Acetophenone compound, preparation method thereof, and application thereof in fatty liver prevention and treatment

Abstract

Disclosed is a compound represented by formula I or a pharmaceutically acceptable salt thereof, preparation method thereof, and use thereof in preventing or treating fatty liver or in preparing pharmaceuticals for weight loss. ##STR00001##

Claims

1. A compound of Formula I or a pharmaceutically acceptable salt thereof, ##STR00047## wherein, X is selected from oxygen; Z is selected from imino; Q is selected from methylene (CH.sub.2); R.sup.1 is selected from ##STR00048## R.sup.2 is selected from ##STR00049## R.sup.3 is selected from H; halogen; hydroxyl; amino; nitro; cyano; C1-C10 alkyl; C1-C10 alkoxyl; or C3-C10 cycloalkyl, n is an integer selected from 0 to 1; p is 0; wherein, R.sup.4 is selected from H or C1-C10 alkyl; R.sup.5 or R.sup.6 is independently selected from the optionally substituted groups of: phenyl; 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatom(s) independently selected from nitrogen; or ##STR00050## wherein R.sup.7 or R.sup.8 is independently selected from H or from substituted or unsubstituted C1-C10 alkyl; R.sup.9 is selected from phenyl, monosubstituted phenyl or multi-substituted phenyl, wherein the substituent for phenyl is selected from halogen; hydroxyl; C1-C10 alkyl; or C1-C10 alkoxyl, m is an integer selected from 0 to 8; said substituted refers to substituents chosen from halogen; C1-C10 alkyl; C3-C10 cycloalkyl; C1-C10 alkyl substituted with C5-C10 aryl; C5-C10 aryl; 3- to 10-membered heterocyclic group having 1 to 3 heteroatom(s) independently selected from nitrogen or oxygen; or 5- to 10-membered heteroaryl having 1 to 4 heteroatom(s) independently selected from nitrogen or oxygen.

2. The compound of Formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R.sup.4 is selected from H or from C1-C6 alkyl; R.sup.7 or R.sup.8 is independently selected from H or from substituted or unsubstituted C1-C6 alkyl; R.sup.9 is selected from phenyl, monosubstituted phenyl or multi-substituted phenyl, wherein the substituent for phenyl is selected from halogen; hydroxyl; C1-C6 alkyl; or C1-C6 alkoxyl.

3. The compound of Formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R.sup.3 is selected from H; halogen; hydroxyl; amino; nitro; cyano; C1-C3 alkyl; C1-C3 alkoxyl; or C3-C6 cycloalkyl, R.sup.7 or R.sup.8 is independently selected from CH.sub.3; R.sup.9 is selected from monosubstituted phenyl or disubstituted phenyl, wherein the substituent for phenyl is halogen or CH.sub.3.

4. The compound of Formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.5 and R.sup.6 are pyridin-3-yl.

5. The compound of Formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.7 and R.sup.8 is methyl.

6. The compound of Formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.9 is 2,5-dimethyl phenyl.

7. The compound of Formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein m is 3.

8. The compound of Formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the halogen is chlorine; R.sup.4 is H.

9. The compound of Formula I or a pharmaceutically acceptable salt thereof according to claim 1, comprising compounds having the following structures: ##STR00051## ##STR00052##

10. The compound of Formula I or a pharmaceutically acceptable salt thereof according to claim 2, wherein R.sup.5 and R.sup.6 are pyridin-3-yl.

11. The compound of Formula I or a pharmaceutically acceptable salt thereof according to claim 2, wherein R.sup.7 and R.sup.8 is methyl.

12. The compound of Formula I or a pharmaceutically acceptable salt thereof according to claim 2, wherein R.sup.9 is 2,5-dimethyl phenyl.

13. The compound of Formula I or a pharmaceutically acceptable salt thereof according to claim 3, wherein R.sup.5 and R.sup.6 are pyridin-3-yl.

14. The compound of Formula I or a pharmaceutically acceptable salt thereof according to claim 3, wherein R.sup.7 and R.sup.8 is methyl.

15. The compound of Formula I or a pharmaceutically acceptable salt thereof according to claim 3, wherein R.sup.9 is 2,5-dimethyl phenyl.

16. A method for preparing the compounds of Formula I or a pharmaceutically acceptable salt thereof as defined in claim 1, wherein the compounds of Formula I in which R.sup.2 is ##STR00053## are represented by Formula I-A and the reaction is as follows: ##STR00054## the method comprising: Method I, comprising a step of directly condensing an acid ##STR00055## and a compound ##STR00056## in the presence of a condensing agent and a solvent; or Method II, comprising a step of condensing an acyl chloride and a compound ##STR00057## in a solvent, wherein the acyl chloride is obtained by a reaction of an acid ##STR00058## with a chlorinating agent.

17. A pharmaceutical composition comprising the compound of Formula I or a pharmaceutically acceptable salt thereof as defined in claim 1, and a pharmaceutically acceptable additive.

18. The pharmaceutical composition according to claim 17, wherein the pharmaceutical composition is in a form of tablet, pill, powder, liquid, suspension, emulsion, granule, capsule, suppository or injection.

Description

DETAILED DESCRIPTION OF THE EMBODIMENTS

Example 1: Preparation of Compound 01

(1) ##STR00025##

(2) 3.0 g of p-aminoacetophenone and 2.5 g of nicotinic acid were dissolved in 20 mL of N,N-dimethylformamide, and 11.4 g of 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate and 7.8 g of diisopropylethylamine were added. The resulted mixture was stirred at room temperature for 2 hours, washed by adding 150 mL of ethyl acetate, and then washed successively with 30 mL of water and 30 mL of saturated brine. Then, the solvent was evaporated to dryness, and 2.5 g of the target compound was obtained through silica-gel column chromatography. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.69 (d, J=19.2 Hz, 1H), 9.09 (t, J=9.7 Hz, 1H), 8.79-8.70 (m, 1H), 8.32-8.23 (m, 1H), 7.97 (d, J=8.8 Hz, 2H), 7.91 (d, J=8.8 Hz, 2H), 7.59-7.50 (m, 1H), 2.54 (s, 3H). MS (ESI) m/z: 241.0 [M+1].sup.+.

Example 2: Preparation of Compound 02

(3) ##STR00026##

(4) 4.0 g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid was dissolved in 40 mL of dichloromethane, and 3.0 g of oxalyl chloride and 2 drops of N,N-dimethylformamide were added under cooling in an ice bath. Then, the ice bath was removed and the mixture was warmed to room temperature and stirred for 3 hours. The solvent was evaporated to dryness to give corresponding acyl chloride.

