CN102977085A - 2-aryl-benzo[d]oxazole and 2-aryl-benzo[d]thiazole derivatives, and preparation methods and application thereof - Google Patents

2-aryl-benzo[d]oxazole and 2-aryl-benzo[d]thiazole derivatives, and preparation methods and application thereof Download PDF

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CN102977085A
CN102977085A CN201210414975XA CN201210414975A CN102977085A CN 102977085 A CN102977085 A CN 102977085A CN 201210414975X A CN201210414975X A CN 201210414975XA CN 201210414975 A CN201210414975 A CN 201210414975A CN 102977085 A CN102977085 A CN 102977085A
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fluorine
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CN102977085B (en
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何谷
宋相容
魏于全
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Sichuan University
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Abstract

The invention belongs to the technical field of chemical synthetic drugs and especially relates to a 2-aryl-benzo[d]oxazole derivative and a preparation method and application thereof. The invention provides the novel 2-aryl-benzo[d]oxazole derivative which has a structure as represented by formula I. The 2-aryl-benzo[d]oxazole derivative is prepared on the basis of considerable screening, has substantial capability in increasing HDL-C and provides a new choice for development and application of a drug used for preventing and/or treating atherosclerosis and/or hyperlipidemia.

Description

2-aryl-benzo [d] oxazole, 2-aryl-benzo [d] thiazole derivative and its production and use
Technical field
The invention belongs to the chemical synthetic drug technical field, particularly 2-aryl-benzo [d] oxazole, 2-aryl-benzo [d] thiazole derivative and its production and use.
Background technology
Atherosclerosis and clinical effectiveness thereof, coronary heart disease (CHD), apoplexy etc. cause quite huge burden to developed country health management system arranged.According to statistics, only in the U.S., have approximately 13,000,000 patients to be diagnosed with CHD, the patient who dies from CHD every year surpasses 500,000.In addition, estimate that this spends in the four following/century and continues to spread along with obesity and diabetes are epiphytotics and increase.
For a long time, have realized that in Mammals that the variation that circulation lipoprotein distributes is relevant with the danger of atherosclerosis and CHD.The HMG-CoA reductase enzyme suppresses chaste tree, particularly statins, successfully reduces clinically coronary artery events and is based on minimizing cyclic low-density lipoprotein cholesterol (LDL-C), and it is dangerous that the LDL-C level is directly involved in the atherosclerosis of increase.Recently, epidemiological study shows, high density lipoprotein cholesterol (HDL-C) level and atherosclerosis retrocorrelation, and the conclusion that draws is that low Serum HDL-C level is relevant with the CHD danger of increase.
The Metabolism control of lipoprotein levels is complexity and the dynamic process that involves many factors.A human important Metabolism control is cholesteryl ester transfer protein (CETP), a kind of plasma glycoprotein, its catalysis cholesteryl ester from HDL to the lipoprotein that contains apoB the transfer of (particularly to VLDL) (referring to Hesler, C.B. wait the people, (1987) Purification and characterization of human plasma cholesteryl ester transfer protein, J.Biol.Chem, 262 (5), 2275-2282)).Under physiological condition, be that CETP carries triglyceride level to HDL and the allos exchange (heteroexchange) from HDL transportation cholesteryl ester to apoB lipoprotein from apoB lipoprotein.In human body, CETP works in the transportation of counter-rotating cholesterol, and by its Umklapp process, cholesterol is returned liver from peripheral tissues.
Although by the great therapeutics progress of statins such as lovastatin representative, statins has only been realized about 1/3rd danger reduction in atherosclerosis with in the treatment of the atheromatosis event that occurs subsequently and the prevention.At present, only has seldom pharmacological treatment can be used for advantageously the raising cyclical level of HDL-C.Some statins and some fibrates provide the appropriateness of HDL-C to increase.Being provided for of having good grounds clinically raise HDL-C the nicotinic acid of effective treatment be subject to the puzzlement of patient's compliance issues, part is because side effect such as flush etc.
Summary of the invention
Technical problem to be solved by this invention provide the novel 2-aryl-benzo of a class [d] oxazole derivative, structure is suc as formula shown in the I:
Figure BDA00002311406700021
Wherein, R 1-R 14Independently be hydrogen, fluorine, chlorine, bromine, OH, NO 2, NH 2, CF 3, C1-C8 alkyl, C1-C8 alkoxyl group, cyano group.
Be R as the preferred scheme of the present invention 1-R 14Independently be hydrogen, fluorine, chlorine, bromine, C1-C8 alkyl, cyano group, CF, alkoxyl group.
