CN102898332B - Hydroxamic acid derivative, its pharmaceutical composition, preparation method and application - Google Patents
Hydroxamic acid derivative, its pharmaceutical composition, preparation method and application Download PDFInfo
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- CN102898332B CN102898332B CN201210260628.6A CN201210260628A CN102898332B CN 102898332 B CN102898332 B CN 102898332B CN 201210260628 A CN201210260628 A CN 201210260628A CN 102898332 B CN102898332 B CN 102898332B
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Abstract
The invention belongs to the pharmaceutical chemicals field, and relates to a hydroxamic acid derivative, its pharmaceutical composition, a preparation method and an application. The invention relates to a compound shown in a formula I or a formula II, or its pharmaceutical salt. The compound can effectively adjust the activity and/or level of CLA-1, and has a prospect for preventing and treating cardiovascular and cerebrovascular diseases (such as atherosclerosis).
Description
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, Lipitor, Lipitor) of Pfizer (Pfizer) and the Simvastatin (simvastatin, Zocor, Zocor) of Merck & Co., Inc. (Merck).But statins also only can reduce cardiovascular event (the Brugts JJ of 20%-40%, YetginT, Hoeks SE, et al.The benefits of statins in people withoutestablished cardiovascular disease but with cardiovascularrisk 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 classB type I, SR-BI) be high-density lipoprotein (HDL) receptor (the Acton SL with function, RigottiA, Landschulz KT, et al.Identification of scavenger receptorSR-BI as a high density lipoprotein receptor [J] .Science, 1996,271 (5248): 518-520.).Mankind SR-BI(hSR-BI) 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 foratherosclerosis [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, there is the prospect as control cardiovascular and cerebrovascular diseases (such as atherosclerosis) medicine.Thus provide following invention:
One aspect of the present invention relates to formula I or 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,
N is 0,1,2 or 3;
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 substituting group is selected from halogen atom, C
1-6alkyl, C
1-6alkoxyl group, amino and C
1-6alkylamino, and described substituting group is that one or more (namely 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 identical or different substituting group in alkylamino 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, described C
1-6alkoxyl group is methoxy or ethoxy, described C
1-6alkylamino 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 table 2, or its pharmacologically acceptable salt:
Table 1: the part particular compound meeting formula I
Table 2: 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:
Or,
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, backflow; R, R ', n, m be 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 " C
1-6alkyl " refer 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 " C
1-6alkoxyl 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 " C
1-6alkylamino ", refer to C
1-6arbitrary carbon potential or many carbon potentials contain one or more amino to alkyl.C
1-4alkylamino or C
1-3alkylamino also can do similar understanding.
Term " C
6-12aryl " term " C
5-20aryl " example comprise phenyl, benzyl, styroyl, hydrocinnamyl, etc.These aryl can by alkyl (such as C
1-6alkyl) or alkoxyl group (such as C
1-6alkoxyl group) or halogen atom replacement.Substituting group can at the ortho position of phenyl ring, a position or contraposition.
Term " C
6-12aryloxy " example comprise benzyloxy etc.These aryloxy can by one or more alkoxyl group (such as C
1-6alkoxyl group) or alkyl (such as C
1-6alkyl) or halogen atom replacement.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.
Accompanying drawing explanation
Fig. 1: the impact that compound is expressed CLA-1 in HepG2 cell.Fig. 1 (A): compound 7 is on the impact of CLA-1mRNA level; Fig. 1 (B): Flow Cytometry detection compound 7 is on the impact of CLA-1 protein expression; Fig. 1 (C): the Western Blot impact of detection compound 7 on CLA-1 protein expression; The quantification result that Fig. 1 (D): Western Blot detection compound 7 affects CLA-1 protein expression.