(5) 2.2 g of p-aminoacetophenone was dissolved in 30 mL of pyridine, and the above acyl chloride in 20 mL of dichloromethane solution was added dropwise under cooling in an ice bath. After addition, the ice bath was removed; the mixture was warmed to room temperature and stirred for 1 hour. The solvent was evaporated to dryness, and the residue was dissolved by adding 200 mL of ethyl acetate, and washed successively with 100 mL of 3N hydrochloric acid, 100 mL of water and 100 mL of saturated brine. Then, the solvent was evaporated to dryness, and 5.4 g of the target compound was obtained through silica-gel column chromatography. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.95-7.89 (m, 2H), 7.62 (d, J=8.8 Hz, 2H), 7.56 (s, 1H), 6.99 (d, J=7.5 Hz, 1H), 6.66 (d, J=7.5 Hz, 1H), 6.59 (s, 1H), 3.97-3.88 (m, 2H), 2.57 (s, 3H), 2.28 (s, 3H), 2.14 (s, 3H), 1.82 (dd, J=15.4, 2.8 Hz, 4H), 1.35 (s, 6H). MS (ESI) m/z: 390.2 [M+23].sup.+.

Example 3: Preparation of Compound 03

(6) ##STR00027##

(7) 5.85 g of 2-amino-1-(4-nitrophenyl)ethanone hydrochloride was dissolved in 50 mL of pyridine, and 5.8 g of nicotinyl chloride hydrochloride was added under cooling in an ice bath. Then, the ice bath was removed, and the mixture was warmed to room temperature and stirred for 2 hours. The solvent was evaporated to dryness, and 100 mL of water was added and 6.4 g of N-(2-(4-nitrophenyl)-2-oxoethyl)nicotinamide was obtained by filtration.

(8) The above N-(2-(4-nitrophenyl)-2-oxoethyl)nicotinamide was dissolved in a mixed solvent of 50 mL of dichloromethane and 100 mL of methanol, and added with 2.0 g of Raney nickel. The resulted mixture was stirred overnight at room temperature in a hydrogen atmosphere. The catalyst was removed by filtration, and the solvent of the filtrate was evaporated to dryness. 1.4 g of the target compound was obtained through silica-gel column chromatography. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.04 (d, J=1.7 Hz, 1H), 8.90 (t, J=5.6 Hz, 1H), 8.71 (dd, J=4.8, 1.5 Hz, 1H), 8.21 (m, 1H), 7.72 (m, 2H), 7.51 (m, 1H), 6.57 (t, J=9.5 Hz, 2H), 6.11 (s, 2H), 4.68-4.59 (m, 2H). MS (ESI) m/z: 256.0 [M+1].sup.+.

Example 4: Preparation of Compound 04

(9) ##STR00028##

(10) 8.0 g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid was dissolved in 100 mL of dichloromethane, and 6.1 g of oxalyl chloride and 2 drops of N,N-dimethylformamide were added under cooling in an ice bath. Then, the ice bath was removed and the mixture was warmed to room temperature and stirred for 3 hours. The solvent was evaporated to dryness to give corresponding acyl chloride.

(11) 6.9 g of 2-amino-1-(4-nitrophenyl)ethanone hydrochloride was dissolved in 80 mL of pyridine, and the above acyl chloride in 50 mL of dichloromethane solution was added dropwise under cooling in an ice bath. After addition, the ice bath was removed; the mixture was warmed to room temperature and stirred for 2 hours. The solvent was evaporated to dryness, and the residue was dissolved by adding 200 mL of ethyl acetate, and washed successively with 100 mL of 3N hydrochloric acid, 100 mL of water and 50 mL of saturated brine. The solvent was evaporated to dryness, and 6.2 g of 5-(2,5-dimethylphenoxy)-2,2-dimethyl-N-(2-(4-nitrophenyl)-2-oxoethyl)-pentanamide was obtained through silica-gel column chromatography.

(12) The above 5-(2,5-dimethylphenoxy)-2,2-dimethyl-N-(2-(4-nitrophenyl)-2-oxoethyl)pentan-amide was dissolved in 100 mL of methanol, 1.0 g of Raney nickel was added, and the mixture was stirred overnight at room temperature in a hydrogen balloon atmosphere. The catalyst was removed by filtration, and the solvent of the filtrate was evaporated to dryness. 3.5 g of the target compound was obtained through silica-gel column chromatography. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.80 (d, J=8.7 Hz, 2H), 6.98 (d, J=7.4 Hz, 1H), 6.89 (s, 1H), 6.63 (m, 4H), 4.62 (d, J=4.0 Hz, 2H), 4.27 (s, 2H), 3.91 (d, J=4.8 Hz, 2H), 2.29 (s, 3H), 2.16 (s, 3H), 1.80-1.72 (m, 4H), 1.29 (s, 6H). MS (ESI) m/z: 384 [M+1].sup.+.

Example 5: Preparation of Compound 05

(13) ##STR00029##

(14) 3.5 g of 1-(3-amino-[[3]]4hydroxyphenyl)ethanone was dissolved in 100 mL of pyridine, and 9.3 g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride in 20 mL of dichloromethane solution was added dropwise under cooling in an ice bath. After addition, the ice bath was removed, and the mixture was warmed to room temperature and stirred for 2 hours. The solvent was evaporated to dryness, and the residue was dissolved by adding 200 mL of ethyl acetate, and washed successively with 100 mL 3N hydrochloric acid, 60 mL of water and 30 mL of saturated brine. Then, the solvent was evaporated to dryness, and 5.1 g of the target compound was obtained through recrystallization using ethyl acetate as the solvent. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.99 (s, 1H), 7.82 (s, 1H), 7.71 (dt, J=6.2, 2.0 Hz, 2H), 7.04 (d, J=8.3 Hz, 1H), 6.99 (d, J=7.4 Hz, 1H), 6.65 (d, J=7.5 Hz, 1H), 6.60 (s, 1H), 3.95 (t, J=5.4 Hz, 2H), 2.53 (s, 3H), 2.29 (s, 3H), 2.16 (s, 3H), 1.91-1.78 (m, 4H), 1.40 (s, 6H). MS (ESI) m/z: 406.2 [M+23].sup.+.

Example 6: Preparation of Compound 06

(15) ##STR00030##

(16) 2.7 g of 1-(3-amino-4-hydroxylphenyl)ethanone was dissolved in 50 mL of pyridine, and 6.4 g of nicotinyl chloride was added under cooling in ice bath. Then, the ice bath was removed and the mixture was warmed to room temperature and stirred for 2 hours. The solvent was evaporated to dryness. 50 mL of water and 50 mL of saturated sodium carbonate aqueous solution was added. The mixture was extracted with 300 mL of dichloromethane. The organic phase was washed with 100 mL of saturated brine, and the solvent was evaporated to dryness. The residue was dissolved in 100 mL of methanol, and added with 30 mL of 4N sodium hydroxide aqueous solution. The mixture was stirred at room temperature for 1 hour, and was adjusted to pH 8-9 by adding hydrochloric acid. The solid was collected by filtration and 3.0 g of the target compound was obtained through silica-gel column chromatography. .sup.1H NMR (400 MHz, DMSO-d.sub.6) b 10.82 (s, 1H), 9.24 (d, J=1.5 Hz, 1H), 8.89 (dd, J=4.8, 1.6 Hz, 1H), 8.45 (dt, J=8.0, 1.9 Hz, 1H), 7.85-7.74 (m, 2H), 7.67-7.59 (m, 1H), 7.07 (d, J=8.4 Hz, 1H), 2.49 (s, 3H). MS (ESI) m/z: 257.1 [M+1].sup.+.

