2-aryl selenazole compound and pharmaceutical composition thereof
A 2-aryl selenazole compound and a pharmaceutical composition are disclosed, wherein the 2-aryl selenazole compound is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The 2-aryl selenazole compound has the activity of inhibiting xanthine oxidase. The compound or a pharmaceutically acceptable salt thereof can be applied in terms of preparing a drug used for prevention or treatment of hyperuricemia, gout, diabetic nephropathy, an inflammatory disease or a neurological disease.
1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
wherein,
X is selected from C 1-2 alkyl or substituted C 1-2 alkyl;
Y is selected from —COOR a or —CONHR a ;
R 1 is selected from halogen, —CN, C 1-2 alkyl, substituted C 1-2 alkyl, C 1-3 alkoxy, or substituted C 1-3 alkoxy;
R 2 is selected from H, D, halogen, C 1-2 alkyl, substituted C 1-2 alkyl, C 1-3 alkoxy, or substituted C 1-3 alkoxy; and
R 3 is selected from —(CH 2 ) n —O—R b , —(CH 2 ) n —S—R b , —C(O)R b , —NR c R d , —S(O)CHR c R d , —S(O) 2 CHR c R d , —(CH 2 ) n C(O)NR c R d , aryl, substituted aryl, a heterocyclic radical, a substituted heterocyclic radical, a heteroaryl radical, or a substituted heteroaryl radical, wherein,
n is 0 to 2;
R a is selected from H, C 1-6 alkyl or substituted C 1-6 alkyl;
R b is selected from H, methyl, ethyl, propyl, 2-propyl, butyl, tertiary butyl, amyl, substituted C 1-8 alkyl, aryl, substituted aryl, a heterocyclic radical, a substituted heterocyclic radical, a heteroaryl radical, or a substituted heteroaryl radical; and
R c and R d are respectively independently selected from H, C 1-8 alkyl, or substituted C 1-8 alkyl; or R c and R d are cyclized to form cycloalkyl, substituted cycloalkyl, a heteroaryl radical, or a substituted heteroaryl radical; and
a substituent in groups X, Y, R 1 , R 2 , R 3 , R a , R b , R c or R d is selected from one or more of D, —OH, —CN, —NH 2 , acyl, acylamino, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-2 alkoxy, or C 1-2 alkylamino.
2. The compound according to claim 1 , wherein the compound is a compound represented by formula (II), or a pharmaceutically acceptable salt thereof
3. The compound according to claim 2 , wherein X is —CH 3 , —CH 2 CH 3 , —CH 2 OH, or —CF 3 .
4. The compound according to claim 3 , wherein R a is H, C 1-3 alkyl, or substituted C 1-3 alkyl.
5. The compound according to claim 4 , wherein R 1 is selected from halogen, —CN, —CH 3 , —CH 2 CH 3 , —CF 3 , —OCHF 2 , or —OCF 3 .
6. The compound according to claim 5 , wherein R 2 is selected from H or D.
7. The compound according to claim 6 , wherein the compound is a compound represented by formula (III), or a pharmaceutically acceptable salt thereof
8. The compound according to claim 7 , wherein,
R 3 is selected from —OR b , —SR b , —C(O)R b , —NR c R d , —S(O)CHR c R d , —S(O) 2 CHR c R d , —C(O)NR c R d , phenyl, substituted phenyl, pyridyl, substituted pyridyl, naphthyl, substituted naphthyl, phenoxy, substituted phenoxy, thiophenyl, substituted thiophenyl, morpholinyl, substituted morpholinyl, N-ethyl morpholinyl, substituted N-ethyl morpholinyl, piperazinyl, substituted piperazinyl, 4,5,6,7-tetrahydrothieno[3,2-c]pyridyl, methylphenyl sulfonyl, or substituted methylphenyl sulfonyl;
R b is methyl, ethyl, propyl, 2-propyl, butyl, tertiary butyl, amyl, substituted C 1-8 alkyl, phenyl or substituted phenyl; R c or R d is independently selected from H, C 1-8 alkyl, or substituted C 1-8 alkyl; or R c and R d are cyclized to form cycloalkyl, substituted cycloalkyl, a heteroaryl radical, or a substituted heteroaryl radical; and
the substituent is selected from one or more of D, —OH, —NH 2 , —CN, acyl, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, or C 1-2 alkoxy.