R further preferably 10-R 14Independently be hydrogen, structure is suc as formula shown in the II:
Figure BDA00002311406700022
R 1-R 9Independently be hydrogen, fluorine, chlorine, bromine, OH, NO 2, NH 2, CF 3, C1-C8 alkyl, C1-C8 alkoxyl group, cyano group.
Further preferably, R 2, R 4Be hydrogen independently, structure is shown in formula III:
Figure BDA00002311406700023
R 1, R 3, R 5-R 9Independently be hydrogen, fluorine, chlorine, bromine, CF 3, C1-C8 alkyl, C1-C8 alkoxyl group, cyano group.
As the preferred scheme of the compound of structure of the present invention shown in formula III be,
R 1Be hydrogen or methyl;
R 3For hydrogen, fluorine, chlorine, bromine ,-CF 3, C1-C8 alkyl, C1-C8 alkoxyl group, cyano group;
R 5-R 9Independently be hydrogen, fluorine, chlorine, bromine, C1-C8 alkyl, C1-C8 alkoxyl group;
R preferably 3For hydrogen, fluorine, chlorine, bromine ,-CF 3, methyl, methyl or cyano group; R 5-R 9Independently be hydrogen, fluorine, chlorine, bromine, methyl or methoxy.
Be R as the preferred scheme of the compound of structure of the present invention shown in formula III 8, R 9Independently be hydrogen, structure is suc as formula shown in the IV:
R 5-R 7Independently be hydrogen, fluorine, chlorine, bromine, C1-C8 alkyl, C1-C8 alkoxyl group;
R preferably 5-R 7Independently be hydrogen, fluorine, chlorine, bromine, methyl or methoxy.
Be R as the preferred scheme of the compound of structure of the present invention shown in formula III 6Be hydrogen, fluorine, chlorine, bromine, methyl, methoxyl group or CF 3R preferably 6Be hydrogen, methoxyl group or methyl.
Be R as structure of the present invention suc as formula the preferred scheme of the compound shown in the IV 6Be hydrogen, structure is suc as formula shown in the V:
Wherein, R 5, R 7Independently be hydrogen, fluorine, chlorine, bromine, methyl or methoxy.
Be R as structure of the present invention suc as formula the preferred scheme of the compound shown in the V 7Be hydrogen, structural formula is suc as formula shown in the VI:
Wherein, R 3Be fluorine, chlorine or bromine, cyano group ,-CF 3Or C1-C8 alkyl; R 5Be hydrogen, fluorine, chlorine, bromine or methyl;
Preferably, R 3For fluorine, chlorine, bromine, cyano group ,-CF 3Or methyl; R 5Be hydrogen or methyl;
More optimizedly, R 3Be cyano group or methyl; R 5Be hydrogen or methyl;
Further preferably, R 3Be methyl; R 5Be hydrogen or methyl;
Optimum is R 3Be methyl; R 5Be methyl.
Be R as structure of the present invention suc as formula the preferred scheme of the compound shown in the VI 5Be hydrogen, structure is suc as formula shown in the VII:
Figure BDA00002311406700041
R 6, R 7Independently be hydrogen, fluorine, chlorine, bromine, CF 3, methyl or methoxy;
R preferably 6Be hydrogen, R 7Be hydrogen, fluorine, chlorine, bromine, CF 3, methyl or methoxy;
R further preferably 6Be hydrogen, R 7Be bromine, CF 3, methyl or methoxy;
Another is R preferably 6Be methyl or methoxy, R 7Be hydrogen, methyl or methoxy;
R further preferably 6Be methyl or methoxy, R 7Be methoxyl group.
Be R as the preferred scheme of the compound of structure of the present invention shown in formula III 3Be cyano group; R 6, R 8, R 9Be hydrogen independently, structure is shown in VII:
Figure BDA00002311406700042
R 5, R 7Independently be H, fluorine, chlorine, bromine or methyl;
R preferably 5Be H, fluorine, chlorine, bromine or methyl, R7 is hydrogen;
R further preferably 5Be fluorine, chlorine, bromine or methyl; R7 is hydrogen;
More optimizedly R 5Be methyl, R 7Be hydrogen.
As the preferred scheme of the compounds of this invention be,
Figure BDA00002311406700051
Figure BDA00002311406700061
The present invention also provides above-mentioned 2-aryl-benzo, and [d] oxazole and organic salt thereof or inorganic salt prevent and/or treat purposes in the atherosclerosis medicine in preparation; Described purposes is for preventing and/or treating the purposes in the hyperlipidemia in preparation.Further, described purposes is the purposes in preparation raising HDL-C medicine.
