CN104892457B - A kind of hydroxamic acid derivatives, its pharmaceutical composition, Preparation method and use - Google Patents
A kind of hydroxamic acid derivatives, its pharmaceutical composition, Preparation method and use Download PDFInfo
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Abstract
The present invention relates to a kind of hydroxamic acid derivatives, its pharmaceutical composition, Preparation method and use.The compound of the present invention can effectively adjust CLA 1 activity and/or level, with the prospect as preventing and treating cardiovascular and cerebrovascular disease (such as atherosclerosis), anti-inflammatory, body weight control (lose weight, maintain body weight) or antineoplastic.The compound structure is shown below：Wherein, R ' is selected from C6-12Aryl, the C of substitution6-12Aryl, C6-12Aryloxy group and the C of substitution6-12Aryloxy group, m is 1,2 or 3；Described substitution, which is each independently, is selected from halogen atom, C1-6Alkyl, C1-6Alkoxy, amino and C1-6Any one or more substituents in alkyl amino are replaced.
Description
Technical field
The invention belongs to field of medicine and chemical technology, it is related to a kind of hydroxamic acid derivatives, its pharmaceutical composition, preparation method
And purposes.
Background technology
Cardiovascular and cerebrovascular disease is current China and World Developed Countries incidence of disease highest disease, and its lethal disability rate is in
First of various diseases, and atherosclerosis (Atherosclerosis, AS) is the main pathological basis of cardiovascular and cerebrovascular disease.
Disorders of lipid metabolism especially cholesterol metabolic disorder is generally acknowledged main risk factor.Predicted according to WHO, to the year two thousand twenty because of painstaking effort
Pipe disease and cause death number will be added to about 2,500,000/year, wherein mostly it is directly relevant with dyslipidemia.In the past ten
Between for many years, level, the reduction symptom relevant with angiocardiopathy in reduction plasma low density lipoprotein cholesterol (LDL-C) and
In the risk for reducing major cardiovascular event, statins all shows important function.Such medicine is fried including many heavy pounds
Bullet level product, the Atorvastatin (atorvastatin, Lipitor, Lipitor) and Merck of such as Pfizer (Pfizer) is public
Take charge of the Simvastatin (simvastatin, simvastatin, Zocor) of (Merck).But statins is also only capable of reducing 20%-
40% cardiovascular event (Brugts JJ, YetginT, 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, angiocardiopathy be still endanger human health primary killers.Further to reduce the danger of angiocardiopathy
Evil, must have new role machine while LDL-C is reduced from preventing and/or reversing AS new therapy target to go out to send searching
The medicine of system.
Long-term clinical research shows, the cholesterol level (HDL-C) of HDL and the hair of atherosclerosis
Hair tonic exhibition is in reversely related.HDL study of anti-atherogenic effect is in addition to the anti-oxidant, antiinflammatory action that it has, it is important that
One reason be HDL be reverse cholesterol transport (reverse cholesterol transfer, RCT) major vectors.
