CN104892457A - Hydroxamic acid derivative, its pharmaceutical composition, preparation method and purpose thereof - Google Patents
Hydroxamic acid derivative, its pharmaceutical composition, preparation method and purpose thereof Download PDFInfo
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Abstract
The invention relates to a hydroxamic acid derivative, its pharmaceutical composition, a preparation method and a purpose thereof. The compound can effectively adjust CLA-1 activity and/or level, and has prospect for preparing a medicine to prevent or treat cardio cerebrovascular disease (such as atherosclerosis), anti inflammatory, body weight control (such as body weight losing and maintaining) or anti-tumor. The compound has a structure shown in a following formula, wherein, R' is selected from C6-12 aryl, substituted C6-C12 aryl, C6-C12 aryloxy and substituted C6-C12 aryloxy, m is 1, 2 or 3; and the substituent groups can be respectively and independently substituted by any one or more of halogen atom, C1-C6 alkyl, C1-6 alkyloxy, amino and C1-6 alkyl amino.
Description
The divisional application of the application's to be application number be patent of invention of CN201210260628.6.
Technical field
The invention belongs to field of medicine and chemical technology, relate to a kind of hydroxamic acid derivatives, its pharmaceutical composition, Preparation method and use.
Background technology
Cardiovascular and cerebrovascular diseases is the disease that current China and World Developed Countries sickness rate are the highest, and its lethal disability rate is in first of various diseases, and atherosclerosis (Atherosclerosis, AS) is the main pathological basis of cardiovascular and cerebrovascular diseases.Lipid metabolism disorders especially cholesterol metabolic disorder is generally acknowledged main risk factor.According to WHO prediction, cause dead number will be increased to about 2,500,000/year to the year two thousand twenty because of cardiovascular disorder, wherein mostly directly relevant with hyperlipemia.In the past between more than ten years, reducing level, the minimizing symptom relevant with cardiovascular disorder of plasma low density lipoprotein cholesterol (LDL-C) and reducing in the risk of major cardiovascular event, statins all shows vital role.This type of medicine comprises many cookle level products, as the atorvastatin (atorvastatin of Pfizer (Pfizer), Lipitor, and the Simvastatin (simvastatin of Merck & Co., Inc. (Merck) Lipitor), Zocor, Zocor).But statins also only can reduce cardiovascular event (the Brugts JJ of 20%-40%, Yetgin T, Hoeks SE, et al.The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors:meta-analysis of randomised controlled trials [J] .BMJ, 2009,338:b2376.), so cardiovascular disorder is still the primary killers of harm humans health.The harm of cardiovascular disorder to be reduced further, must go out send from the new therapy target of prevention and/or reverse AS the medicine found and there is novel mechanism while reducing LDL-C.
Long-term clinical study shows, the cholesterol level (HDL-C) of high-density lipoprotein (HDL) develops in oppositely relevant to atherosclerotic generation.The study of anti-atherogenic effect of HDL except anti-oxidant, the anti-inflammatory action that it has, the major vectors of a very important reason to be HDL be reverse cholesterol transport (reverse cholesterol transfer, RCT).Acton in 1996 etc. find that the membrane receptor SR-BI alternative picked-up on liver cell utilizes the cholesteryl ester in HDL-C, first time confirms B race I type scavenger receptor (Scavenger receptor class B type I, SR-BI) be high-density lipoprotein (HDL) receptor (the Acton SL with function, Rigotti A, Landschulz KT, et al.Identification of scavenger receptor SR-BI as a high density lipoprotein receptor [J] .Science, 1996,271 (5248): 518-520.).Mankind SR-BI (hSR-BI) is independently found as CD36 membranin superfamily and LIMP associated protein, so be also called CLA-1 (CD36and LIMPII Analogous-1).In recent years, the effect of high-density lipoprotein (HDL) in atherosclerosis becomes study hotspot, correlative study progressively disclose that the receptor-mediated reverse cholesterol transport mechanism of HDL makes to be not easy in peripheral tissues to regulate and utilize cholesterol can be transported to liver and carry out disposal metabolism, and then the formation of atherosclerosis Lipid Plaque may be made to be eased by the counter transport mode of cholesterol even reverse.Result of study in recent years shows, SR-BI/CLA-1 participates in the selectivity picked-up of cholesterol in the outflow of cholesterol in peripheral tissues and liver, all keying action is played in the initial and whole last step of reverse cholesterol transport, be considered to potential target (the Acton SL finding Novel cardiovascular medicine, Kozarsky KF, Rigotti A.The HDL receptor SR-BI:a new therapeutic target for atherosclerosis? [J] .Mol Med Today, 1999,5 (12): 518-524).
