CN104224781A - 2-acylamino-3-alkoxyl substituted pyridine compounds and novel use thereof - Google Patents
2-acylamino-3-alkoxyl substituted pyridine compounds and novel use thereof Download PDFInfo
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Abstract
The invention discloses 2-acylamino-3-alkoxyl substituted pyridine compounds and an application of the compounds in treatment and/or prevention of atherosclerosis-induced cardiovascular diseases. Experiments verify that the compounds or pharmaceutical compositions have the function of up-regulating or stabilizing ABCA1 and SR-BI/CLA-1 and can be used for inhibiting bubblization of macrophage or enhancing cholesterol efflux of macrophage. Experiments show that the compounds have the effects of reducing blood fat and cholesterol and have an application prospect of becoming a medicine for reducing blood fat, treating atherosclerosis, cardiovascular diseases and the like.
Description
Technical field
The present invention relates to a class 2-amide groups-3-alkoxy pyridines compounds, be applied to treating and/or preventing of Atherosclerotic cardiovascular disease, belong to pharmaceutical field; The present invention relates to described compound at rise or stable ABCA1, SR-BI/CLA-1, the purposes of blood fat reducing, anticholesteremic agent; The present invention relates to again the preparation method of described compound; The invention still further relates to the pharmaceutical composition of described compound.
Background technology
Cardiovascular disease is the primary killers of harm humans health in developed country and most developing countries, in recent years along with the raising of people's living standard, the sickness rate of cardiovascular and cerebrovascular disease is obvious ascendant trend, and the formation that cardiovascular and cerebrovascular disease death accounts for population in the world death reaches 1/3.Atherosclerosis (Atherosclerosis) is the pathologic basis of multiple severe cardiovascular disease (as coronary heart diseases and angina pectoris, myocardial infarction, apoplexy etc.).
Peripheral cells inner cholesterol dysbolismus is atherosclerotic important pathogenesis, and excess cholesterol is the atherosclerotic committed step of prevention and therapy from the removing extrahepatic tissue.High density lipoprotein (HDL) is by the cholesterol transport in peripheral tissues to liver metabolism or drain with the form of cholic acid again, and this process is called as reverse cholesterol transport (RCT) [1,2].It is the atherosclerotic effective means for the treatment of that RCT and cholesterol get rid of approach.
The atherosclerosis Drug therapy of application at present comprises blood vessel dilating medicine, adjustment hypolipidemic medicine, antiplatelet drug etc. clinically.The Statins of current extensive use is the first-line drug for the treatment of relevant disease, its mechanism of action suppresses HMG-CoA reductase in body active, suppress the biosynthesis of cholesterol and strengthen peripheral cells to regulate path to realize antiatherogenic to the ldl receptor that cholesterol absorbs, but only can reduce the cardiovascular event of 20% ~ 40%, long-term taking also can cause the serious adverse reactions such as gastrointestinal dysfunction syndrome, erythra, spirit depressing, rhabdomyolysis and hepar damnification.Therefore, in the urgent need to developing new cardiovascular drugs [3-5].
Scavenger receptor BI (scavenger receptor class B type I, SR-BI) is functional HDL receptor, and the HDL receptor of people is also referred to as CLA-1.SR-BI/CLA-1 is one of main moderator of HDL metabolism, in RCT process, play pivotal role, is considered to the new target drone [6] finding that Novel cardiovascular medicine is potential.The cholesterol being conducive to AS focus savings reduces and the reverse of pathological changes by the enhancing of RCT, therefore can accelerate RCT by raising SR-BI/CLA-1 expression, and promotion body is had more than needed the removing of cholesteryl ester.
ATP binding cassette transporter body A1 (ATP-binding cassette transporter A1, ABCA1) be one of ATP binding cassette transporter body superfamily member, be a kind of important take ATP as the protein called membrane transporters that the energy transports the cell metabolites such as various ion, lipid.ABCA1 phospholipid and free cholesterol can be transported to poor fat or the apolipoprotein A-1 (apoA-I) without fat in mediated cell, thus promote that high density lipoprotein (HDL) generates, start reverse cholesterol transport process, remove at body in the process of unnecessary lipid and play a significant role.ABCA1 gene mutation can cause serious HDL to lack syndrome-Tangier Disease (TD), patient increases as principal character, often with hypercholesterolemia, cardiovascular disease and AS[7 with blood plasma HDL and apoA-I famine and tissue macrophages inner cholesterol ester].Show that the Cholesterol Efflux that ABCA1 overexpression makes apoA-I mediate obviously increases to the research of transgenic mice, plasma HDL levels significantly raises, and ABCA1 protein level increases to Cholesterol Efflux and HDL level raises obviously relevant.Therefore, SR-BI/CLA-1 and/or ABCA1 can as the novel targets of the cardiovascular and cerebrovascular disease based on treatment hyperlipidemia and atherosclerosis.The compound that can increase SR-BI/CLA-1 and/or ABCA1 gene expression or function promises to be effectively primer such as newtype drug such as cardiovascular disease such as treatment hyperlipidemia and atherosclerosis etc.