Example 7: Preparation of Compound 07

(17) ##STR00031##

(18) 11.5 g of 2-(4-(3-chlorobenzoyl)phenoxy)-2-methylpropionic acid was dissolved in 100 mL of dichloromethane, and 6.9 g of oxalyl chloride and 2 drops of N,N-dimethylformamide were added under cooling in an ice bath. Then, the ice bath was removed and the mixture was warmed to room temperature and stirred for 3 hours. The solvent was evaporated to dryness to give corresponding acyl chloride.

(19) 4.05 g of p-aminoacetophenone was dissolved in 50 mL of pyridine, and the above acyl chloride in 50 mL of dichloromethane solution was added dropwise under cooling in an ice bath. After addition, the ice bath was removed; the mixture was warmed to room temperature and stirred for 2 hours. The solvent was evaporated to dryness, and the residue was dissolved by adding 200 mL of ethyl acetate, and washed successively with 200 mL of water and 100 mL of saturated brine. Then, the solvent was evaporated to dryness, and 10.5 g of the target compound was obtained through silica-gel column chromatography. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.53 (s, 1H), 7.95 (s, 2H), 7.82-7.60 (m, 6H), 7.46 (d, J=6.4 Hz, 2H), 7.26 (d, J=1.5 Hz, 1H), 7.05 (d, J=6.6 Hz, 2H), 2.58 (d, J=1.4 Hz, 3H), 1.68 (s, 6H). MS (ESI) m/z: 458.3 [M+23].sup.+.

Example 8: Preparation of Compound 08

(20) ##STR00032##

(21) 7.1 g of 2-(4-chlorophenoxy)-2-methylpropionic acid was dissolved in 100 mL of dichloromethane, and 6.3 g of oxalyl chloride and 2 drops of N,N-dimethylformamide were added under cooling in an ice bath. Then, the ice bath was removed and the mixture was warmed to room temperature and stirred for 3 hours. The solvent was evaporated to dryness to give corresponding acyl chloride.

(22) 4.05 g of p-aminoacetophenone was dissolved in 50 mL of pyridine, and the above acyl chloride in 50 mL of dichloromethane solution was added dropwise under cooling in an ice bath. After addition, the ice bath was removed; the mixture was warmed to room temperature and stirred for 2 hours. The solvent was evaporated to dryness, and the residue was added with 300 mL of water. The solid was collected through filtration, and then was homogenized with 50 mL of a mixed solvent of petroleum ether:ethyl acetate in 5:1. The solid was collected through filtration and dried to give 8.5 g of the target compound. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.72 (s, 1H), 7.96 (d, J=8.6 Hz, 2H), 7.69 (d, J=8.6 Hz, 2H), 7.27 (d, J=9.1 Hz, 2H), 6.93 (d, J=8.7 Hz, 2H), 2.58 (s, 3H), 1.57 (s, 6H). MS (ESI) m/z: 332.3 [M+1].sup.+.

Example 9: Preparation of Compound 09

(23) ##STR00033##

(24) 2-(4-([[3]]4-chlorobenzoyl)phenoxy)-2-methyl-propionic acid were dissolved in 50 mL of N,N-dimethylformamide, and 11.4 g of 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate and 7.8 g of diisopropylethylamine were added. The resulted mixture was stirred overnight at room temperature, washed by adding 400 mL of ethyl acetate, and washed successively with 200 mL of water and 100 mL of saturated brine. Then, the solvent was evaporated to dryness, and 7.3 g of the target compound was obtained through silica-gel column chromatography. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.80 (s, 1H), 7.99-7.90 (m, 2H), 7.69 (d, J=8.7 Hz, 2H), 7.65-7.58 (m, 2H), 7.40-7.31 (m, 2H), 7.16 (d, J=8.4 Hz, 2H), 6.98-6.90 (m, 2H), 6.19 (s, 1H), 3.67 (dd, J=13.1, 6.8 Hz, 2H), 2.90 (t, J=7.0 Hz, 2H), 2.58 (s, 3H), 1.57 (s, 6H). MS (ESI) m/z: 501.3 [M+23].sup.+.

Example 10: Preparation of Compound 10

(25) ##STR00034##

(26) 9.5 g of 2-(4-(2,2-dichlorocyclopropyl)phenoxy)-2-methylpropionic acid was dissolved in 100 mL of dichloromethane, and 6.3 g of oxalyl chloride and 2 drops of N,N-dimethylformamide were added under cooling in an ice bath. Then, the ice bath was removed and the mixture was warmed to room temperature and stirred for 3 hours. The solvent was evaporated to dryness to give corresponding acyl chloride.

(27) 4.05 g of p-aminoacetophenone was dissolved in 50 mL of pyridine, and the above acyl chloride in 50 mL of dichloromethane solution was added dropwise under cooling in an ice bath. After addition, the ice bath was removed; the mixture was warmed to room temperature and stirred for 2 hours. The solvent was evaporated to dryness, and the residue was dissolved by adding 200 mL of ethyl acetate, and washed successively with 200 mL of water and 100 mL of saturated brine. Then, the solvent was evaporated to dryness, and 7.2 g of the target compound was obtained through silica-gel column chromatography. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.76 (s, 1H), 7.96 (d, J=8.6 Hz, 2H), 7.68 (t, J=9.5 Hz, 2H), 7.18 (t, J=9.9 Hz, 2H), 6.95 (m, 2H), 2.86 (dd, J=10.4, 8.6 Hz, 1H), 2.58 (s, 3H), 1.97 (m, 1H), 1.81 (t, J=7.9 Hz, 1H), 1.58 (s, 6H). MS (ESI) m/z: 406 [M+1].sup.+.

Example 11: Preparation of Compound 11

(28) ##STR00035##

(29) 1.5 g of Compound 04 was dissolved in 20 mL of pyridine, and 0.75 g of nicotinyl chloride hydrochloride was added under cooling in an ice bath. Then the ice bath was removed, and the mixture was warmed to room temperature and stirred for 2 hours. The solvent was evaporated to dryness, and the residue was added with 100 mL of water. The solid was collected through filtration, and then was homogenized with 20 ml of a mixed solvent of petroleum ether:ethyl acetate in 3:1. The solid was collected through filtration and dried to give 1.9 g of the target compound. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.22 (s, 1H), 8.95 (d, J=24.2 Hz, 1H), 8.77 (s, 1H), 8.29 (d, J=7.7 Hz, 1H), 7.97-7.89 (m, 2H), 7.89-7.82 (m, 2H), 7.46 (b, J=3.2 Hz, 1H), 6.97 (d, J=7.4 Hz, 1H), 6.80 (b, J=3.9 Hz, 1H), 6.63 (d, J=7.5 Hz, 1H), 6.59 (s, 1H), 4.66 (s, 2H), 4.01-3.75 (m, 2H), 2.28 (s, 3H), 2.15 (s, 3H), 1.82-1.68 (m, 4H), 1.27 (s, 6H). MS (ESI) m/z: 488.4 [M+1].sup.+.

