Acetophenone Compound, Preparation Method Therefor, And Application Thereof In Blood Lipid Regulation

Abstract

Disclosed are a compound represented by Formula I or a pharmaceutically acceptable salt thereof, a preparation method therefor, the Formula I, and an application thereof in preparing drugs for regulating blood lipids.

##STR00001##

Claims

1. A compound of Formula I or a pharmaceutically acceptable salt thereof, ##STR00019## wherein, X is selected from oxygen or NH; R.sub.1 is selected from hydroxyl; R.sub.2 is selected from the substituted 5 to 6 membered monocyclic heteroaryl having 1 to 2 heteroatom(s) independently selected from nitrogen and oxygen; or ##STR00020## when X is NH; R.sub.3 is independently selected from monosubstituted phenyl or disubstituted phenyl, wherein the substituent for phenyl is halogen; hydroxyl; C1-C6 alkyl; C1-C6 alkoxy; n is an integer selected from 0 to 3.

2. The compound of Formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R.sub.2 is selected from the substituted groups of: phenyl; 6 membered monocyclic heteroaryl having 1 to 2 heteroatom(s) independently selected from nitrogen; or ##STR00021## R.sub.3 is independently selected from monosubstituted phenyl or disubstituted phenyl, wherein the substituent for phenyl is halogen; hydroxyl; C1-C6 alkyl; C1-C6 alkoxy.

3. The compound of Formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R.sub.2 is selected from the substituted groups of: 6 membered monocyclic heteroaryl having 1 to 2 heteroatom(s) independently selected from nitrogen; or ##STR00022## R.sub.3 is independently selected from monosubstituted phenyl or disubstituted phenyl, wherein the substituent for phenyl is halogen; hydroxyl; C1-C3 alkyl; C1-C3 alkoxy.

4. The compound of Formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R.sub.2 is selected from the substituted groups of: 6 membered monocyclic heteroaryl having 1 to 2 heteroatom(s) independently selected from nitrogen; or ##STR00023## R.sub.3 is independently selected from monosubstituted phenyl or disubstituted phenyl, wherein the substituent for phenyl is halogen; or C1-C3 alkyl, n is an integer selected from 0 to 3.

5. The compound of Formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.2 is pyridin-3-yl.

6. The compound of Formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.3 is 2,5-dimethyl phenyl.

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

8. A compound or a pharmaceutically acceptable salt thereof, comprising any of the compounds having the following structural formulae: ##STR00024##

9. A method for preparing the compound of Formula I or a pharmaceutically acceptable salt thereof ##STR00025## Wherein, X is selected from oxygen or NH; R.sub.1 is selected from hydroxyl; R.sub.2 is selected from the substituted 5 to 6 membered monocyclic neteroaryl having to 2 heteroatom(s) independently selected from nitrogen and oxygen or ##STR00026## when X is NH, R.sub.3 is independently selected from monosubstituted phenyl or disubstituted phenyl, wherein the substitutent for phenyl is halogen; hydroxyl; C1-C6 alkyl; C1-C6 alkoxy; n is an integer selected from 0 to 3, the method comprising: ##STR00027## Method I, comprising a step of directly condensing an acid ##STR00028## and a compound ##STR00029## in the presence of a condensing agent and a solvent; or Method II, comprising a step of condensing an acyl chloride and a compound ##STR00030## in a solvent, wherein the acyl chloride is obtained by a reaction of an acid ##STR00031## with a chlorinating agent.

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

11. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is in a form of tablet, pill, powder, liquid, suspension, emulsion, granule, capsule, suppository or injection.

12. A medicament fo regulating blood lipids comprising the compound of Formula I or a pharmaceutically acceptable salt thereof as defined in claim 1.

13. The compound of Formula I or a pharmaceutically acceptable salt thereof according to claim 2, wherein, R.sub.2 is selected from the substituted groups of: 6 membered monocyclic heteroaryl having 1 to 2 heteroatom(s) independently selected from nitrogen; or ##STR00032## R.sub.3 is independently selected from monosubstituted phenyl or disubstituted phenyl, wherein the substituent for phenyl is halogen; hydroxyl; C1-C3 alkyl; C1-C3 alkoxy.

14. The compound of Formula I or a pharmaceutically acceptable salt thereof according to claim 2, wherein, R.sub.2 is selected from the substituted groups of: 6 membered monocyclic heteroaryl having 1 to 2 heteroatom(s) independently selected from nitrogen; or ##STR00033## R.sub.3 is independently selected from monosubstituted phenyl or disubstituted phenyl, wherein the substituent for phenyl is halogen; or C1-C3 alkyl, n is an integer selected from 0 to 3.