In a word, also there is heavier side effect in the Statins medicine used clinically, still lacks the atherosclerotic specific medicament for the treatment of at present.Stronger for obtaining tissue specificity, by regulating RCT key receptor thus promoting cholesterol efflux, reduce lipid accumulation, thus play and prevent and/or treat atherosclerosis newtype drug, screening model that ABCA1 and SR-BI/CLA-1 utilizing country of Inst. of Medicinal Biological Technology, Chinese Academy of Medical Sciences new drug (microorganism) screening experiment room to build adjusts extensively screens, find that the pyridine compounds and their that one group of 2-amide groups-3-alkoxyl replaces has the activity obviously raising ABCA1 and SR-BI/CLA-1, and determine in vitro and confirm that it has atherosclerosis cardiovascular disease active.The pyridine compounds and their that 2-amide groups-3-alkoxyl replaces there are no bibliographical information, is the Late Cambrian of present patent application in study of anti-atherogenic effect.The pyridine compounds and their that this group 2-amide groups-3-alkoxyl replaces is compared with the statins used clinically, structure does not have similarity, and it is different to play study of anti-atherogenic effect mechanism, be expected to become specificity regulate RCT key receptor, reduce lipid, reduce cholesterol, thus become the medicine of atherosclerosis and even Cardiovascular.Therefore, the pyridine compounds and their that this group 2-amide groups-3-alkoxyl replaces is likely the atherosclerosis compound with novel mechanism, has wide development prospect.
Summary of the invention
The application that the pyridine compounds and their that 2-amide groups-3 alkoxyl of the present invention replaces is transferred person in the medicine of ATP binding cassette transporter body A1 (ABCA1) and/or scavenger receptor BI (CLA-1/SR-B1) expression activity on preparation has, its structure is as shown in general formula (I):
Wherein, n=0-4, representative comprises the linear paraffin base of atom number between 0-4 of hetero atom; R1 represents the alkyl of H atom or C1-C4; R2, R3, R4 independently represent the alkyl of C1-C3, the oxyl of C1-C3, halogen atom or H atom; R5 independently represents and includes H, C1-C4 alkyl, C1-C3 alcoxyl (sulfur) base, halogen atom, the cycloalkane, 1 of the phenyl ring that 1,3-dioxy (sulfur) Pentamethylene. base replaces, pyridine ring, pyrimidine ring, piperidine ring, piperazine ring, C3-C6,2,3-triazole, 1,2,4-triazole, pyrrole ring, furan nucleus, oxazole ring, imidazole ring, thiphene ring, thiazole ring and benzimidazole, benzothiazole, benzoxazole, benzofuran, benzothiophene or indole ring.
In compound shown in formula (I), R1 is H preferably, alkyl is preferably methyl or the tert-butyl group, and alcoxyl (sulfur) base is preferably trifluoromethoxy or trifluoromethylthio, and the ring system representated by R5 is phenyl ring, furan nucleus, pyrrole ring, imidazole ring or benzimidazole ring preferably; N preferably 0, namely represents benzoic acids structure fragment.
Prepare the universal method of the employing amides compound of described compound.Key step is, 2-amino-3-alkoxy pyridines compounds (II) of the carboxylic acid (III) replaced by different ring system and replacement is as raw material, using EDCI as condensing agent, under suitable solvent and temperature conditions, final synthesis obtains corresponding compound in general formula (I), and general formula synthetic route is as follows:
According to the above route and method, can stablize, repeatable synthesis obtain all compounds of the present invention.
It is the medicine treating and/or preventing cardiovascular disease that upper mediator ATP binding cassette transporter body A1 (ABCA1) of the present invention and/or scavenger receptor BI (CLA-1/SR-B1) express medicine.
The medicine of upper mediator ATP binding cassette transporter body A1 (ABCA1) of the present invention and/or scavenger receptor BI (CLA-1/SR-B1) expression activity is the medicine reducing Lipid pharmaceutical or reduce cholesterol.
The medicine of upper mediator ATP binding cassette transporter body A1 (ABCA1) of the present invention and/or scavenger receptor BI (CLA-1/SR-B1) expression activity is antiatherogenic medicine.
Application in the medicine that the present invention also provides the compositions of described compound to transfer person ATP binding cassette transporter body A1 (ABCA1) and/or scavenger receptor BI (CLA-1/SR-B1) expression activity on preparation has.
The compositions of compound of the present invention is transferred person ATP binding cassette transporter body A1 (ABCA1) and/or scavenger receptor BI (CLA-1/SR-B1) express or the medicine that increases stabilizing active be reduce Lipid pharmaceutical or reduce cholesterol medicine.
The medicine of ATP binding cassette transporter body A1 (ABCA1) and/or scavenger receptor BI (CLA-1/SR-B1) expression activity that the compositions of compound of the present invention is transferred person is antiatherogenic medicine.
The compositions of compound of the present invention is transferred person the medicine of ATP binding cassette transporter body A1 (ABCA1) and/or scavenger receptor BI (CLA-1/SR-B1) expression activity for treating and/or preventing cardiovascular disease medicine.
The various dosage forms of pharmaceutical composition of the present invention, can prepare according to the conventional production process of pharmaceutical field, such as, make active component mix with one or more carriers, be then made into required dosage form.
The pharmaceutical composition of compound of the present invention, is characterized in that it with the described compound containing treatment effective dose for active component, and containing one or more pharmaceutically acceptable carriers.
People ABCA1, CLA-1/SR-B1 and CLAp-3 that the present inventor utilizes this laboratory to set up ' activity of UTR screening model to patents is evaluated, 0.1%DMSO is selected to be negative control, 9CRA is positive control, measures the rise rate of all compounds under 10 μ g/ml concentration in model (ABCA1, CLA-1, CLAp-3 ' UTR).Repeatedly determination of activity the results show, all compounds of the present invention all have rise effect on ABCA1CLAp-3 ' UTR model, and activity and the measurement result of part of compounds are as shown in table 1.Table 1 is only and helps those skilled in the art to understand the present invention better, but does not limit the present invention in any way.