Example 12: Preparation of Compound 12

(30) ##STR00036##

(31) 1.8 g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid was dissolved in 30 mL of dichloromethane, and 1.4 g of oxalyl chloride and 2 drops of N,N-dimethylformamide were added under cooling in an ice bath. Then, the ice bath was removed and the mixture was warmed to room temperature and stirred for 3 hours. The solvent was evaporated to dryness to give corresponding acyl chloride.

(32) 1.7 g of compound JSI000844 was dissolved in 30 mL of pyridine, and the above acyl chloride in 10 mL of dichloromethane solution was added dropwise under cooling in an ice bath. After addition, the ice bath was removed; the mixture was stirred at room temperature for 3 hours. The solvent was concentrated and evaporated to dryness, and the residue was diluted by adding 100 mL of ethyl acetate, and washed successively with 50 mL of water and 50 mL of saturated brine. The solvent was evaporated to dryness, and 1.2 g of the intermediate was obtained through silica-gel column chromatography. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.13 (s, 1H), 8.77 (d, J=4.2 Hz, 1H), 8.20 (d, J=7.8 Hz, 1H), 7.99 (d, J=8.6 Hz, 2H), 7.69 (d, J=8.6 Hz, 2H), 7.61 (s, 1H), 7.43 (dd, J=7.7, 4.8 Hz, 1H), 7.39-7.32 (m, 1H), 6.99 (d, J=7.5 Hz, 1H), 6.66 (d, J=7.5 Hz, 1H), 6.60 (s, 1H), 4.92 (d, J=3.9 Hz, 2H), 3.95 (s, 2H), 2.28 (s, 3H), 2.16 (s, 3H), 1.89-1.77 (m, 4H), 1.36 (s, 6H). MS (ESI) m/z: 488.9 [M+1].sup.+.

Example 13: Preparation of Compound 13

(33) ##STR00037##

(34) 0.91 g of 1-(3,4-dihydroxyphenyl)ethanone and 0.91 g of triethylamine were dissolved in 50 mL of dichloromethane, and 1.8 g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride was added under cooling in an ice bath. Then, the ice bath was removed and the mixture was warmed to room temperature and stirred for 30 min. The reaction mixture was diluted with 50 mL of dichloromethane, washed successively with 50 mL of water and 50 mL of saturated brine. The solvent was evaporated to dryness, and 2.1 g of the target compound was obtained through silica-gel column chromatography. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.71 (s, 1H), 7.73 (dd, J=8.5, 2.1 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 6.97 (dd, J=11.1, 8.0 Hz, 2H), 6.71 (s, 1H), 6.60 (d, J=7.4 Hz, 1H), 3.94 (s, 2H), 3.33 (s, 3H), 2.22 (s, 3H), 2.05 (s, 3H), 1.81 (m, 4H), 1.28 (s, 6H). MS (ESI) m/z: 407.2 [M+1]+.

Example 14: Preparation of Compound 14

(35) ##STR00038##

(36) 0.46 g of 1-(3,4-dihydroxyphenyl)ethanone and 0.40 g of triethylamine were dissolved in 25 mL of dichloromethane, and 0.54 g of nicotinyl chloride was added under cooling in an ice bath. Then, the ice bath was removed, and the mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was diluted with 50 mL of dichloromethane, and washed successively with 20 mL of water and 20 mL of saturated brine, followed by evaporating the solvent to dryness. The residue was added with 10 mL of saturated sodium carbonate aqueous solution and stirred, and then extracted twice with 30 mL of ethyl acetate. After the aqueous phase was separated, the mixture was adjusted to pH 7-8 with 1N hydrochloric acid, and was extracted three times with 30 mL of a mixed solution of dichloromethane and methanol (dichloromethane:methanol=10:1). The organic phases were combined and washed with 30 mL of saturated brine. The solvent was evaporated to give 0.14 g of the target compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.81 (s, 1H), 9.24 (d, J=1.6 Hz, 1H), 8.89 (dd, J=4.8, 1.6 Hz, 1H), 8.45 (dt, J=8.0, 1.9 Hz, 1H), 7.86-7.75 (m, 2H), 7.64 (dd, J=7.9, 4.9 Hz, 1H), 7.05 (t, J=9.9 Hz, 1H), 2.48 (s, 3H). MS (ESI) m/z: 258.2 [M+1].sup.+.

Example 15: Preparation of Compound 15

(37) ##STR00039##

(38) 1.93 g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid was dissolved in 20 mL of dichloromethane, and 1.5 g of oxalyl chloride and 2 drops of N,N-dimethylformamide were added under cooling in an ice bath. Then, the ice bath was removed and the mixture was warmed to room temperature and stirred for 3 hours. The solvent was evaporated to dryness to give corresponding acyl chloride.

(39) 2.0 g of 1-(4-phenoxy-3-(3-hydroxy)propyl)phenylethanone and 2.1 g of triethylamine were dissolved in 20 mL of dichloromethane, and the above 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride in 10 mL of dichloromethane was added under cooling in an ice bath. Then, the ice bath was removed and the mixture was warmed to room temperature and stirred overnight. The solvent was evaporated to dryness and 1.9 g of an benzyl-protected intermediate of the target compound was obtained through silica-gel column chromatography.

(40) The above benzyl-protected intermediate in 1.9 g and 2.3 g of ammonium formate were dissolved in 20 mL of methanol, and 0.2 g of a 5% palladium carbon hydrogenation catalyst was added, followed by stirring overnight at room temperature. The solid catalyst was removed by filtration, and the solvent of the filtrate was evaporated to dryness. Then, the residue was dissolved by adding 100 mL of ethyl acetate, and washed successively with 30 mL of water and 30 mL of saturated brine. The solvent was evaporated to dryness, and 1.5 g of the target compound was obtained through silica-gel column chromatography. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.77 (d, J=2.1 Hz, 1H), 7.72 (dd, J=8.4, 2.2 Hz, 1H), 6.99 (d, J=7.5 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 6.65 (d, J=7.5 Hz, 1H), 6.61 (s, 1H), 4.12 (t, J=6.3 Hz, 2H), 3.93 (t, J=4.9 Hz, 2H), 2.79-2.71 (m, 2H), 2.53 (s, 3H), 2.29 (s, 3H), 2.16 (s, 3H), 2.03-1.93 (m, 2H), 1.76-1.72 (m, 4H), 1.24 (s, 6H). MS (ESI) m/z: 427.3 [M+1].sup.+.

