 rats pooled in a 96-well round bottom culture plate was seeded at each 180 L/well. 3) It was cultured (37 C., 5% CO.sub.2, 95% air) for about 1 hour. 4) The test compound solution was added each 10 L/well, and cultured for 1 hour. 5) LPS solution was added each 10 L/well. 6) The sample in which 2% dimethylsulfoxide-containing PBS() was added with each 10 L/well in place of each test compound solution, and RPMI 1640 was added with each 10 L/well in place of the LPS solution was made a negative control. 7) The sample in which 2% dimethylsulfoxide-containing PBS() was added with each 10 L/well in place of each test compound solution was made a positive control. 8) After completion of 20 hours cultivation, the supernatant was recovered and the amount of TNF released in the supernatant was measured by using an ELISA Kit. 9) The TNF production inhibitory ratio was calculated according to the following calculation formula.
(Calculation of TNF Production Inhibitory Ratio)

(140) TNF production inhibitory ratio (%) was calculated according to the following formula.
TNF production inhibitory ratio (%)=100{1(TNF production amount of each test compound solutionaverage value of TNF production amount of negative control group)/(average value of TNF production amount of positive control groupaverage value of TNF production amount of negative control group)}(%)

(141) Further, a TNF production inhibitory ratio (Efficacy (% DEX)) when the DEX treated group was made 100 was calculated.
Efficacy (% DEX)=100{(average value of TNF production inhibitory ratio of each test compound solution)/(average value of TNF production inhibitory ratio of DEX treated group)}(%)

(142) (Test Result and Consideration)

(143) The TNF production inhibitory ratios (Efficacy (% DEX)) when the compound 1-1, the compound 1-2, the compound 1-3, the compound 1-4, the compound 2-1, the compound 2-2, the compound 5-2, the compound 10-2, the compound 14-1, the control compound B, the control compound E and the control compound F were used as the test compound are shown in Table III.

(144) As a result of the TNF production inhibitory action evaluation test, the present compounds showed excellent TNF production inhibitory action.

(145) TABLE-US-00054 TABLE III Table 54 TNF production inhibitory ratio Test compound (% DEX) Compound 1-1 81 Compound 1-2 94 Compound 1-3 93 Compound 1-4 94 Compound 2-1 97 Compound 2-2 95 Compound 5-2 >99 Compound 10-2 >99 Compound 14-1 86 Control compound B 77 Control compound E 0 Control compound F 69
4. IL-2 and IL-4 Production Inhibitory Actions Evaluation Test

(146) In order to evaluate an action of the present compound as a GR agonist, IL-2 and IL-4 production inhibitory actions in a normal human CD4.sup.+T cell after stimulation by an anti-CD3/CD28 antibody were investigated. For the measurement of the IL-2 and IL-4 production amounts, the ELISA method (manufactured by R&D Systems, Cat No. D2050, HS400) was used, and a procedure was carried out according to the protocol attached thereto. Hereinafter, the specific method will be described.

(147) (Preparation of Reagent)

(148) Dynabeads (Registered Trademark) Human T-Activator CD3/CD28 (410.sup.7 beads/mL) (Dynabeads) was used, and prepared according to the protocol attached thereto.

(149) (Preparation of Test Compound Solution)

(150) After the test compound was dissolved in dimethylsulfoxide, the solution was diluted with an RPMI medium to prepare 400 M of a test compound solution. The solution was diluted with a 4% dimethylsulfoxide-containing RPMI medium to prepare 40 M of a test compound solution.