Summary of the invention
The present inventor is through deep research and a large amount of experiments, find a class hydroxamic acid derivatives, and be surprised to find, these compounds can regulate activity and/or the level of CLA-1 effectively, have the prospect as control cardiovascular and cerebrovascular diseases (such as atherosclerosis) medicine.Thus provide following invention:
One aspect of the present invention relates to the compound shown in formula II, or its pharmacologically acceptable salt,
Wherein,
The C6-12 aryloxy that R ' is selected from C6-12 aryl, the C6-12 aryl of replacement, C6-12 aryloxy and replaces,
M is 1,2 or 3;
Described substituting group is selected from halogen atom, C1-6 alkyl, C1-6 alkoxyl group, amino and C1-6 alkylamino, and described substituting group is one or more (namely described replacement is independently of one another by any one or more identical or different substituting group be selected from halogen atom, C1-6 alkyl, C1-6 alkoxyl group, amino and C1-6 alkylamino is replaced).
Compound according to any one of the present invention, or its pharmacologically acceptable salt, wherein,
The hydrocinnamyl that R and R ' is separately selected from phenyl, the phenyl of replacement, benzyl, the benzyl of replacement, styroyl, the styroyl of replacement, hydrocinnamyl and replaces.
Compound according to any one of the present invention, or its pharmacologically acceptable salt, wherein, the ortho position of wherein said substituting group on phenyl ring, a position or contraposition.
Compound according to any one of the present invention, or its pharmacologically acceptable salt, wherein,
Described halogen is fluorine, chlorine, bromine or iodine, and described C1-6 alkoxyl group is methoxy or ethoxy, and described C1-6 alkylamino is dimethylamino or diethylin.
Compound according to any one of the present invention, or its pharmacologically acceptable salt, it is selected from compound shown in following table 1, or its pharmacologically acceptable salt:
Table 1: the part particular compound meeting formula II
Another aspect of the present invention relates to the preparation method of the compound above described in any one, comprises the steps:
Wherein,
A represents 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC), the aminated compounds corresponding with product, CH
2cl
2;
B represents NH
2oHHCl, NaOH, MeOH;
C represents NaHCO
3, the aminated compounds corresponding with product, CH
3cN; R ', m are respectively as described in any one above.
Those skilled in the art can understand, and term " aminated compounds corresponding with product " or " corresponding amine " are the general and usual descriptions of correlated response process in chemosynthesis, are also found in the report of this area document; To the understanding of this term, should in conjunction with front and back reaction process, namely according to the difference of object product, for introducing R-amido or R '-amido to the product of synthesis, wherein symbol R or R ' has the implication of the above-mentioned any one of the present invention; " aminated compounds that product is corresponding " or " corresponding amine " includes but not limited to aniline, 3-chloroaniline, 4-methoxybenzylamine described in embodiments of the invention, etc.
It is in addition, as described herein that " a represents 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC), the aminated compounds corresponding with product, CH
2cl
2" in fact represent that reaction adds EDC, the aminated compounds corresponding with product and CH
2cl
2.Also similar understanding can be done for b and c.
Another aspect of the invention relates to a kind of pharmaceutical composition, and it comprises the compound or pharmaceutically acceptable salt thereof according to any one of the present invention; Alternatively, pharmaceutically acceptable carrier or auxiliary material is also comprised.
Usual pharmaceutical composition of the present invention contains the formula I of 0.1-90 % by weight or formula II compound and/or its pharmacy acceptable salt.Pharmaceutical composition can be prepared according to methods known in the art.During for this object, if needed, formula I or formula II compound and/or its pharmacy acceptable salt and one or more solids or liquid pharmaceutical excipients and/or assistant agent can be combined, make the suitable administration form or dosage form that can be used as people.