Example 16: Preparation of Compound 16

(41) ##STR00040##

(42) 2.8 g of 1-(4-phenoxy-3-(3-hydroxyl)propyl)phenylethanone and 3.0 g of triethylamine were dissolved in 50 mL of dichloromethane, and 2.3 g of nicotinyl chloride hydrochloride was added under cooling in an ice bath. Then, the ice bath was removed, and the mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was diluted by adding 100 mL of dichloromethane, and washed successively with 50 mL of saturated aqueous sodium carbonate, 50 mL of water and 50 mL of saturated brine. The solvent was evaporated to dryness, and 2.4 g of a benzyl-protected intermediate of the target compound was obtained through silica-gel column chromatography.

(43) The resulted benzyl-protected intermediate in 2.4 g and 3.9 g of ammonium formate were dissolved in 40 mL of methanol, and 0.3 g of a 5% palladium carbon hydrogenation catalyst was added, followed by stirring overnight at room temperature. The solid catalyst was removed by filtration, and the filtrate was evaporated to dryness. Then, the residue was dissolved by adding 100 mL of ethyl acetate, and washed successively with 30 mL of water and 30 mL of saturated brine. The solvent was evaporated to dryness, and 1.5 g of the target compound was obtained through silica-gel column chromatography. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.15 (s, 1H), 8.78-8.68 (m, 1H), 8.33 (dt, J=8.0, 1.8 Hz, 1H), 7.81 (d, J=1.9 Hz, 1H), 7.69 (dd, J=8.4, 2.2 Hz, 1H), 7.44 (dd, J=7.9, 5.0 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 4.44 (t, J=6.2 Hz, 2H), 2.87 (t, J=7.4 Hz, 2H), 2.58-2.47 (m, 3H), 2.22-2.10 (m, 2H). MS (ESI) m/z: 300.3 [M+1].sup.+.

Example 17: Preparation of Compound 17

(44) ##STR00041##

(45) 2.8 g of 2-(4-chlorophenoxyl)-2-methylpropanoic acid was dissolved in 30 mL of dichloromethane, and 2.5 g of oxalyl chloride and 2 drops of N,N-dimethylformamide were added under cooling in an ice bath. Then, the ice bath was removed and the mixture was warmed to room temperature and stirred for 3 hours. The solvent was evaporated to dryness to give corresponding acyl chloride.

(46) 3.0 g of compound JSI000844 was dissolved in 30 mL of pyridine, and the above acyl chloride in 10 mL of dichloromethane solution was added dropwise under cooling in an ice bath. After addition, the ice bath was removed; the mixture was stirred at room temperature for 3 hours. The solvent was concentrated and evaporated to dryness, and the residue was added with 300 mL of ice water and extracted three times with 200 mL of ethyl acetate. The organic phases were combined and washed successively with 200 mL of water and 200 mL of saturated brine. The solvent was evaporated to dryness, and 2.4 g of intermediate was obtained through silica-gel column chromatography. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.13 (d, J=1.6 Hz, 1H), 8.81 (s, 1H), 8.77 (dd, J=4.8, 1.3 Hz, 1H), 8.24-8.19 (m, 1H), 8.04 (d, J=8.7 Hz, 2H), 7.78 (d, J=8.7 Hz, 2H), 7.44 (dd, J=7.9, 4.9 Hz, 1H), 7.41-7.37 (m, 1H), 7.31-7.25 (m, 3H), 6.99-6.88 (m, 2H), 4.94 (d, J=4.1 Hz, 2H), 1.58 (s, 6H). MS (ESI) m/z: 452.0 [M+1].sup.+.

Example 18: Preparation of Compound 18

(47) ##STR00042##

(48) 11.3 g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid was dissolved in 100 mL of dichloromethane, and 8.6 g of oxalyl chloride and 5 drops of N,N-dimethylformamide were added under cooling in an ice bath. Then, the ice bath was removed and the mixture was warmed to room temperature and stirred for 3 hours. The solvent was evaporated to dryness to give corresponding acyl chloride.

(49) 4.5 g of 1-(4-amino-3-hydroxyphenyl)ethanone was dissolved in 50 mL of pyridine, and the resulted acyl chloride in 30 mL of dichloromethane was added dropwise under cooling in an ice bath. After addition, the ice bath was removed and the mixture was warmed to room temperature and stirred for 2 hours. The solvent was concentrated and evaporated to dryness, and the residue was added with 200 mL of ice water and extracted three times with 200 mL of ethyl acetate. The organic phases were combined and washed successively with 200 mL of 1N hydrochloric acid, 200 mL of water and 200 mL of saturated brine. The solvent was evaporated to dryness to give a diacylated intermediate.

(50) The above intermediate was dissolved in 50 mL of methanol, and added with 15 mL of 4N aqueous sodium hydroxide solution. The resulted mixture was stirred at room temperature for 30 min, followed by pressure distillation to remove methanol. Then, the mixture was diluted by adding 50 mL of water, adjusted to pH 4-5 with 3N hydrochloric acid, and extracted with 300 mL of ethyl acetate. The organic phase was washed successively with 100 mL of water and 100 mL of saturated brine. The solvent was evaporated to dryness, and 8.3 g of the target compound was obtained through silica-gel column chromatography. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.44 (s, 1H), 8.58 (s, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.48 (dd, J=8.4, 1.9 Hz, 1H), 7.43 (d, J=1.9 Hz, 1H), 6.97 (d, J=7.5 Hz, 1H), 6.68 (s, 1H), 6.61 (d, J=7.4 Hz, 1H), 3.91 (t, J=5.8 Hz, 2H), 2.50 (s, 3H), 2.22 (s, 3H), 2.07 (s, 3H), 1.82-1.63 (m, 4H), 1.27 (s, 6H). MS (ESI) m/z: 406.0 [M+23].sup.+.

Example 19: Preparation of Compound 19

(51) ##STR00043##

(52) 9.7 g of 2-(4-chlorophenoxy)-2-methylpropanoic acid was dissolved in 100 mL of dichloromethane, and 8.6 g of oxalyl chloride and 5 drops of N,N-dimethylformamide were added under cooling in an ice bath. Then, the ice bath was removed and the mixture was warmed to room temperature and stirred for 3 hours. The solvent was evaporated to dryness to give corresponding acyl chloride.

(53) 4.5 g of 1-(4-amino-3-hydroxyphenyl)ethanone was dissolved in 50 mL of pyridine, and the above resulted acyl chloride in 30 mL of dichloromethane was added dropwise under cooling in an ice bath. Then, the ice bath was removed and the mixture was warmed to room temperature and stirred for 2 hours. The solvent was concentrated and evaporated to dryness, and the residue was added with 200 mL of ice water and extracted three times with 200 mL of ethyl acetate. The organic phases were combined and washed successively with 200 mL of 1N hydrochloric acid, 200 mL of water and 200 mL of saturated brine. The solvent was evaporated to dryness to give a diacylated intermediate.