The present invention provides also that [d] oxazole derivative or its salt add the pharmaceutical composition that the complementary composition of acceptable pharmaceutically is prepared from by above-mentioned 2-aryl-benzo.This pharmaceutical composition can be used for preparing the medicine that prevents and/or treats atherosclerosis and/or hyperlipidaemia.
Beneficial effect of the present invention is: [d] oxazole, 2-aryl-benzo [d] thiazole derivative are to obtain on the basis of a large amount of screenings to 2-aryl-benzo of the present invention, have obvious CETP and suppress active and regulate the circulation lipid active, for the development and application of the medicine that prevents and/or treats atherosclerosis and/or hyperlipidaemia provides new selection.
Description of drawings
Fig. 1 be the compound of the embodiment of the invention 1 on the impact of HDL-C, can find out among the figure that the compound of embodiment 1 can obviously increase HDL-C.
Fig. 2 be the compound of the embodiment of the invention 1 on the impact of LDL-C, can find out among the figure that the compound of embodiment 1 can obviously reduce LDL-C.
Fig. 3 is the embodiment of the invention 2, and the compound of embodiment 3 and embodiment 4 can find out among the figure the impact of HDL-C,
The compound of embodiment 2, embodiment 3 and embodiment 4 preparations can obviously increase HDL-C.
Embodiment
Technical problem to be solved by this invention provide the novel 2-aryl-benzo of a class [d] oxazole derivative, structure is suc as formula shown in the I:
Figure BDA00002311406700071
Wherein, R 1-R 14Independently be hydrogen, fluorine, chlorine, bromine, OH, NO 2, NH 2, CF 3, C1-C8 alkyl, C1-C8 alkoxyl group, cyano group.
Be R as the preferred scheme of the present invention 1-R 14Independently be hydrogen, fluorine, chlorine, bromine, C1-C8 alkyl, cyano group, CF, alkoxyl group.
R further preferably 10-R 14Independently be hydrogen, structure is suc as formula shown in the II:
Figure BDA00002311406700072
R 1-R 9Independently be hydrogen, fluorine, chlorine, bromine, OH, NO 2, NH 2, CF 3, C1-C8 alkyl, C1-C8 alkoxyl group, cyano group.
Further preferably, R 2, R 4Be hydrogen independently, structure is shown in formula III:
Figure BDA00002311406700081
R 1, R 3, R 5-R 9Independently be hydrogen, fluorine, chlorine, bromine, OH, NO 2, NH 2, CF 3, C1-C8 alkyl, C1-C8 alkoxyl group, cyano group.
In the such scheme, that optimum is R 1Be hydrogen or methyl.
Work as R 1During for methyl, structure is shown below:
Figure BDA00002311406700082
Wherein, R 5-R 9Independently be hydrogen, fluorine, chlorine, bromine, C1-C8 alkyl, C1-C8 alkoxyl group;
R preferably 5-R 9Independently be hydrogen, fluorine, chlorine, bromine, methyl or methoxy.
Further preferably, R 8, R 9Be hydrogen independently, structure is shown below:
Further preferably, R 6Be hydrogen, methyl, methoxyl group, CF 3
Further preferably, R 6Be hydrogen, structure is shown below:
Wherein, R 5, R 7Independently be hydrogen, fluorine, chlorine, bromine, methyl or methoxy.
Further preferably, R 7Be hydrogen, structural formula is shown below:
Figure BDA00002311406700091
Wherein, R 3Be fluorine, chlorine or bromine, R 5Be hydrogen or methyl.
In the scheme shown in the above-mentioned formula III, work as R 1Be hydrogen, structure is shown below:
Figure BDA00002311406700092
Wherein, R 3For fluorine, chlorine, bromine, cyano group ,-CF 3Or C1-C8 alkyl;
R preferably 3For fluorine, chlorine, bromine, cyano group ,-CF 3Or methyl;
More optimizedly R 3Be cyano group or methyl; That optimum is R 3Be methyl.
As following formula preferably, R 5-R 9Independently be hydrogen, fluorine, chlorine, bromine, C1-C8 alkyl, C1-C8 alkoxyl group; R preferably 5-R 9Independently be hydrogen, fluorine, chlorine, bromine, methyl or methoxy.
Further preferably, R 8, R 9Independently be hydrogen, R 3Be methyl, structure is shown below:
Figure BDA00002311406700093
Further preferably, R 6Be hydrogen, fluorine, chlorine, bromine, methyl, methoxyl group, CF 3R preferably 6Be hydrogen, methoxyl group or methyl.