The present invention finds LX-1 in general formula (I), and 3,5,7,10,19,20,22,23 etc. have the effect of raising ABCA1 and CLA-1.Wherein, especially LX-1, LX-3, LX-5, LX-7 demonstrate the activity of good rise ABCA1 and CLA-1, and provide them treating the application in atherosclerosis, lay a good foundation for this analog derivative develops into the novel Antiatherosclerosis medicine of a class.LX-1 equal energy dose dependent on ABCA1, CLA-1, CLAp-3 ' UTR tri-model raises the expression of ABCA1, CLA-1, CLAp-3 ' UTR, and EC50 is respectively 0.089,0.027 and 3.5 μ g/ml (Fig. 1).LX-1 (0.24,1.2,6.0 and 30.0 μ g/ml) is acted on RAW264.7 or HepG2 cell 18-24h, western blot result shows, and these two compounds obviously can raise the expression of ABCA1 and SR-BI in RAW264.7 cell in albumen (Fig. 2) level.Prove thus, compound of the present invention or compositions can as the medicines raising the sub-ABCA1 of ATP binding cassette transporter or HDL receptor CLA-1/SR-B1 expression activity.
In the present invention, described suppression macrophage foam cell formation refers to and utilizes people or mice nascent generation or immortal mononuclear cell to be formed after macrophage through induced denaturation, the accumulation of a large amount of neutral lipids formed after a large amount of denatured lipoprotein of picked-up or elecrtonegativity phospholipid, a large amount of red fat formed after oil red O stain drips remarkable minimizing.After LX-1, LX-3, LX-5, LX-7 (compound concentration is 10 μ g/ml) act on the mouse monokaryon-macrophage RAW264.7 of rich fat respectively, oil red O stain result shows, described compound obviously can reduce the accumulation of lipid in macrophage, there is the significant activity suppressing macrophage foam cell formation (Fig. 3), reduce lipid content.Prove thus, compound of the present invention or compositions can as the fat-reducing medicaments reducing lipid accumulation.
By LX-1, LX-3, LX-5, LX-7, (compound concentration is 10, μ g/ml) act on the mouse monokaryon-macrophage RAW264.7 of Cholesterol Accumulation respectively after, using apoA-I or HDL as cholesterol acceptor, scintiloscope measures in cell and the content of extracellular cholesterol respectively, calculate Cholesterol Efflux rate (in cell and the ratio of the amount of the total cholesterol of cell, T-CHOL be in born of the same parents and outside born of the same parents and).Compared with blank, LX-1, LX-3, LX-5, LX-7 all can promote that Cholesterol Efflux is to extracellular, and cholesterol efflux amount can be increased to more than 150%, illustrate that LX-1, LX-3, LX-5, LX-7 have the effect (Fig. 4) promoting cholesterol efflux, reduce cholesterol level.Prove thus, compound of the present invention or compositions can as the cholesterol lowering drug things reducing cholesterol.
ApoE-/-mice high fat diet two months, build Atherosclerosis Model, LX-1 administration 2 months, blood fat result shows, and LX-1 significantly can reduce Triglycerides in Serum (TG), T-CHOL (TC), low-density protein cholesterol (LDL-C) level (table 2).Prove thus, compound of the present invention or compositions can reduce cholesterol in animal body, can as atherosclerosis cardiovascular drugs.
The beneficial effect of the invention
1) novelty of action target spot: research at present shows that ABCA1 and CLA-1 is antiatherogenic novel targets, has material impact in atherosclerotic generation, development, but not yet has the medicine acting on this target spot to occur.
2) novelty of compound: the present invention has set forth the definite effect of pyridine compounds and their in artereosclerotic cardiovascular that 2-amide groups-3-alkoxyl replaces first time, and from setting forth the reason of its arteriosclerosis effect first from molecular mechanism, this at home and abroad belongs to first, and this Antiatherosclerosis medicine having independent intellectual property right for China's exploitation has great importance.Meanwhile, the present invention also illustrates, effective antiatherogenic lead compound new for target spot can screen with ABCA1 and CLA-1.
3) artereosclerotic cardiovascular prevention and treatment of diseases: angiopathy especially atherosclerosis serious threat is to the life and health of the mankind, early oneself can not meet clinical demand for existing medicine, can not fundamentally treat.The compound that the present invention finds has good anti-atherosclerotic effect in animal body, for exploitation arteriosclerosis medicine provides good lead compound, has broad application prospects.
Table 1 part of compounds in 10 μ g/ml concentration to the rate of change of CLAp-3 ' UTR, ABCA1 and CLA-1/SR-B1
Table 2LX-1 is on the impact (mg/dL) of the high fat diet apoE-/-lipid of mice of high fat diet
Accompanying drawing explanation
Fig. 1 is the amount effect relation curve of LX-1 in ABCA1, CLA-1, CLAp-3 ' UTR screening model.
Fig. 2 is that LX-1 increases ABCA1 and SR-BI/CLA-1 expression in HepG2 cell, and wherein LX-1 concentration is respectively 0.24,1.2,6.0 and 30.0 μ g/ml.
Fig. 3 compound suppresses macrophage foam cell formation, wherein a: blank; B: positive control (Ox-LDL); C-f is followed successively by: LX-1, LX-3, LX-5, LX-7 (compound concentration is 10 μ g/ml).
Fig. 4 compound promoted Cholesterol Efflux, wherein in LX-1, LX-3, LX-5, LX-7 induction RAW264.7 cell, Cholesterol Efflux is to ApoA-I, and compound concentration is 10.0 μ g/ml.
Detailed description of the invention
The preparation embodiment of following part of compounds can make professional and technical personnel more fully understand the present invention, but does not limit the present invention in any way, and the structure of all compounds all determined through 1H NMR and MS (ESI).