Fig. 2: compound absorbs the impact of ability to HepG2 cell DiI-HDL.Fig. 2 (A): 0.3 μM compound 7 is on the impact of HepG2 cellular uptake DiI-HDL ability; Fig. 2 (B): 0.75 μM compound 7 is on the impact of HepG2 cellular uptake DiI-HDL ability; Fig. 2 (C): 1.5 μMs compounds 7 are on the impact of HepG2 cellular uptake DiI-HDL ability; Fig. 2 (D): 0.3 μM SAHA is on the impact of HepG2 cellular uptake DiI-HDL ability; Fig. 2 (E): 0.6 μM SAHA is on the impact of HepG2 cellular uptake DiI-HDL ability; Fig. 2 (F): compound 7 and SAHA absorb the quantification result of ability to HepG2 cell DiI-HDL.
Fig. 3: compound is on the impact of Mouse Weight.
Fig. 4: compound is on the impact (* represents P < 0.05) of mouse aorta patch.Fig. 4 (A): the mouse aorta Mottling formation situation of high fat diet control (HFC); To the protection situation of mouse aorta Fig. 4 (B): compound 7(25mg/Kg); Fig. 4 (C): the quantitative result (n=4) of mouse aorta plaque area.
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: the preparation of hexanedioyl aniline hydroxamic acid (compound 1)
1) preparation of 5-anilino formyl-methyl valerate.
Monoethyl adipatee (3.20g, 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%Na
2hCO
3(30ml) wash, 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 hexanedioyl aniline hydroxamic acid (compound 1)
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 GEL20Y post (water/methyl alcohol) purifying, obtains yellow solid 698mg, yield: 59.2%; M.p.180-181.5 ° of C.1HNMR (DMSO-d6,400MHz, δ ppm) 1.52 (4H; m, 2CH2), DEG C 1.96 (2H; t, J=6.8, CH2); 2.28 (2H, t, J=6.8; CH2), 7.00 (1H, t; J=8.0, Ar-H), 7.27 (2H; t, J=8.0, Ar-H); 7.55 (2H, d, J=8.0; Ar-H), 8.65 (1H, s; CONHOH), 9.84 (1H, s; NHCO), 10.34 (1H, s; CONHOH) .MS (ESI) m/z:237 (M+H)+.HRMS (ESI) m/z:(M+H)+calcd.for C12H17N2O3,237.1234; Found, 237.1227.
embodiment 2-9: the preparation of compound 2-9
Embodiment 2-9 has prepared compound 2-9 respectively.The preparation process of compound 2-9 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 3 below:
Table 3: the preparation process of compound 2-9 and the difference of embodiment 1
embodiment 10:N-hydroxyl-4-{ [(phenacyl)-amido] methyl } benzamide (change
compound 10) preparation
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%Na
2hCO
3(30ml) wash, 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 GEL20Y 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 GEL20Y post (water/methyl alcohol) purifying, obtains white solid 71.3mg, yield: 47.7%; M.p.124-126 ° of C.
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 11-24: the preparation of compound 11-24
Embodiment 11-24 has prepared compound 11-24 respectively.The preparation process of compound 11-24 is identical with the preparation process of compound 10 in embodiment 10, distinguishes to some extent except raw materials used.Difference is as shown in Table 4 below:
Table 4: the preparation process of compound 11-24 and the difference of embodiment 10
embodiment 25: the structure verification of compound 1-24
As shown in Table 5 below.
Table 5: the nuclear magnetic resonance data of compound 1-24
embodiment 26: in liver cell HepG2, CLA-1 promoter activity raises experiment
1. reagent and material
Test sample: compound 1-24.
The equal available from Sigma of positive control: SAHA and TSA().
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 1-24.Separately establish containing final concentration 0.1%DMSO(solvent) hole of substratum does 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 EC
50.Concrete operation step is with reference to Luciferase Assay System(Promega) specification sheets.
3. experimental result
Result is as shown in table 6 below and table 7.