15. The compound of Formula I or a pharmaceutically acceptable salt thereof according to claim 3, wherein, R.sub.2 is selected from the substituted groups of: 6 membered monocyclic heteroaryl having 1 to 2 heteroatom(s) independently selected from nitrogen; or ##STR00034## R.sub.3 is independently selected from monosubstituted phenyl or disubstituted phenyl, wherein the substituent for phenyl is halogen; or C1-C3 alkyl, n is an integer selected from 0 to 3.

16. The compound of Formula I or a pharmaceutically acceptable salt thereof according to claim 2, wherein R.sub.2 is pyridin-3-yl.

17. The compound of Formula I or a pharmaceutically acceptable salt thereof according to claim 3, wherein R.sub.2 is pyridin-3-yl.

18. The compound of Formula I or a pharmaceutically acceptable salt thereof according to claim 4, wherein R.sub.2 is pyridin-3-yl.

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

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

Description

DETAILED DESCRIPTION OF THE EMBODIMENTS

Example 1: Preparation of Compound 01

[0055] ##STR00013##

[0056] 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.

[0057] 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, and 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 to give 5.4 g of the target product by 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 02: Preparation of Compound 02

[0058] ##STR00014##

[0059] 3.5 g of 1-(3-amino-4-hydroxylphenyl)ethanone was dissolved in 100 mL of pyridine. 9.3 g of 5-(2,5-dimethylphenoxy)-2,2-dimethyl valeryl chloride in 20 mL of dichloromethane was added dropwise under cooling in an ice bath, after which 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 of 3N hydrochloric acid, 60 mL of water and 30 mL of saturated brine. The solvent was evaporated to dryness. With ethyl acetate as the solvent, 5.1 g of the target compound was obtained through recrystallization. .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 03: Preparation of Compound 03

[0060] ##STR00015##

[0061] 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. Extraction with 300 mL of dichloromethane was conducted. 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. 3.0 g of the target product was obtained by silica-gel column chromatography. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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 4: Preparation of Compound 04

[0062] ##STR00016##

[0063] 7.1 g of 2-(4-chlorophenoxy)-2-methylpropanoic acid was dissolved in 100 mL of dichloromethane, and 6.3 g of oxalyl chloride and 2 drops of N,N-dimethylformamide was added under cooling in 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.

[0064] 4.05 g of p-aminoacetophenone was dissolved in 50 mL of pyridine. The above acyl chloride in 50 mL of dichloromethane solution was added dropwise under cooling in ice bath, after which the ice bath was removed and the mixture was warmed to room temperature and stirred for 2 hours. Then, the solvent was evaporated to dryness, and the residue was added with 300 mL of water. The solid was collected by filtration, and then was homogenized with 50 ml of mixed solvents of petroleum ether:ethyl acetate in 5:1. The solid was collected by 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 05: Preparation of Compound 05

[0065] ##STR00017##

[0066] 0.46 g of 1-(3,4-dihydroxylphenyl)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, washed successively with 20 mL of water and 20 mL of saturated brine. Then the solvent was evaporated to dryness. The residue was added with 10 mL of saturated sodium carbonate aqueous solution and stirred. The resulted mixture was extracted twice with 30 mL of ethyl acetate. The aqueous phase was separated and adjusted to pH 7-8 by adding 1N hydrochloric acid, and then extracted three times with 30 mL of a mixture 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 dryness to give 0.14 g of the target product. .sup.1H NMIR (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.+.

Pharmacological and Biological Activity Tests

[0067] 1. Therapeutic Effect on Hyperlipidemia of SD Rats

[0068] Preparation process of lipid emulsion: 500 g of lard oil was taken, placed in a container, and heated to melt. When the temperature rose to 100 C., 200 g of cholesterol was added. After complete dissolution, 20 g of propylthiouracil was further added. 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, and then was added with 40 g of sodium deoxycholate. The resulted mixture was stirred well until complete dissolution was achieved, so as to give an aqueous phase. The aqueous phase was added into the oil phase and mixed well to give a lipid emulsion.

[0069] Process for modeling: Animals were fed adaptively for 3 days. Then, according to the body weight, 5 animals were selected as control and the remaining animals were intragastrically administered with the lipid emulsion during 9:00 to 11:00 am every day with 1 mL/100 g body weight for 2 weeks. After fasted 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). The animals having 4-7 mmol/L of CHO were used in the experiments.