The preparation of embodiment 1N-(3-hydroxyl-2-pyridine radicals)-4-(1,3-dithio-2-Pentamethylene. base) Benzoylamide (LX-1)
According to the operational approach of embodiment 1, with 0.23g (0.001mol) 4-(1,3-dithio-2-Pentamethylene. base) benzoic acid and 0.11g (0.001mol) 2-amino-3-pyridine alcohol feeds intake, and obtains LX-1 sterling 0.31g white solid, productive rate 97%.MS(ESI，?m/z)：319[M]+，1H?NMR(500MHz，d6-DMSO)δ(ppm)：10.568(s，1H，NH-CO)，9.856(s，1H，-OH)，7.977(m，2H，Ph-H)，7.655(m，2H，Ph-H)，7.341(dd，1H，J=8.0Hz，1.5Hz,Py-6H)，7.224(dd，1H，J=8.0Hz，5.0Hz，Py-4H)，5.843(s，1H，SCHS)，5.337(t，1H，J=5.0Hz，Py-5H)，3.57(m，2H，CH2)，3.396(m，2H,CH2)
The preparation of embodiment 2N-(3-hydroxyl-2-pyridine radicals)-4-trifluoromethoxy Benzoylamide (LX-3)
According to the operational approach of embodiment 1, feed intake with 0.21g (0.001mol) 4-trifluoro-methoxy-benzoic acid and 0.11g (0.001mol) 2-amino-3-pyridine alcohol, obtain LX-3 sterling 0.25g yellow solid, productive rate 84%.MS(ESI，m/z)：299[M]+，1H?NMR(500MHz，d6-DMSO)δ(ppm)：8.151(m，1H，Ph-H)，7.960(d，1H，J=5.0Hz，Py-6H)，7.530(m，1H，Ph-H)，7.326(d，1H，J=7.5Hz，Py-4H)，7.203(m，1H，NH-CO)，6.654(s，1H，-OH)，5.337(t，1H，J=5.0Hz，Py-5H)，
The preparation of embodiment 3N-(3-hydroxyl-2-pyridine radicals)-4-iodobenzamide (LX-5)
According to the operational approach of embodiment 1, feed intake with 0.25g (0.001mol) 4-iodo-benzoic acid and 0.11g (0.001mol) 2-amino-3-pyridine alcohol, obtain LX-5 sterling 0.36g white solid, productive rate 90%.MS(ESI，m/z)：341[M]+，1H?NMR(500MHz，d6-DMSO)δ(ppm)：7.957(s，1H，NH)，7.924(m，2H，Ph-2H)，7.650(s，1H，Py-6)，7.323(m，2H，Ph-2H)，7.199(s，1H，OH)，5.337(m，2H，Py-4,5H)，
The preparation of embodiment 4N-(3-hydroxyl-2-pyridine radicals)-4-trifluoromethylthio Benzoylamide (LX-7)
4-trifluoromethylthio benzoic acid 0.25g (0.0011mol) is dissolved in 30mL dichloromethane, continue to add 0.23g (0.0012mol) EDCI, in stirring at room temperature after 30 minutes, add 2-amino-3-pyridine alcohol 0.11g (0.001mol), room temperature reaction 12h, TLC detection reaction is complete, stopped reaction.Reactant liquor uses saturated sodium bicarbonate solution, saturated common salt water washing successively, anhydrous sodium sulfate drying.Be separated eluting through silica gel column chromatography after steaming desolventizes and obtain LX-7 sterling 0.27g white solid, productive rate 96%.MS(ESI，m/z)：315[M]+，1H?NMR(500MHz，d6-DMSO)δ(ppm)：8.126(m，2H，Ph-H)，7.968(d，1H，J=5.0Hz，Py-6H)，7.885(m，2H，Ph-H)，7.340(d，1H，J=8.0Hz，Py-4H)，7.223(m，1H，NH-CO)，6.654(s，1H，-OH)，5.337(t，1H，J=5.0Hz，Py-5H)
The preparation of embodiment 5N-(3-hydroxyl-2-pyridine radicals)-5-methylfuran-2-Methanamide (LX-9)
According to the operational approach of embodiment 1, feed intake with 0.13g (0.001mol) 5-methylfuran-2-formic acid and 0.11g (0.001mol) 2-amino-3-pyridine alcohol, obtain LX-9 sterling 0.32g brown solid, productive rate 89%.MS(ESI，m/z)：357[M]+，1H?NMR(500MHz，d6-DMSO)δ(ppm)：10.239(s，1H，NH)，7.951(d，1H，J=4.5Hz)，7.381(d，1H，J=3.0Hz，Py-4H)，7.319(d，1H，J=8.0Hz，Py-6H)，7.202(d，1H，J=4.5Hz，3-H)，7.186(d，1H，J=4.5Hz，4-H)，6.657(s，1H，OH)，6.354(d，1H，3.0Hz，Py-5H)，5.342(m，2H,)，2.383(s，3H，CH3)，
The preparation of embodiment 6N-(3-hydroxyl-2-pyridine radicals)-4-tert-butyl benzene acetamide oxide (LX-11)
According to the operational approach of embodiment 1, feed intake with 0.21g (0.001mol) 4-tert-butyl benzene fluoroacetic acid and 0.11g (0.001mol) 2-amino-3-pyridine alcohol, obtain LX-11 sterling 0.27g light yellow solid, productive rate 90%.MS(ESI，m/z)：301[M]+，1H?NMR(500MHz，d6-DMSO)δ(ppm)：7.674(d，1H，J=7.0Hz，Ph-H)，7.445(d，1H，J=7.0Hz，Ph-H)，7.353(d，1H，J=5.0Hz，Py-6H)，7.251(m，2H，Ph-2H)，7.201(m，1H，NH)，7.036(d，1H，J=5.0Hz，Py-4H)，6.953(d，1H，J=5.0Hz，Py-5H)，6.558(s，1H，OH)，3.524(s，2H，CH2O)，2.006(m，9H，CH3*3)
The preparation of embodiment 7N-(3-hydroxyl-2-pyridine radicals) furan-3-Methanamide (LX-13)