(151) (Used Cells and Culturing Method)

(152) Used cells: normal peripheral blood human CD4.sup.+T cell (human CD4.sup.+T cell) (Lonza)

(153) Culturing method:

(154) 1) Frozen human CD4.sup.+T cells were thawed in a warm water bath at 37 C., and added to an RPMI medium (RPMI 1640 containing 10% FBS, 100 U/mL of Penicillin, and 100m/mL of Streptomycin). 2) The above suspension was recovered and centrifuged at 900 rpm for 10 minutes to give a cell sediment. 3) The cell sediment was suspended in an RPMI medium and the operation of 2) was carried out. 4) The cell sediment was adjusted to 410.sup.5 cells/mL with an RPMI medium. 5) The above suspension was cultured in a CO.sub.2 incubator (temperature: 37 C., CO.sub.2 concentration: 5%) for 1 hour or longer.
(Test Method and Measurement Method) 1) The cultured human CD4.sup.+T cells were recovered and the cells were seeded in 96-well flat bottom culture plates at each 8.010.sup.4 cells/0.2 mL/well. 2) The test compound solution was added with each 5 L/well. 3) The prepared Dynabeads were added with each 2 L/well. 4) The sample in which 4% dimethylsulfoxide-containing RPMI medium was added with each 5 L/well in place of each test compound solution, and the RPMI medium was added with each 2 L/well in place of the Dynabeads was made a negative control. 5) The sample in which 4% dimethylsulfoxide-containing RPMI medium was added with each 5 L/well in place of each test compound solution was made a positive control. 6) After completion of 24 hours cultivation, the supernatant was recovered and the amounts of IL-2 and IL-4 released in the supernatant was measured by using an ELISA Kit. 7) The IL-2 and IL-4 production inhibitory ratios were calculated according to the following calculation formula.
(Calculation of IL-2 and IL-4 Production Inhibitory Ratios)

(155) The IL-2 and IL-4 production inhibitory ratios (%) were calculated by the following formula, respectively.
IL-2 or IL-4 production inhibitory ratio (%)=100{1(IL-2 or IL-4 production amounts of each test compound solutionaverage value of IL-2 or IL-4 production amount of negative control group)/(average value of IL-2 or IL-4 production amount of positive control groupaverage value of IL-2 or IL-4 production amount of negative control group)}(%)
(Test Result and Consideration)

(156) The IL-2 and IL-4 production inhibitory ratios (% of 1 M) when the compound 1-1, the compound 2-1, the compound 11-1, the control compound B, the control compound C, the control compound D, the control compound E and the control compound F were used as the test compounds are shown in Table IV.

(157) As a result of the IL-2 and IL-4 production inhibitory action evaluation test, the present compounds showed excellent IL-2 and IL-4 production inhibitory actions.

(158) TABLE-US-00055 TABLE IV Table 55 IL-2 production IL-4 production inhibitory ratio inhibitory ratio Test compound (% of 1 M) (% of 1 M) Compound 1-1 73 91 Compound 2-1 79 83 Compound 11-1 72 87 Control compound B 35 51 Control compound C 26 56 Control compound D <0 46 Control compound E <0 32 Control compound F <0 29
5. MCP-1 Production Inhibitory Action Evaluation Test

(159) In order to evaluate an action of the present compound as a GR agonist, an MCP-1 production inhibitory action in human monocyte cell after stimulation by LPS was investigated. For the measurement of the MCP-1 production amount in the sample, the ELISA method (manufactured by R&D Systems, Cat No. DCP00) was used, and a procedure was carried out according to the protocol attached thereto. Hereinafter, the specific method will be described.

(160) (Preparation of Reagent)

(161) LPS solution: After LPS was dissolved in PBS(), the solution was diluted with 10% FBS-containing RPMI 1640 to prepare an LPS solution with a 40 g/mL concentration.

(162) (Preparation of Test Compound Solution)

(163) After the test compound was dissolved in dimethylsulfoxide, the solution was diluted with an RPMI medium to prepare 400 M of a test compound solution. The solution was diluted with a 4% dimethylsulfoxide-containing RPMI 1640 medium to prepare 40 M of a test compound solution.