Formula I of the present invention or formula II compound and/or its pharmacy acceptable salt or pharmaceutical composition of the present invention can administrations in a unit, route of administration can be enteron aisle or non-bowel, as oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritonaeum or rectum etc.Form of administration is tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, liposome, transdermal agent, buccal tablet, suppository, lyophilized injectable powder etc. such as.Can be ordinary preparation, sustained release preparation, controlled release preparation and various particulate delivery system.In order to unit dosage forms for administration is made tablet, various carrier well known in the art can be widely used.Example about carrier is, such as thinner and absorption agent, as starch, dextrin, calcium sulfate, lactose, N.F,USP MANNITOL, sucrose, sodium-chlor, glucose, urea, calcium carbonate, white bole, Microcrystalline Cellulose, pure aluminium silicate etc.; Wetting agent and tackiness agent, as water, glycerine, polyoxyethylene glycol, ethanol, propyl alcohol, starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, Xylo-Mucine, lac, methylcellulose gum, potassiumphosphate, polyvinylpyrrolidone etc.; Disintegrating agent, such as dry starch, alginates, agar powder, laminaran, sodium bicarbonate and Citric Acid, calcium carbonate, polyoxyethylene, sorbitan fatty acid ester, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.; Disintegration inhibitor, such as sucrose, Tristearoylglycerol, theobroma oil, hydrogenation wet goods; Absorption enhancer, such as quaternary ammonium salt, sodium lauryl sulphate etc.; Lubricant, such as talcum powder, silicon-dioxide, W-Gum, stearate, boric acid, whiteruss, polyoxyethylene glycol etc.Tablet can also be made coating tablet further, such as sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.In order to administration unit is made pill, various carrier well known in the art can be widely used.Example about carrier is, such as thinner and absorption agent, as glucose, lactose, starch, theobroma oil, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talcum powder etc.; Tackiness agent is as gum arabic, tragacanth gum, gelatin, ethanol, honey, liquid sugar, rice paste or batter etc.; Disintegrating agent, as agar powder, dry starch, alginates, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.In order to administration unit is made suppository, various carrier well known in the art can be widely used.Example about carrier is, the ester, gelatin, semi-synthetic glyceryl ester etc. of such as polyoxyethylene glycol, Yelkin TTS, theobroma oil, higher alcohols, higher alcohols.In order to administration unit is made capsule, effective constituent type I compound or its steric isomer are mixed with above-mentioned various carriers, and the mixture obtained thus is placed in hard obviously capsule or soft capsule.Also effective constituent formula I or formula II compound and/or its pharmacy acceptable salt or pharmaceutical composition of the present invention can be made microcapsule, be suspended in aqueous medium and form suspensoid, also can load in hard capsule or make injection application.In order to administration unit is made injection preparation, as solution, emulsion, lyophilized injectable powder and suspensoid, all thinners that this area is conventional can be used, such as, the isooctadecanol of water, ethanol, polyoxyethylene glycol, 1,3-PD, ethoxylation, polyoxygenated isooctadecanol, Polyoxyethylene Sorbitol Fatty Acid Esters etc.In addition, in order to prepare isotonic injection liquid, appropriate sodium-chlor, glucose or glycerine can be added in injection preparation, in addition, conventional solubility promoter, buffer reagent, pH adjusting agent etc. can also be added.
In addition, as needs, also tinting material, sanitas, spices, correctives, sweeting agent or other material can be added in pharmaceutical preparation.
The dosage of formula I of the present invention or formula II compound and/or its pharmacy acceptable salt or pharmaceutical composition of the present invention depends on many factors, such as to prevent or the character of disease therapy and severity, the sex of patient or animal, age, body weight and individual reaction, particular compound used, route of administration and administration number of times etc.Above-mentioned dosage can single dose form or be divided into several, such as two, three or four dosage forms for administration.
Term used herein " composition " means to comprise the product of each appointment composition comprising specified amount, and any product directly or indirectly produced from the combination of each appointment composition of specified amount.
The active compound amount of gained the actual dose level of each activeconstituents in pharmaceutical composition of the present invention can be changed, so that effectively can obtain required therapeutic response for concrete patient, composition and administering mode.Dosage level must according to the activity of particular compound, route of administration, treat the severity of the patient's condition and the patient's condition of patient to be treated and medical history and select.But the way of this area is, the dosage of compound, from lower than for obtaining level that required result for the treatment of requires, increases dosage, gradually until obtain required effect.