Further preferably, R 6Be hydrogen, structure is shown below:
Figure BDA00002311406700101
Wherein, R 5, R 7Independently be hydrogen, fluorine, chlorine, bromine, methyl or methoxy.
Further preferably, R 7Be hydrogen, structure is shown below:
Figure BDA00002311406700102
Wherein, R 5, fluorine, chlorine, bromine or methyl.R preferably 5Be methyl.
As the preferred scheme of following formula of the present invention, R 5Be hydrogen, structure is shown below:
R 6, R 7Independently be hydrogen, fluorine, chlorine, bromine, CF 3, methyl or methoxy;
R preferably 6Be hydrogen, R 7Be hydrogen, fluorine, chlorine, bromine, CF 3, methyl or methoxy; R further preferably 7Be bromine, CF 3, methyl or methoxy.
R preferably 6Be methyl or methoxy, R 7Be hydrogen, methyl or methoxy; R further preferably 7Be methoxyl group.
As the preferred scheme of formula VII of the present invention, R 6, R 8, R 9Independently be hydrogen, R 3Be cyano group, structure is shown below:
Figure BDA00002311406700104
R 5, R 7Independently be H, fluorine, chlorine, bromine or methyl; R preferably 7Be hydrogen; R further preferably 5Be fluorine, chlorine, bromine or methyl; More optimizedly R 5Be methyl.
2-aryl-benzo of the present invention [preparation method is as follows for d] oxazole derivative:
Figure BDA00002311406700111
The present invention also provides above-mentioned 2-aryl-benzo, and [d] oxazole and organic salt thereof or inorganic salt prevent and/or treat purposes in the atherosclerosis medicine in preparation; Described purposes is for preventing and/or treating the purposes in the hyperlipidemia in preparation.Further, described purposes is the purposes in preparation raising HDL-C medicine.
The present invention also provides above-mentioned 2-aryl-benzo, and [d] oxazole derivative or its salt add the pharmaceutical composition that the complementary composition of acceptable pharmaceutically is prepared from.This pharmaceutical composition can be used for preparing the medicine that prevents and/or treats atherosclerosis and/or hyperlipidaemia.
Below in conjunction with embodiment the present invention is further set forth but be not limitation of the present invention; All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1N-(5-(the preparation of the furans of 5-chloro-7-methyl benzo [d] oxazole-2-)-2-)-2-(O-o-methyl-phenyl-)-ethanamide
Figure BDA00002311406700121
2-amino-4-chloro-6-methylphenol and 2-amino-5-carboxyl furans generation ring-closure reaction obtains the amino 5-of the 2-(furans of 5-chloro-7-methyl benzo [d] oxazole-2-); then ((furans of 5-chloro-7-methyl benzo [d] oxazole-2-)-2-)-2-chloro-acetamide, ((furans of 5-chloro-7-methyl benzo [d] oxazole-2-)-2-)-2-chloro-acetamide and ortho-methyl phenol generation nucleophilic substitution reaction get end product to 5-to N-to 5-to obtain N-with chloro-acetyl chloride generation chlorine acetylation.
The product characteristics that obtain: white powder, M.P.:180-184 ℃
Molecular formula: C 21H 17ClN 2O 4
1H?NMR(400MHz，DMSO-d6)：2.12(s，3H)，2.35(s，3H)，4.81(s，2H)，6.68-6.84(m，3H)，7.02-7.27(m，3H)，7.39(s，1H)，7.67(s，1H)；
ESI-MS：(m/z，％)396.9(M+H) +
Embodiment 2N-(5-(the 5-bromine-7-methyl benzo [preparation of the furans of d] oxazole-2-)-2-)-2-(O-o-methyl-phenyl-)-ethanamide
Figure BDA00002311406700122
2-amino-4-bromo-6-methylphenol and 2-amino-5-carboxyl furans generation ring-closure reaction obtains the amino 5-of the 2-(furans of 5-bromine-7-methyl benzo [d] oxazole-2-); then (([furans of d] oxazole-2-)-2-)-2-chloro-acetamide, (([furans of d] oxazole-2-)-2-)-2-chloro-acetamide and ortho-methyl phenol generation nucleophilic substitution reaction get end product to 5-bromine-7-methyl benzo to 5-to N-to 5-bromine-7-methyl benzo to 5-to obtain N-with chloro-acetyl chloride generation chlorine acetylation.