(164) (Used Cells and Culturing Method)

(165) Used cells: human monocyte cell (THP-1) (ATCC)

(166) Culturing Method

(167) 1) Subcultured THP-1 was recovered and centrifuged at 1,100 rpm for 5 minutes to give a cell sediment. 2) An RPMI medium (RPMI 1640 containing 10% FBS, 100 U/mL of penicillin, 100 g/mL of streptomycin, 55 M of 2-Mercaptoethanol, 10 ng/mL of human EGF, and 40 g/mL of gentamicin) was added. 3) The above suspension was seeded in a culture flask and cultured in a CO.sub.2 incubator (temperature: 37 C., CO.sub.2 concentration: 5%). The cells continued to subculture according to this method were used for the test.
(Test Method and Measurement Method) 1) The subcultured THP-1 was recovered and the cells were each seeded at 1.910.sup.5 cells/0.19 mL/well in a 96-well round bottom culture plate. 2) The test compound solution was added with each 5 L/well and cultured for 2 hours. 3) LPS solution was added with each 5 L/well. 4) The sample to which 4% dimethylsulfoxide-containing RPMI medium was added with each 5 L/well in place of each test compound solution, and 10% FBS-RPMI 1640 was added with each 5 L/well in place of the LPS solution was made a negative control. 5) The sample to 4% dimethylsulfoxide-containing RPMI medium was added with each 5 L/well in place of each test compound solution was made a positive control. 6) After completion of 18 hours cultivation, the supernatant was recovered and the amount of MCP-1 released in the supernatant was measured by using an ELISA Kit. 7) The MCP-1 production inhibitory ratio was calculated according to the following calculation formula.
(Calculation of MCP-1 Production Inhibitory Ratio)

(168) MCP-1 production inhibitory ratio (%) was calculated by the following formula.
MCP-1 production inhibitory ratio (%)=100{1(MCP-1 production amount of each test compound solutionaverage value of MCP-1 production amount of negative control group)/(average value of MCP-1 production amount of positive control groupaverage value of MCP-1 production amount of negative control group)}(%)

(169) (Test Result and Consideration)

(170) The MCP-1 production inhibitory ratios (% of 1 M) when the compound 1-1, the compound 2-1, the compound 11-1, the control compound B, the control compound C, the control compound E and the control compound F were used as the test compounds are shown in Table V.

(171) As a result of the MCP-1 production inhibitory action evaluation test, the present compounds showed an excellent MCP-1 production inhibitory action.

(172) TABLE-US-00056 TABLE V Table 56 MCP-1 production inhibitory ratio Test compound (% of 1 M) Compound 1-1 86 Compound 2-1 91 Compound 11-1 88 Control compound B 65 Control compound C 65 Control compound E 40 Control compound F 27

(173) From the above results, the present compounds are confirmed to be useful as a GR agonist than the control compounds, and to be useful as a disease to which the GR agonist such as a steroid is effective, in particular, as a prophylactic or therapeutic agent for inflammatory diseases (bone and joint diseases, ocular inflammatory diseases, or the like).

(174) 6. Conjunctivitis Model Evaluation Test

(175) In order to evaluate an anti-inflammatory action of the present compound to conjunctivitis, an inhibitory effect on edema formation in a carrageenin-caused conjunctivitis model of rats was investigated. Incidentally, this effect was evaluated by calculating an edema formation inhibitory ratio from a weight of the edema in a base agent administered group (control group) and a weight of the edema in the test compound administered group.

(176) (Preparation of Eye Drop Solution of Test Compound)

(177) A base agent containing a general additive(s) was added to the test compound to prepare test compound suspensions with 0.001% (W/V), 0.003% (W/V), 0.01% (W/V) and 1% (W/V).

(178) (Preparation of Carrageenin-caused Conjunctivitis Model and Evaluation Method)

(179) By using male Wistar/ST rats, a urethane solution was administered and general anesthesia was applied, then a physiological saline solution in which 1.0% (W/V) of carrageenan had been dissolved was injected into the upper palpebral conjunctiva with both eyes each in an amount of 50 L/eye to induce inflammation.

(180) The compound 1-1 was once eye dropped (instillation dose: 5 L/time) to both eyes 30 minutes before induction. In the base agent administered group (control group), the base agent was similarly eye dropped. The control compounds B and C were eye dropped (instillation dose: 5 L/time) five times in total from 1 hour before induction to 3 hours after induction with an interval of 1 hour. In the base agent administered group (control group), the base agent was similarly eye dropped.

