Tree ketonic acid A structural analogue, composition thereof and application thereof in medicines
阅读说明：本技术 树豆酮酸a结构类似物、其组合物及其在药物中的应用 (Tree ketonic acid A structural analogue, composition thereof and application thereof in medicines ) 是由 汤磊 陈文章 夏晶 樊玲玲 王建塔 于 2016-05-13 设计创作，主要内容包括：本发明是申请号为2016103161377,申请日2016年05月13日,发明名称为“树豆酮酸A结构类似物、其组合物及其在药物中的应用”的分案申请。本发明公开了一类树豆酮酸A结构类似物,如式(II)所示,及其立体异构体,几何异构体,互变异构体,氮氧化物,水合物,溶剂化物,代谢产物,酯,药学上可接受的盐或它的前药：<Image he="391" wi="569" file="DDA0002201213380000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>本发明还公开了包含式(II)所示的树豆酮酸A结构类似物,其立体异构体,水合物或药学上可接受的盐的药物组合物,所述化合物或所述药物组合物主要用于防护、处理、治疗或减轻患者2型糖尿病及其并发症,以及降低血脂、减肥等方面的用途。(The invention is a divisional application with the title of pigeon pea ketonic acid A structural analogue, a composition thereof and application thereof in medicines, wherein the application number is 2016103161377, and the application date is 2016, 05 and 13. The invention discloses a pigeon pea ketonic acid A structural analogue, which is shown as a formula (II), and a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof of the analogue: The invention also discloses a pharmaceutical composition containing the pigeon pea ketonic acid A structural analogue shown in the formula (II), a stereoisomer, a hydrate or a pharmaceutically acceptable salt thereof, and the compound or the pharmaceutical composition is mainly used for preventing, treating and treating or relieving type 2 diabetes mellitus and complications thereof of a patient, and has the purposes of reducing blood fat, losing weight and the like.)
1.A compound having a structure according to formula (II), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof of a structure according to formula (II):
Wherein R is1Is H, hydroxy, amino, or alkoxy, or R1Represents the following structural formula:
R2And R3Each independently H, allyl, isopentyl, or propyl, or R2And R3Each independently represents the following structural formula:
And R is1、R2And R3At least one of them is any one of the structural formulas represented by (a) to (l);
Each R4independently is H, F, Cl, Br, I, hydroxy, alkyl, haloalkyl, alkoxy, R7-S(＝O)2o-, or R7a-S(＝O)2NH-；
R5is hydroxy, alkoxy, or-NR6R6a；
Z is O or NR6；
Each R6And R6aIndependently is H, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl;
Each R7And R7aIndependently is H, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl; and
n is 0, 1, 2, 3 or 4;
Wherein the compound represented by formula (II) is not: 8-hydroxy-6-methoxy-5- (3-methylbut-2-en-1-yl) -3-phenyl-1H-isochroman-1-one, and 6, 8-dimethoxy-5- (3-methylbut-2-en-1-yl) -3-phenyl-1H-isochroman-1-one, 8-isopentenyl-6-methoxy-3-phenylbenzoisoquinolin-1-one, and 8-hydroxy-6-methoxy-5-isopentenyl-3-phenylbenzoisoquinolin-1-one.
2. The compound of claim 1, wherein R1Is H, hydroxy, methoxy or ethoxy, or R1Represents the following structural formula:
3. The compound of claim 1, wherein each R4Independently H, F, Cl, Br, I, hydroxyl, C1-4Alkyl radical, C1-4Haloalkyl, or C1-4An alkoxy group.
4. The compound of claim 1, wherein R5Is hydroxy, methoxy, ethoxy, or propoxy.
5. The compound of claim 1, wherein each R6and R6aIndependently H, C1-4Alkyl radical, C1-4Haloalkyl, C6-10aryl radical, C6-10Aryl radical C1-4Alkyl radical, C1-9Heteroaryl, or C1-9Heteroaryl C1-4An alkyl group;
each R7And R7aindependently H, C1-4Alkyl radical, C1-4Haloalkyl, C6-10Aryl radical, C6-10Aryl radical C1-4Alkyl radical, C1-9Heteroaryl, or C1-9Heteroaryl C1-4An alkyl group.
6. The compound of claim 1, which is a compound of one of the following:
7. A pharmaceutical composition comprising a compound according to any one of claims 1-6, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.