According to the operational approach of embodiment 1, feed intake with 0.11g (0.001mol) furan-3-formic acid and 0.11g (0.001mol) 2-amino-3-pyridine alcohol, obtain LX-13 sterling 0.18g pink solid, productive rate 88%.MS(ESI，m/z)：205[M]+，1H?NMR(500MHz，d6-DMSO)δ(ppm)：10.556(s，1H，NH)，8.494(s，1H，Fu-2H)，7.977(d，1H，J=3.5Hz，Fu-5H)，7.824(s，1H，OH)，7.351(dd，1H，J=8.0Hz，1.5Hz，Py-4H)，7.226(dd，1H，J=5.0Hz，1.5Hz，Py-6H)，7.085(d，1H，J=1.0Hz，Fu-4H)，5.337(t，1H，J=5.0Hz，Py-5H)
The preparation of the chloro-5-brombenzamide (LX-15) of embodiment 8N-(3-hydroxyl-2-pyridine radicals)-2-
According to the operational approach of embodiment 1, feed intake with the chloro-5-bromobenzoic acid of 0.25g (0.0011mol) 2-and 0.11g (0.001mol) 2-amino-3-pyridine alcohol, obtain LX-15 sterling 0.31g yellow solid, productive rate 94.5%.MS(ESI，m/z)：327[M]+，1H?NMR(500MHz，d6-DMSO)δ(ppm)：7.910(s，1H，Py-6H)，7.815(s，1H，6-H)，7.705(d，1H，J=8.5Hz，4-H)，7.514(d，1H，J=8.5Hz，3-H)，7.320(d，1H，J=7.5Hz，Py-4H)，7.201(m，1H，NH-CO)，6.654(s，1H，-OH)，5.337(t，1H，J=5.0Hz，Py-5H)
The preparation of embodiment 9N-(3-hydroxyl-2-pyridine radicals)-2,4-dibromo-phenoxy acetamides (LX-18)
According to the operational approach of embodiment 1, feed intake with 0.31g (0.001mol) 2,4-dibromo-phenoxy acetic acid and 0.11g (0.001mol) 2-amino-3-pyridine alcohol, obtain LX-18 sterling 0.37g light yellow solid, productive rate 92%.MS(ESI，m/z)：401[M]+，1H?NMR(500MHz，d6-DMSO)δ(ppm)：7.809(d，1H，J=2.5Hz，3-H)，7.515(dd，1H，J=9.0Hz，2.5Hz，5-H)，7.201(br-s，1H，Py-6H)，7.106(br-s，1H，Py-4H)，6.985(d，1H，J=9.0Hz，6-H)，6.656(s，1H，-OH)，5.336(t，1H，J=5.0Hz，Py-5H)，4.822(s，2H，CH2)
The preparation of embodiment 10N-(3-hydroxyl-2-pyridine radicals) the chloro-3-of 4-(N-pi-allyl sulfoamido) Benzoylamide (LX-20)
According to the operational approach of embodiment 1, feed intake with the chloro-3-of 0.28g (0.001mol) 4-(N-pi-allyl sulfoamido) benzoic acid and 0.11g (0.001mol) 2-amino-3-pyridine alcohol, obtain LX-20 sterling 0.35g white solid, productive rate 95%.MS(ESI,m/z)：368[M]+，1H?NMR(500MHz，d6-DMSO)δ(ppm)：9.847(s，1H，NH-SO2)，8.538(s，1H，OH)，8.254(t，1H，J=5.0Hz，Py-6H)，8.209(d，1H，J=9.0Hz，Py-4H)，7.964(d，1H，J=4.0Hz，2-H)，7.838(d，1H，J=8.0Hz，6-H)，7.343(d，1H，J=8.0Hz，5-H)，7.229(m，1H，NH-CO)，5.680(m，1H，=CH)，5.337(t，1H，J=5.0Hz，Py-5H)，5.145(d，1H，J=15.0Hz，=CH)，5.007(d，1H，J=10.0Hz，=CH)，3.182(d，2H，J=5.0Hz，CH2)
The preparation of embodiment 11N-(3-hydroxyl-2-pyridine radicals)-4-(N-acetoxyl group-2,6-lupetidine) Benzoylamide (LX-22)
According to the operational approach of embodiment 1, with 0.29g (0.001mol) 4-(N-2,6-lupetidine) phenoxy acetamide yl benzoic acid and 0.11g (0.001mol) 2-amino-3-pyridine alcohol feeds intake, and obtains LX-22 sterling 0.35g yellow solid, productive rate 91%.MS(ESI，m/z)：384[M]+，1H?NMR(500MHz，d6-DMSO)δ(ppm)：10.539(s，1H，NH)，8.030(m，2H，J=8.5Hz，Ph-2H)，7.978(d，1H，J=4.5Hz，Py-4H)，7.346(d，1H，J=7.0Hz，Py-6H)，7.221(dd，1H，J=7.0Hz，4.5Hz，Py-5H)，7.028(m，2H，J=8.5Hz，Ph-2H)，6.555(s，1H，OH)，5.335(s，2H，OCH2)，2.006(m，2H，CH2)，1.561(m，2H，CH2)，1.468(t，3H，J=6.5Hz，CH3)，1.163(m，2H，CH2)，0.888(t，3H,J=6.5Hz,CH3)
The preparation of embodiment 12N-(3-hydroxyl-2-pyridine radicals)-4-(5-trifluoromethyl-2-pyridyloxy) Benzoylamide (LX-25)
According to the operational approach of embodiment 1, feed intake with 0.28g (0.001mol) 4-(5-trifluoromethyl-2-pyridyloxy) benzoic acid and 0.11g (0.001mol) 2-amino-3-pyridine alcohol, obtain LX-25 sterling 0.36g white solid, productive rate 96%.MS(ESI，m/z)：376[M]+，1H?NMR(500MHz，d6-DMSO)δ(ppm)：8.137(m，2H，Ph-H)，7.975d，1H，J=5.0Hz，Py-6H)，7.846(m，2H，Ph-H)，7.643(d，1H，J=8.0Hz，Py-4′H)，7.546(s，1H，Py-6′H)，7.352(d，1H，J=8.0Hz，Py-4H)，7.226(m，1H，NH-CO)，6.852(d，1H，Py-3′H)，6.654(s，1H，-OH)，5.336(t，1H，J=5.0Hz，Py-5H)
The preparation of embodiment 13N-(3-hydroxyl-4-chloro-2-pyridyl)-4-chlorobenzamide (LX-27)