The product characteristics that obtain: yellow powder, M.P.:175-177 ℃
Molecular formula: C 21H 17BrN 2O 4
1H?NMR(400MHz，DMSO-d6)：2.16(s，3H)，2.32(s，3H)，4.75(s，2H)，6.72-6.97(m，3H)，7.10-7.35(m，3H)，7.44(s，1H)，7.80(s，1H)；
ESI-MS：(m/z，％)440.1(M+H) +442.1(M+2+H) +
The embodiment 3 N-(5-(preparation of the furans of 5-methyl benzo [d] oxazole-2-)-2-)-2-(O-o-methyl-phenyl-)-ethanamide
Figure BDA00002311406700131
2-amino-4-methylphenol and 2-amino-5-carboxyl furans generation ring-closure reaction obtains the amino 5-of the 2-(furans of 5-methyl benzo [d] oxazole-2-); then ((furans of 5-methyl benzo [d] oxazole-2-)-2-)-2-chloro-acetamide, ((furans of 5-methyl benzo [d] oxazole-2-)-2-)-2-chloro-acetamide and ortho-methyl phenol generation nucleophilic substitution reaction get end product to 5-to N-to 5-to obtain N-with chloro-acetyl chloride generation chlorine acetylation.
The product characteristics that obtain: yellow powder, M.P.:155-158 ℃
Molecular formula: C 21H 18N 2O 4
1H?NMR(400MHz，DMSO-d6)：2.08(s，3H)，2.29(s，3H)，4.75(s，2H)，6.55-6.71(m，3H)，7.01-7.87(m，6H)；
ESI-MS：(m/z，％)362.3(M+H) +
Embodiment 4 N-(5-(the 5-cyano group benzo [preparation of the furans of d] oxazole-2-)-2-)-2-(O-o-methyl-phenyl-)-ethanamide
Figure BDA00002311406700132
2-amino-4-cyanophenol and 2-amino-5-carboxyl furans generation ring-closure reaction obtains the amino 5-of the 2-(furans of 5-cyano group benzo [d] oxazole-2-); then (([furans of d] oxazole-2-)-2-)-2-chloro-acetamide, (([furans of d] oxazole-2-)-2-)-2-chloro-acetamide and ortho-methyl phenol generation nucleophilic substitution reaction get end product to 5-cyano group benzo to 5-to N-to 5-cyano group benzo to 5-to obtain N-with chloro-acetyl chloride generation chlorine acetylation.
The product characteristics that obtain: yellow powder, M.P.:166-170 ℃
Molecular formula: C 21H 15N 3O 4
1H?NMR(400MHz，DMSO-d6)：2.08(s，3H)，4.75(s，2H)，6.47-6.69(m，3H)，7.06-7.17(m，2H)，7.46-7.85(m，3H)；
ESI-MS：(m/z，％)373.3(M+H) +
The embodiment 5 N-(5-(preparation of the furans of 5-methyl benzo [d] oxazole-2-)-2-)-2-(O-is to bromophenyl)-ethanamide
Figure BDA00002311406700141
2-amino-4-methylphenol and 2-amino-5-carboxyl furans generation ring-closure reaction obtains the amino 5-of the 2-(furans of 5-methyl benzo [d] oxazole-2-); then ((furans of 5-methyl benzo [d] oxazole-2-)-2-)-2-chloro-acetamide, ((furans of 5-methyl benzo [d] oxazole-2-)-2-)-2-chloro-acetamide and p bromophenol generation nucleophilic substitution reaction get end product to 5-to N-to 5-to obtain N-with chloro-acetyl chloride generation chlorine acetylation.
The product characteristics that obtain: brown color powder, M.P.:197-201 ℃
Molecular formula: C 20H 15BrN 2O 4
1H?NMR(400MHz，DMSO-d6)：2.20(s，3H)，4.76(s，2H)，6.68-6.84(m，4H)，7.02-7.25(m，2H)，7.36-7.69(m，3H)；
ESI-MS：(m/z，％)425.9(M+H) +，428.0(M+2+H) +
The embodiment 6 N-(5-(preparation of the furans of 5-methyl benzo [d] oxazole-2-)-2-)-2-(O-4 '-trifluoromethyl)-ethanamide
Figure BDA00002311406700151
2-amino-4-methylphenol and 2-amino-5-carboxyl furans generation ring-closure reaction obtains the amino 5-of the 2-(furans of 5-methyl benzo [d] oxazole-2-); then ((furans of 5-methyl benzo [d] oxazole-2-)-2-)-2-chloro-acetamide, ((furans of 5-methyl benzo [d] oxazole-2-)-2-)-2-chloro-acetamide and 4-trifloro methyl phenol generation nucleophilic substitution reaction get end product to 5-to N-to 5-to obtain N-with chloro-acetyl chloride generation chlorine acetylation.