8. The pharmaceutical composition of claim 7, further comprising an additional therapeutic agent, wherein the additional therapeutic agent is selected from the group consisting of antidiabetic agents that are DPP-IV inhibitors, biguanide agents, sulfonylurea agents, glucosidase inhibitors, PPAR agonists, α P2 inhibitors, PPAR α/γ dual activators, SGLT-2 inhibitors, glinide agents, insulin, glucagon-like peptide-1 (GLP-1) inhibitors, PTP1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, antihyperglycemic agents, antiobesity agents, antihypertensive agents, antiplatelet agents, antiatherosclerotic agents, lipid lowering agents, anti-inflammatory agents, or combinations thereof.
9. The pharmaceutical composition according to claim 8, wherein the lipid lowering drug is selected from the group consisting of MTP inhibitors, HMGCoA reductase inhibitors, squalene synthetase inhibitors, fibric acid derivatives, ACAT inhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors, ileal sodium/bile acid cotransporter inhibitors, upregulators of LDL receptor activity, nicotinic acid or derivatives thereof, bile acid chelates, or combinations thereof; or wherein the lipid lowering drug is selected from pravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, atorvastatin, rosuvastatin, or a combination thereof.
10. Use of a compound according to any one of claims 1 to 6 or a pharmaceutical composition according to any one of claims 7 to 9 for the manufacture of a medicament for the prevention or treatment of, alleviating symptoms of, or delaying the progression or onset of, type II diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications, atherosclerosis, hypertension, acute anemia, or neutropenia.
Technical Field
The invention relates to a pigeon pea ketonic acid A structural analogue and a composition thereof, and also relates to application of the compound in the aspects of reducing blood sugar and blood fat.
Background
Diabetes Mellitus (DM) is a systemic chronic secretory metabolic disease associated with genetic factors, and is a metabolic disorder of sugar, fat, and protein due to absolute or relative insufficiency of insulin secretion in the body. It is mainly characterized by hyperglycemia and urine glucose, and is clinically accompanied with various complications such as atherosclerotic cardiovascular and cerebrovascular diseases, diabetic nephropathy, nervous system diseases and eye diseases such as cataract, retinopathy and the like. With the continuous improvement of living standard, the prevalence rate of diabetes is on the rapid rising trend, and the diabetes is the third major chronic disease which endangers human health. China has leaped into the countries with the most diabetes patients in the world, the number of the diabetes patients in China in 2013 is as high as 1.14 hundred million, and nearly 10 people in each hundred are diabetes patients. The global diabetes medication market scale in 2010 reaches 344.3 billion dollars, the compound growth rate in nearly five years is 12.7 percent, and the compound growth rate is obviously higher than the synchronous growth rate of other disease medication markets. The market scale of diabetes medicine in China in 2013 reaches 173.3 million yuan, and the market scale of diabetes medicine in 2018 is expected to reach 341.4 million yuan. Therefore, the prevention and treatment of diabetes is a major subject of research in the international diabetes world, and the search for effective methods and means for treating diabetes and its complications is not slow.
Diabetes is clinically classified into type 1 and type 2, with type 2 diabetes accounting for more than 90% of the total diabetic patients. Insulin resistance is an important etiological and prominent feature of type 2 diabetes. Improving insulin resistance or increasing insulin sensitivity is one of the effective means for treating type 2 diabetes.
In recent years, PPAR (peroxisome proliferator-activated receptor gamma) inhibitors have been reported to improve insulin resistance, have a significant hypoglycemic effect while avoiding a series of side effects of water-sodium retention, weight gain, cardiovascular toxicity and the like, namely, anti-metabolic activities of a non-agonist PPAR gamma ligand and blocking Cdk5-mediated phosphorylation [ J ]. Nature,477:477-481.An ERK/Cdk5 axis controls the metabolic activities of PPAR gamma inhibitors [ J ]. Acuiture, 517:391-393. Denn, synthesis, and biological evaluation of antibiotic biochemical acids as PPAR gamma antagonists [ J ]. ACS ] Chemistry Letter,6(9): 998-1003). Therefore, the PPAR gamma inhibitor is a very potential research direction for the research of insulin sensitizers.