(181) Four hours after induction, rats under general anesthesia were sacrificed by decapitation method, conjunctival edema areas of both eyes were removed, and the weight of each was measured. The edema formation inhibitory ratio was calculated from the average value of the weight of the edema.

(182) (Calculation of Inhibitory Ratio)

(183) Based on the average value of the weight of the edema of the base agent administered group (control group), the edema formation inhibitory ratio of the test compound suspension eye drop group was calculated by the following calculation formula.
Edema formation inhibitory ratio (%)=100{1(average value of the weight of the edema in the test compound eye drop group)/(average value of the weight of the edema in the base agent administered group (control group))}(%)
(Test Result and Consideration)

(184) The edema formation inhibitory ratios (%) when the compound 1-1, the control compound B, the control compound C, commercially available drug A (active ingredient: 0.5% loteprednol etabonate) and commercially available drug B (active ingredient: 0.1% fluorometholone) which are existing ophthalmic solutions were used as the test compounds are shown in Table VI. The average value of the weight of the edema is each 8 to 10 eyes (4 to 5 rats).

(185) As a result of the conjunctivitis model evaluation test, the present compounds showed an excellent edema formation inhibitory effect.

(186) TABLE-US-00057 TABLE VI Table 57 Edema formation Test compound inhibitory ratio (%) Compound 1-1 (0.001%) 26 Compound 1-1 (0.003%) 30 Compound 1-1 (0.01%) 37 Control compound B (1%) 14 Control compound C (1%) 14 Commercially available drug A (0.5%) 33 Commercially available drug B (0.1%) 37

(187) From the above results, the present compounds are confirmed to be useful as a treatment agent for anterior eye inflammatory diseases, in particular, as a prophylactic or therapeutic agent for ocular inflammatory diseases such as keratitis, keratoconjunctivitis, conjunctivitis, inflammation by blepharitis, or the like.

(188) 7. Anterior Eye Inflammation Model Evaluation Test

(189) In order to evaluate an anti-inflammatory action of the present compound on anterior eye inflammation, an inhibitory effect on a number of infiltrated cells into aqueous humor in a paracentesis induced intraocular inflammation model of rabbits was investigated. Incidentally, this effect was evaluated by calculating an inhibitory ratio from a number of infiltrated cells into aqueous humor in the base agent administered group (control group) and a number of infiltrated cells into aqueous humor in the test compound administered group.

(190) (Preparation of Eye Drop Solution of Test Compound)

(191) A base agent containing a general additive(s) was added to the test compound to prepare a test compound suspension with 3% (W/V).

(192) (Preparation of Paracentesis Induced Intraocular Inflammation Model and Evaluation Method)

(193) 1) Male JW rabbits underwent local anesthesia with 0.4% oxybuprocaine hydrochloride (trade name: Benoxil ophthalmic solution 0.4%), and about 0.1 mL of anterior aqueous humor was collected by using a syringe for tuberculin so as not to touch the iris to carry out primary puncture, whereby an inflammatory response was induced. 2) Thirty minutes before the primary puncture, heparin was intravenously administered so as to be about 50 unit/kg. 3) The test compound suspension was eye dropped (instillation dose: 50 L/time) to both eyes in total four times, 210 minutes before, 60 minutes before, 15 minutes after, and 90 minutes after the primary puncture. To the base agent administered group (control group), the base agent was similarly eye dropped. 4) 120 minutes after the primary puncture, about 1.5 mL/kg of pentobarbital sodium (trade name: Somnopentyl) was intravenously administered from the rabbit ear vein. Thereafter, about 0.1 mL of anterior aqueous humor was collected by using a syringe for tuberculin, and the sample was stored in ice. 5) The number of infiltrated cells into the aqueous humor was measured using a TC10 full-automatic cell counter (Bio-Rad).
(Calculation Formula)
Inhibitory ratio (%) of infiltrated cells into aqueous humor in the test compound administered group=100{1(average value of the number of infiltrated cells into aqueous humor in the test compound eye drop group)/(average value of the number of infiltrated cells into aqueous humor in the base agent administered group (control group))}(%)
(Test Result and Discussion)

(194) The inhibitory ratio (%) of the number of infiltrated cells into aqueous humor in the case where the compound 11-1 was used as the test compound showed 37%. Incidentally, the average value of the score is each 7 eyes (14 rabbits).