(54) The above intermediate was dissolved in 50 mL of methanol, and added with 15 mL of 4N aqueous sodium hydroxide solution. The resulted mixture was stirred at room temperature for 30 min, followed by pressure distillation to remove methanol. Then, the mixture was diluted by adding 50 mL of water, adjusted to pH 4-5 with 3N hydrochloric acid, and extracted with 300 mL of ethyl acetate. The organic phase was washed successively with 100 mL of water and 100 mL of saturated brine. The solvent was evaporated to dryness, and the residual solid was homogenized with 50 mL of methanol. The solid was collected by filtration and dried to give 8.2 g of the target compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.61 (s, 1H), 9.35 (s, 1H), 8.27 (d, J=8.4 Hz, 1H), 7.53 (dd, J=8.4, 1.9 Hz, 1H), 7.43 (d, J=1.9 Hz, 1H), 7.39 (d, J=8.9 Hz, 2H), 7.06 (d, J=8.9 Hz, 2H), 1.52 (s, 6H). MS (ESI) m/z: 348.0 [M+1].sup.+.

Example 20: Preparation of Compound 20

(55) ##STR00044##

(56) 2.8 g of 1-(4-amino-3-hydroxyphenyl)ethanone was dissolved in 50 mL of pyridine, and 4.9 g of nicotinyl chloride hydrochloride was added under cooling in an ice bath. Then, the ice bath was removed and the reaction mixture was warmed to room temperature and stirred for 2 hours. The solvent was concentrated and evaporated to dryness, and the residue was added with 100 mL of ice water. The solid was collected by filtration and dried to give a diacylated intermediate.

(57) The above intermediate was dissolved in 50 mL of methanol, and added with 10 mL of 4N aqueous sodium hydroxide solution. The resulted mixture was stirred at room temperature for 2 hours, followed by pressure distillation to remove methanol. Then, the mixture was diluted by adding 50 mL of water, adjusted to pH 3-4 with 3N hydrochloric acid, and adjusted back to pH 7-8 with saturated sodium bicarbonate solution. The solid was collected by filtration and dried to give 3.7 g of the target compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.30 (s, 1H), 9.84 (s, 1H), 9.12 (d, J=1.8 Hz, 1H), 8.77 (dd, J=4.8, 1.5 Hz, 1H), 8.36-8.20 (m, 1H), 7.98 (d, J=8.3 Hz, 1H), 7.60-7.55 (m, 1H), 7.52 (dd, J=8.3, 1.9 Hz, 1H), 7.48 (d, J=1.9 Hz, 1H), 2.54 (s, 3H). MS (ESI) m/z: 257.0 [M+1].sup.+.

Example 21: Preparation of Compound 21

(58) ##STR00045##

(59) 15 g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid was dissolved in 150 mL of dichloromethane, and 11.4 g of oxalyl chloride and 2 drops of N,N-dimethylformamide were added under cooling in an ice bath. Then, the ice bath was removed and the mixture was warmed to room temperature and stirred for 3 hours. The solvent was evaporated to dryness to give corresponding acyl chloride.

(60) 10 g of 2-amino-1-(3,4-dihydroxyphenyl)ethyl ketone was dissolved in 100 mL of pyridine, and the above acyl chloride in 50 mL of dichloromethane solution was added dropwise under cooling in an ice bath. After the addition, the ice bath was removed and the mixture was stirred at room temperature for 2 hours. The solvent was concentrated and evaporated to dryness, and the residue was diluted by adding 300 mL of ethyl acetate, and washed successively with 100 mL of 3N hydrochloric acid, 100 mL of water and 100 mL of saturated brine. The solvent was evaporated to dryness, and 7.2 g of the target compound was obtained through silica-gel column chromatography. .sup.1H NMR (400 MHz, CD.sub.3OD) 7.46-7.37 (m, 2H), 6.92 (d, J=7.4 Hz, 1H), 6.83 (d, J=8.1 Hz, 1H), 6.65 (s, 1H), 6.59 (d, J=7.3 Hz, 1H), 4.55 (s, 2H), 3.92 (t, J=5.6 Hz, 2H), 2.25 (s, 3H), 2.12 (s, 3H), 1.82-1.67 (m, 4H), 1.26 (s, 6H). MS (ESI) m/z: 422.0 [M+23].sup.+.

Example 22: Preparation of Compound 22

(61) ##STR00046##

(62) 5.4 g of Compound 21 and 2.7 g of triethylamine were dissolved in 200 mL of dichloromethane, and 2.9 g of nicotinyl chloride was added under cooling in an ice bath. Then, the ice bath was removed and the mixture was stirred overnight at room temperature. The reaction mixture was diluted by adding 100 mL of dichloromethane, and washed successively with 100 mL of water and 100 mL of saturated brine. The solvent was evaporated to dryness, and 3.5 g of the target compound was obtained through silica-gel column chromatography. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.34 (d, J=1.2 Hz, 1H), 8.78-8.72 (m, 1H), 8.39-8.33 (m, 1H), 7.78 (d, J=2.0 Hz, 1H), 7.64 (dd, J=8.6, 2.0 Hz, 1H), 7.41 (dd, J=7.7, 5.0 Hz, 1H), 7.11 (d, J=8.5 Hz, 1H), 6.96 (d, J=7.5 Hz, 1H), 6.89 (s, 1H), 6.62 (d, J=7.6 Hz, 1H), 6.58 (s, 1H), 4.60 (d, J=4.1 Hz, 3H), 3.89 (s, 3H), 2.27 (s, 3H), 2.14 (s, 3H), 1.74 (s, 4H), 1.27 (s, 6H). MS (ESI) m/z: 505.0 [M+1]+.

(63) Pharmacological and Biological Activity Tests

(64) 1. Therapeutic Effect on Fatty Liver Diseases of SD Rats

(65) Preparation Process of Lipid Emulsion:

(66) 500 g of lard oil was taken, placed in a container, and heated to melt. When the temperature rose to 100 C., it was added with 200 g of cholesterol to dissolve completely, and then further added with 20 g of propylthiouracil. The resulted mixture was stirred well, and added with 500 ml of Tween 80 after dissolution, resulting in an oil phase. At the same time, 600 mL of distilled water and 400 mL of 1,2-propanediol were taken and heated to 60 C. in a water bath, then were added with 40 g of sodium deoxycholate. The resulted mixture was stirred well until realizing complete dissolution, so as to give an aqueous phase. The aqueous phase was added into the oil phase and mixed well to give a lipid emulsion. The lipid emulsion was heated in a water bath of 37 C. before intragastric administration to animals.