9. The compound according to claim 8 , wherein,
R 3 is selected from —OR b , —SR b , —C(O)R b , —NR c R d , —S(O) 2 CHR c R d , —C(O)NR c R d , phenyl, substituted phenyl, pyridyl, substituted pyridyl, naphthyl, substituted naphthyl, quinolyl, substituted quinolyl, thiophenyl, substituted thiophenyl, phenoxy, substituted phenoxy, pyridylthio, morpholinyl, piperazinyl, substituted piperazinyl, or 4,5,6,7-tetrahydrothieno[3,2-c]pyridyl;
R b is methyl, ethyl, propyl, 2-propyl, butyl, tertiary butyl, amyl, substituted C 1-8 alkyl, phenyl or substituted phenyl; R c or R d is independently selected from H, C 1-8 alkyl, or substituted C 1-8 alkyl; or R c and R d are cyclized to form cycloalkyl, substituted cycloalkyl, a heteroaryl radical, or a substituted heteroaryl radical; and
the substituent is selected from one or more of D, —OH, —CN, —NH 2 , —NHCH 3 , —F, —Cl, —Br, —CH 3 , —CH 2 CH 3 , —CHDCH 2 D, —CF 3 , —OCH 3 , or —OCH 2 CH 3 .
10. The compound according to claim 1 , wherein the compound is selected from the following compounds or pharmaceutically acceptable salts thereof:
2-(3-cyano-4-ethoxyphenyl)-4 -methyl- selenazole-5-carboxylic acid,
2-(3-cyano-4-isopropoxyphenyl)-4-methyl-selenazole-5-carboxylic acid,
2-[3 -cyano-4-(3 -methyl-butoxy)phenyl]-4-methyl-selenazole-5-carboxylic acid,
2-[3-cyano-4-(cyclohexylmethoxy)phenyl]-4-methyl-selenazole-5-carboxylic acid,
2-[3 -cyano-4-(benzyloxy)phenyl]-4-methyl-selenazole-5-carboxylic acid,
2-[3 -cyano-4-(cyclopropylmethoxy)phenyl]-4-methyl-selenazole-5-carboxylic acid,
2-(2-cyano-biphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid,
2-(2-cyano-3′,4′-dimethoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid,
2-(2-cyano-3′-fluoro-4′-methoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid,
2-(2-cyano-3′,4′,5′-trimethoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid,
2-(2-cyano-4′-methoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid,
2-(2-cyano-3′-methoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid,
2-(2-cyano-3′-trifluoromethoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid,
2-(2-cyano-4′-chlorobiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid,
2-(2-cyano-3′,4′-difluorobiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid,
2-(2-cyano-2′,3′,4′,5′,6′-pentadeuterobiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid,
2-(2-cyano-2′-methoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid,
2-(2-cyano-2′,4′-dimethoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid,
2-[3-cyano-4-(1-naphthyl)-phenyl]-4-methyl-selenazole-5-carboxylic acid,
2-[3-cyano-4-(4-pyridyl)-phenyl-4-yl]-4-methyl-selenazole-5-carboxylic acid,
2-(3-cyano-4-(3-pyridyl)-phenyl-4-yl]-4-methyl-selenazole-5-carboxylic acid,
2-[2-cyano-4′-(1,2-deuteroethyl)-biphenyl-4-yl]-4-methyl-selenazole-5-carboxylic acid,
2-(2-cyano-6-deuterobiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid,
2-(3-cyano-4-isopropylthiophenyl)-4-methyl-selenazole-5-carboxylic acid,
2-(3-cyano-4-isobutylthiophenyl)-4-methyl-selenazole-5-carboxylic acid,
2-[3-cyano-4-(4-chrolophenylthio)-phenyl]-4-methyl-selenazole-5-carboxylic acid,
2-[3-cyano-4-(3-trifluoromethylphenylthio)-phenyl]-4-methyl-selenazole-5-carboxylic acid,
2-[3-cyano-4-(2-pyridylthio)-phenyl]-4-methyl-selenazole-5-carboxylic acid,
