CN107915701B - PPAR alpha/gamma dual agonist and application thereof - Google Patents
PPAR alpha/gamma dual agonist and application thereof Download PDFInfo
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- CN107915701B CN107915701B CN201610884266.6A CN201610884266A CN107915701B CN 107915701 B CN107915701 B CN 107915701B CN 201610884266 A CN201610884266 A CN 201610884266A CN 107915701 B CN107915701 B CN 107915701B
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- carbonyl
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- benzopyran
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- 108010028924 PPAR alpha Proteins 0.000 title claims abstract description 26
- 102000000536 PPAR gamma Human genes 0.000 title claims abstract description 26
- 108010016731 PPAR gamma Proteins 0.000 title claims abstract description 26
- 229940125542 dual agonist Drugs 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 claims abstract description 24
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- 239000001257 hydrogen Substances 0.000 claims description 17
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- 239000000556 agonist Substances 0.000 claims description 14
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/20—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 hydrogenated in the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/12—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 3 and unsubstituted in position 7
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/92—Naphthopyrans; Hydrogenated naphthopyrans
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Abstract
The invention discloses a PPAR α/gamma dual agonist and application thereof, wherein the PPAR α/gamma dual agonist contains an effective amount of derivatives shown in a formula I or a formula II and pharmaceutically acceptable salts thereof, wherein each substituent group is defined as the specification and the specification, experiments prove that the compounds shown in the formula I or the formula II can obviously improve the transcription activity of PPAR α/gamma and the mRNA level of related target genes thereof, have the PPAR α/gamma dual agonist activity, can be used as the effective component of the PPAR α/gamma dual agonist, can be applied to the preparation of medicaments and health-care food for preventing or (and) treating metabolic syndrome, particularly can be applied to the preparation of medicaments and health-care food for preventing or (and) treating glucose metabolism disorder or (and) lipid metabolism disorder diseases, and have wide application prospect.
Description
Technical Field
The invention relates to a PPAR alpha/gamma dual agonist and application thereof, belonging to the technical field of medicines.
Background
Metabolic syndrome is a common disorder characterized by abnormal glucose and lipid metabolism, accompanied by elevated low density lipoprotein and reduced high density lipoprotein cholesterol, and its common disorders are obesity, diabetes, hyperlipidemia and atherosclerosis. Among them, diabetes patients are often complicated with hyperlipidemia, cardiovascular disease, diabetic nephropathy, diabetic neuropathy, etc.
According to the publication of the world health organization, more than 2.2 million people suffer from diabetes in the world at present, wherein, China has become the country with the most diabetes patients all over the world, 9200 million diabetes patients are in total, according to the data of the research report of the New England medical journal published on 3/25/2010, more than 9200 million diabetes patients exist in China at present, and the current morbidity of China is in an ascending period, the growth speed is obviously accelerated, and the current diabetes early-stage patients in China are estimated to be 1.5 million. The continuously expanding population of diabetics has brought enormous economic and medical burden to society. The world health organization indicates that heart disease, stroke, and diabetes alone are expected to cause economic losses of at least 5500 billion dollars in China within the next 10 years if no effective measures are taken to address the development of diabetes.
It can be seen that metabolic syndrome has become a serious disease threatening the health of humans. In the aspect of treatment of metabolic syndrome, the hypoglycemic agent or the lipid-lowering agent used clinically at present has single effect, and has the effects of lowering lipid and lowering blood sugar when the two effects are different, and the novel drug with two effects is expected clinically. Therefore, peroxisome proliferator-activated receptor PPAR α/γ dual agonists have become a hot spot for recent research.
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor transcription factor superfamily that regulate the expression of target genes, and there are 3 subtypes, namely PPAR α, β/, γ. Research has now confirmed that: PPAR plays an important role in lipogenesis and glycolipid metabolism by regulating and controlling related gene expression, and is related to the occurrence and development of various diseases including obesity, diabetes and hyperlipidemia [ Azadeh mater et al, j.med.chem.2009.52, 6835-6850; shen et al, J.Nutr.2006.899-905 ]. Therefore, screening of compounds having PPAR α/γ dual agonist activity is very important for preventing or (and) treating metabolic disorders.
Disclosure of Invention
In view of the above problems and needs in the prior art, the present invention aims to provide a PPAR α/γ dual agonist and its application, which is a new class of drugs for preventing or (and) treating metabolic disorders.
The invention solves the technical problem of providing the derivatives shown as the formula (I) or (II) and pharmaceutically acceptable salts and solvates thereof:
wherein:
R1，R2，R3，R4can independently be hydrogen, C1-C10Alkyl, halogen, C1-C10Alkoxy, nitro, hydroxy, C3-C8Cycloalkyl, halo C1-C10Alkyl radical, C3-C8Alkenyl radical, C2-C8Alkynyl, cyano, amino or substituted amino (substituent C)1-C10Alkyl), adjacent two substituents may also further form a 5-6 membered aromatic or heterocyclic ring;
R5、R6、R7、R8independently is hydrogen or C1-C10An alkyl group;
x may be a single bond or a double bond.
The present invention preferably relates to derivatives of formula (I) or (II) and pharmaceutically acceptable salts, solvates thereof:
R1，R2，R3，R4can independently be hydrogen, C1-C6Alkyl, fluoro, chloro, bromo, C1-C6Alkoxy, nitro, hydroxy, C3-C6Cycloalkyl, halo C1-C6Alkyl radical, C3-C5Alkenyl radical, C2-C5Alkynyl, cyano, amino or substituted amino (substituent C)1-C6Alkyl), or two adjacent substituents constitute a benzene ring.
R5、R6、R7、R8Independently is hydrogen or C1-C6An alkyl group;
x may be a single bond or a double bond.
The invention preferably relates to derivatives of formula (I) or (II) and pharmaceutically acceptable salts, solvates thereof:
R1，R2，R3，R4can independently be hydrogen, C1-C4Alkyl, fluoro, chloro, bromo, C1-C4Alkoxy, nitro, hydroxy, C3-C6Cycloalkyl, halo C1-C4Alkyl radical, C3-C4Alkenyl radical, C3-C4Alkynyl, cyano, amino or substituted amino (substituent C)1-C4Alkyl), or two adjacent substituents constitute a benzene ring.
R5、R6、R7、R8Independently is hydrogen or C1-C4An alkyl group;
x may be a single bond or a double bond.
The invention preferably relates to derivatives of formula (I) or (II) and pharmaceutically acceptable salts, solvates thereof:
R1，R2，R3，R4can independently be hydrogen, C1-C4Alkyl, fluoro, chloro, bromo, C1-C4Alkoxy, nitro, hydroxy, C3-C6Cycloalkyl, halo C1-C4Alkyl radical, C3-C4Alkenyl radical, C3-C4Alkynyl, cyano, amino or substituted amino (substituent C)1-C4Alkyl), or two adjacent substituents constitute a benzene ring.
R5、R6、R7、R8Independently hydrogen or ethyl;
x may be a single bond or a double bond.
The pharmaceutically acceptable salts according to the invention are meant to include salts of the compounds of formula I or formula II and pharmaceutically acceptable bases, such as alkali metal salts, e.g. Na-and K-salts, alkaline earth metal salts, e.g. Ca-and Mg-salts, and ammonium or substituted ammonium salts, e.g. trimethylammonium salts.