Acton in 1996 etc. has found that the membrane receptor SR-BI alternatives intake on liver cell utilizes the cholesteryl ester in HDL-C, first
Secondary confirmation B races I types scavenger receptor (Scavenger receptor class B type I, SR-BI) is that tool functional is high
Density lipoprotein receptor (Acton SL, RigottiA, 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 whole as CD36 memebrane proteins superfamily and lysosome
Close what memebrane protein GAP-associated protein GAP was independently found, so also known as CLA-1 (CD36and LIMPII Analogous-1).In recent years
Come, effect of the HDL in atherosclerosis turns into study hotspot, correlative study progressively discloses HDL acceptors Jie
The reverse cholesterol transport mechanism led the cholesterol for being not easy to adjust in peripheral tissues and utilizing to be transported to liver to enter
Row 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 peripheral tissues courage in the outflow of cholesterol and liver
The selectivity intake of sterol, all plays key effect, it is considered to be find in the initial of reverse cholesterol transport and eventually in last step
Potential target (Acton SL, Kozarsky KF, the Rigotti A.The HDL receptor SR- of Novel cardiovascular medicine
BI:a new therapeutic target for atherosclerosis[J].Mol Med Today,1999,5(12):
518-524)。
The content of the invention
The present inventor passes through in-depth study and substantial amounts of experiment, it was found that a class hydroxamic acid derivatives, and shies
Very find, these compounds can effectively adjust CLA-1 activity and/or level, cardiovascular and cerebrovascular disease is prevented and treated with being used as
The prospect of sick (such as atherosclerosis) medicine.Thus provide following inventions：
One aspect of the present invention is related to formula I or the compound shown in formula II, or its officinal salt,
Wherein,
R is selected from C6-12Aryl, the C of substitution6-12Aryl, C6-12Aryloxy group and the C of substitution6-12Aryloxy group,
N is 0,1,2 or 3；
Wherein,
R ' is selected from C6-12Aryl, the C of substitution6-12Aryl, C6-12Aryloxy group and the C of substitution6-12Aryloxy group,
M is 1,2 or 3；
Described substituent is selected from halogen atom, C1-6Alkyl, C1-6Alkoxy, amino and C1-6Alkyl amino, and institute
Stating substituent, (substitution described in i.e. is each independently and is selected from halogen atom, C to be one or more1-6Alkyl, C1-6Alcoxyl
Base, amino and C1-6Any one or more identical or different substituents in alkyl amino are replaced).
Compound according to any one of the present invention, or its officinal salt, wherein,
R and R ' are separately selected from phenyl, the phenyl of substitution, benzyl, the benzyl of substitution, phenethyl, the benzene second replaced
The phenylpropyl of base, phenylpropyl and substitution.
Compound according to any one of the present invention, or its officinal salt, wherein, wherein the substituent is in phenyl ring
On ortho position, meta or contraposition.
Compound according to any one of the present invention, or its officinal salt, wherein,
The halogen is fluorine, chlorine, bromine or iodine, the C1-6Alkoxy is methoxy or ethoxy, the C1-6Alkyl ammonia
Base is dimethylamino or lignocaine.
Compound according to any one of the present invention, or its officinal salt, it is selected from shown in table 1 below or table 2
Compound, or its officinal salt:
Table 1：The part particular compound of meeting formula I
Table 2：The part particular compound of meeting formula II
Another aspect of the present invention is related to the preparation method of the compound described in any of the above item, comprises the steps：
Wherein, a represents 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDC), corresponding with product
Aminated compounds, CH2Cl2；B represents NH2OHHCl, NaOH, MeOH；C represents NaHCO3, the amine chemical combination corresponding with product
Thing, CH3CN, backflow；R, R ', n, m be respectively as described in any one above.
Those skilled in the art are it is understood that term " aminated compounds corresponding with product " or " corresponding amine " are chemical conjunctions
Into the general and usual description of middle correlated response process, the report of this area document is also found in；Understanding to the term, Ying Jie
Course of reaction before and after closing, i.e., according to the difference of purpose product, R- amidos or R '-amido are introduced for the product to synthesis, wherein
Symbol R or R ' have the implication of the above-mentioned any one of the present invention；" the corresponding aminated compounds of product " or " corresponding amine " is wrapped
Include but be not limited to the aniline described in embodiments of the invention, 3- chloroanilines, 4- methoxybenzylamines, etc..
In addition, as described herein " a represents 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDC), with
The corresponding aminated compounds of product, CH2Cl2" actually represent that reaction adds EDC, the aminated compounds corresponding with product
And CH2Cl2.For b similar understanding can be also done with c.
Another aspect of the invention is related to a kind of pharmaceutical composition, its comprising the present invention any one of compound or
Its officinal salt；Alternatively, in addition to pharmaceutically acceptable carrier or auxiliary material.
Generally the present invention pharmaceutical composition contain 0.1-90 weight % formula I or the compound of formula II and/or its pharmaceutically
Acceptable salt.Pharmaceutical composition can be prepared according to methods known in the art.When for this purpose, if it is desired, can be by formula I
Or the compound of formula II and/or its pharmaceutically acceptable salt and one or more solids or liquid pharmaceutical excipients and/or assistant agent
With reference to, be made can as people appropriate administration form or dosage form.