(67) Pharmaceuticals:

(68) An appropriate amount of pharmaceutical was weighed, added with 0.5% CMC-Na, and mixed homogeneously by grinding. There are groups for Compound 01 (80 mg/kg), Compound 02 (80 mg/kg), Compound 03 (80 mg/kg), Compound 04 (80 mg/kg), Compound 05 (80 mg/kg), Compound 06 (80 mg)/kg), Compound 07 (80 mg/kg), Compound 08 (80 mg/kg), Compound 09 (80 mg/kg), Compound 10 (80 mg/kg), Compound 11 (80 mg/kg), Compound 12 (80 mg/kg), Compound 13 (80 mg/kg), Compound 14 (80 mg/kg), Compound 15 (80 mg/kg), Compound 16 (80 mg/kg), Compound 17 (80 mg/kg), Compound 18 (80 mg/kg), Compound 19 (80 mg/kg), Compound 20 (80 mg/kg), Compound 21 (80 mg/kg), and Compound 22 (80 mg/kg).

(69) Experimental Animals:

(70) Male SD rats weighing 180-200 g were fed adaptively for 7 days. Based on body weight, 10 animals were used as control and the remaining animals were intragastrically administered with the lipid emulsion every day, 1 ml/100 g body weight for 14 days. After fasting for 12 hours, 1 mL of blood was collected from the orbits of the animals, and was determined by Hitachi Automatic Biochemical Analyzer 7080 for serum cholesterol (CHO), triglyceride (TG), low density lipoprotein (LDL-C) and high density lipoprotein (HDL-C).

(71) According to TC values, the animals, which were administrated with the lipid emulsion, were divided into Model group, Simvastatin group (Sim, 10 mg/kg), Obeticholic Acid group (10 mg/kg) and Compound 0122 groups (80 mg/kg). The modeled rats were continued with the intragastric administration of the lipid emulsion. At the same time, the pharmaceutical-administered groups were administrated with a corresponding dose of pharmaceuticals, while the Model group was administrated with an equal volume of solvent. The pharmaceutical-administered groups were administrated with the lipid emulsion in the morning, and with the pharmaceuticals in the afternoon. The animals were measured for the body weight once a week, and were observed. After 14 days of continuous administration, 1 mL of blood was collected from the orbits, and was determined for the contents of triglyceride, cholesterol, low density lipoprotein and high density lipoprotein in blood serum. It was shown by the experimental results that the blood lipid levels of the pharmaceutical-administered groups had no obvious change, and Obeticholic Acid had no blood lipid-reducing effect. The experimental results are shown in Table 1. The functions of liver and kidney were tested after 4 weeks and the results are shown in Table 2.

(72) TABLE-US-00001 TABLE 1 Influence of the Compounds on the contents of triglyceride, cholesterol, low density lipoprotein and high density lipoprotein in blood serum. Groups CHO TG HDL-C LDL-C Control 1.65 0.13 0.52 0.17 1.06 0.10 0.43 0.03 Model 4.54 0.27.sup..box-tangle-solidup. 1.01 0.19 1.68 0.09.sup..box-tangle-solidup. 2.78 0.75.sup..box-tangle-solidup. Compound 02 4.29 0.65 0.51 0.19 1.74 0.29 2.18 0.71 80 mg/kg Compound 09 4.56 1.24 0.71 0.16 1.77 0.41 2.47 1.06 80 mg/kg Compound 12 4.03 0.47 0.33 0.05* 1.92 0.11* 2.16 0.05 80 mg/kg Compound 21 4.37 0.62 0.80 0.13 1.99 0.44 2.09 0.68 80 mg/kg Compound 22 4.36 1.08 0.57 0.27 1.47 0.51 2.87 1.25 80 mg/kg Obeticholic 4.74 0.34 0.52 0.06 1.68 0.22 2.85 1.00* Acid 10 mg/kg Note: .sup..box-tangle-solidup.p < 0.05, .sup..box-tangle-solidup..box-tangle-solidup. p < 0.01 vs Control; *p < 0.05, ** p < 0.01 vs Model.

(73) TABLE-US-00002 TABLE 2 Liver functions of rats after administration for 4 weeks Groups AST ALT ALP TBIL Control 134.67 50.56 48.67 2.08 896.00 75.48 1.33 0.35 Model 263.67 137.59.sup..box-tangle-solidup. 152.00 137.07.sup..box-tangle-solidup. 1170.33 227.29.sup..box-tangle-solidup. 4.67 0.21.sup..box-tangle-solidup..box-tangle-solidup. Compound 02 187.00 36.44* 62.52 13.24* 1001.52 273.34 1.98 0.81** 80 mg/kg Compound 09 172.08 21.93* 77.52 8.13* 996.33 275.12 2.73 1.11* 80 mg/kg Compound 12 137.75 31.74* 54.00 5.72** 994.50 150.68* 3.25 2.11 80 mg/kg Compound 21 184.40 18.68 65.6 27.20* 1074.00 181.32 3.23 1.35 80 mg/kg Compound 22 180.60 27.19 58.00 2.55* 874.33 251.66 2.97 1.53* 80 mg/kg Obeticholic Acid 248.20 156.61 136.40 62.68 999.60 354.29 4.06 1.40 10 mg/kg Note: .sup..box-tangle-solidup.p < 0.05, .sup..box-tangle-solidup..box-tangle-solidup.p < 0.01 vs Control; *p < 0.05, **p < 0.01 vs Model.

(74) Experimental Results:

(75) The results of pathological sections after pharmaceutical treatment of fatty liver of the SD rats are shown in Table 3. In Table 3, the pathological results were scored, and the lesion degrees were expressed as follows: 0-: 0-25% of hepatocytes undergoing steatosis; +: 25-45% of hepatocytes undergoing steatosis; ++: 45-65% of hepatocytes undergoing steatosis; +++: 65-85% or more of hepatocytes undergoing steatosis; ++++: a large amount of macrovesicular changes; 0-: no or suspicious infiltration of inflammatory cells; +++: a small amount of infiltration of inflammatory cells; +++++: moderate infiltration of inflammatory cells; ++++: severe infiltration of inflammatory cells.