(195) As a result of the anterior eye inflammation model evaluation test, the present compounds showed an excellent inhibitory effect on the number of infiltrated cells into aqueous humor.

(196) From the above results, the present compounds are confirmed to be useful as a treatment agent for anterior eye inflammatory diseases, in particular, as a prophylactic or therapeutic agent for ocular inflammatory diseases such as uveitis, inflammation after surgery and inflammation due to rejection of ocular tissue transplantation, or the like.

(197) 8. Dry Eye Syndrome (Dry Eye) Model Evaluation Test

(198) In order to evaluate the treatment effect of the present compounds on corneal disorder accompanied by dry eye syndrome (dry eye), a treatment effect on corneal disorder in an exorbital lacrimal gland-removed rat dry eye model was investigated. This model was prepared in accordance with the method of Fujihara, et al. (Invest. Ophthalmol. Vis. Sci., 42(1): 96-100 (2001)). Incidentally, this effect was scored according to the method of Murakami et al. (New Ophthalmologist 21(1): 87-90 (2004)), the extent of corneal disorder was scored and the improvement ratio was calculated from the corneal disorder score of the base agent administered group (control group), the corneal disorder score of the test compound administered group and the corneal disorder score of the normal rat.

(199) (Preparation of Eye Drop Solution of Test Compound)

(200) A base agent containing a general additive(s) was added to the test compound to prepare test compound suspensions with 0.03% (W/V) and 0.1% (W/V). In addition, a base agent was added to the commercially available drug A to prepare a diluted solution with 0.05% (V/V).

(201) (Preparation of Exorbital Lacrimal Gland-Removed Dry Eye Model and Evaluation Method)

(202) 1) By using male SD rats, somnopentyl was administered to the rats to apply them general anesthesia, exorbital lacrimal glands were removed, and corneal disorder was induced over 8 weeks thereafter. 2) The test compound suspension was eye-dropped (instillation dose: 5 L/time) to both eyes four times a day for 14 days. Incidentally, the base agent was similarly eye-dropped to the administered group (control group), and the commercially available drug A and its diluted solution were similarly eye-dropped. 3) Fourteen days after the start of eye dropping, the cornea was stained with fluorescein. For each of the upper part, the middle part and the lower part of the cornea, scores of the degree of staining with fluorescein were determined according to the following criteria, and an average value of the total of the scores was calculated. Incidentally, 0.5 was set as an intermediate value between each score of 0, 1, 2 and 3.
<<Judgement Standard>>

(203) 0: not dyed

(204) 1: Dyeing is sparse, and the dyed portions of each dot are separated

(205) 2: Dyeing is a middle degree and part of the dotted dyed portions is adjacent

(206) 3: Dyeing is dense, and the dyed portions of each point are almost adjacent

(207) (Calculation Formula)
Corneal disorder improvement ratio (%) of the test compound administered group=(AoAx)/(AoAn)100 Ao: Average value of corneal disorder score of the base agent administered group (control group) Ax: Average value of corneal disorder score of the test compound administered group An: Average value of corneal disorder score of normal rat
(Test Result and Consideration)

(208) The corneal disorder improvement ratios (%) when the compound 1-1, the compound 2-1, the compound 11-1, the compound 12-1, the compound 13-1, the commercially available drug A (active ingredient: 0.5% loteprednol etabonate) which is existing ophthalmic solution and a diluted solution of the commercially available drug A were used as the test compounds are shown in Table VII. Incidentally, the average value of the score is each 8 eyes (4 rats).