The product characteristics that obtain: buff powder, M.P.:159-162 ℃
Molecular formula: C 21H 15F 3N 2O 4
1H?NMR(400MHz，DMSO-d6)：2.27(s，3H)，4.92(s，2H)，6.55-6.82(m，4H)，7.02-7.58(m，5H)；
ESI-MS：(m/z，％)416.3(M+H) +
The embodiment 7 N-(5-(preparation of the furans of 5-methyl benzo [d] oxazole-2-)-2-)-2-(aminomethyl phenyl between O-)-ethanamide
2-amino-4-methylphenol and 2-amino-5-carboxyl furans generation ring-closure reaction obtains the amino 5-of the 2-(furans of 5-methyl benzo [d] oxazole-2-); then ((furans of 5-methyl benzo [d] oxazole-2-)-2-)-2-chloro-acetamide, ((furans of 5-methyl benzo [d] oxazole-2-)-2-)-2-chloro-acetamide and m-methyl phenol generation nucleophilic substitution reaction get end product to 5-to N-to 5-to obtain N-with chloro-acetyl chloride generation chlorine acetylation.
The product characteristics that obtain: buff powder, M.P.:172-174 ℃
Molecular formula: C 21H 18N 2O 4
1H?NMR(400MHz，DMSO-d6)：2.22(s，3H)，2.38(s，3H)，4.90(s，2H)，6.55-6.92(m，4H)，7.12-7.26(m，3H)，7.42(s，1H)，7.63(s，1H)；
ESI-MS：(m/z，％)362.1(M+H) +
The embodiment 8 N-(5-(preparation of the furans of 5-methyl benzo [d] oxazole-2-)-2-)-2-(O-4 '-p-methoxy-phenyl)-ethanamide
Figure BDA00002311406700161
2-amino-4-methylphenol and 2-amino-5-carboxyl furans generation ring-closure reaction obtains the amino 5-of the 2-(furans of 5-methyl benzo [d] oxazole-2-); then ((furans of 5-methyl benzo [d] oxazole-2-)-2-)-2-chloro-acetamide, ((furans of 5-chloro-7-methyl benzo [d] oxazole-2-)-2-)-2-chloro-acetamide and p methoxy phenol generation nucleophilic substitution reaction get end product to 5-to N-to 5-to obtain N-with chloro-acetyl chloride generation chlorine acetylation.
The product characteristics that obtain: white powder, M.P.:152-157 ℃
Molecular formula: C 21H 18N 2O 5
1H?NMR(400MHz，DMSO-d6)：2.32(s，3H)，3.40(s，3H)，4.78(s，2H)，6.68-7.04(m，6H)，7.02-7.47(m，3H)；
ESI-MS：(m/z，％)378.2(M+H) +
The embodiment 9 N-(5-(preparation of the furans of 5-methyl benzo [d] oxazole-2-)-2-)-2-(O-3 ', 4 '-Dimethoxyphenyl)-ethanamide
Figure BDA00002311406700162
2-amino-4-methylphenol and 2-amino-5-carboxyl furans generation ring-closure reaction obtains the amino 5-of the 2-(furans of 5-methyl benzo [d] oxazole-2-); then obtain the N-(5-(furans of 5-methyl benzo [d] oxazole-2-)-2-)-2-chloro-acetamide with chloro-acetyl chloride generation chlorine acetylation; ((furans of 5-methyl benzo [d] oxazole-2-)-2-)-2-chloro-acetamide and 3,4-syringol generation nucleophilic substitution reaction get end product to 5-to N-.
The product characteristics that obtain: buff powder, M.P.:151-155 ℃
Molecular formula: C 22H 20N 2O 5
1H?NMR(400MHz，DMSO-d6)：2.25(s，3H)，3.42(s，3H)，3.46(s，3H)，4.77(s，2H)，6.38-6.84(m，5H)，7.10-7.47(m，3H)；
ESI-MS：(m/z，％)408.2(M+H) +
The embodiment 10 N-(5-(preparation of the furans of 5-methyl benzo [d] oxazole-2-)-2-)-2-(the adjacent fluorophenyl of O-)-ethanamide
Figure BDA00002311406700171
2-amino-4-methylphenol and 2-amino-5-carboxyl furans generation ring-closure reaction obtains the amino 5-of the 2-(furans of 5-methyl benzo [d] oxazole-2-); then ((furans of 5-methyl benzo [d] oxazole-2-)-2-)-2-chloro-acetamide, ((furans of 5-methyl benzo [d] oxazole-2-)-2-)-2-chloro-acetamide and adjacent fluorophenol generation nucleophilic substitution reaction get end product to 5-to N-to 5-to obtain N-with chloro-acetyl chloride generation chlorine acetylation.