According to the operational approach of embodiment 1, feed intake with 0.16g (0.001mol) 4-chlorobenzoic acid and 0.15g (0.001mol) 2-amino-4-chloro-3-pyridyl alcohol, obtain LX-27 sterling 0.25g light green solid, productive rate 88%.MS(ESI，m/z)：283[M]+，1H?NMR(500MHz，d6-DMSO)δ(ppm)：10.523(s，1H，NH)，7.978(m，2H，Ph-2H)，7.724(d，1H，J=5.0Hz，Py-5H)，7.656(m，2H，Ph-2H)，6.855(d，1H，J=5.0Hz，Py-6H)，6.524(s，1H，OH)
The preparation of embodiment 14N, N-bis-(3-hydroxyl-2-pyridine radicals)-Isosorbide-5-Nitrae-hexamethylene diformamide (LX-28)
According to the operational approach of embodiment 1, feed intake with 0.17g (0.001mol) Isosorbide-5-Nitrae-cyclohexyldicarboxylic acids and 0.22g (0.002mol) 2-amino-3-pyridine alcohol, obtain LX-28 sterling 0.32g yellow solid, productive rate 89%.MS(ESI，m/z)：357[M]+，1H?NMR(500MHz，d6-DMSO)δ(ppm)：7.912(s，1H，NH)，7.294(d，1H，J=7.5Hz，Py-6H)，7.199(s，1H，NH)，7.166(m，1H，Py-5H)，6.656(s，1H，OH)，5.337(t，1H，J=6.0Hz，Py-6′H)，4.379(t，2H，J=6.0Hz，Py-4′5′H)，3.524(s，1H，OH)，3.438(m，1H，CH)，3.382(m，1H，CH)，2.006(m,4H，CH2CH2)，1.661(m，2H，CH2)1.468(m，2H，CH2)
The preparation of embodiment 15N-(3-hydroxy-5-methyl oxygen base-2-pyridine radicals)-4-chlorobenzamide (LX-30)
According to the operational approach of embodiment 1, feed intake with 0.16g (0.001mol) 4-chlorobenzoic acid and 0.14g (0.001mol) 2-amino-5-methoxyl group-3-pyridine alcohol, obtain LX-30 sterling 0.26g light yellow solid, productive rate 93%.MS(ESI，m/z)：279[M]+，1H?NMR(500MHz，d6-DMSO)δ(ppm)：10.521(s，1H，NH)，7.976(m，2H，Ph-2H)，7.744(d，1H，?J=1.5Hz，Py-6H)，7.656(m，2H，Ph-2H)，6.823(d，1H，J=1.5Hz，Py-4H)，6.524(s，1H，OH)，3.843(s，3H，OCH3)
Embodiment 16 the compounds of this invention is to the activity of adjustment screening model on ABCA1
ABCA1-LUC HepG2 cell is inoculated in 96 porocyte culture plates with 5 × 104/hole, about 6h is after cell attachment, remove the culture medium containing serum, with PBS, rinsing cell is once gently, each experimental port adds not containing the MEM-EBSS culture medium 200 μ l of serum, add 2 μ l compound sample to be measured (final concentration 2.5 or 10 μ g/ml) more respectively, the hole of final concentration 0.1%DMSO culture medium is as blank.Continue at 37 DEG C, after cultivating 18-24h under 5%CO2 condition, PBS (200 μ l/ hole) washes plate 2 times, abandons PBS.Add cell pyrolysis liquid (20 μ l/ hole) (Promega), after 15-30min, after basis of microscopic observation lysis completely, add luciferase (60 μ l/ hole), measure uciferase activity (microplate reader reading) immediately.
With following Equation for Calculating testing sample to the rate of change of uciferase activity:
Rate of change (%)=A/B × 100
Wherein, A is cell fluorescence element enzymatic activity (RLU) measured after adding testing sample, cell fluorescence element enzymatic activity (RLU) that B measures afterwards for adding blank control sample (DMSO).
Embodiment 17 the compounds of this invention is to the activity of adjustment screening model on CLA-1
CLAP-LUC HepG2 cell is inoculated in 96 porocyte culture plates with 5104 cells/well, about 6h is after cell attachment, remove the culture medium containing serum, with PBS, rinsing cell is once gently, each experimental port adds not containing the MEM-EBSS culture medium 200 μ l of serum, add 2 μ l compound sample to be measured (final concentration 2.5 or 10 μ g/ml) more respectively, the hole of final concentration 0.1%DMSO culture medium is as blank.Continue at 37 DEG C, cultivate after 18 hours under 5%CO2 condition, PBS (200 μ l/ hole) washes plate 2 times, abandons PBS.Add cell pyrolysis liquid (20 μ l/ hole) (Promega), after 15-30min, basis of microscopic observation cell splits completely, adds luciferase (60 μ l/ hole), measures uciferase activity (microplate reader reading) immediately.