Another aspect of the invention relates to the purposes of compound or pharmaceutically acceptable salt thereof in preparation adjustment CLA-1 activity or the medicine of CLA-1 level or the medicine of reagent or adjusting blood lipid level or total cholesterol level according to any one of the present invention.It is active that described adjustment CLA-1 activity comprises rise CLA-1.Described adjustment CLA-1 level comprises raising CLA-1 level.Described adjusting blood lipid level comprises reduction blood lipid level.Described adjustment total cholesterol level comprises reduction total cholesterol level.
Another aspect of the invention relates to the method for in vivo a kind of or external adjustment CLA-1 activity or CLA-1 level, comprises the step of the compound or pharmaceutically acceptable salt thereof according to any one of the present invention using significant quantity.
Another aspect of the invention relates to compound or pharmaceutically acceptable salt thereof according to any one of the present invention and treats and/or prevents and/or purposes in adjuvant therapy of heart cerebrovascular diseases, anti-inflammatory, weight management (lose weight, maintain body weight) or anti-tumor drug in preparation; Particularly, described cardiovascular and cerebrovascular diseases is selected from atherosclerosis, hyperlipidemia, hypercholesterolemia, acute myocardial infarction, cerebral apoplexy and coronary heart disease.
Another aspect of the invention relates to one and treats and/or prevents and/or adjuvant therapy of heart cerebrovascular diseases, anti-inflammatory, weight management (lose weight, maintain body weight) or antineoplastic method, comprises the step of the compound or pharmaceutically acceptable salt thereof according to any one of the present invention giving significant quantity.Particularly, described cardiovascular and cerebrovascular diseases is selected from atherosclerosis, hyperlipidemia, hypercholesterolemia, acute myocardial infarction, cerebral apoplexy and coronary heart disease.
When for above-mentioned treat and/or prevent and/or assisting therapy time, the one compound or pharmaceutically acceptable salt thereof of the present invention treating and/or preventing significant quantity can be applied in a pure form, or with the acceptable ester of pharmacy or prodrug forms (when there are these forms) application.Or described compound can accept the pharmaceutical composition administration of vehicle containing this object compound and one or more medicines.The compounds of this invention that word " prevents and/or treats significant quantity " refers to the compound of the q.s of the reasonable effect/Hazard ratio treatment obstacle being applicable to any medical prophylaxis and/or treatment.But it should be understood that total daily dosage portion of the compounds of this invention and composition must be maked decision within the scope of reliable medical judgment by attending physician.For any concrete patient, concrete treatment effective dose level must be determined according to many factors, and described factor comprises treated obstacle and the severity of this obstacle; The activity of the particular compound adopted; The concrete composition adopted; Age of patient, body weight, general health situation, sex and diet; The administration time of the particular compound adopted, route of administration and excretion rate; The treatment time length; The medicine combinationally using with adopted particular compound or use simultaneously; And the known similar factor of medical field.Such as, the way of this area is, the dosage of compound, from lower than for obtaining level that required result for the treatment of requires, increases dosage, gradually until obtain required effect.In general, compound of the present invention is used for the dosage of Mammals particularly people can between 0.001-1000mg/kg body weight/day, such as, between 0.01-100mg/kg body weight/day, such as, between 0.01-10mg/kg body weight/day.
Various disease of the present invention or illness effectively can be prevented and/or treated according to compound of the present invention.
In the present invention, term " C1-6 alkyl " refers to the straight or branched alkyl with 1-6 carbon atom, such as methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, amyl group, 2-amyl group, isopentyl, neo-pentyl, hexyl, 2-hexyl, 3-hexyl, 3-methyl amyl etc.
Term " C1-6 alkoxyl group ", refer to the straight or branched alkoxyl group with 1-6 carbon atom, such as methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy, sec-butoxy, tert.-butoxy, pentyloxy, 2-oxygen amyl group, different oxygen amyl group, neopentyl oxygen, hexyloxy, 2-hexyloxy, 3-oxygen hexyl, 3-methyl pentyloxy etc.
Term " C1-6 alkylamino ", refers to and arbitrary carbon potential or many carbon potentials contains one or more amino to C1-6 alkyl.C1-4 alkylamino or C1-3 alkylamino also can do similar understanding.