Table 6: compound 1-24 is to the average rise multiple of CLA-1 promoter activity
| Compound number | Average rise multiple | Standard deviation |
| 1 | 5.4 | 1.4 |
| 2 | 9.4 | 1.3 |
| 3 | 5.9 | 1.8 |
| 4 | 3.6 | 0.3 |
| 5 | 13.8 | 2.1 |
| 6 | 9.2 | 2.3 |
| 7 | 13.3 | 3.4 |
| 8 | 10.4 | 1.4 |
| 9 | 15.7 | 2.5 |
| 10 | 10.1 | 0.8 |
| 11 | 6.6 | 0.02 |
| 12 | 0.89 | 0.05 |
| 13 | 12.4 | 1.1 |
| 14 | 10.5 | 0.6 |
| 15 | 2.9 | 0.4 |
| 16 | 8.1 | 0.3 |
| 17 | 4.6 | 0.1 |
| 18 | 5.0 | 0.4 |
| 19 | 1.9 | 0.4 |
| 20 | 8.2 | 1.6 |
| 21 | 13.4 | 4.8 |
| 22 | 5.2 | 1.1 |
| 23 | 1.4 | 0.3 |
| 24 | 7.2 | 1.8 |
| SAHA(positive control) | 25.9 | 0.5 |
| TSA(positive control) | 23.9 | 1.3 |
Table 7: compound 1-9 is to the maximum rise multiple of CLA-1 promoter activity and EC
50
| Compound number | EC 50(μM) | Maximum rise multiple |
| 1 | 4.7 | 12.2 |
| 2 | 2.4 | 13.3 |
| 3 | 3.7 | 13.0 |
| 4 | 10.2 | 10.6 |
| 5 | 1.8 | 19.2 |
| 7 | 0.32 | 21.8 |
| 9 | 1.3 | 18.5 |
| SAHA | 2.6 | 25.9 |
| TSA | 1.2 | 23.9 |
The result display of table 6 and table 7, compound of the present invention can both raise the activity/level of CLA-1 effectively.
embodiment 27: compound 7 couples of liver cell HepG2 high-density lipoprotein (HDL) receptor CLA-1 show
reach the impact with function
One, reagent and material
Test sample: compound 7(pimeloyl 3-chloroaniline hydroxamic acid, sometimes also referred to as " Cpd-7 " in the present invention).
The equal available from Sigma of positive control: SAHA and TSA().
MEM-EBSS substratum (Hyclone company) (containing 10% standard foetal calf serum <Hyclone company >) for liver cell HepG2(purchased from American Type type culture collection center, ATCC) cultivation.
Two, experimental technique and experimental result
1. real-time quantitative RT-PCR technique study Cpd-7 is on the impact of CLA-1 transcriptional level
(1) extraction of cell total rna
Human liver cell HepG2 is with 5 × 10
5individual inoculation 60mm Tissue Culture Plate, 37 DEG C, 5%CO
2cultivate under condition after 24 hours, ice-cold PBS rinsing cell 2 times, add the serum-free MEM-EBSS substratum containing 0.75,1.5 μM of (DMSO content is 0.1%) Cpd-7 respectively, positive control adds the TSA containing 0.6 μM (containing 0.1%DMSO).37 DEG C, 5%CO
2cultivate after 24 hours under condition, with Trizol reagent (Invitrogen company) carry out cell total rna extraction (concrete operation step carries out according to the specification sheets of test kit) and measure extract the concentration of RNA.
(2) synthesis of reverse transcription reaction--cDNA
Adopt ThermoScript
tMrT-PCR System test kit (Invitrogen company) carries out, and concrete operation step is according to described in test kit specification sheets.The each 4 μ g of template ribonucleic acid respectively with ThermoScript
tMwith primer RT Oligo (dT)
20mixing, 55 DEG C of insulation 60min carry out reverse transcription reaction, heat 5min with termination reaction after reaction terminates in 85 DEG C.Gained cDNA can preserve or continue the following PCR reaction of row in-20 DEG C.