The following derivatives shown in formula I and pharmaceutically acceptable salts and solvates thereof are preferred in the invention: :
2-methyl-2- [4- (2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid ethyl ester,
2-methyl-2- [4- (6-fluoro-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid ethyl ester,
2-methyl-2- [4- (6-chloro-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionic acid ethyl ester,
2-methyl-2- [4- (6-bromo-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionic acid ethyl ester,
2-methyl-2- [4- (6-nitro-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionic acid ethyl ester,
2-methyl-2- [4- (6-amino-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionic acid ethyl ester,
2-methyl-2- [4- (6-dimethylamino-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid ethyl ester,
2-methyl-2- [4- (6-methyl-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionic acid ethyl ester,
2-methyl-2- [4- (6-hydroxy-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionic acid ethyl ester,
2-methyl-2- [4- (7-hydroxy-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionic acid ethyl ester,
2-methyl-2- [4- (6-methoxy-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionic acid ethyl ester,
2-methyl-2- [4- (7-methoxy-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionic acid ethyl ester,
2-methyl-2- [4- (8-methoxy-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionic acid ethyl ester,
2-methyl-2- [4- (6, 7-dimethoxy-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionic acid ethyl ester,
2-methyl-2- [4- (7-diethylamino-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionic acid ethyl ester,
2-methyl-2- [4- (6, 8-di-tert-butyl-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionic acid ethyl ester,
2-methyl-2- [4- (3-oxo-3H-naphtho [2,1-b ] pyran-2-carbonyl) phenoxy ] propanoic acid ethyl ester,
2-methyl-2- [4- (2-oxochroman-3-carbonyl) phenoxy ] propanoic acid ethyl ester,
2-methyl-2- [4- (6-methyl-2-oxochroman-3-carbonyl) phenoxy ] propanoic acid ethyl ester,
2-methyl-2- [4- (6, 7-dimethoxy-2-oxochroman-3-carbonyl) phenoxy ] propanoic acid ethyl ester,
2-methyl-2- [4- (2, 3-dihydro-3-oxo-1H-naphtho [2,1-b ] pyran-2-carbonyl) phenoxy ] propanoic acid ethyl ester,
2-methyl-2- [4- (2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionic acid,
2-methyl-2- [4- (6-methyl-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid,
2-methyl-2- [4- (3-oxo-3H-naphtho [2,1-b ] pyran-2-carbonyl) phenoxy ] propanoic acid
The following derivatives represented by formula I and pharmaceutically acceptable salts, solvates thereof are particularly preferred in the present invention:
2-methyl-2- [4- (2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid ethyl ester,
2-methyl-2- [4- (6-fluoro-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid ethyl ester,
2-methyl-2- [4- (6-bromo-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionic acid ethyl ester,
2-methyl-2- [4- (6-nitro-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionic acid ethyl ester,
2-methyl-2- [4- (8-methoxy-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionic acid ethyl ester,
2-methyl-2- [4- (2-oxochroman-3-carbonyl) phenoxy ] propanoic acid ethyl ester,
2-methyl-2- [4- (6-methyl-2-oxochroman-3-carbonyl) phenoxy ] propanoic acid ethyl ester,
2-methyl-2- [4- (6, 7-dimethoxy-2-oxochroman-3-carbonyl) phenoxy ] propanoic acid ethyl ester,
2-methyl-2- [4- (2, 3-dihydro-3-oxo-1H-naphtho [2,1-b ] pyran-2-carbonyl) phenoxy ] propanoic acid ethyl ester,
2-methyl-2- [4- (2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionic acid,
2-methyl-2- [4- (6-methyl-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid,
2-methyl-2- [4- (3-oxo-3H-naphtho [2,1-b ] pyran-2-carbonyl) phenoxy ] propanoic acid
The following derivatives shown in formula II and pharmaceutically acceptable salts and solvates thereof are preferred in the invention:
ethyl 2- { [4- (2-methyl-1-ethoxy-1-oxopropyl-2-yl) oxy ] phenyl } quinoline-3-carboxylate,
2- { [4- (2-methyl-1-ethoxy-1-oxopropyl-2-yl) oxy ] phenyl } quinoline-3-carboxylic acid,
5-methyl-2- { [4- (2-methyl-1-ethoxy-1-oxopropyl-2-yl) oxy ] phenyl } quinoline-3-carboxylic acid ethyl ester
5-methyl-2- { [4- (2-methyl-1-ethoxy-1-oxopropyl-2-yl) oxy ] phenyl } quinoline-3-carboxylic acid
6-methyl-2- { [4- (2-methyl-1-ethoxy-1-oxopropyl-2-yl) oxy ] phenyl } quinoline-3-carboxylic acid ethyl ester
6-methyl-2- { [4- (2-methyl-1-ethoxy-1-oxopropyl-2-yl) oxy ] phenyl } quinoline-3-carboxylic acid
7-methyl-2- { [4- (2-methyl-1-ethoxy-1-oxopropyl-2-yl) oxy ] phenyl } quinoline-3-carboxylic acid ethyl ester
7-methyl-2- { [4- (2-methyl-1-ethoxy-1-oxopropyl-2-yl) oxy ] phenyl } quinoline-3-carboxylic acid
8-methyl-2- { [4- (2-methyl-1-ethoxy-1-oxopropyl-2-yl) oxy ] phenyl } quinoline-3-carboxylic acid ethyl ester
8-methyl-2- { [4- (2-methyl-1-ethoxy-1-oxopropyl-2-yl) oxy ] phenyl } quinoline-3-carboxylic acid
5-methyl-2- { [4- (2-methyl-1-ethoxy-1-oxopropyl-2-yl) oxy ] phenyl } quinoline-3-carboxylic acid methyl ester
6-methyl-2- { [4- (2-methyl-1-ethoxy-1-oxopropyl-2-yl) oxy ] phenyl } quinoline-3-carboxylic acid methyl ester
7-methyl-2- { [4- (2-methyl-1-ethoxy-1-oxopropyl-2-yl) oxy ] phenyl } quinoline-3-carboxylic acid methyl ester
8-methyl-2- { [4- (2-methyl-1-ethoxy-1-oxopropyl-2-yl) oxy ] phenyl } quinoline-3-carboxylic acid methyl ester
5-Ethyl-2- { [4- (2-methyl-1-ethoxy-1-oxopropyl-2-yl) oxy ] phenyl } quinoline-3-carboxylic acid methyl ester
6-Ethyl-2- { [4- (2-methyl-1-ethoxy-1-oxopropyl-2-yl) oxy ] phenyl } quinoline-3-carboxylic acid methyl ester
7-Ethyl-2- { [4- (2-methyl-1-ethoxy-1-oxopropyl-2-yl) oxy ] phenyl } quinoline-3-carboxylic acid methyl ester
8-Ethyl-2- { [4- (2-methyl-1-ethoxy-1-oxopropyl-2-yl) oxy ] phenyl } quinoline-3-carboxylic acid methyl ester
5-Ethyl-2- { [4- (2-methyl-1-ethoxy-1-oxopropyl-2-yl) oxy ] phenyl } quinoline-3-carboxylic acid ethyl ester
6-Ethyl-2- { [4- (2-methyl-1-ethoxy-1-oxopropyl-2-yl) oxy ] phenyl } quinoline-3-carboxylic acid ethyl ester
7-Ethyl-2- { [4- (2-methyl-1-ethoxy-1-oxopropyl-2-yl) oxy ] phenyl } quinoline-3-carboxylic acid ethyl ester
8-Ethyl-2- { [4- (2-methyl-1-ethoxy-1-oxopropyl-2-yl) oxy ] phenyl } quinoline-3-carboxylic acid ethyl ester
Particularly preferred derivatives of formula II of the present invention are the following and pharmaceutically acceptable salts, solvates thereof:
ethyl 2- { [4- (2-methyl-1-ethoxy-1-oxopropyl-2-yl) oxy ] phenyl } quinoline-3-carboxylate,
2- { [4- (2-methyl-1-ethoxy-1-oxopropyl-2-yl) oxy ] phenyl } quinoline-3-carboxylic acid,
2- { [4- (2-methyl-1-ethoxy-1-oxopropyl-2-yl) oxy ] phenyl } quinoline-3-carboxylic acid methyl ester,
7-methyl-2- { [4- (2-methyl-1-ethoxy-1-oxopropyl-2-yl) oxy ] phenyl } quinoline-3-carboxylic acid ethyl ester
5-methyl-2- { [4- (2-methyl-1-ethoxy-1-oxopropyl-2-yl) oxy ] phenyl } quinoline-3-carboxylic acid ethyl ester
The PPAR alpha/gamma dual agonist can be applied to the preparation of medicaments and health-care foods for preventing or (and) treating metabolic syndrome.