The example of term " C6-12 aryl " term " C5-20 aryl " comprises phenyl, benzyl, styroyl, hydrocinnamyl, etc.These aryl can be replaced by alkyl (such as C1-6 alkyl) or alkoxyl group (such as C1-6 alkoxyl group) or halogen atom.Substituting group can at the ortho position of phenyl ring, a position or contraposition.
The example of term " C6-12 aryloxy " comprises benzyloxy etc.These aryloxy can be replaced by one or more alkoxyl group (such as C1-6 alkoxyl group) or alkyl (such as C1-6 alkyl) or halogen atom.Substituting group can at the ortho position of phenyl ring, a position or contraposition.
The beneficial effect of the invention
Compound of the present invention can regulate activity and/or the level of CLA-1 effectively, has the prospect as preventing and treating cardiovascular and cerebrovascular diseases (such as atherosclerosis), anti-inflammatory, weight management (lose weight, maintain body weight) or antitumor drug.
Embodiment
Below in conjunction with embodiment, embodiment of the present invention are described in detail, but it will be understood to those of skill in the art that the following example only for illustration of the present invention, and should not be considered as limiting scope of the present invention.Unreceipted actual conditions person in embodiment, the condition of conveniently conditioned disjunction manufacturers suggestion is carried out.Agents useful for same or the unreceipted production firm person of instrument, being can by the conventional products of commercial acquisition.
Embodiment 1:N-hydroxyl-4-{ [(phenacyl)-amido] methyl } preparation of benzamide (compound 1)
1) preparation of acetobromanilide
Bromoacetic acid (2.78g, 20.0mmol) is dissolved in CH
2cl
2(20.0ml) in, be chilled to-5 DEG C, add EDC.HCl (3.84g, 20.0mmol), be then added dropwise to the CH of aniline (1.86g, 20.0mmol)
2cl
2(10.0ml) solution, reaction solution rises to room temperature naturally, and stirring is spent the night.
Add 1mol/L HCl (30ml) in reaction solution to wash, 5%Na2HCO3 (30ml) washes, and saturated common salt is washed.Organic phase anhydrous sodium sulfate drying.Concentrate and obtain crude product, yield about 60%.Need not purifying, be directly used in the next step.
2) preparation of 4-[(benzoyl methylamino)-methyl]-methyl benzoate
5-anilino formyl-methyl valerate (1.18g, 5.0mmol) be dissolved in (50mL) in methyl alcohol, add oxammonium hydrochloride (1.40g, 20.0mmol) and be cooled to 0 DEG C, be added dropwise to NaOH (10mL) solution of 8mol/L, stirring at room temperature 1-2 hour.
In solution, be added dropwise to 1mol/L HCl (50mL) at 0 DEG C adjust Ph=7-8, solution decompression concentrates, and crosses MCI GEL 20Y post (water/methyl alcohol) purifying, obtains yellow solid
Acetobromanilide (10.0mmol), 4-(amine methyl) benzoate hydrochloride (2.02g, 10.0mmol) be dissolved in acetonitrile (100ml) with saleratus (1.50g, 15.0mmol), solution return stirs 3-4 hour.
Concentrating under reduced pressure, resistates adds water and ethyl acetate separatory, adds HCl solution (1mol/L) in organic phase, separates out precipitation, and filter, solid washed with water, obtains crude product, yield about 50%.Need not purifying, be directly used in the next step.
3) N-hydroxyl-4-{ [(phenacyl)-amido] methyl } preparation of benzamide
4-[(benzoyl methylamino)-methyl]-methyl benzoate (149mg, 0.5mmol) be dissolved in (5mL) in methyl alcohol, add oxammonium hydrochloride (140mg, 2.0mmol) be cooled to 0 DEG C, be added dropwise to NaOH (1mL) solution of 8mol/L, stirring at room temperature 1-2 hour.
In solution, be added dropwise to 1mol/L HCl (50mL) at 0 DEG C adjust Ph=7-8, solution decompression concentrates, and crosses MCI GEL 20Y post (water/methyl alcohol) purifying, obtains white solid 71.3mg, yield: 47.7%; M.p.124-126 DEG C of .1HNMR (DMSO-d6,400MHz, δ ppm) 3.26 (2H, s, CH
2cO), 3.77 (2H, s, NHCH
2), 7.01-7.71 (9H, m, Ar-H), 9.80 (1H, s, CONH) .MS (ESI) m/z:300 (M+H)+.HRMS (ESI) m/z:(M+H)+calcd.for C
16h
18n
3o
3, 334.0953; Found, 334.0952.