(76) TABLE-US-00003 TABLE 3 Therapeutic effect of tested compounds on fatty liver of rats and pathological grading Pathological grading Steatotic hepatocytes Infiltration of inflammatory cells Groups 1 2 3 4 5 1 2 3 4 5 Control 0 0 0 0 0 0 0 0 Model +++ ++++ +++ ++++ ++++ ++ +++ ++ +++ +++ Sim ++ ++ +++ ++ ++ ++ ++ ++ ++ ++ OCA ++ ++ ++ +++ ++ ++ ++ + ++ ++ Compound 01 ++ ++ ++ ++ ++ + + + + + Compound 02 + + ++ + ++ + + + + Compound 03 ++ + +++ ++ ++ + + ++ + + Compound 04 ++ ++ ++ +++ ++ + + ++ ++ + Compound 05 + +++ ++ ++ + + ++ ++ + + Compound 06 + ++ ++ + ++ + ++ + + ++ Compound 07 ++ ++ ++ ++ + ++ ++ + + ++ Compound 08 ++ ++ + ++ + + + + + + Compound 09 + + + + + 0 + + 0 + Compound 10 ++ ++ + ++ ++ + ++ + + + Compound 11 + ++ ++ ++ + + + + + + Compound 12 0 0 0 0 0 0 Compound 13 + ++ + ++ ++ ++ + + + + Compound 14 + + + + + 0 + + Compound 15 ++ +++ ++ ++ ++ + ++ + + ++ Compound 16 + ++ +++ ++ + + + ++ ++ + Compound 17 + ++ ++ ++ ++ + + + + ++ Compound 18 + + ++ ++ ++ + ++ + + + Compound 19 ++ ++ ++ +++ + + + ++ + + Compound 20 ++ +++ ++ ++ ++ ++ + + + + Compound 21 + 0 + + + + + + 0 + Compound 22 + + ++ + + + + + + +

(77) Simple fatty liver has the following characteristics: more than 30% of hepatocytes in a low-power field have steatosis, but there are no other obvious histological changes, that is, no inflammation, necrosis and fibrosis. The one having, in the visual field, 30% to 50% of hepatocytes with steatosis has low-grade fatty liver; 50% to 75% of hepatocytes with steatosis would be mid-grade fatty liver; more than 75% of hepatocytes with steatosis would be severe fatty liver. The one having, in a low-power field, <30% of hepatocytes with steatosis is called fatty change of liver.

(78) The results in Table 3 show that the compounds can significantly reduce hepatic steatosis and the infiltration of inflammatory cells. Thus, it is demonstrated that Compounds 1-22 have significant therapeutic effect on fatty liver.

(79) 2. Experiments of Weight Loss

(80) 2.1 Therapeutic Effect on Nutritive Obesity C57 Mice

(81) Animals:

(82) C57 mice, male, 18-20 g of body weight. The mice were randomly divided into Control group, Model group, Orlistat group, Compound 13 group and Compound 14 group, with 6 mice in each group.

(83) Pharmaceuticals:

(84) appropriate amounts of orlistat, Compound 13 and Compound 14 were weighed respectively, added with 0.5% CMC-Na and grinded to dissolve.

(85) Experimental Process:

(86) The mice in Control group were fed with normal diet, and the other mice were fed with high-fat diet. All of the mice had free access to water. After one week of feeding, the pharmaceuticals were intragastrically administrated. The dose was 40 mg/kg body weight for orlistat, 80 mg/kg for Compounds 13 and 14. The body weight of the mice was weighed every week during the experiment which lasted for 28 days.

(87) The experimental results are shown in Table 4.

(88) TABLE-US-00004 TABLE 4 effect of tested compounds on body weight of mice in the experiment with nutritive obesity C57 mice (x s, n = 6) Experiment Days Control Model Orlistat Compound 13 Compound 14 0 17.83 0.54 18.08 0.64 18.28 0.65 17.20 1.92 17.21 1.57 7 19.20 0.92 20.44 0.62 20.29 0.63 19.97 0.57 19.83 0.71 14 20.84 1.07 23.01 0.54 21.39 0.70 21.04 0.29 20.87 0.75 21 21.62 0.82 25.09 0.61 22.51 0.73 22.14 0.31 21.89 0.77 28 23.73 1.11 26.30 0.71.sup.## 24.47 0.79** 23.25 0.26**.sup..box-tangle-solidup. 22.92 0.88**.sup..box-tangle-solidup. Note: .sup..box-tangle-solidup.p < 0.05, .sup..box-tangle-solidup..box-tangle-solidup. p < 0.01 vs Orlistat; *p < 0.05, **p < 0.01 vs Model, .sup.# p < 0.05, .sup.##p < 0.01 vs Control

(89) As shown by Table 4, Compounds 13 and 14 can significantly decrease the body weight of the mice from Day 14 as compared with Model group, and have better effect than Orlistat.

(90) 2.2 Experiment of the Weight Loss Effect of Tested Compounds on Ob/Ob Mice

(91) Animals:

(92) 36 ob/ob mice, male, 18-20 g of body weight, fed adaptively for one week before use. The mice were randomly divided into Control group, Model group, Orlistat group, Compound 13 group and Compound 14 group, with 6 mice in each group.

(93) Pharmaceuticals:

(94) appropriate amounts of orlistat, Compound 13 and Compound 14 were weighed respectively, added with 0.5% CMC-Na and grinded to dissolve.

(95) Experimental Process:

(96) After feeding for one week, the mice were intragastrically administrated with the pharmaceuticals except the mice of Control group. The dose was 40 mg/kg body weight for orlistat, 80 mg/kg for the other pharmaceuticals. The body weight of the mice was weighed every week during the experiment which lasted for 28 days.

(97) TABLE-US-00005 TABLE 5 Experiment of the weight loss effect of tested compounds on ob/ob mice (x s, n = 6). Experiment Days Control Orlistat Compound 13 Compound 14 0 21.02 1.05 20.53 0.50 20.74 1.10 20.79 0.39 7 27.68 2.11 22.82 1.79 21.43 0.61 21.22 0.38 14 30.95 1.47 23.98 1.85 22.10 0.16 22.18 0.42 21 35.25 1.86 26.86 1.99 24.53 1.76 24.10 0.45 28 38.64 1.55 31.23 2.31* 26.10 1.95**.sup..box-tangle-solidup. 26.17 0.86**.sup..box-tangle-solidup. Note: .sup..box-tangle-solidup.p < 0.05, .sup..box-tangle-solidup..box-tangle-solidup. p < 0.01 vs Orlistat; *p < 0.05, **p < 0.01 vs Control

(98) As shown by Table 5, Compounds 13 and 14 can significantly decrease the body weight of the ob/ob mice as compared with Model group, and have better effect than Orlistat.

(99) 3. Acute Toxicity Test

(100) A single oral-dose method was employed.

(101) Animals:

(102) ICR mice, 18-20 g of body weight, 20 mice in each group, half male and half female.

(103) Experimental Pharmaceuticals:

(104) Compound 01 (5 g/kg), Compound 02 (5 g/kg), Compound 08 (5 g/kg), Compound 09 (5 g/kg), Compound 12 (5 g/kg), Compound 13 (5 g/kg), compound 14 (5 g/kg), compound 18 (5 g/kg), compound 21 (5 g/kg), compound 22 (5 g/kg). The pharmaceuticals were added with 0.5% CMC-Na, ground and mixed well for reserve.

(105) Experimental Process:

(106) After fasting for 16 h, the animals were orally and intragastrically administrated with the tested pharmaceuticals in a single dose respectively. After administration, the mice were fasted for another 3-4 h. The general conditions of the animals were closely observed for 6 h after the administration, and further observed for 14 days.

(107) Experimental Results:

(108) No animal died during the experiment and no abnormal condition was observed.

(109) Acute toxicity: ID505 g/kg.