Furthermore, the PPAR alpha/gamma dual agonist can be applied to the preparation of medicaments and health-care foods for preventing or (and) treating diseases with abnormal glucose metabolism or (and) abnormal lipid metabolism. The PPAR alpha/gamma dual agonist can be applied to preparing medicaments and health-care food for preventing or (and) treating at least one disease of diabetes, obesity, hyperlipidemia and atherosclerosis.
The agents of the present invention may be administered to a patient by a variety of routes of administration, including, but not limited to, oral, transdermal, intramuscular, subcutaneous, and intravenous injection.
Experiments prove that the compounds of the formula I and the formula II can obviously improve PPAR alpha/gamma transcriptional activity and mRNA level of related target genes, have PPAR alpha/gamma dual-agonist activity, and can be used as effective components of PPAR alpha/gamma dual-agonists. Can be applied to preparing medicaments and health-care food for preventing or (and) treating metabolic syndrome, in particular to preparing medicaments and health-care food for preventing or (and) treating glucose metabolism disorder or (and) lipid metabolism disorder diseases, and has wide application prospect.
The compounds of formula I or formula II may be prepared by the methods given below, by the methods given in the examples, or by analogous methods. Suitable reaction conditions for each reaction step are known to those skilled in the art. The starting materials are either commercially available or can be prepared by methods analogous to those given below, as described in the references cited in the text or in the examples, or by synthetic methods known in the art.
The synthesis of the compounds of general structural formula I of the present invention can be accomplished according to scheme 1.
The starting materials p-hydroxyacetophenone (1) and starting material 2 described above are either commercially available, known or can be synthesized by methods known in the art, both by conventional methods: for example at K2CO3Or Cs2CO3Reaction between 10 ℃ or reflux temperature in a solvent such as acetonitrile or acetone in the presence of a solvent to give intermediate 3. The intermediate 3 can be subjected to condensation reaction with diethyl carbonate to obtain an intermediate 4; finally, the intermediate 4 is subjected to Knoevenagel condensation reaction to obtain a compound 5, and then the compound 5 can be subjected to reduction (such as sodium borohydride) to obtain a compound 6.
The synthesis of the compounds of general structural formula II of the present invention can be accomplished according to scheme 2.
The following tests were performed simultaneously in the present invention to determine the biological activity of the compounds of formula I and II. Specific methods can be found in the following references: de Filippus B, Giancristofaro A, Ammazzalorso A, et al, discovery of gemfibrozil antibodies which are activated PPAR α and enhance the expression of genecPT1A inactivated in the absence of antibodies [ J ]. European Journal of medicinal chemistry 2011,46(10): 5218) 5224.
Instantly transfecting HepG2 cells by using pBIND-PPAR α -LBD or pBIND-PPAR gamma-LBD and GAL4 plasmids (10:1, 200 ng/well) on a 96-well plate by using a transfection reagent lipo2000, replacing the original culture medium with a culture medium containing a drug to be detected at a certain concentration after 6h, detecting after 18h, cleaning by using PBS during detection, adding CCLR cell lysate, incubating at 37 ℃ for 30min, adding a luciferase substrate, measuring the luciferase expression activity value by using a microplate reader, preparing the selected samples into ten concentrations of 0.0004, 0.002, 0.01, 0.05, 0.25, 1.25, 6.25, 12.5, 25 and 50Gradient (. mu.M), repeat the above experiment (in duplicate, replicates). Processing the data to determine the EC for the corresponding compound50。
The activity data is used to demonstrate claims.
The following table shows the EC for some selected compounds of the invention50Measured values (in. mu.M in each case).
Drawings
FIG. 1 shows the agonist activity curves of example 5 at various concentrations of PPAR α.
Figure 2 represents the agonist activity curves of example 5 at different concentrations of PPAR γ.
Figure 3 represents the agonist activity curves of example 19 at different concentrations of PPAR γ.
Figure 4 represents the agonist activity curves of example 28 at different concentrations of PPAR γ.
Detailed Description
The following examples serve to illustrate the invention in more detail, without limiting its scope in any way.
Example 1
a) 2-methyl-2- (4-acetylphenyl) oxopropanoic acid ethyl ester
27.2g (0.2mol) of p-hydroxyacetophenone was added to 250ml of acetonitrile, 83g (0.6mol) of anhydrous potassium carbonate was added under stirring, and after stirring for 15min, 43.0g (0.22mol) of ethyl bromoisobutyrate was further added to conduct a reflux reaction for 4 hours. After the reaction, the reaction mixture was filtered, and the filtrate was concentrated to give a tan oil, and 80ml of a 1mol/L sodium hydroxide solution was added thereto, followed by extraction with methylene chloride (80 ml. times.2). The organic layers were combined, washed with water (50 ml. times.2) and brine (50 ml. times.1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 12.3g of a pale yellow oily liquid in a yield of 49.2%.
b)3- {4- [ (2-methyl-1-ethoxy-1-oxopropyl) -2-oxy ] phenyl } -3-oxopropanoic acid ethyl ester
3.8g (0.096mol) of 60% sodium hydride and 22.7g (0.192mol) of dried diethyl carbonate were dissolved in 100ml of dried tetrahydrofuran, and 12.3g (0.048mol) of ethyl 2-methyl-2- (4-acetylphenyl) oxopropionate mixed with 30ml of dried tetrahydrofuran was slowly added dropwise at 0 ℃. And after dripping, continuously reacting for 4-5 h at room temperature. After the reaction, the reaction solution was concentrated, 50ml of ice water was slowly added, and the pH was adjusted to 2 with concentrated hydrochloric acid. The mixture was extracted twice with ethyl acetate (20 ml), and the organic layers were combined, washed with water, and dried over anhydrous sodium sulfate. And (3) carrying out suction filtration, carrying out reduced pressure concentration to obtain a dark brown oily substance, and carrying out column chromatography (petroleum ether: ethyl acetate: 30-10: 1) to obtain 9.1g of a light yellow oily liquid with the yield of 58.3%.
c) 2-methyl-2- [4- (2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid ethyl ester
2.3g (0.007mol) of 3- {4- [ (2-methyl-1-ethoxy-1-oxopropyl) -2-oxy]Ethyl phenyl } -3-oxopropanoate, 0.94g (0.0077mol) salicylaldehyde were dissolved in 50ml absolute ethanol, 20 drops of piperidine and 10 drops of glacial acetic acid were added, and the reaction was refluxed at 80 ℃ for 1h under nitrogen protection. After the reaction, the reaction product is cooled to room temperature, white solid is separated out, the filtration is carried out, a small amount of absolute ethyl alcohol is used for washing a filter cake, and the filter cake is dried in vacuum at 65 ℃ to obtain 2.0g of white solid with the yield of 74.1%. m.p.122.0-122.8 ℃. ESI-MS of M/z 381.1[ M + H ]]+,403.1[M+Na]+.1H NMR(400MHz,DMSO-d6):8.37(s,1H,chromene-4-H),7.90(d,J＝8.9Hz,2H,phenyl-H),7.84(dd,J＝7.7,1.3Hz,1H,chromene-5-H),7.77-7.68(m,1H,chromene-7-H),7.49(d,J＝8.3Hz,1H,chromene-8-H),7.43(t,J＝7.5Hz,1H,chromene-6-H),6.86(d,J＝8.9Hz,2H,phenyl-H),4.17(q,J＝7.1Hz,2H,OCH2),1.61(s,6H,CH3),1.15(t,J＝7.1Hz,3H,CH3).