With following Equation for Calculating testing sample to the rate of change of uciferase activity:
Rate of change (%)=A/B × 100
Wherein, A is cell fluorescence element enzymatic activity (RLU) measured after adding testing sample, cell fluorescence element enzymatic activity (RLU) that B measures afterwards for adding blank control sample (DMSO).
Embodiment 18 the compounds of this invention is to the activity of CLA-1p-3 ' UTR screening model
CLA-1p-3 ' UTR HepG2 cell is inoculated in 96 porocyte culture plates with 5104 cells/well, about 6h is after cell attachment, remove the culture medium containing serum, with PBS, rinsing cell is once gently, each experimental port adds not containing the MEM-EBSS culture medium 200 μ l of serum, add 2 μ l compound sample to be measured (final concentration 2.5 or 10 μ g/ml) more respectively, the hole of final concentration 0.1%DMSO culture medium is as blank.Continue at 37 DEG C, cultivate after 18 hours under 5%CO2 condition, PBS (200 μ l/ hole) washes plate 2 times, abandons PBS.Add cell pyrolysis liquid (20 μ l/ hole) (Promega), after 15-30min, basis of microscopic observation cell splits completely, adds luciferase (60 μ l/ hole), measures uciferase activity (microplate reader reading) immediately.
With following Equation for Calculating testing sample to the rate of change of uciferase activity:
Rate of change (%)=A/B × 100
Embodiment 19 suppresses macrophage foam cell formationization to be tested
The DMEM-high sugared culture fluid adhere-wall culture of monocytes/macrophages RAW264.7 containing 10%FBS of mice.Cell is inoculated on 96 porocyte culture plates with 6 × 104/hole, in 37 DEG C, under 5%CO2 condition after incubated overnight, is changed to serum-free DMEM-high glucose medium (100 μ l/ hole).Cell is divided into matched group, foam cell group and application of sample group (each final compound concentration 10 μ g/ml), add final concentration be the Ox-LDL of 80mg/L to foam cell group and application of sample group, application of sample group will add certain density testing sample simultaneously.37 DEG C, after cultivating 24h under 5%CO2 condition, carry out oil red O stain.
Taken out from CO2 incubator by 96 orifice plates, 4% paraformaldehyde is fixed (15 μ l/ hole) 10min, abandon solution, distilled water washes twice, then adds 60% isopropyl alcohol (150 μ l/ hole), places 5min, discards solution.Liquid is used to add in each hole oil red O, 150 μ l/ holes, dyeing 1h.Discard solution, with 60% isopropyl alcohol (150 μ l/ hole) hole flushing, then use distilled water (150 μ l/ hole) to wash twice, last every hole adds 150 μ l distilled waters and is placed in basis of microscopic observation, takes pictures.
Embodiment 20 [3H] Cholesterol Efflux is tested
The DMEM-high glucose medium (500 μ l/ hole) of mouse monokaryon-macrophage RAW264.7 containing 10%FBS, with 2 × 105/hole, is inoculated on 24 porocyte culture plates, in 37 DEG C, and incubated overnight under 5%CO2 condition.
Abandon Cell sap, be changed to the DMEM-high glucose medium (500 μ l/ hole) containing 0.2% (w/v) BSA, add 1,2-[3H] cholesterol and make its final concentration be 1 μ Ci/ml, 37 DEG C, under 5%CO2 condition, hatching 24h.
Cell is washed 2 times with PBS (1ml/ hole), (DMEM adds 0.2%BSA to the mensuration culture medium adding containing finite concentration compound (final concentration 10 μ g/ml), 0.1%DMSO, 25mM HEPES, pH7.4), 18-24h is hatched for 37 DEG C.
Wash cell 2 times with PBS (1ml/ hole), add culture medium (DMEM adds 0.2%BSA, 0.1%DMSO, 25mM HEPES, pH7.4), have or without the apoA-I of 10 μ g/ml, hatch 4h.
Collect culture medium, the centrifugal 5min of 10000 × g, gets supernatant to be measured.
With 0.1M NaOH0.5ml lysis at room temperature cell 30min, collect lysate to be measured.
Measure: testing sample is transferred to respectively on 3MM filter paper, 75 DEG C of oven dry, the scraps of paper being placed on liquid dodges in cup, (mass concentration is 0.5%PPO (2 to add 10ml liquid sudden strain of a muscle liquid, 5-diphenyloxazole) and 0.05%POPOP (Isosorbide-5-Nitrae-bis--2-15-oxazolyl phenyl benzene) and volume fraction be the solvent mixed preparing of 55% dimethylbenzene and 45% glycol dimethyl ether, be placed in brown container and put, to spend the night use), liquid scintillation counter counts.Whole experimental cell is divided into matched group (not adding cholesterol still to add apoA-I, add cholesterol) and application of sample group (simultaneously adding cholesterol, apoA-I and certain density testing sample [15,20]).
Cholesterol Efflux rate %=culture fluid cpm value/total cpm value × 100%
=culture fluid cpm value/(culture fluid cpm value+cell cpm value) × 100%
The pharmacodynamic evaluation of embodiment 21LX-1 in apoE-/-Mice Body
ApoE-/-mice, in 7 week age, normal diet is fed one week;
ApoE-/-mice is weighed, random packet, be divided into 5 groups (model group, high dose group (10mg/Kg), middle dosage group (30mg/Kg), low dose group (90mg/Kg), negative control group, positive drug groups (5mg/Kg)), only often organize 6-8;
From 8 week age, model group and administration group fed high lipid food, and negative control group continues to feed normal diet; Gastric infusion;
By administration or the carboxymethyl cellulose apoE-of 8 weeks/-mice fasting 6h; Pluck eyeball and get blood, blood is collected with the EP pipe of heparin rinse, turn upside down, be placed on ice, 4000rpm/min, 4 DEG C of centrifugal 3min, measure the content of serum total cholesterol (TC), triglyceride (TG), HDL-C (HDL-C) and low-density lipoprotein cholesterol (LDL-C) according to the world and explanation by the serum be separated.Above detection kit is Chen Bei in Beijing and controls clinical reagent Products.