Embodiment 2: the preparation of compound 2-15
Compound 2-15 has been prepared respectively in embodiment 2.The preparation process of compound 2-15 is identical with the preparation process of compound 1 in embodiment 1, distinguishes to some extent except raw materials used.Difference is as shown in Table 2 below:
Table 2: the preparation process of compound 2-15 and the difference of embodiment 10
| Embodiment is numbered | With the difference of embodiment 1 step |
| 2 | Aniline is replaced with 2-chloroaniline |
| 3 | Aniline is replaced with 3-chloroaniline |
| 4 | Aniline is replaced with 4-chloroaniline |
| 5 | Aniline is replaced with 4-anisidine |
| 6 | Aniline is replaced with 3,4-dimethoxyaniline |
| 7 | Aniline is replaced with 4-dimethylin aniline |
| 8 | Aniline is replaced with 4-methoxybenzylamine |
| 9 | Aniline is replaced with phenylethylamine |
| 10 | Aniline is replaced with 3,4-dimethoxy-phenylethylamine |
| 11 | Bromoacetic acid is replaced with bromo-propionic acid, aniline is replaced with 2-chloroaniline |
| 12 | Bromoacetic acid is replaced with bromo-propionic acid, aniline is replaced with 4-chloroaniline |
| 13 | Bromoacetic acid is replaced with bromo-propionic acid, aniline is replaced with 4-anisidine |
| 14 | Bromoacetic acid is replaced with bromo-propionic acid, aniline is replaced with 3,4-dimethoxyaniline |
| 15 | Bromoacetic acid is replaced with bromo-propionic acid, aniline is replaced with 4-methoxybenzylamine |
Embodiment 3: the structure verification of compound 1-15
As shown in Table 3 below.
Table 3: the nuclear magnetic resonance data of compound 1-15
Embodiment 4: in liver cell HepG2, CLA-1 promoter activity raises experiment
1. reagent and material
Test sample: compound 1-15.
Positive control: SAHA and TSA (equal available from Sigma).
The compound of all tests is all through HPLC screening, and purity is greater than 95%, and experimental concentration is 10 μ g/mL.
CLAP-Luc HepG2 cell is that (method that construction process can adopt those skilled in the art to know, such as can with reference to Liu Xiaohui, Hong Bin for the HepG2 cell of luciferase reporter gene of the promotor containing CLA-1 that this laboratory builds, Wang Lifei, Yang Yuan, Si Shuyi, Li Yuan; The foundation [J] of human high-density lipoprotein receptor expression up regulating agent screening model. Chinese Academy of Medical Sciences's journal, 2004,26 (4): 354-358.)。
2. experimental technique and step
Detection compound is to the impact of promotor (CLA-1promoter, the CLAP) activity of CLA-1.
By CLAP-Luc HepG2 cell with 5 × 10
4individual/hole is inoculated in 96 porocyte culture plates, and about 6h is after cell attachment, and being changed to respectively containing concentration is the serum-free medium of 10 μ g/ml compound 1-15.The hole containing final concentration 0.1%DMSO (solvent) substratum is separately established to do blank.Continue at 37 DEG C, 5%CO
2after cultivating 18h under condition, active by the luciferase expression measuring each compound group process cell, computerized compound is to the average rise multiple of CLA-1 promotor.Quantitative dose-effect relationship is carried out to the obvious compound of rise multiple, analyzes the relation between the compound concentration of serial dilution and promoter activity (luciferase expression is active), calculate EC50.Concrete operation step is with reference to the specification sheets of Luciferase Assay System (Promega).
3. experimental result as shown in Table 4 below.