[0070] According to the body weight, the animals, which were administrated with the lipid emulsion for 2 weeks, were divided into Model group, Simvastatin group (Sim, 10 mg/kg), Compound 01 group (80 mg/kg), Compound 02 group (80 mg/kg), Compound 03 group (80 mg/kg), Compound 04 group (80 mg/kg), Compound 05 group (80 mg/kg), Compound A group (80 mg/kg), with 5 animals in each group. The animals were continued with the intragastric administration of the lipid emulsion, and at the same time, the pharmaceutical-administered groups were administrated with the corresponding doses of pharmaceuticals, while the Model group was administrated with an equal volume of the solvent. The animals were administrated with the lipid emulsion in the morning and pharmaceuticals in the afternoon. The animals were measured for the body weight every Monday, and were observed. After 21 days of continuous administration, the animals were fasted for 12 hours. Then, 1 mL of blood was collected from the orbits, and was determined by Hitachi Automated Biochemical Analyzer 7080 for serum cholesterol (CHO), triglyceride (TG), low density lipoprotein (LDL-C) and high density lipoprotein (HDL-C).

[0071] The controls used in this experiment comprised Compound A and Simvastatin (also referred to as Sim herein).

[0072] Compound A is disclosed by a Chinese patent with application no. 201110174070.5, and has the following formula.

##STR00018##

[0073] The experimental results were shown by Table 1. The formula for calculating the blood lipid-reducing effect is: (CHO of Model group CHO of pharmaceutical-administrated group)/CHO of Model group*100%. According to this formula, the blood lipid-reducing effect of each compound was obtained and shown in Table 1 with reference to the reduction ratio of cholesterol and the level of triglyceride of each group, wherein the reduction ratio of cholesterol of each group of compound is as follows: Compound 01: (10.664.29)/10.66*100%=59.75%; Compound 02: (10.664.86)/10.66*100%=54.40%; Compound 03: (10.664.56)/10.66*100%=57.22%; Compound 04: (10.664.90)/10.66*100%=54.03%; Compound 05: (10.664.63)/10.66*100%=56.56%; Compound A: (10.666.15)/10.66*100%=42.30%. In this experiment, the effects of the compounds obtained herein for regulating blood lipids can be determined by using the blood cholesterol reduction as the main indicator, with reference to the decrease of triglyceride.

TABLE-US-00001 TABLE 1 the level of blood lipids in rats administrated with samples (X SD) HDL-C LDL-C TG (mmol/L) CHO (mmol/L) (mmol/L) (mmol/L) Compound 01 0.47 0.27** 4.29 0.65** 2.02 0.27 3.07 1.25** (80 mg/kg) Compound 02 0.51 0.19** 4.86 1.08** 1.94 0.49 3.18 0.71** (80 mg/kg) Compound 03 0.71 0.16 4.56 1.24** 1.81 0.27 3.14 1.06** (80 mg/kg) Compound 04 0.50 0.15** 4.90 1.09** 2.00 0.52 3.27 1.34** (80 mg/kg) Compound 05 0.56 0.23** 4.63 0.41** 1.95 0.50 3.12 0.34** (80 mg/kg) Compound A 0.58 0.11** 6.15 2.12* 1.41 0.28 4.97 1.07** (80 mg/kg) Sim (10 mg/kg) 0.60 0.07* 6.28 0.76* 1.65 0.26 4.54 0.36** Model 0.81 0.23 10.66 2.55.sup.## .sup.1.87 0.51.sup.# 8.37 2.16.sup.## Control 0.59 0.15 1.36 0.21 1.20 0.20 0.35 0.04 Note: pharmaceutical-adminstered groups compared with Model group, *P < 0.05, **P < 0.01; .sup.#p < 0.05, .sup.##p < 0.01 vs Control

[0074] As shown by Table 1, all of Compounds 01, 02, 03, 04 and 05 have relatively good blood lipid-reducing effects, and can significantly reduce the level of cholesterol.

[0075] 2. Acute Toxicity Test

[0076] Single oral dose method was used.

[0077] Animal: ICR mice, body weight of 18-20 g, 20 mice in each group, half male and half female. Experimental pharmaceuticals: Compound 01 (5 g/kg), Compound 02 (5 g/kg), Compound 03 (5 g/kg), Compound 04 (5 g/kg), Compound 05 (5 g/kg). The pharmaceuticals were added with 0.5% CMC-Na, ground and mixed well, stored until use.

[0078] Experimental process: After fasted for 16 h, the animals were orally and intragastrically administered with 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.

[0079] Experimental results: No animal died during the experiment and no abnormal condition was observed.

[0080] Acute toxicity: ID505 g/kg.