PTP1B (protein tyrosine phosphatase 1B) belongs to protein tyrosine phosphatase family, and through dephosphorylation of tyrosine residue on insulin receptor or its substrate, negative regulation is carried out on insulin signal transduction, so that insulin receptor can not be combined with insulin, and insulin resistance is caused, and finally type 2 diabetes is caused. Is a recognized novel target for the treatment of diabetes and obesity (PTP1B as a Drug target: diabetes and obesity in PTP1Binhibitor discovery [ J ]. Drug discovery today,12(9-10):373-381.Natural and synthetic protein type phosphorus 1B (PTP1B) inhibitors as anti-metabolic agents [ J ]. RSC Advances,5(60): 48822-48834.). The PTP1B inhibitor can promote the improvement of insulin resistance and abnormal fat metabolism in vivo and in vitro pharmacological experiments, and is another important research direction of insulin sensitizers.
Researches show that the compound pigeon pea ketonic acid A extracted and separated from pigeon pea leaves has PPAR gamma and PTP1B inhibitor activities, can inhibit the expression of PTP1B at the protein level, and has remarkable insulin sensitizing activity. In view of the above, pigeon pea ketonic acid a has great potential in treating diabetes and other cardiovascular diseases, and thus has received much attention, for example, patent CN102670576A mentions pigeon pea ketonic acid a can treat or improve diabetes accompanied by hyperlipidemia. However, at present, pigeon pea ketonic acid A is mainly administered by injection, and the compliance of patients to the injection administration mode is poor. The improvement of the solubility is also the research direction of the pigeon pea ketonic acid A at present.
Coulonic acid A
The invention takes pigeon pea ketonic acid A as a lead compound, carries out multi-site structural modification and reformation on the pigeon pea ketonic acid A to obtain a plurality of series of analogues, and results of tests on glucose consumption promotion activity of human liver HepG2 cells show that the synthesized analogues have good glucose consumption promotion activity. The in vivo absorption after oral administration is measured by PAMPA (parallel artificial membrane permeability assay), and the result shows that the synthesized analogue has better absorption. Therefore, the pigeon pea ketonic acid A analogue protected by the invention has great potential in the aspect of treating type 2 diabetes.
Disclosure of Invention
The invention synthesizes a large amount of novel compounds with stilbene structural skeleton for the first time, and performs pharmacological action activity screening on the synthesized pigeon pea keto acid analogues; meanwhile, the invention aims to disclose the application of the pigeon pea ketonic acid analogues and the pharmaceutically acceptable salts thereof in the aspect of treating diabetes; another object of the present invention is to disclose a pharmaceutical composition comprising such a pigeon pea keto acid analog or a pharmaceutically acceptable salt thereof.
In one aspect, the present invention relates to a compound having a structure according to formula (I) or formula (II), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof, of a structure according to formula (I) or formula (II):
Wherein R is1Is H, hydroxy, amino, or alkoxy, or R1Represents the following structural formula:
R2And R3Each independently H, allyl, isopentyl, or propyl, or R2And R3each independently represents the following structural formula:
And R is1、R2And R3At least one of them is any one of the structural formulas represented by (a) to (l);
Each R4Independently is H, F, Cl, Br, I, hydroxy, alkyl, haloalkyl, alkoxy, R7-S(＝O)2O-, or R7a-S(＝O)2NH-；
R5Is hydroxy, alkoxy, or-NR6R6a；
Z is O or NR6；
each R6And R6aIndependently is H, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl;
Each R7And R7aIndependently is H, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl; and
n is 0, 1, 2, 3 or 4;
Wherein the compound represented by formula (I) is not: 6-hydroxy-4-methoxy-3- (3-methylbut-2-en-1-yl) -2- (2-oxo-2-phenylethyl) benzoic acid, and 4, 6-dimethoxy-3- (3-methylbut-2-en-1-yl) -2- (2-oxo-2-phenylethyl) benzoic acid;
The compound represented by formula (II) is not: 8-hydroxy-6-methoxy-5- (3-methylbut-2-en-1-yl) -3-phenyl-1H-isochroman-1-one, and 6, 8-dimethoxy-5- (3-methylbut-2-en-1-yl) -3-phenyl-1H-isochroman-1-one.
In some of these embodiments, the compounds of the present invention, wherein R1Is H, hydroxy, methoxy or ethoxy, or R1Represents the following structural formula:
In some of these embodiments, the compounds of the present invention wherein each R is4Independently H, F, Cl, Br, I, hydroxyl, C1-4Alkyl radical, C1-4Haloalkyl, or C1-4An alkoxy group.
In some of these embodiments, the compounds of the present invention, wherein R5Is hydroxy, methoxy, ethoxy, or propoxy.