Table 4: compound 1-15 is to the average rise multiple of CLA-1 promoter activity
| Compound number | Average rise multiple | Standard deviation |
| 1 | 10.1 | 0.8 |
| 2 | 6.6 | 0.02 |
| 3 | 0.89 | 0.05 |
| 4 | 12.4 | 1.1 |
| 5 | 10.5 | 0.6 |
| 6 | 2.9 | 0.4 |
| 7 | 8.1 | 0.3 |
| 8 | 4.6 | 0.1 |
| 9 | 5.0 | 0.4 |
| 10 | 1.9 | 0.4 |
| 11 | 8.2 | 1.6 |
| 12 | 13.4 | 4.8 |
| 13 | 5.2 | 1.1 |
| 14 | 1.4 | 0.3 |
| 15 | 7.2 | 1.8 |
| SAHA (positive control) | 25.9 | 0.5 |
| TSA (positive control) | 23.9 | 1.3 |
Above result of study shows, compound effect of the present invention is similar to Simvastatin group drug effect, effectively can reduce total plasma cholesterol, have study of anti-atherogenic effect.
Finally it is pointed out that above embodiment only for helping skilled in the art to understand essence of the present invention, being not used as limiting the scope of the invention.
Claims (10)
1. the compound shown in formula II, or its pharmacologically acceptable salt,
Wherein,
R ' is selected from C
6-12the C of aryl, replacement
6-12aryl, C
6-12aryloxy and the C replaced
6-12aryloxy,
M is 1,2 or 3;
Described replacement is independently of one another for being selected from halogen atom, C
1-6alkyl, C
1-6alkoxyl group, amino and C
1-6any one or more substituting groups in alkylamino replaced.
2. compound according to claim 1, or its pharmacologically acceptable salt, wherein,
The hydrocinnamyl that R ' is separately selected from phenyl, the phenyl of replacement, benzyl, the benzyl of replacement, styroyl, the styroyl of replacement, hydrocinnamyl and replaces.
3. according to the arbitrary described compound of claim 1 or 2, or its pharmacologically acceptable salt, wherein, the ortho position of wherein said substituting group on phenyl ring, a position or contraposition.
4. according to the arbitrary described compound of claim 1 or 2, or its pharmacologically acceptable salt, wherein,
Described halogen is fluorine, chlorine, bromine or iodine, described C
1-6alkoxyl group is methoxy or ethoxy, described C
1-6alkylamino is dimethylamino or diethylin.
5. compound according to claim 1 and 2, or its pharmacologically acceptable salt, it is selected from following compound:
N-hydroxyl-4-{ [(phenacyl)-amido] methyl } benzamide,
N-hydroxyl-4-{ [(2-Chlorophenacyl)-amido] methyl } benzamide,
N-hydroxyl-4-{ [(3-Chlorophenacyl)-amido] methyl } benzamide,
N-hydroxyl-4-{ [(4-Chlorophenacyl)-amido] methyl } benzamide,
N-hydroxyl-4-{ [(2-methoxyphenacyl)-amido] methyl } benzamide,
N-hydroxyl-4-{ [(3,4-dimethoxybenzoyl methyl)-amido] methyl } benzamide,
N-hydroxyl-4-{ [(4-dimethylin phenacyl)-amido] methyl } benzamide,
N-hydroxyl-4-{ [(4-anisole acetylmethyl)-amido] methyl } benzamide,
N-hydroxyl-4-{ [(phenylpropyl alcohol acyl methyl)-amido] methyl } benzamide,
N-hydroxyl-4-{ [(3,4-dimethoxy benzene propionyl methyl)-amido] methyl } benzamide,
N-hydroxyl-4-{ [(2-Chlorophenacyl)-amido] ethyl } benzamide,
N-hydroxyl-4-{ [(4-Chlorophenacyl)-amido] ethyl } benzamide,
N-hydroxyl-4-{ [(4-methoxyphenacyl)-amido] ethyl } benzamide,
N-hydroxyl-4-{ [(3,4-dimethoxybenzoyl methyl)-amido] ethyl } benzamide, and
N-hydroxyl-4-{ [(4-anisole acetylmethyl)-amido] ethyl } benzamide;
Or its pharmacologically acceptable salt.
6. the preparation method of the compound according to any one of claim 1 to 5, comprises the steps:
wherein,
A represents 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, the aminated compounds corresponding with product, CH
2cl
2;
B represents NH
2oHHCl, NaOH, MeOH;
C represents NaHCO
3, the aminated compounds corresponding with product, CH
3cN;
R ', m are respectively according to any one of claim 1 to 5.