(3) Real-time PCR detects
Adopt SYBR Green PCR Master Mix that the cDNA sample of acquisition is prepared Real-Time PCR reaction system respectively.System configurations is as follows:
2 × PCR Master Mix damping fluid 12.5 μ l; The each 2.5 μ l of upstream and downstream primer (2 μMs); Template 7.5 μ l; Cumulative volume 25 μ l.Mixed by solution, 5000rpm is of short duration centrifugal.
PCR reaction solution is placed in Real-time PCR instrument, carries out PCR reaction by following reaction conditions:
95 DEG C, 10 minutes, 1 circulation; 95 DEG C, 15 seconds, 60 DEG C, 30 seconds, 78 DEG C, 15 seconds (collection fluorescence), 40 circulations; 55 DEG C, 1 minute, 95 DEG C, 1 minute, 1 circulation; 55 to 95 DEG C, within every 5 seconds, raise 1 DEG C, 81 cycle detection solubility curves (Melting Curve).
The goal gene of each sample and housekeeping gene phosphoglyceraldehy-de dehydrogenase (GAPDH, internal reference) carry out Real-time PCR reaction respectively.In each sample, the relative content of goal gene utilizes △ △ Ct method to calculate, and calculation formula is:
Experimental result is shown in Fig. 1 (A), and compound 7 can raise the mRNA level in-site of CLA-1 gene in HepG2 cell, and after the Cpd-7 effect of 0.75 μM and 1.5 μMs, its rise rate is respectively 89.6% and 74.4%.
2. adopt flow cytomery Cpd-7 on the impact of CLA-1 protein level
(1) HepG2 cell is by 5 × 10
56 orifice plates are inoculated in individual/hole;
(2) 37 DEG C, 5%CO
2cultivate under condition with PBS rinsing cell 2 times after 24h, every hole adds respectively with the compound 7 of the respective concentration of serum free medium dilution and SAHA and TSA, does without compound control simultaneously;
(3) after 24h with each porocyte of trysinization, PBS rinsing cell 1 time;
(4) with 4% (w/v) paraformaldehyde (with PBS preparation, 65 DEG C of water-baths are constantly stirred to dissolves completely, 0.22 μm of membrane filtration, 4 DEG C of preservation, and 2 weeks interior effective) 2ml, 4 DEG C of fixed cells spend the night or room temperature fixes 40min;
(5) fixing terminate after, the centrifugal 5min of 1000rpm, abandons paraformaldehyde, and with PBS rinsing cell 1 time;
(6) with the PBS re-suspended cell of 1ml containing 5%FBS, 15min is placed for 4 DEG C;
(7) 1ml PBS washes cell 1 time, cell is divided into two parts;
(8) primary antibodie is hatched (1 ﹕ 50 dilutes): corresponding control tube does not add primary antibodie diluent, only adds the PBS of same volume, mixing, and after 4 DEG C of placement 50min, 1ml PBS washes cell 2 times;
(9) two anti-hatch (FITC marks, and 1:100-1:150 dilutes): mixed by cell after adding two anti-diluents, 4 DEG C place 50min after, 1ml PBS rinsing cell 2 times;
(10) often pipe sample adds 0.5ml PBS re-suspended cell, and 300 order nylon membranes filter, flow cytomery.
Experimental result is shown in Fig. 1 (B), and compound 7 can raise CLA-1 protein level in HepG2 cell, and after the Cpd-7 effect of 0.3 μM, rise rate is 224.6%, is better than the SAHA(63.5% of 0.3 μM) and TSA(135.4%).