Example 2
2-methyl-2- [4- (6-fluoro-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid ethyl ester
0.32g (0.001mol) of 3- {4- [ (2-methyl-1-ethoxy-1-oxopropyl) -2-oxy]Ethyl phenyl } -3-oxopropanoate, 0.15g (0.0011mol) of 5-fluorosalicylaldehyde were dissolved in 10ml of absolute ethanol, 5 drops of piperidine and 1 drop of glacial acetic acid were added, and the reaction was refluxed at 80 ℃ for 1h under nitrogen protection. Cooling to room temperature after the reaction is finished, separating out white solid, filtering, and removing anhydrous ethylThe filter cake was washed with alcohol and dried under vacuum to give 0.2g of a white solid with a yield of 50.2%. m.p.101.4-101.9 ℃. ESI-MS of M/z 399.1[ M + H ]]+,421.1[M+Na]+,437.1[M+K]+.1H NMR(400MHz,DMSO-d6):8.31(s,1H,chromene-4-H),7.91(d,J＝8.9Hz,2H,phenyl-H),7.70(dd,J＝8.4,3.0Hz,1H,chromene-8-H),7.61(td,J＝8.8Hz,8.5Hz,3.0Hz,1H,chromene-7-H),7.56(dd,J＝9.1,4.5Hz,1H,chromene-5-H),6.86(d,J＝8.9Hz,2H,phenyl-H),4.17(q,J＝7.1Hz,2H,OCH2),1.61(s,6H,CH3),1.15(t,J＝7.1Hz,3H,CH3).
Example 3
2-methyl-2- [4- (6-chloro-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid ethyl ester
The preparation method is the same as example 2 with 5-chlorosalicylaldehyde as the raw material to obtain 0.21g of white powdery solid with the yield of 50.6%. m.p.100.6-101.0 ℃. ESI-MS M/z 415.1[ M + H ]]+,437.1[M+Na]+.1H NMR(400MHz,DMSO-d6):8.30(s,1H,chromene-4-H),7.95(d,J＝2.5Hz,1H,chromene-5-H),7.91(d,J＝8.9Hz,2H,phenyl-H),7.76(dd,J＝8.9,2.6Hz,1H,chromene-7-H),7.54(d,J＝8.9Hz,1H,chromene-8-H),6.86(d,J＝8.9Hz,2H,phenyl-H),4.17(q,J＝7.1Hz,2H,OCH2),1.61(s,6H,CH3),1.15(t,J＝7.1Hz,3H,CH3).
Example 4
2-methyl-2- [4- (6-bromo-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid ethyl ester
The preparation method is the same as example 2 with 5-bromosalicylaldehyde as a raw material to obtain 0.12g of white powdery solid with the yield of 26.1%. m.p.113.1-114.2 ℃. ESI-MS of M/z 461.1[ M + H ]]+,483.1[M+Na]+,499.0[M+K]+.1HNMR(400MHz,DMSO-d6):8.29(s,1H,chromene-4-H),8.08(d,J＝2.4Hz,1H,chromene-5-H),7.91(d,J＝8.9Hz,2H,phenyl-H),7.88(dd,J＝8.9,2.4Hz,1H,chromene-7-H),7.47(d,J＝8.9Hz,1H,chromene-8-H),6.86(d,J＝8.9Hz,2H,phenyl-H),4.17(q,J＝7.1Hz,2H,OCH2),1.61(s,6H,CH3),1.15(t,J＝7.1Hz,3H,CH3).
Example 5
2-methyl-2- [4- (6-nitro-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid ethyl ester
The preparation method is the same as example 1 with 5-nitro salicylaldehyde as a raw material to obtain 1.5g of light yellow solid with the yield of 50.4%. m.p.126.0-127.0 ℃. ESI-MS M/z 426.2[ M + H ]]+,448.2[M+Na]+,464.1[M+K]+.1H NMR(400MHz,DMSO-d6):8.82(d,J＝2.7Hz,1H,chromene-4-H),8.51(m,J＝9.1,2.7Hz,2H,chromene-5-H,chromene-7-H),7.95(d,J＝8.9Hz,2H,phenyl-H),7.72(d,J＝9.1Hz,1H,chromene-8-H),6.87(d,J＝8.9Hz,2H,phenyl-H),4.17(q,J＝7.1Hz,2H,OCH2),1.62(s,6H,CH3),1.15(t,J＝7.1Hz,3H,CH3).13C-NMR(100MHz,DMSO-d6)189.77,173.04,160.70,158.10,157.71,144.14,143.60,132.53,129.29,128.88,128.05,125.75,119.24,118.36,117.62,79.62,61.87,49.06,25.50,14.31.
Example 6
2-methyl-2- [4- (6-amino-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid ethyl ester
1.06g (0.0025mol) of 2-methyl-2- [4- (6-nitro-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy]Ethyl propionate (NHD-A5) was dissolved in a solution of 20ml of absolute ethanol, 10ml of water and 10ml of methylene chloride, 0.56g (0.01mol) of reduced iron powder was added thereto, and 5 drops of concentrated hydrochloric acid were added dropwise to the solution to conduct a reaction at room temperature for 1 hour. After the reaction, the iron powder is filtered, and the pH of the filtrate is adjusted to 8 by using 10% sodium hydroxide aqueous solution. The aqueous phase was extracted with dichloromethane, the organic phase was washed with water, saturated brine and dried over anhydrous sodium sulfate. The next day, anhydrous sodium sulfate is filtered, the solvent is evaporated to dryness to obtain a yellow-brown solid, the crude product is recrystallized by using 20ml of anhydrous ethanol to obtain 0.36g of yellow powdery solid, and the yield is 36.4%. m.p.121.0-121.9 ℃. ESI-MS of M/z 396.3[ M + H ]]+,418.2[M+Na]+.1H NMR(400MHz,DMSO-d6):8.18(s,1H,chromene-4-H),7.85(d,J＝8.8Hz,2H,phenyl-H),7.19(d,J＝8.8Hz,1H,chromene-8-H),6.96(dd,J＝8.9,2.6Hz,1H,chromene-7-H),6.85(d,J＝8.7Hz,3H,phenyl-H,chromene-5-H),5.37(s,2H,NH2),4.17(q,J＝7.1Hz,2H,OCH2),1.60(s,6H,CH3),1.15(t,J＝7.1Hz,3H,CH3).
Example 7
2-methyl-2- [4- (6-dimethylamino-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid ethyl ester
The preparation method is the same as example 2 with 5- (N, N-dimethylamino) salicylaldehyde as a raw material to obtain 0.2g of orange red powder, and the yield is 47.3%. m.p.131.8-132.5 ℃. ESI-MS of M/z 424.4[ M + H ]]+,469.2[M+K]+.1H NMR(400MHz,DMSO-d6):8.25(s,1H,chromene-4-H),7.86(d,J＝8.8Hz,2H,phenyl-H),7.35(d,J＝9.1Hz,1H,chromene-8-H),7.18(dd,J＝9.2Hz,3.0Hz,1H,chromene-7-H),7.07(d,J＝3.0Hz,1H,chromene-5-H),6.87(d,J＝8.9Hz,2H,phenyl-H),4.18(q,J＝7.1Hz,2H,OCH2),2.94(s,6H,NCH3),1.62(s,6H,CH3),1.16(t,J＝7.1Hz,3H,CH3).