In some of these embodiments, the compounds of the present invention wherein each R is6And R6aIndependently H, C1-4Alkyl radical, C1-4Haloalkyl, C6-10Aryl radical, C6-10Aryl radical C1-4Alkyl radical, C1-9Heteroaryl, or C1-9Heteroaryl C1-4An alkyl group;
each R7And R7aindependently H, C1-4Alkyl radical, C1-4Haloalkyl, C6-10Aryl radical, C6-10Aryl radical C1-4Alkyl radical, C1-9Heteroaryl, or C1-9Heteroaryl C1-4An alkyl group.
In another aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.
In some of these embodiments, the pharmaceutical composition of the present invention further comprises an additional therapeutic agent, wherein the additional therapeutic agent is selected from the group consisting of antidiabetic agents that are DPP-IV inhibitors, biguanide agents, sulfonylurea agents, glucosidase inhibitors, PPAR agonists, α P2 inhibitors, PPAR α/γ dual activators, SGLT-2 inhibitors, glinide agents, insulin, glucagon-like peptide-1 (GLP-1) inhibitors, PTP1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, antihyperglycemic agents, antiobesity agents, antihypertensive agents, antiplatelet agents, anti-atherosclerotic agents, lipid-lowering agents, anti-inflammatory agents, and combinations thereof.
In some of these embodiments, the pharmaceutical composition of the invention, wherein the lipid-lowering drug is selected from the group consisting of an MTP inhibitor, an HMGCoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an ACAT inhibitor, a lipoxygenase inhibitor, a cholesterol absorption inhibitor, an ileal sodium ion/bile acid cotransporter inhibitor, an up-regulator of LDL receptor activity, niacin or a derivative thereof, a bile acid chelate, or a combination thereof.
In some embodiments, the pharmaceutical composition of the present invention, wherein the lipid lowering drug is selected from pravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, atorvastatin, rosuvastatin, or a combination thereof.
In another aspect, the present invention relates to the use of a compound or a pharmaceutical composition according to the present invention for the manufacture of a medicament for preventing or treating, alleviating the symptoms of, or delaying the progression or onset of type II diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications, atherosclerosis, hypertension, acute anemia, or neutropenia.
The pharmaceutically acceptable salts refer to salts formed by reacting carboxyl or amino groups with corresponding bases, and the salts are selected from: potassium salt, sodium salt, etc., and the preparation method thereof is a conventional method well known to those skilled in the art.
The pharmaceutical compositions disclosed herein comprise a compound of the present invention, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof. The term "composition" refers to a product formed by mixing more than one substance or component; the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition or vehicle, such as: fillers, excipients, diluents.
The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 20 carbon atoms. In some of these embodiments, the alkoxy group contains 1 to 10 carbon atoms; in other embodiments, the alkoxy group contains 1 to 8 carbon atoms; in other embodiments, the alkoxy group contains 1 to 6 carbon atoms; in other embodiments, the alkoxy group contains 1 to 4 carbon atoms; in other embodiments, the alkoxy group contains 1 to 3 carbon atoms.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH (CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH2CH (CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH (CH3) CH2CH3), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH3)3), and the like. The alkoxy groups may be independently unsubstituted or substituted with one or more substituents described herein.
The term "halogen atom" means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
The term "substituted or unsubstituted amino" means isopentenyl, geranyl, alkyl groups attached to the rest of the molecule through a nitrogen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkyl group contains 1 to 20 carbon atoms. In some of these embodiments, the alkyl group contains 1 to 10 carbon atoms; in other embodiments, the alkyl group contains 1 to 8 carbon atoms; in other embodiments, the alkyl group contains 1 to 6 carbon atoms; in other embodiments, the alkyl group contains 1 to 4 carbon atoms; in other embodiments, the alkyl group contains 1 to 3 carbon atoms.
Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH (CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-l-propyl (i-Bu, i-butyl, -CH2CH (CH3)2), 2-butyl (s-Bu, s-butyl, -CH (CH3) CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH3)3), and the like. The alkyl groups may be independently unsubstituted or substituted with one or more substituents described herein.
The following acronyms are used throughout the invention:
CDC13Deuterated chloroform
DMF N, N' -dimethylformamide
FBS fetal bovine serum
THF tetrahydrofuran
DMF N, N-dimethylformamide
LDA lithium diisopropylamide
h hours
mL of
mol mole of
g
Volume V
The invention discloses a pigeon pea keto acid analogue selected from the following compounds:
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.