The product characteristics that obtain: yellow powder, M.P.:160-172 ℃
Molecular formula: C 20H 15FN 2O 4
1H?NMR(400MHz，DMSO-d6)：2.30(s，3H)，4.77(s，2H)，6.48-6.99(m，6H)，7.35-7.77(m，3H)；
ESI-MS：(m/z，％)365.9(M+H) +
The embodiment 11 N-(5-(preparation of the furans of 5-methyl benzo [d] oxazole-2-)-2-)-2-(O-2 ', 4 '-dichlorophenyl)-ethanamide
2-amino-4-methylphenol and 2-amino-5-carboxyl furans generation ring-closure reaction obtains the amino 5-of the 2-(furans of 5-methyl benzo [d] oxazole-2-); then obtain the N-(5-(furans of 5-methyl benzo [d] oxazole-2-)-2-)-2-chloro-acetamide with chloro-acetyl chloride generation chlorine acetylation; ((furans of 5-methyl benzo [d] oxazole-2-)-2-)-2-chloro-acetamide and 2,4 dichloro phenol generation nucleophilic substitution reaction get end product to 5-to N-.
The product characteristics that obtain: yellow powder, M.P.:173-175 ℃
Molecular formula: C 20H 14Cl 2N 2O 4
1H?NMR(400MHz，DMSO-d6)：2.25(s，3H)，4.75(s，2H)，6.48-6.66(m，3H)，7.04-7.37(m，5H)；
ESI-MS：(m/z，％)415.9(M+H) +
Pharmacodynamic experiment:
Atherosis and the coronary heart disease that diabetes, metabolic syndrome, obesity cause is low take HDL-C, TG is high, LDL is small and dense is feature.Below in the experiment, HDL-C refers to highdensity lipoprotein-cholesterol, and LDL-C refers to LDL-C.
The CETP inhibitor increases the ability of HDL cholesterol (HDL-C), can by method known to persons of ordinary skill in the art, in mammalian object, realize (consulting Evans, the people such as G.F., J.Lipid Research, 35:1634-1645 (1994).For example, the compounds of this invention has been proved the HDL-C of effective rising hamster.Hamster is contained the Oleum Cocois of different ratios and the medium fatty diet of cholesterol by feeding, to change its HDL-C and LDL-C level.Hamster through the medium fat of feeding is also taken a blood sample by fasting, and with establishment of base line HDL-C level, then oral administration continues three days with the compound in the suitable vehicle.Animal is by fasting, and again takes a blood sample when taking medicine second day and the 4th day, and its result is compared with baseline HDL-C and LDL-C level.Compound increases HDL-C in this pattern in dosage dependence mode and reduces simultaneously LDL-C, and this shows that it can be used for changing the blood plasma lipide level.
The result shows, reduces LDL-C (Fig. 2) when embodiment 1 can obviously increase HDL-C (Fig. 1), compares with the control group Simvastatin, and the ability of the rising HDL-C of embodiment 1 has improved 102%; The ability that reduces LDL has improved 15%.Embodiment 2, and the compound of embodiment 3 and embodiment 4 preparations can obviously improve HDL-C.

Claims (14)

1.2-aryl-benzo [d] oxazole derivative, structure is suc as formula shown in the I:
Figure FDA00002311406600011
Wherein, R 1-R 14Independently be hydrogen, fluorine, chlorine, bromine, OH, NO 2, NH 2, CF 3, C1-C8 alkyl, C1-C8 alkoxyl group, cyano group.
2. [d] oxazole derivative is characterized in that: R 2-aryl-benzo according to claim 1 1-R 14Independently be hydrogen, fluorine, chlorine, bromine, C1-C8 alkyl, cyano group, CF, alkoxyl group.
3. [d] oxazole derivative is characterized in that: R 2-aryl-benzo according to claim 2 10-R 14Independently be hydrogen, structure is suc as formula shown in the II:
Figure FDA00002311406600012
R 1-R 9Independently be hydrogen, fluorine, chlorine, bromine, OH, NO 2, NH 2, CF 3, C1-C8 alkyl, C1-C8 alkoxyl group, cyano group.
4. [d] oxazole derivative is characterized in that: R 2-aryl-benzo according to claim 3 2, R 4Be hydrogen independently, structure is shown in formula III:
Figure FDA00002311406600013
R 1, R 3, R 5-R 9Independently be hydrogen, fluorine, chlorine, bromine, CF 3, C1-C8 alkyl, C1-C8 alkoxyl group, cyano group.