(209) As a result of the dry eye syndrome (dry eye) model evaluation test, the present compounds showed an excellent corneal disorder improvement ratio.

(210) TABLE-US-00058 TABLE VII Table 58 Corneal disorder Corneal disorder improvement ratio improvement ratio (%) (%) After 7 days After 14 days Test compound eye dropping eye dropping Compound 1-1 (0.03%) 22 41 Compound 1-1 (0.1%) 36 61 Compound 2-1 (0.1%) 40 45 Compound 11-1 (0.03%) 35 33 Compound 11-1 (0.1%) 44 64 Compound 12-1 (0.03%) 33 48 Compound 12-1 (0.1%) 42 58 Compound 13-1 (0.1%) 38 46 Commercially available drug A 21 38 diluted solution (0.05%) Commercially available drug A 54 54 (0.5%)

(211) From the above results, the present compounds are confirmed to be useful as a treatment agent for anterior eye inflammatory diseases, in particular, as a prophylactic or therapeutic agent for ocular inflammatory diseases such as keratitis, keratoconjunctivitis, conjunctivitis, blepharitis, dry eye syndrome (dry eye), or the like.

(212) 9. Allergic Conjunctivitis Model Evaluation Test

(213) In order to evaluate an anti-allergic action of the present compounds on allergic conjunctivitis, an inhibitory effect on hyperemia in an ovalbumin actively sensitized allergic conjunctivitis model of rabbits was investigated. Incidentally, this effect was evaluated by calculating an inhibitory ratio from the score of the base agent administered group (control group) and the score of the test compound administered group.

(214) (Preparation of Eye Drop Solution of Test Compound)

(215) A base agent containing a general additive(s) was added to the test compound to prepare test compound suspensions with 1% (WN) and 3% (W/V).

(216) (Preparation of Ovalbumin Actively Sensitized Allergic Conjunctivitis Model and Evaluation Method)

(217) By using male JW rabbits, ovalbumin (200 g/mL/physiological saline solution) adsorbed on aluminum hydroxide gel was injected 200 L per eye into bulbar conjunctiva of both eyes of rabbits, respectively, to perform active sensitization.

(218) After 14 days from sensitization or later, the test compound suspension was eye-dropped four times a day for 4 days, and then, at the next day, it was eye-dropped (instillation dose: 50 L/time) once to both eyes. Incidentally, the base agent was similarly eye-dropped to the base agent administered group (control group).

(219) One hour after the final eye dropping of the test compound suspension, a physiological saline solution containing 0.02% (W/V) of ovalbumin was administered from rabbit ear vein at a dose of 1.5 mL per 1 kg of rabbit to induce allergic conjunctivitis.

(220) After 0.5 hour of the challenge, the degree of hyperemia symptoms of both ocular conjunctiva of rabbits was evaluated according to the following criteria, and the average value of the total of these scores was calculated.

(221) <<Judgement standard>>

(222) 0: No findings

(223) 1: A state in which several expanded blood vessels are observed in part of the superior rectus muscle of the eyeball or the corneal limbus

(224) 2: A state in which many expanded blood vessels are observed in the superior rectus muscle of the eyeball, or a state in which several expanded blood vessels are observed in the superior rectus muscle of the eyeball and expansions of several blood vessels are observed in part of the corneal limbus

(225) 3: A state in which a large number of expanded blood vessels are observed the superior rectus muscle of the eyeball and in part of the corneal limbus

(226) 4: A state in which a large number of expanded blood vessels are observed the superior rectus muscle of the eyeball and all around the corneal limbus

(227) 5: A state in which expanded blood vessels are observed on the superior rectus muscle of the eyeball, the entire circumference of the corneal limbus, and on the other ocular conjunctiva

(228) (Calculation Formula)
Inhibitory ratio (%) of hyperemia of the test compound administered group={(AoAp1)(AxAp2)}/(AoAp1)100 Ao: Average value of hyperemia score of the base agent administered group (control group) Ax: Average value of hyperemia score of the test compound administered group Ap1: Average value of hyperemia score before challenge of the base agent administered group Ap2: Average value of hyperemia score before challenge of the test compound administered group
(Test Result and Consideration)

(229) The hyperemia inhibitory ratios (%) when the compound 1-1, the compound 2-1, the compound 5-2, the compound 11-1 and the compound 14-1 were used as the test compounds are shown in Table VIII. Incidentally, the average value of the score is each 8 eyes (8 rabbits).