3. adopt Western Blot to detect Cpd-7 to the impact of CLA-1 protein level
(1) human hepatoma HepG2 cell is with 6 × 10
5individual inoculation 6 orifice plate, 37 DEG C, 5%CO
2after cultivating 24h under condition, with PBS rinsing cell 2 times, add the serum-free MEM substratum 1ml containing respective concentration Compound C pd-7 and TSA respectively, contrast ware simultaneously and add serum-free MEM substratum containing 0.1%DMSO.37 DEG C, 5%CO
224h ~ 48h is cultivated under condition;
(2) the PBS rinsing cell 2 times of ice precooling, trypsin digestion cell;
(3) use in the MEM substratum containing 10% serum and the effect of pancreatin, cell suspension is transferred in 1.5ml EP pipe;
(4) 4 DEG C, the centrifugal 5min of 800rpm, abandons nutrient solution, collecting cell, ice-cold PBS rinsing cell 1 time, recentrifuge collecting cell;
(5) often pipe adds the RIPA cell pyrolysis liquid (50mM Tris-HCL, pH7.4,150mM NaCl, 1%NP40,0.1%SDS) of 100 μ l, in lysing cell 20min on ice.Every 5min vortex mixed 30s;
(6) 4 DEG C, the centrifugal 5min of 12,000rpm.Supernatant is transferred in new centrifuge tube, obtains total protein of cell product.Be stored in-70 DEG C;
(7) with BCA test kit, protein quantification is carried out to supernatant, each histone sample is adjusted to same concentration.Get and a certain amount ofly carry out protein electrophoresis.Transferring film reaction (0.45 μm of pvdf membrane) is carried out after electrophoresis completes;
(8) room temperature closes transfer film 1h, the pvdf membrane of corresponding target protein and respective primary antibodie (1 ﹕ 1000) overnight incubation;
(9) film is washed three times, each 10min with TBST.With two anti-incubated at room 1h of each self-corresponding HRP mark after washing;
(10) fully rear enhancement type luminescent detection system (Millipore Products) that adopts of washing carries out imaging, and is calculated by the gray-scale value of the gray value standardization to respective internal reference albumen that scan band separately.
Experimental result is shown in Fig. 1 (C) and 1(D), and compound 7 dose-dependently can raise the protein expression level of CLA-1 in HepG2 cell, and after the Cpd-7 effect of 0.75 μM and 1.5 μMs, its rise rate is respectively 91.2% and 119.6%.
4. adopt flow cytomery Cpd-7 on the impact of cellular uptake DiI-HDL
1,1 '-bis-octadecane-3,3,3 ', 3 '-tetramethyl-indoles carbocyanine-perchlorate (1,1'-dioctadecyl-3,3,3 ', 3 '-tetramethylindocarbocyanineperchlorate, referred to as DiI) be a kind of red-purple fluorescent tracing coloring matter, belong to lipotropy carbonyl cyanine dye.Utilize it to mark HDL, the picked-up ability of cell to high density lipoprotein cholesterol can be studied by the fluorescence signal intensity detected in born of the same parents.
(1) human liver cell HepG2 is with 5 × 10
4individual inoculation 24 porocyte culture plate, 37 DEG C, 5%CO
2cultivate 24 hours under condition;
(2) ice-cold PBS rinsing cell 2 times, adds the serum-free MEM-EBSS substratum containing 0.3,0.75,1.5 μM of (DMSO content is 0.1%) Cpd-7 respectively, and control wells adds the corresponding substratum containing 0.1%DMSO simultaneously.37 DEG C, 5%CO
2cultivate 24 hours under condition;
(3) every hole adds 2 μ g/ml DiI-HDL, hatches 4h for 37 DEG C;
(4) with cold PBS rinsing cell 1 time, each hole adds the PBS that 1ml contains 0.5%BSA and 2mM EDTA respectively, places 1h in 4 DEG C;
(5) gently piping and druming and cell dispersion, cell suspension in 4 DEG C, the centrifugal 3min of 800g;
(6) collecting cell is resuspended in 0.5ml PBS, through flow cytomery fluorescent value after mistake 300 order nylon wires.