2-aryl-benzo according to claim 4 [d] oxazole derivative is characterized in that:
R 1Be hydrogen or methyl;
R 3For hydrogen, fluorine, chlorine, bromine ,-CF 3, C1-C8 alkyl, C1-C8 alkoxyl group, cyano group;
R 5-R 9Independently be hydrogen, fluorine, chlorine, bromine, C1-C8 alkyl, C1-C8 alkoxyl group;
R preferably 3For hydrogen, fluorine, chlorine, bromine ,-CF 3, methyl, methyl or cyano group; R 5-R 9Independently be hydrogen, fluorine, chlorine, bromine, methyl or methoxy.
6. [d] oxazole derivative is characterized in that: R 2-aryl-benzo according to claim 5 8, R 9Independently be hydrogen, structure is suc as formula shown in the IV:
Figure FDA00002311406600021
R 5-R 7Independently be hydrogen, fluorine, chlorine, bromine, C1-C8 alkyl, C1-C8 alkoxyl group;
R preferably 5-R 7Independently be hydrogen, fluorine, chlorine, bromine, methyl or methoxy.
7. [d] oxazole derivative is characterized in that: R 2-aryl-benzo according to claim 6 6Be hydrogen, fluorine, chlorine, bromine, methyl, methoxyl group or CF 3R preferably 6Be hydrogen, methoxyl group or methyl.
8. [d] oxazole derivative is characterized in that: R 2-aryl-benzo according to claim 8 6Be hydrogen, structure is suc as formula shown in the V:
Figure FDA00002311406600022
Wherein, R 5, R 7Independently be hydrogen, fluorine, chlorine, bromine, methyl or methoxy.
9. [d] oxazole derivative is characterized in that: R 2-aryl-benzo according to claim 8 7Be hydrogen, structural formula is suc as formula shown in the VI:
Figure FDA00002311406600031
Wherein, R 3Be fluorine, chlorine or bromine, cyano group ,-CF 3Or C1-C8 alkyl; R 5Be hydrogen, fluorine, chlorine, bromine or methyl;
Preferably, R 3For fluorine, chlorine, bromine, cyano group ,-CF 3Or methyl; R 5Be hydrogen or methyl;
More optimizedly, R 3Be cyano group or methyl; R 5Be hydrogen or methyl;
Further preferably, R 3Be methyl; R 5Be hydrogen or methyl;
Optimum is R 3Be methyl; R 5Be methyl.
10. [d] oxazole derivative is characterized in that: R 2-aryl-benzo according to claim 5 5Be hydrogen, structure is suc as formula shown in the VII:
Figure FDA00002311406600032
R 6, R 7Independently be hydrogen, fluorine, chlorine, bromine, CF 3, methyl or methoxy;
R preferably 6Be hydrogen, R 7Be hydrogen, fluorine, chlorine, bromine, CF 3, methyl or methoxy;
R further preferably 6Be hydrogen, R 7Be bromine, CF 3, methyl or methoxy;
Another is R preferably 6Be methyl or methoxy, R 7Be hydrogen, methyl or methoxy;
R further preferably 6Be methyl or methoxy, R 7Be methoxyl group.
11. [d] oxazole derivative is characterized in that: R 2-aryl-benzo according to claim 5 3Be cyano group; R 6, R 8, R 9Be hydrogen independently, structure is shown in VIII:
Figure FDA00002311406600033
VIII
R 5, R 7Independently be H, fluorine, chlorine, bromine or methyl;
R preferably 5Be H, fluorine, chlorine, bromine or methyl, R7 is hydrogen;
R further preferably 5Be fluorine, chlorine, bromine or methyl; R7 is hydrogen;
More optimizedly R 5Be methyl, R 7Be hydrogen.
12. 2-aryl-benzo according to claim 5 [d] oxazole derivative is characterized in that: its structural formula is as follows:
Figure FDA00002311406600041
Figure FDA00002311406600051
13. [d] oxazole and organic salt thereof or inorganic salt are preparing in preparation each described 2-aryl-benzo of claim 1-12
Prevent and/or treat the purposes in the atherosclerosis medicine; Further, the purposes in preparation raising HDL-C medicine.
14. pharmaceutical composition is characterized in that: [d] oxazole derivative or its salt add pharmaceutically, and the complementary composition of acceptable is prepared from by each described 2-aryl-benzo of claim 1-12.
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CN115057860B (en) * 2022-05-20 2024-02-09 四川大学华西医院 ERK inhibitor and pharmaceutical application thereof

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