(230) As a result of the allergic conjunctivitis model evaluation test, the present compounds showed an excellent hyperemia inhibitory effect.

(231) TABLE-US-00059 TABLE VIII Table 59 Eye congestion Test compound inhibitory ratio (%) Compound 1-1 (1%) 35 Compound 2-1 (1%) 29 Compound 5-2 (3%) 35 Compound 11-1 (1%) 44 Compound 14-1 (1%) 22

(232) From the above results, the present compounds are confirmed to be useful as a treatment agent for anterior eye inflammatory diseases, in particular, as a prophylactic or therapeutic agent for ocular inflammatory diseases such as keratitis, keratoconjunctivitis, conjunctivitis, blepharitis, dry eye syndrome (dry eye), allergic conjunctivitis, or the like.

(233) 10. Retinal Vascular Permeability Model Evaluation Test

(234) In order to evaluate the inhibitory effect of the present compounds on VEGF-induced retinal vascular permeability, the inhibitory effect of the present compound on retinal vascular permeability in a VEGF-induced retinal elevated vascular permeability model of rabbits was evaluated. Incidentally, this effect was evaluated by calculating a leaked amount of the fluorescent dye of the base agent administered group (non-induced group), a leaked amount of the fluorescent dye of the base agent administered group (control group) and a leaked amount of the fluorescent dye of the test compound administered group.

(235) (Preparation of Test Compound Suspension or Test Compound Solution)

(236) To the test compound was added 0.01% Polysorbate 80/0.5% sodium carboxymethyl cellulose/PBS (hereinafter referred to as base agent A.), whereby 2% (W/V) or 8% (W/V) of the test compound suspension was prepared. Or else, to the test compound was added PEG400 (hereinafter referred to as base agent B.), whereby 6% (W/W) of the test compound solution was prepared.

(237) (Preparation of Reagent)

(238) VEGF solution: humanVEGF165 was dissolved in PBS to prepare 50 g/mL of VEGF solution.

(239) (Preparation of VEGF-Induced Retinal Vascular Permeability Model and Evaluation Method)

(240) 1) A mixed solution (1 mL/kg) of 5% ketamine hydrochloride injection solution and 2% xylazine hydrochloride injection solution with the ratio of 7:1 was intramuscularly administered to rabbits (Dutch male rabbits), and the rabbits were anesthetized. 2) Tropicamide-phenylephrine hydrochloride ophthalmic solution (trade name: Midlin P) was eye dropped to maintain pupillary mydriasis, and then, the VEGF solution was intravitreally administered. Incidentally, PBS was intravitreally administered to the base agent administration group (non-induced group). 3) Fluorescein was intravenously administered 2 days after intravitreal administration of VEGF. Two hours after the intravenous administration of fluorescein, an amount of the leaked fluorescent dye in the vitreous body was measured by using a fluorophotometer.
(Test Method) 1) One week before or 4 weeks before VEGF-induction, 50 L of the test compound suspension (prepared by the base agent A) was intravitreally administered once, or 5 L of the test compound solution (prepared by the base agent B) was intravitreally administered once. Incidentally, in the base agent administered group (non-induced group) and the base agent administered group (control group), the base agent A was used in place of the test compound suspension, or the base agent B was used in place of the test compound solution. 2) Inhibition ratio of elevated retinal vascular permeability was calculated according to the following calculation formula.
(Calculation Formula)
Inhibitory ratio (%) on elevated retinal vascular permeability of the test compound administered group=100{1(average value of a leaked fluorescent dye amount in the test compound administered groupaverage value of a leaked fluorescent dye amount in the base agent administered group (non-induced group))/(average value of a leaked fluorescent dye amount in the base agent administered group (control group)average value of a leaked fluorescent dye amount of the base agent administered group (non-induced group))}