The pharmaceutical composition of the formula I or the compound of formula II of the present invention and/or its pharmaceutically acceptable salt or the present invention
Can be administered in a unit, method of administration can be enteron aisle or non-bowel, such as oral, muscle, subcutaneous, nasal cavity, oral mucosa,
Skin, peritonaeum or rectum etc..Form of administration for example tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, supensoid agent,
Emulsion, granule, liposome, transdermal agent, buccal tablet, suppository, freeze drying powder injection etc..Can be ordinary preparation, sustained release preparation, control
Release formulation and various particulate delivery systems.In order to which unit dosage forms for administration is made into tablet, it can widely use well known in the art
Various carriers.Example on carrier is, such as diluent and absorbent, such as starch, dextrin, calcium sulfate, lactose, mannitol,
Sucrose, sodium chloride, glucose, urea, calcium carbonate, white bole, microcrystalline cellulose, alumina silicate etc.；Wetting agent and adhesive, such as
Water, glycerine, polyethylene glycol, ethanol, propyl alcohol, starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatin
Slurry, sodium carboxymethylcellulose, lac, methylcellulose, potassium phosphate, polyvinylpyrrolidone etc.；Disintegrant, for example, dry and form sediment
Powder, alginate, agar powder, laminaran, sodium acid carbonate and citric acid, calcium carbonate, polyoxyethylene, polyoxyethylensorbitan fatty acid
Ester, dodecyl sodium sulfate, methylcellulose, ethyl cellulose etc.；Disintegration inhibitor, such as sucrose, glyceryl tristearate,
Cocoa butter, hydrogenated oil and fat etc.；Sorbefacient, such as quaternary ammonium salt, lauryl sodium sulfate；Lubricant, such as talcum powder, dioxy
SiClx, cornstarch, stearate, boric acid, atoleine, polyethylene glycol etc..Coating tablet can also be further made in tablet,
Such as sugar coated tablet, thin membrane coated tablet, enteric coated tablets, or double-layer tablets and multilayer tablet., can in order to which administration unit is made into pill
To widely use various carriers well known in the art.Example on carrier is, such as diluent and absorbent, such as glucose,
Lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talcum powder etc.；Adhesive is such as
Arabic gum, bassora gum, gelatin, ethanol, honey, liquid sugar, rice paste or batter etc.；Disintegrant, such as agar powder, dry starch, sea
Alginates, dodecyl sodium sulfate, methylcellulose, ethyl cellulose etc.., can be extensive in order to which administration unit is made into suppository
Use various carriers well known in the art.Example on carrier is, for example polyethylene glycol, lecithin, cocoa butter, higher alcohol,
Ester, gelatin, semi-synthetic glyceride of higher alcohol etc..In order to which administration unit is made into capsule, by active ingredient type I compound or its
Stereoisomer is mixed with above-mentioned various carriers, and thus obtained mixture is placed in hard obviously capsule or soft capsule
In.Also can be by active ingredient formula I or the compound of formula II and/or its pharmaceutically acceptable salt or the pharmaceutical composition of the present invention
Microcapsules is made, is suspended in aqueous medium formation supensoid agent, can also be fitted into hard shell capsules or injection application is made.In order to incite somebody to action
Injection preparation is made in administration unit, and such as solution, emulsion, freeze drying powder injection and supensoid agent can be used commonly used in the art
All diluents, for example, water, ethanol, polyethylene glycol, 1,3-PD, the isooctadecanol of ethoxylation, polyoxygenated different tristearin
Alcohol, Polyoxyethylene Sorbitol Fatty Acid Esters etc..In addition, in order to prepare isotonic parenteral solution, can add suitable into injection preparation
Sodium chloride, glucose or the glycerine of amount, further, it is also possible to add conventional cosolvent, buffer, pH adjusting agent etc..