Example 8
2-methyl-2- [4- (6-methyl-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid ethyl ester
The preparation method is the same as example 1 with 5-methyl salicylaldehyde as a raw material to obtain 2.1g of white solid with the yield of 73.5%. m.p.92.5-93.0 ℃. ESI-MS of M/z 395.1[ M + H ]]+,417.1[M+Na]+.1H NMR(400MHz,DMSO-d6):8.29(s,1H,chromene-4-H),7.88(d,J＝8.8Hz,2H,phenyl-H),7.61(s,1H,chromene-5-H),7.55(d,J＝8.7Hz,1H,chromene-7-H),7.39(d,J＝8.5Hz,1H,chromene-8-H),6.85(d,J＝8.9Hz,2H,phenyl-H),4.17(q,J＝7.1Hz,2H,OCH2),2.39(s,3H,chromene-6-CH3),1.61(s,6H,CH3),1.15(t,J＝7.1Hz,3H,CH3).
Example 9
2-methyl-2- [4- (6-hydroxy-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid ethyl ester
The preparation method is the same as example 2 with 5-hydroxy salicylaldehyde as the raw material to obtain 0.25g of off-white solid with the yield of 63.1%. m.p.197.5-198.5 ℃. ESI-MS: M/z 397.2[ M + H ]]+,419.2[M+Na]+,435.1[M+K]+.1HNMR(400MHz,DMSO-d6):9.85(s,1H,chromene-6-OH),8.27(s,1H,chromene-4-H),7.87(d,J＝8.9Hz,2H,phenyl-H),7.39–7.26(m,1H,chromene-5-H),7.18–7.07(m,2H,chromene-7-H,chromene-8-H),6.86(d,J＝8.9Hz,2H,phenyl-H),4.17(q,J＝7.1Hz,2H,OCH2),1.61(s,6H,CH3),1.15(t,J＝7.1Hz,3H,CH3).
Example 10
2-methyl-2- [4- (7-hydroxy-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid ethyl ester
The preparation method is the same as example 2 with 4-hydroxy salicylaldehyde as the raw material, 0.17g of milk white solid is obtained, and the yield is 42.9%. m.p.136.7-137.5 ℃. ESI-MS: M/z 397.2[ M + H ]]+,419.2[M+Na]+,435.1[M+K]+.1HNMR(400MHz,DMSO-d6):10.91(s,1H,chromene-7-OH),8.27(s,1H,chromene-4-H),7.82(d,J＝8.8Hz,2H,phenyl-H),7.68(d,J＝8.6Hz,1H,chromene-5-H),6.89–6.80(m,3H,phenyl-H,chromene-6-H),6.78(d,J＝2.1Hz,1H,chromene-8-H),4.17(q,J＝7.1Hz,2H,OCH2),1.60(s,6H,CH3),1.15(t,J＝7.1Hz,3H,CH3).
Example 11
2-methyl-2- [4- (6-methoxy-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid ethyl ester
The preparation method is the same as example 2 with 5-methoxysalicylaldehyde as a raw material to obtain 0.37g of yellow-green powder, and the yield is 90.2%. m.p.140.8-141.5 ℃. ESI-MS of M/z 411.1[ M + H ]]+,433.1[M+Na]+.1H NMR(400MHz,DMSO-d6):8.29(s,1H,chromene-4-H),7.88(d,J＝8.9Hz,2H,phenyl-H),7.44(d,J＝9.1Hz,1H,chromene-8-H),7.39(d,J＝3.0Hz,1H,chromene-5-H),7.32(dd,J＝9.1,3.0Hz,1H,chromene-7-H),6.86(d,J＝8.9Hz,2H,phenyl-H),4.17(q,J＝7.1Hz,2H,OCH2),3.82(s,3H,OCH3),1.61(s,6H,CH3),1.15(t,J＝7.1Hz,3H,CH3).
Example 12
2-methyl-2- [4- (7-methoxy-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid ethyl ester
The preparation method is the same as example 2 with 4-methoxysalicylaldehyde as a raw material to obtain 0.15g of white powder, and the yield is 36.5%. m.p.80.7-81.1 ℃. ESI-MS: m/z 411.2[M+H]+,433.2[M+Na]+.1H NMR(400MHz,DMSO-d6):8.32(s,1H,chromene-4-H),7.85(d,J＝8.9Hz,2H,phenyl-H),7.77(d,J＝8.7Hz,1H,chromene-5-H),7.09(d,J＝9.1Hz,1H,chromene-8-H),7.03(dd,J＝8.6Hz,2.4Hz,1H,chromene-6-H),6.85(d,J＝8.9Hz,2H,phenyl-H),4.18(q,J＝7.1Hz,2H,OCH2),3.90(s,3H,OCH3),1.61(s,6H,CH3),1.16(t,J＝7.1Hz,3H,CH3).
Example 13
2-methyl-2- [4- (8-methoxy-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid ethyl ester
The preparation method was the same as in example 2 using 3-methoxysalicylaldehyde as a starting material to give 0.39g of white powder with a yield of 95.0%. m.p.117.8-118.5 ℃. ESI-MS of M/z 411.3[ M + H ]]+,433.3[M+Na]+.1H NMR(400MHz,DMSO-d6):8.34(s,1H,chromene-4-H),7.89(d,J＝8.9Hz,2H,phenyl-H),7.44–7.30(m,3H,chromene-5-H,chromene-6-H,chromene-7-H),6.86(d,J＝8.9Hz,2H,phenyl-H),4.17(q,J＝7.1Hz,2H,OCH2),3.94(s,3H,OCH3),1.61(s,6H,CH3),1.15(t,J＝7.1Hz,3H,CH3).
Example 14
2-methyl-2- [4- (6, 7-dimethoxy-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid ethyl ester
The preparation method was the same as example 1 using 4, 5-dimethoxysalicylaldehyde as a starting material to give 2.4g of yellow powder in 77.8% yield. m.p.165.3-166.2 ℃. ESI-MS of M/z 441.2[ M + H ]]+,463.2[M+Na]+,479.1[M+K]+.1HNMR(400MHz,DMSO-d6):8.27(s,1H,chromene-4-H),7.83(d,J＝8.9Hz,2H,phenyl-H),7.39(s,1H,chromene-8-H),7.17(s,1H,chromene-5-H),6.85(d,J＝8.9Hz,2H,phenyl-H),4.18(q,J＝7.1Hz,2H,OCH2),3.91(s,3H,OCH3),3.81(s,3H,OCH3),1.61(s,6H,CH3),1.15(t,J＝7.1Hz,3H,CH3).IR(KBr):cm-13423.6,2921.4,2851.2,1731.0,1644.3,1602.1,1143.2,961.9,836.9,787.8.
Example 15
2-methyl-2- [4- (7-diethylamino-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionic acid ethyl ester
The preparation method was the same as in example 2 using 4-diethylamino salicylaldehyde as a raw material to obtain 0.42g of yellow powder with a yield of 93.0%. m.p.109.3-110.1 ℃. ESI-MS of M/z 452.2[ M + H ]]+,474.2[M+Na]+.1H NMR(400MHz,DMSO-d6):8.19(s,1H,chromene-4-H),7.75(d,J＝8.8Hz,2H,phenyl-H),7.59(d,J＝9.0Hz,1H,chromene-5-H),6.83(d,J＝8.8Hz,2H,phenyl-H),6.78(dd,J＝9.0,2.4Hz,1Hchromene-6-H),6.59(d,J＝2.2Hz,1H,chromene-8-H),4.18(q,J＝7.1Hz,2H,OCH2),3.48(q,J＝7.0Hz,4H,NCH2),1.60(s,6H,CH3),1.15(td,J＝7.0,4.4Hz,9H,CH3).13C-NMR(100MHz,DMSO-d6)190.58,172.73,159.12,159.03,157.51,152.11,146.68,131.36,131.26,130.60,117.42,116.94,109.66,107.20,96.19,78.93,61.32,44.31,25.06,13.84,12.33.IR(KBr):cm-13430.0,2969.9,2923.0,1721.7,1516.7,1236.8,1181.6,1134.7,920.7,850.4,818.5,785.2.