List of references
[1]Fielding?CJ?and?Fielding?PE：Molecular?physiology?of?reverse?cholesterol?transport.J?Lipid?Res1995；36：211-228.
[2]Oram?JF?and?Yokoyama?S：Apolipoprotein-mediated?removal?of?cellular?cholesterol?and?phospholipids.J?Lipid?Res1996；37：2473-2491.
[3]Alan?D.Attie，John?P.Kastelein?and?Michael?R.Hayden.Pivotal?role?of?ABCA1in?reverse?cholesterol?transport?influencing?HDL?levels?and?susceptibito?atherosclerosis.J?Lipid?Res2001；42：1717-1726.
[4]S?Soumian，C?Albrecht，AH?Davies?and?RGJ?Gibbs.ABCA1and?atherosclerosis.Vascular?Medicine2005；10：109-119.
[5]John?F.Oram?and?Jay?W.Heinecke.ATP-binding?cassette?transporter?A1：a?cell?cholesterol?exporter?that?protects?against?cardiovascular?disease.Physiol?Rev2005；85：1343-1372.
[6]Silver?DL，Tall?AR.The?cellular?biology?of?scavenger?receptor?class?B?type?I.Curr?Opin?Lipidol2001；12(5)：497-504.
[7]Miller?NE：Associations?of?high-density?lipoprotein?subclasses?and?apolipoproteins?with?ischemic?heart?disease?and?coronary?atherosclerosis.Am?Heart?J1987；113：589-597。
Claims (10)
- The application that the pyridine compounds and their that 1.2-amide groups-3 alkoxyl replaces is transferred person in the medicine of ATP binding cassette transporter body A1 (ABCA1) and/or scavenger receptor BI (CLA-1/SR-B1) expression activity on preparation has, its structure is as shown in general formula (I):Wherein, n=0-4, representative comprises the linear paraffin base of atom number between 0-4 of hetero atom; R1 represents the alkyl of H atom or C1-C4; R2, R3, R4 independently represent the alkyl of C1-C3, the oxyl of C1-C3, halogen atom or H atom; R5 independently represents and includes H, C1-C4 alkyl, C1-C3 alcoxyl (sulfur) base, halogen atom, the cycloalkane, 1 of the phenyl ring that 1,3-dioxy (sulfur) Pentamethylene. base replaces, pyridine ring, pyrimidine ring, piperidine ring, piperazine ring, C3-C6,2,3-triazole, 1,2,4-triazole, pyrrole ring, furan nucleus, oxazole ring, imidazole ring, thiphene ring, thiazole ring and benzimidazole, benzothiazole, benzoxazole, benzofuran, benzothiophene or indole ring.In compound shown in formula (I), R1 is H preferably, alkyl is preferably methyl or the tert-butyl group, and alcoxyl (sulfur) base is preferably trifluoromethoxy or trifluoromethylthio, and the ring system representated by R5 is phenyl ring, furan nucleus, pyrrole ring, imidazole ring or benzimidazole ring preferably; N preferably 0, namely represents benzoic acids structure fragment.
- 2. application according to claim 1, it is the medicine treating and/or preventing cardiovascular disease that upper mediator ATP binding cassette transporter body A1 (ABCA1) and/or scavenger receptor BI (CLA-1/SR-B1) express medicine.
- 3. purposes according to claim 1, the medicine of wherein said upper mediator ATP binding cassette transporter body A1 (ABCA1) and/or scavenger receptor BI (CLA-1/SR-B1) expression activity is the medicine reducing Lipid pharmaceutical or reduce cholesterol.
- 4. purposes according to claim 1, the medicine of wherein said upper mediator ATP binding cassette transporter body A1 (ABCA1) and/or scavenger receptor BI (CLA-1/SR-B1) expression activity is antiatherogenic medicine.
- 5. the application that the compositions comprising the compound of claim 1 is transferred person in the medicine of ATP binding cassette transporter body A1 (ABCA1) and/or scavenger receptor BI (CLA-1/SR-B1) expression activity on preparation has.
- 6. purposes according to claim 5, wherein said upper mediator ATP binding cassette transporter body A1 (ABCA1) and/or the medicine of scavenger receptor BI (CLA-1/SR-B1) expression activity be reduce Lipid pharmaceutical or reduce cholesterol medicine.
- 7. purposes according to claim 5, the medicine of described upper mediator ATP binding cassette transporter body A1 (ABCA1) and/or scavenger receptor BI (CLA-1/SR-B1) expression activity is antiatherogenic medicine.
- 8. purposes as claimed in claim 5, the medicine of described upper mediator ATP binding cassette transporter body A1 (ABCA1) and/or scavenger receptor BI (CLA-1/SR-B1) expression activity is for treating and/or preventing cardiovascular disease medicine.
- 9. the purposes according to any one of claim 5-8, its various dosage form of described compositions can be prepared according to the conventional production process of pharmaceutical field, as made active ingredient mix with one or more carriers, is then made into required dosage form.
- 10. the purposes according to any one of claim 5-8, described compositions can the above-claimed cpd containing treatment effective dose be active ingredient, and containing one or more pharmaceutically acceptable carriers.
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| CN108250194A (en) * | 2018-02-12 | 2018-07-06 | 李化绪 | A kind of difluoro benzothiazole compound and its application in blood lipid-lowering medicine |
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| CN108250194A (en) * | 2018-02-12 | 2018-07-06 | 李化绪 | A kind of difluoro benzothiazole compound and its application in blood lipid-lowering medicine |
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