Experimental result is shown in Fig. 2, the ability of compound 7 pairs of HepG2 cellular uptake cholesterol has certain rise effect (A)-(C), the Cpd-7 of 0.3 μM, 0.75 μM and 1.5 μMs has raised 62.5%, 60.3% and 132.9% respectively to HepG2 cellular uptake DiI-HDL, sees Fig. 2 (F).Wherein the effect of Cpd-7 to cellular uptake DiI-HDL of 0.3 μM is better than SAHA(Fig. 2 (E) of 0.3 μM, 24.1%) effect.
embodiment 28: compound is to Apo E deficient mice body weight, blood lipid level and artery
atherosis impact
1. reagent and material
Test sample: compound 7(Cpd-7).
Positive control: Simvastatin (purchased from friendship pharmaceuticals of Hisense in medicine-feeding group).
Testing compound detects through HPLC, and purity is greater than 95%, and administration concentration is defined as 25mg/kg and 100mg/kg through toxicity trial test.
Apo E deficient mice (Apo E
-/-), male, in eight week age, body weight 22 ~ 25g, purchased from laboratory animal portion of Department Of Medicine, Peking University.
Blood lipids index detects the test kit adopting Beijing Zhong Shengbei to control bio-engineering corporation and measures.
2. experimental technique and step
Apo E
-/-mouse is divided into four groups at random, high fat control group (High Fat Control, HFC), low dose compounds group (Cpd-7,25mg/Kg), high doses of compounds group (Cpd-7,100mg/Kg) with positive controls (Simvastatin, 5mg/Kg), often organize 5.Raise with high lipid food (containing 20% lard and 0.15% cholesterol), simultaneously gastric infusion 8 weeks, high fat control group gives isopyknic physiological saline.Within every three days, take body weight once.
Raise after expiring, fasting (can't help water) 12h, mouse orbit venous blood collection.After separated plasma, total cholesterol (TC), triglyceride level (TG), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C) are measured with Hitachi 7060 type automatic biochemical analyzer.Separating mouse aorta, from aortic arch to pubis bifurcated section, peels off outer-layer fat, and the fat of oil red O to Wall of Artery patch dyes.Under stereoscopic microscope, aorta is half-and-half cut open, carries out en face(anteposition) analyze.
3. experimental result
When experiment starts, each group body weight is without marked difference.After this, each treated animal body weight all slowly rises along with time lengthening.Administration each group of effect due to medicine, all can the growth of obvious control ApoE-/-Mouse Weight, wherein compound group (high doses of compounds group and low dose compounds group) all with high fat control group significant difference (P < 0.01), Fig. 3 shows administration and respectively organizes low than high fat control group body weight, and the effect of compound 7 is better than positive control Simvastatin, between high low dosage, present dose-dependently.
Table 8: compound is on the impact (mean ± SD) of ApoE deficient mice blood lipid level
Compared with high fat control group, * represents P < 0.01
The result display of table 8, the Apo E that the compound pharmacological agent of 7 eight weeks can make high lipid food feed
-/-mouse total cholesterol (TC) level significantly declines 25%-30%, and drug effect is better than Simvastatin group, has obvious significant difference (P < 0.01) compared with high fat control group.Also downward trend is there is in the Other blood lipids index of administration group with high fat control group.
By Apo E
-/-the staining analysis of mouse en face aorta lipidosis, find that obvious plaque all appears in the whole aorta of high fat control group, at three large branch (truncus brachiocephalicuss of aortic arch position and upper limb thereof, left common carotid artery and left subclavian artery) there is a large amount of lipid accumulation, see Fig. 4 (A), plaque lesions area percentage is 10.2 ± 2.2%; Form sharp contrast therewith, compound group (Cpd-7,25mg/Kg) mouse lesion degree is comparatively light, and see Fig. 4 (B), Aortic Plaque area obviously reduces (P < 0.05), and per-cent is 4.5 ± 2.6%.Illustrate that compound can be played a positive role to arteriosclerosis treatment.