2-(3-cyano-4-benzylthio-phenyl)-4-methyl-selenazole-5-carboxylic acid,
2-(3-cyano-4-isopropyl sulfone-phenyl)-4-methyl-selenazole-5-carboxylic acid,
2-(3-cyano-4-morpholinyl-4-yl-phenyl)-4-methyl-selenazole-5-carboxylic acid,
2-[3-cyano-4-(4-methylpiperazine-1-yl)phenyl]-4-methyl-selenazole-5-carboxylic acid,
2-{3 -cyano-4-(6,7 -dihydro-4H-thieno [3 ,2-c]pyridyl)-phenyl}-4-methyl-selenazole-5-carboxylic acid,
2-(3-cyano-4-dimethylamino-phenyl)-4-methyl-selenazole-5-carboxylic acid,
2-(3-fluoro-4-isobutoxyphenyl)-4-methyl-selenazole-5-carboxylic acid,
2-(3-trifluoromethyl-4-isobutoxyphenyl)-4-methyl-selenazole-5-carboxylic acid,
2-[3 -cyano-4-(isopropylthiomethyl)-phenyl]-4-methyl-selenazole-5-carboxylic acid,
2-[3-bromo-4-(aniline formyl)-phenyl]-4-methyl-selenazole-5-carboxylic acid,
2-(2-cyano-4′-trifluoromethylbiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid,
2-(2-cyano-3′-trifluoromethylbiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid,
2-(2-cyano-2′-trifluoromethylbiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid,
2-(3-cyano-4-isobutoxyphenyl)-4-hydroxymethyl-selenazole-5-carboxylic acid,
2-(3-bromo-4-isobutoxyphenyl)-4-methyl-selenazole-5-carboxylic acid,
2-(3-cyano-4-isopropylthiophenyl)-4-methyl-selenazole-5-carboxylic acid-(2-N-acetyl)ethyl ester, 2-(3-cyano-4-tertbutylthiophenyl)-4-methyl-selenazole-5-carboxylic acid, 2-(3-cyano-4-cyclohexylthiophenyl)-4-methyl-selenazole-5-carboxylic acid, or
2-(3-trifluoromethylphenyl)-4-methyl-selenazole-5-carboxylic acid.
11. A pharmaceutical composition, comprising any compound or a pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient.
12. The pharmaceutical composition according to claim 11 , for use in the treatment of hyperuricemia, gout, diabetic nephropathy, an inflammatory disease or a neurological disease.
13. A method for inhibiting the activity of xanthine oxidase, the method comprising administering, to an organism in need of such inhibition, an effective amount of the compound or the pharmaceutically acceptable salt of claim 1 .
14. The method of claim 13 , wherein the organism is a human.
15. A method of reducing uric acid generation, the method comprising administering, to an organism in need of such reduction, an effective amount of the compound or the pharmaceutically acceptable salt of claim 1 .
16. The method of claim 15 , wherein the organism is a human.
17. A method for the treatment of hyperuricemia, gout, diabetic nephropathy, an inflammatory disease or a neurological disease, the method comprising administering, to an organism in need of such treatment, an effective amount of the compound or the pharmaceutically acceptable salt of claim 1 .
18. The method of claim 17 , wherein the effective amount of the compound or the pharmaceutically acceptable salt is effective for inhibiting the activity of xanthine oxidase.
19. The method of claim 17 , wherein the organism is a human.
20. A method for the treatment of hyperuricemia and gout, the method comprising administering, to an organism in need of such treatment, an effective amount of a xanthine oxidase inhibitor, wherein the xanthine oxidase inhibitor comprises the compound or the pharmaceutically acceptable salt of claim 1 .
21. The method of claim 20 , wherein the organism is a human.