Example 16
2-methyl-2- [4- (6, 8-di-tert-butyl-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid ethyl ester
The preparation method is the same as example 2 with 3, 5-di-tert-butyl salicylaldehyde as a raw material to obtain 0.32g of white solid with the yield of 65.0%. m.p.99.4-100.4 ℃. ESI-MS M/z 493.4[ M + H ]]+,515.4[M+Na]+.1H NMR(400MHz,DMSO-d6):8.32(s,1H,chromene-4-H),7.90(d,J＝8.9Hz,2H,phenyl-H),7.72(d,J＝2.2Hz,1H,chromene-5-H),7.64(d,J＝2.3Hz,1H,chromene-7-H),6.87(d,J＝8.9Hz,2H,phenyl-H),4.18(q,J＝7.1Hz,2H,OCH2),1.61(s,6H,CH3),1.49(s,9H,CH3),1.33(s,9H,CH3),1.15(t,J＝7.1Hz,3H,CH3).IR(KBr):cm-13431.1,2919.6,2850.6,1722.0,1140.8,779.2,719.2,619.6.
Example 17
2-methyl-2- [4- (3-oxo-3H-naphtho [2,1-b ] pyran-2-carbonyl) phenoxy ] propanoic acid ethyl ester
The preparation method of the 2-hydroxy-1-naphthaldehyde serving as the raw material is the same as that of the example 1 to obtain the product2.1g of a yellow solid, yield 69.7%. m.p.107.6-108.0 ℃. ESI-MS M/z 431.1[ M + H ]]+,453.2[M+Na]+.1H NMR(400MHz,DMSO-d6):9.17(s,1H,benzo[f]chromene-1-H),8.61(d,J＝8.5Hz,1H,benzo[f]chromene-6-H),8.31(d,J＝9.0Hz,1H,benzo[f]chromene-5-H),8.11(d,J＝8.0Hz,1H,benzo[f]chromene-7-H),7.95(d,J＝8.9Hz,2H,phenyl-H),7.75(t,J＝7.1Hz,1H,benzo[f]chromene-10-H),7.66(t,J＝8.0Hz,2H,benzo[f]chromene-8-H,benzo[f]chromene-9-H),6.87(d,J＝8.9Hz,2H,phenyl-H),4.17(q,J＝7.1Hz,2H,OCH2),1.61(s,6H,CH3),1.15(t,J＝7.1Hz,3H,CH3).IR(KBr):cm-13432.7,2919.8,2850.7,1734.7,1656.3,1598.3,1252.5,1178.2,1140.7,873.4,847.7,816.9,786.7,748.8.
Example 18
2-methyl-2- [4- (6, 8-dibromo-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionic acid ethyl ester
The preparation method of 3, 5-dibromo salicylaldehyde serving as a raw material is the same as that of example 1, and 0.3g of off-white solid is obtained, wherein the yield is 71%. m.p.128.3-129.2 ℃. ESI-MS of M/z 539.0[ M + H ]]+,561.0[M+Na]+.1H NMR(400MHz,DMSO):8.28(s,1H,chromene-4-H),8.26(d,J＝2.1Hz,1H,chroman-7-H),8.09(d,J＝2.1Hz,1H,chroman-5-H),7.94(d,J＝8.8Hz,2H,phenyl-H),6.86(d,J＝8.8Hz,2H,phenyl-H),4.17(q,J＝7.1Hz,2H,OCH2),1.61(s,6H,CH3),1.15(t,J＝7.1Hz,3H,CH3).
Example 19
2-methyl-2- [4- (2-oxochroman-3-carbonyl) phenoxy ] propanoic acid ethyl ester
0.38g (0.001mol) of 2-methyl-2- [4- (2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy]Ethyl propionate (example 1) was dissolved in 10mL of dry pyridine solvent, to which 0.038g (0.001mol) of sodium borohydride was added, and stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was poured into 50ml of a 10% diluted aqueous hydrochloric acid solution, and stirred sufficiently for 30 minutes, whereby a yellow solid appeared. After suction filtration, the solid was recrystallized from 10mL of absolute ethanol to give 0.27g of a white powdery solid with a yield of 70.7%. m.p.83.9-84.3 ℃. ESI-MS of M/z 383.3[ M + H ]]+,405.3[M+Na]+.1H NMR(400MHz,Acetone):8.05(d,J＝8.9Hz,2H,phenyl-H),7.35-7.27(m,2H,chroman-6-H,chroman-7-H),7.13(td,J＝7.5,1.0Hz,1H,chroman-5-H),7.07(d,J＝8.1Hz,1H,chroman-8-H),6.91(d,J＝8.9Hz,2H,phenyl-H),5.02(dd,J＝9.7,6.5Hz,1H,chroman-3-H),4.21(q,J＝7.1Hz,2H,OCH2),3.47(dd,J＝16.2,9.7Hz,1H,chroman-4-H),3.30(dd,J＝16.2,6.5Hz,1H,chroman-4-H),1.64(s,6H,CH3),1.19(t,J＝7.1Hz,3H,CH3).
Example 20
2-methyl-2- [4- (6-chloro-2-oxochroman-3-carbonyl) phenoxy ] propanoic acid ethyl ester
With 2-methyl-2- [4- (6-chloro-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy group]Ethyl propionate (example 3) was used as a starting material, and its production was carried out in the same manner as in example 19 to give 0.24g of a yellowish brown powder in a yield of 74%. m.p.108.9-109.8 ℃. ESI-MS: M/z 417.3[ M + H ]]+.1H NMR(400MHz,DMSO):8.01(d,J＝8.9Hz,2H,phenyl-H),7.43(d,J＝2.3Hz,1H,chroman-7-H),7.36(dd,J＝8.7,2.5Hz,1H,chroman-8-H),7.16(d,J＝8.7Hz,1H,chroman-5-H),6.86(d,J＝8.9Hz,2H,phenyl-H),5.14(dd,J＝9.4,6.7Hz,1H,chroman-3-H),4.17(q,J＝7.1Hz,2H,OCH2),3.26(dd,J＝16.4,6.6Hz,2H,chroman-4-H),1.61(s,6H,CH3),1.15(t,J＝7.1Hz,3H,CH3).
Example 21
2-methyl-2- [4- (6-methyl-2-oxochroman-3-carbonyl) phenoxy ] propanoic acid ethyl ester
With 2-methyl-2- [4- (6-methyl-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy group]Ethyl propionate (example 8) was used as the starting material, which was prepared in the same manner as in example 19 to give 0.3g of a pale yellow powder with a yield of 75.7%. m.p.77.5-78.0 ℃. ESI-MS M/z 387.3[ M + H ]]+,419.3[M+Na]+.1H NMR(400MHz,DMSO-d6):8.00(d,J＝8.9Hz,2H,phenyl-H),7.12–7.07(m,2H,chroman-5-H,chroman-7-H),7.00(d,J＝8.1Hz,1H,chroman-8-H),6.85(d,J＝8.9Hz,2H,phenyl-H),5.09(dd,J＝9.3,6.8Hz,1H,chroman-3-H),4.17(q,J＝7.1Hz,2H,OCH2),3.23(ddd,J＝22.9,16.2,9.7Hz,2H,chroman-4-H),2.25(s,3H,chroman-6-CH3),1.61(s,6H,CH3),1.15(t,J＝7.1Hz,3H,CH3).