Above result of study shows, compound of the present invention can reduce total plasma cholesterol effectively, and effect is similar to Simvastatin group drug effect, and can significantly reduce Apo E
-/-the plaque area of Atherosclerosis Model mouse, has study of anti-atherogenic effect.
Although the specific embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that can carry out various amendment and replacement to those details, these change all within protection scope of the present invention according to disclosed all instructions.Four corner of the present invention is provided by claims and any equivalent thereof.
Claims (15)
1. the compound shown in formula I, or its pharmacologically acceptable salt,
Wherein,
R is selected from C
6-
12the C of aryl, replacement
6-
12aryl, C
6-
12the C of aryloxy and replacement
6-
12aryloxy, and R is independently selected from the hydrocinnamyl of the styroyl of the benzyl of the phenyl of phenyl, replacement, benzyl, replacement, styroyl, replacement, hydrocinnamyl and replacement;
N is 0,1,2 or 3;
Described replacement is independently of one another for being selected from halogen atom, C
1-
6alkyl and C
1-
6any one or more substituting groups in alkoxyl group replaced.
2. compound according to claim 1, or its pharmacologically acceptable salt, wherein, the ortho position of wherein said substituting group on phenyl ring, a position or contraposition.
3. compound according to claim 1 and 2, or its pharmacologically acceptable salt, wherein,
Described halogen is fluorine, chlorine, bromine or iodine, described C
1-
6alkoxyl group is methoxy or ethoxy.
4. compound according to claim 1 and 2, or its pharmacologically acceptable salt, it is selected from following compound:
Hexanedioyl aniline hydroxamic acid,
Hexanedioyl-3-chloroaniline hydroxamic acid,
Hexanedioyl-4-chloroaniline hydroxamic acid,
Hexanedioyl-4-methoxybenzylamine hydroxamic acid,
Pimeloyl aniline hydroxamic acid,
Pimeloyl 2-chloroaniline hydroxamic acid,
Pimeloyl 3-chloroaniline hydroxamic acid,
Pimeloyl 4-chloroaniline hydroxamic acid,
Pimeloyl 4-methoxybenzylamine hydroxamic acid,
Or its pharmacologically acceptable salt.
5. the preparation method of the compound according to any one of Claims 1-4, 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; R, n are respectively according to any one of Claims 1-4.
6. a pharmaceutical composition, it comprises the compound or pharmaceutically acceptable salt thereof according to any one of Claims 1-4.
7. pharmaceutical composition according to claim 6, it also comprises pharmaceutically acceptable carrier.
8. pharmaceutical composition according to claim 6, it also comprises pharmaceutically acceptable auxiliary material.
9. the purposes of the compound or pharmaceutically acceptable salt thereof according to any one of Claims 1-4 in preparation adjustment CLA-1 activity or the medicine of CLA-1 level or the medicine of adjusting blood lipid level.
10. the compound or pharmaceutically acceptable salt thereof according to any one of Claims 1-4 regulates the purposes in the medicine of total cholesterol level in preparation.
11. 1 kinds of methods regulating the active or CLA-1 level of CLA-1 in vitro, comprise the step of the compound or pharmaceutically acceptable salt thereof according to any one of Claims 1-4 using significant quantity.
Compound or pharmaceutically acceptable salt thereof according to any one of 12. Claims 1-4 is preparing the purposes treated and/or prevented and/or in adjuvant therapy of heart cerebrovascular diseases, anti-inflammatory, weight management or anti-tumor drug.
13. purposes according to claim 12, wherein, described weight management is for losing weight or maintaining body weight.
14. purposes according to claim 12, wherein, described cardiovascular and cerebrovascular diseases is selected from atherosclerosis, hyperlipidemia, acute myocardial infarction, cerebral apoplexy and coronary heart disease.
15. purposes according to claim 12, wherein, described cardiovascular and cerebrovascular diseases is hypercholesterolemia.
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