(241) (Test Result and Consideration)

(242) The inhibitory ratios (%) on elevated retinal vascular permeability when the compound 1-1, the compound 2-1, the compound 5-2, the compound 11-2, the compound 14-3, the control compound B, the control compound D and the control compound E were used as the test compounds are shown in Table IX. Incidentally, the average value of the leaked fluorescent dye amount is each 4 to 6 eyes (2 to 3 rabbits).

(243) As a result of the retinal vascular permeability model evaluation test, the present compounds showed an excellent inhibitory effect on elevated retinal vascular permeability.

(244) TABLE-US-00060 TABLE IX Table 60 Term from Inhibitory administration ratio (%) of test on elevated Administration compound to vascular Test compound dose/base agent induction permeability Compound 1-1 6% 5 L/B 4 weeks 80 Compound 2-1 2% 50 L/A 1 week >99 Compound 2-1 2% 50 L/A 4 weeks 91 Compound 5-2 2% 50 L/A 1 week 96 Compound 5-2 2% 50 L/A 4 weeks 91 Compound 11-2 2% 50 L/A 4 weeks 92 Compound 14-3 8% 50 L/A 4 weeks 89 Control compound B 2% 50 L/A 1 week 36 Control compound D 2% 50 L/A 4 weeks 38 Control compound E 2% 50 L/A 1 week 47

(245) From the above results, the present compounds are confirmed to be useful as a treatment agent for posterior eye inflammatory disease, in particular, as a prophylactic or therapeutic agent for age-related macular degeneration, diabetic macular edema, central retinal vein occlusion, branch retinal vein occlusion, or the like.

PREPARATION EXAMPLES

(246) A general Preparation example of the present compound is shown below.

Preparation Example 1: Tablet

(247) TABLE-US-00061 In 150 mg Present compound 1 mg Lactose 100 mg Corn starch 40 mg Calcium carboxymethyl cellulose 4.5 mg Hydroxypropyl cellulose 4 mg Magnesium stearate 0.5 mg

(248) The tablet of the above-mentioned prescription was subjected to coating by using 3 mg of a coating agent (for example, a coating agent generally used such as hydroxypropylmethyl cellulose, macrogol, a silicone resin, or the like) to obtain the intended tablet. In addition, a desired tablet may also be obtained by optionally changing the present compound, the kind of the additives and/or the amount of the additives.

Preparation Example 2: Capsule

(249) TABLE-US-00062 In 150 mg Present compound 5 mg Lactose 135 mg Calcium carboxymethyl cellulose 4.5 mg Hydroxypropyl cellulose 4 mg Magnesium stearate 1.5 mg

(250) A desired capsule may also be obtained by optionally changing the present compound, the kind of the additives and/or the amount of the additives.

Preparation Example 3: Ophthalmic Agent

(251) TABLE-US-00063 In 100 mL Present compound 100 mg Sodium chloride 900 mg Polysorbate 80 500 mg Sodium hydroxide q.s. Hydrochloric acid q.s. Sterile purified water q.s.

Preparation Example 4: Intravitreal Administration Agent

(252) TABLE-US-00064 In 100 mL Present compound 100 mg Polyethylene glycol 400 q.s.

(253) A desired ophthalmic agent may also be obtained by optionally changing the present compound, the kind of the additives and/or the amount of the additives.

INDUSTRIAL APPLICABILITY

(254) The novel [4-(1,3,3-trimethyl-2-oxo-3,4-dihydro-1H-quinoxalin-7-yl)-phenoxy]ethyloxy compound or a salt thereof according to the present invention has the glucocorticoid receptor agonist activity, and useful as a prophylactic or therapeutic agent of a disease, in particular, glucocorticoid receptor related disease, as a medicine.