Example 22
2-methyl-2- [4- (6, 7-dimethoxy-2-oxochroman-3-carbonyl) phenoxy ] propanoic acid ethyl ester
With 2-methyl-2- [4- (6, 7-dimethoxy-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy group]Ethyl propionate (example 14) was used as a starting material and prepared in the same manner as in example 19 to give 0.15g of a deep red solid in a yield of 33.9%. m.p.146.2-146.8 ℃. ESI-MS of M/z 443.3[ M + H ]]+,465.3[M+Na]+.1H NMR(400MHz,DMSO-d6):8.00(d,J＝8.8Hz,2H,phenyl-H),6.90–6.78(m,4H,phenyl-H,chroman-5-H,chroman-8-H),5.07(t,J＝7.8Hz,1H,chroman-3-H),4.18(q,J＝7.1Hz,2H,OCH2),3.76(s,1H,chroman-6-OCH3),3.70(s,1H,chroman-7-OCH3),3.26–3.10(m,2H,chroman-4-H),1.61(s,6H,CH3),1.15(t,J＝7.1Hz,3H,CH3).IR(KBr):cm-13440.2,2993.5,2935.8,2835.0,1744.5,1683.1,1260.4,1225.6,1142.8,908.0,846.2.
Example 23
2-methyl-2- [4- (2, 3-dihydro-3-oxo-1H-naphtho [2,1-b ] pyran-2-carbonyl) phenoxy ] propanoic acid ethyl ester
With 2-methyl-2- [4- (3-oxo-3H-naphtho [2,1-b ]]Pyran-2-carbonyl) phenoxy]Ethyl propionate (example 17) was used as a starting material, which was prepared in the same manner as in example 19 to give 0.26g of a white powder with a yield of 60.2%. m.p.156.1-156.7 ℃. ESI-MS of M/z 433.2[ M + H ]]+,455.2[M+Na]+.1H NMR(400MHz,DMSO-d6):8.05(d,J＝8.8Hz,2H,phenyl-H),8.01–7.90(m,3H,benzo[f]chromene-7-H,benzo[f]chromene-8-H,benzo[f]chromene-9-H),7.58(t,J＝7.5Hz,1H,benzo[f]chromene-6-H),7.50(t,J＝7.4Hz,1H,benzo[f]chromene-5-H),7.35(d,J＝8.9Hz,1H,benzo[f]chromene-10-H),6.87(d,J＝8.8Hz,2H,phenyl-H),5.27(dd,J＝10.0,7.0Hz,1H,benzo[f]chromene-2-H),4.17(q,J＝7.1Hz,2H,OCH2),3.67(ddd,J＝26.7,16.6,8.6Hz,2H,benzo[f]chromene-1-H),1.61(s,6H,CH3),1.14(t,J＝7.1Hz,3H,CH3).IR(KBr):cm-13428.4,2920.2,2850.9,2835.0,1767.3,1637.3,1172.7,1140.0,813.4,749.6.
Example 24
2-methyl-2- [4- (2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid
0.38g (0.001mol) of 2-methyl-2- [4- (2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy]Ethyl propionate (example 1) was dissolved in a mixed solution of 10ml of absolute ethanol and 2ml of 10% sodium hydroxide and reacted at 50 ℃ for 1 hour. After the reaction is finished, cooling to room temperature, adjusting the pH value to 3-4 by using 10% diluted hydrochloric acid, and continuously stirring until solid is separated out. Suction filtration and isopropanol washing of the filter cake gave 0.11g of white powder with a yield of 31.2%. m.p.151.5-152.0 ℃. ESI-MS M/z 353.2[ M + H ]]+,375.2[M+Na]+.1H NMR(400MHz,DMSO-d6):13.31(s,1H,COOH),8.37(s,1H,chromene-4-H),7.91(d,J＝8.7Hz,2H,phenyl-H),7.84(d,J＝7.4Hz,1H,chromene-5-H),7.73(t,J＝7.7Hz,1H,chromene-7-H),7.50(d,J＝8.3Hz,1H,chromene-8-H),7.43(t,J＝7.5Hz,1H,chromene-6-H),6.90(d,J＝8.7Hz,2H,phenyl-H),1.60(s,6H,CH3).
Example 25
2-methyl-2- [4- (6-chloro-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid
With 2-methyl-2- [4- (6-chloro-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy group]Ethyl propionate (example 3) was used as a starting material, and prepared in the same manner as in example 24 to give 0.02g of an off-white solid in a yield of 31.0%. m.p.141.5-142.1 ℃. ESI-MS of M/z 387.2[ M + H ]]+,409.2[M+Na]+.1H NMR(400MHz,DMSO-d6):13.30(s,1H,COOH),8.29(s,1H,chromene-4-H),7.94(d,J＝2.5Hz,1H,chromene-5-H),7.91(d,J＝8.8Hz,2H,phenyl-H),7.76(dd,J＝8.9,2.5Hz,1H,chromene-7-H),7.53(d,J＝8.9Hz,1H,chromene-8-H),6.89(d,J＝8.8Hz,2H,phenyl-H),1.59(s,6H,CH3).
Example 26
2-methyl-2- [4- (6-methyl-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid
With 2-methyl-2- [4- (6-methyl-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy group]Ethyl propionate (example 8) was used as the starting material, which was prepared in the same manner as in example 24,0.15g of off-white solid was obtained with a yield of 41.0%. m.p.145.8-146.9 ℃. ESI-MS of M/z 367.3[ M + H ]]+,389.2[M+Na]+.1H NMR(400MHz,DMSO-d6):13.30(s,1H,COOH),8.29(s,1H,chromene-4-H),7.88(d,J＝8.8Hz,2H,phenyl-H),7.61(s,1H,chromene-5-H),7.54(d,J＝8.5Hz,1H,chromene-7-H),7.39(d,J＝8.5Hz,1H,chromene-8-H),6.87(dd,J＝11.4,8.9Hz,2H,phenyl-H),2.38(s,3H,chromene-6-CH3),1.59(s,6H,CH3).
Example 27
2-methyl-2- [4- (3-oxo-3H-naphtho [2,1-b ] pyran-2-carbonyl) phenoxy ] propanoic acid
With 2-methyl-2- [4- (3-oxo-3H-naphtho [2,1-b ]]Pyran-2-carbonyl) phenoxy]Ethyl propionate (example 17) was used as a starting material, which was prepared in the same manner as in example 24 to give 0.1g of a yellow solid in 24.9% yield. m.p.100.5-101.5 ℃. ESI-MS of M/z 403.4[ M + H ]]+,425.4[M+Na]+.1H NMR(400MHz,DMSO-d6):13.28(s,1H,COOH),9.17(d,J＝3.1Hz,1H,benzo[f]chromene-1-H),8.61(d,J＝8.3Hz,1H,benzo[f]chromene-6-H),8.31(d,J＝9.1Hz,1H,benzo[f]chromene-5-H),8.10(d,J＝8.0Hz,1H,benzo[f]chromene-7-H),7.95(d,J＝8.8Hz,2H,phenyl-H),7.74(t,J＝7.6Hz,1H,benzo[f]chromene-10-H),7.65(t,J＝8.0Hz,2H,benzo[f]chromene-8-H,benzo[f]chromene-9-H),6.94–6.83(m,2H,phenyl-H),1.62(s,6H,CH3).
Example 28
2- { [4- (2-methyl-1-ethoxy-1-oxopropyl-2-yl) oxy ] phenyl } quinoline-3-carboxylic acid ethyl ester
The preparation method is the same as that of example 2 by using o-aminobenzaldehyde as a raw material, and no solid is precipitated finally. Concentrating the liquid, adding mixed solution of ethyl acetate and water, extracting, layering, washing organic layer with water, washing with saturated salt solution, and drying with anhydrous sodium sulfate. And (3) evaporating the solvent to dryness under reduced pressure to obtain an oily substance, and performing column chromatography on the crude product (petroleum ether: ethyl acetate: 20-1: 1) to obtain 0.07g of light purple liquid with the yield of 17.2%. ESI-MS of M/z 408.3[ M + H ]]+.1H NMR(400MHz,DMSO-d6):8.78(s,1H,quinoline-4-H),8.14(d,J＝8.0Hz,1H,quinoline-5-H),8.07(d,J＝8.4Hz,1H,quinoline-8-H),7.89(t,J＝7.6Hz,1H,quinoline-7-H),7.68(t,J＝7.4Hz,1H,quinoline-6-H),7.53(d,J＝8.6Hz,2H,phenyl-H),6.90(d,J＝8.6Hz,2H,phenyl-H),4.25–4.12(m,4H,OCH2),1.59(s,6H,CH3),1.19(t,J＝7.1Hz,3H,CH2CH3),1.07(t,J＝7.1Hz,3H,CH2CH3).