7. a pharmaceutical composition, it comprises the compound or pharmaceutically acceptable salt thereof according to any one of claim 1 to 5, and preferably, it also comprises pharmaceutically acceptable carrier or auxiliary material.
8. the purposes of the compound or pharmaceutically acceptable salt thereof according to any one of claim 1 to 5 in preparation adjustment CLA-1 activity or the medicine of CLA-1 level or the medicine of adjusting blood lipid level or total cholesterol level.
9. in vivo or external adjustment CLA-1 is active or a method for CLA-1 level, comprise the step of the compound or pharmaceutically acceptable salt thereof according to any one of claim 1 to 5 using significant quantity.
10. the compound or pharmaceutically acceptable salt thereof according to any one of claim 1 to 5 treats and/or prevents and/or purposes in adjuvant therapy of heart cerebrovascular diseases, anti-inflammatory, weight management (lose weight, maintain body weight) or anti-tumor drug in preparation; Particularly, described cardiovascular and cerebrovascular diseases is selected from atherosclerosis, hyperlipidemia, hypercholesterolemia, acute myocardial infarction, cerebral apoplexy and coronary heart disease.
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| CN201510155995.3A CN104892457B (en) | 2011-07-25 | 2012-07-25 | A kind of hydroxamic acid derivatives, its pharmaceutical composition, Preparation method and use |
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| CN201110218075 | 2011-07-25 | ||
| CN2011102180753 | 2011-07-25 | ||
| CN201210260628.6A CN102898332B (en) | 2011-07-25 | 2012-07-25 | Hydroxamic acid derivative, its pharmaceutical composition, preparation method and application |
| CN201510155995.3A CN104892457B (en) | 2011-07-25 | 2012-07-25 | A kind of hydroxamic acid derivatives, its pharmaceutical composition, Preparation method and use |
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| CN108324703B (en) * | 2018-01-26 | 2020-07-28 | 中国医学科学院阜外医院 | Injection for protecting ischemic myocardium and preparation method thereof |
| CN111848454B (en) * | 2019-04-28 | 2021-05-07 | 山东大学 | Histone deacetylase 6 inhibitor and preparation method and application thereof |
Citations (4)
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|---|---|---|---|---|
| EP0920413A1 (en) * | 1996-08-05 | 1999-06-09 | Prolinx, Inc. | Boronic compound complexing reagents and complexes |
| EP0984959A1 (en) * | 1997-03-04 | 2000-03-15 | Monsanto Company | Aromatic sulfonyl alpha-hydroxy hydroxamic acid compounds |
| CN100540530C (en) * | 2004-07-05 | 2009-09-16 | 意大利法尔马科有限公司 | alpha-amino acid derivatives with anti-inflammatory activity |
| CN101683329A (en) * | 2008-09-27 | 2010-03-31 | 中国医学科学院医药生物技术研究所 | Application of histone deacetylase inhibitor in treating atherosclerosis |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101209974A (en) * | 2006-12-31 | 2008-07-02 | 天津药物研究院 | Hydroxamic acids derivatives and use thereof |
-
2012
- 2012-07-25 CN CN201510155995.3A patent/CN104892457B/en active Active
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0920413A1 (en) * | 1996-08-05 | 1999-06-09 | Prolinx, Inc. | Boronic compound complexing reagents and complexes |
| EP0984959A1 (en) * | 1997-03-04 | 2000-03-15 | Monsanto Company | Aromatic sulfonyl alpha-hydroxy hydroxamic acid compounds |
| CN100540530C (en) * | 2004-07-05 | 2009-09-16 | 意大利法尔马科有限公司 | alpha-amino acid derivatives with anti-inflammatory activity |
| CN101683329A (en) * | 2008-09-27 | 2010-03-31 | 中国医学科学院医药生物技术研究所 | Application of histone deacetylase inhibitor in treating atherosclerosis |
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| SUNG BIN Y: "Assembling Ligands In Situ Using Bioorthogonal Boronate Ester Synthesis", 《CHEMISTRY&BIOLOGY》 * |
| 周玉美: "异羟肟酸类组蛋白去乙酰化酶抑制剂的设计合成与活性研究", 《工程科技I辑》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102898332A (en) | 2013-01-30 |
| CN104892457B (en) | 2017-07-28 |
| CN102898332B (en) | 2015-05-06 |
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