Finally, it must be said here that: the above embodiments are only used for further detailed description of the technical solutions of the present invention, and should not be understood as limiting the scope of the present invention, and the insubstantial modifications and adaptations made by those skilled in the art according to the above descriptions of the present invention are within the scope of the present invention.
Claims (14)
1. A PPAR α/γ dual agonist, characterized by: comprises effective amount of derivative shown in formula (I) and pharmaceutically acceptable salt thereof:
wherein: r1，R2，R3，R4Can independently be hydrogen, C1-C10Alkyl, halogen, C1-C10Alkoxy, nitro, hydroxy, C3-C8Cycloalkyl, halo C1-C10Alkyl radical, C3-C8Alkenyl radical, C2-C8Alkynyl, cyano, amino or C1-C10The alkyl substituted amino or two adjacent substituents form a 5-6 membered aromatic or heterocyclic ring;
R5、R6、R7independently is hydrogen or C1-C10An alkyl group;
x may be a single bond or a double bond.
2. The PPAR dual alpha/gamma agonist of claim 1, wherein:
R1，R2，R3，R4can independently be hydrogen, C1-C6Alkyl, fluoro, chloro, bromo, C1-C6Alkoxy, nitro, hydroxy, C3-C6Cycloalkyl, halo C1-C6Alkyl radical, C3-C5Alkenyl radical, C2-C5Alkynyl, cyano, amino or C1-C6The alkyl-substituted amino group, or two adjacent substituents, form a 5-6 membered aromatic or heterocyclic ring.
3. The PPAR dual α/γ agonist of claim 1 or 2, wherein:
R1，R2，R3，R4can independently be hydrogen, C1-C4Alkyl, fluoro, chloro, bromo, C1-C4Alkoxy, nitro, hydroxy, C3-C6Cycloalkyl, halo C1-C4Alkyl radical, C3-C4Alkenyl radical, C3-C4Alkynyl, cyano, amino or C1-C4The alkyl-substituted amino group, or two adjacent substituents, constitutes a benzene ring.
4. The PPAR dual alpha/gamma agonist of claim 1 or 2, wherein:
R5、R6、R7independently is hydrogen or C1-C4An alkyl group.
5. The PPAR dual alpha/gamma agonist of claim 3, wherein:
R5、R6、R7independently is hydrogen or C1-C4An alkyl group.
6. The PPAR dual alpha/gamma agonist of any one of claims 1-2, 5, wherein:
R5、R6、R7independently hydrogen or ethyl.
7. The PPAR dual alpha/gamma agonist of claim 3, wherein:
R5、R6、R7independently hydrogen or ethyl.
8. The PPAR α/γ dual agonist of claim 4, wherein:
R5、R6、R7independently hydrogen or ethyl.
9. A PPAR α/γ dual agonist as described below selected from:
ethyl 2-methyl-2- [4- (2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionate;
2-methyl-2- [4- (6-fluoro-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid ethyl ester;
ethyl 2-methyl-2- [4- (6-chloro-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionate;
2-methyl-2- [4- (6-bromo-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionic acid ethyl ester;
ethyl 2-methyl-2- [4- (6-nitro-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionate;
ethyl 2-methyl-2- [4- (6-amino-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionate;
ethyl 2-methyl-2- [4- (6-dimethylamino-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionate;
ethyl 2-methyl-2- [4- (6-methyl-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionate;
2-methyl-2- [4- (6-hydroxy-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid ethyl ester;
ethyl 2-methyl-2- [4- (7-hydroxy-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionate;
ethyl 2-methyl-2- [4- (6-methoxy-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionate;
ethyl 2-methyl-2- [4- (7-methoxy-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionate;
ethyl 2-methyl-2- [4- (8-methoxy-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionate;
ethyl 2-methyl-2- [4- (6, 7-dimethoxy-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionate;
ethyl 2-methyl-2- [4- (7-diethylamino-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionate;
ethyl 2-methyl-2- [4- (6, 8-di-tert-butyl-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionate;
ethyl 2-methyl-2- [4- (3-oxo-3H-naphtho [2,1-b ] pyran-2-carbonyl) phenoxy ] propionate;
2-methyl-2- [4- (2-oxochroman-3-carbonyl) phenoxy ] propanoic acid ethyl ester;
ethyl 2-methyl-2- [4- (6-methyl-2-oxochroman-3-carbonyl) phenoxy ] propionate;
ethyl 2-methyl-2- [4- (6, 7-dimethoxy-2-oxochroman-3-carbonyl) phenoxy ] propanoate;
ethyl 2-methyl-2- [4- (2, 3-dihydro-3-oxo-1H-naphtho [2,1-b ] pyran-2-carbonyl) phenoxy ] propionate;
2-methyl-2- [4- (2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid;
2-methyl-2- [4- (6-methyl-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid;
2-methyl-2- [4- (3-oxo-3H-naphtho [2,1-b ] pyran-2-carbonyl) phenoxy ] propanoic acid;
2-methyl-2- [4- (6-chloro-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid;
2-methyl-2- [4- (6-methyl-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propanoic acid;
ethyl 2-methyl-2- [4- (6, 8-dibromo-2-oxo-2H-1-benzopyran-3-carbonyl) phenoxy ] propionate;
2-methyl-2- [4- (6-chloro-2-oxochroman-3-carbonyl) phenoxy ] propionic acid ethyl ester.
10. A pharmaceutical composition comprising the PPAR dual alpha/gamma agonist of any one of claims 1-9 and a pharmaceutically acceptable carrier.
11. A process for the preparation of a PPAR dual alpha/gamma agonist as defined in any one of claims 1 to 9, wherein: the p-hydroxyacetophenone is used as a raw material, firstly has alkylation reaction with alpha-bromo alkyl ester, then has condensation reaction with diethyl carbonate, and finally has Knoevenagel reaction with substituted salicylaldehyde.
12. Use of the PPAR α/γ dual agonist of any one of claims 1-9 or the pharmaceutical composition of claim 10 for the preparation of a medicament or health food for the prevention or/and treatment of metabolic syndrome.
13. Use of the PPAR α/γ dual agonist of any one of claims 1 to 9 or the pharmaceutical composition of claim 10 for the preparation of a medicament or health food for preventing or/and treating a disease of abnormal glucose metabolism or/and abnormal lipid metabolism.
14. Use of the PPAR α/γ dual agonist of any one of claims 1 to 9 or the pharmaceutical composition of claim 10 for the preparation of a medicament or health food for the prevention or/and treatment of at least one disease selected from diabetes, obesity, hyperlipidemia, and atherosclerosis.
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| US4637988A (en) * | 1981-07-01 | 1987-01-20 | Eastman Kodak Company | Fluorescent labels for immunoassay |
| CN1348439A (en) * | 1999-04-20 | 2002-05-08 | 诺沃挪第克公司 | New compounds, their preparation and use |
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| EP0068875A2 (en) * | 1981-07-01 | 1983-01-05 | EASTMAN KODAK COMPANY (a New Jersey corporation) | Fluorescent chelates and labeled specific binding reagents prepared therefrom |
| US4637988A (en) * | 1981-07-01 | 1987-01-20 | Eastman Kodak Company | Fluorescent labels for immunoassay |
| CN1348439A (en) * | 1999-04-20 | 2002-05-08 | 诺沃挪第克公司 | New compounds, their preparation and use |
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