In addition, if desired, can also be added into pharmaceutical preparation colouring agent, preservative, spices, flavouring, sweetener or
Other materials.
The pharmaceutical composition of the formula I or the compound of formula II of the present invention and/or its pharmaceutically acceptable salt or the present invention
Dosage depend on many factors, the property and the order of severity for example to be prevented or treated disease, patient or animal
Sex, age, body weight and individual reaction, particular compound used, method of administration and administration number of times etc..Above-mentioned dosage can be single
Dose form is divided into several, and such as two, three or four dosage forms for administration.
Term " composition " used herein means to include the product of each specified composition comprising specified amount, and directly or
Any product produced indirectly from the combination of each specified composition of specified amount.
The actual dose level of each active component in pharmaceutical composition of the present invention can be changed, so as to the reactive compound of gained
Amount can effectively obtain required therapeutic response for specific patient, composition and administering mode.Dosage level must be according to materialization
The activity of compound, method of administration, the patient's condition and medical history of the order of severity for treating the patient's condition and patient to be treated are selected.
But, the way of this area is that the dosage of compound is since the level required less than therapeutic effect needed for obtaining, gradually
Incremental dose, until obtaining required effect.
The compound or pharmaceutically acceptable salt thereof that another aspect of the invention is related to any one of the present invention is preparing regulation
Purposes in the medicine or reagent or regulation blood lipid level or the medicine of total cholesterol level of CLA-1 activity or CLA-1 levels.
The regulation CLA-1 activity includes up-regulation CLA-1 activity.The regulation CLA-1 levels include improving CLA-1 levels.It is described to adjust
Saving blood lipid level includes reduction blood lipid level.The regulation total cholesterol level includes reduction total cholesterol level.
Another aspect of the invention is related to a kind of method of the CLA-1 of regulation in vivo or in vitro activity or CLA-1 levels, bag
Include the step of using the compound or pharmaceutically acceptable salt thereof any one of the present invention of effective dose.
The compound or pharmaceutically acceptable salt thereof that another aspect of the invention is related to any one of the present invention is preparing treatment
And/or prevention and/or adjuvant therapy of heart cerebrovascular diseases, anti-inflammatory, body weight control (lose weight, maintain body weight) or antitumor
Medicine in purposes；Specifically, the cardiovascular and cerebrovascular disease be selected from atherosclerosis, hyperlipemia, hypercholesterolemia,
Acute myocardial infarction AMI, cerebral apoplexy and coronary heart disease.
Another aspect of the invention be related to a kind for the treatment of and/or prevention and/or adjuvant therapy of heart cerebrovascular diseases, anti-inflammatory,
Body weight control (lose weight, maintain body weight) or antineoplastic method, including give any one of present invention of effective dose institute
The step of compound or pharmaceutically acceptable salt thereof stated.Specifically, the cardiovascular and cerebrovascular disease is selected from atherosclerosis, high fat of blood
Disease, hypercholesterolemia, acute myocardial infarction AMI, cerebral apoplexy and coronary heart disease.
When for above-mentioned treatment and/or prevention and/or auxiliary treatment, this kind of hair for the treatment of and/or prevention effective dose
Bright compound or pharmaceutically acceptable salt thereof can be applied in a pure form, or (be existed with pharmaceutically acceptable ester or prodrug forms
In the case of these forms) application.Or, the compound can be with can with one or more medicines containing the purpose compound
Receive the pharmaceutical composition administration of excipient.The compounds of this invention of word " prevention and/or therapeutically effective amount " refer to suitable for
The compound of the sufficient amount of the reasonable effect of any medical science prevention and/or treatment/Hazard ratio treatment obstacle.It is to be understood that this
Total consumption per day of invention compound and composition must be maked decision by attending physician in reliable medical judgment scope.For appointing
What specific patient, depending on specific treatment effective dose level must be according to many factors, the factor includes treated barrier
Hinder and the obstacle the order of severity；The activity of the particular compound used；The concrete composition used；The age of patient,
Body weight, general health, sex and diet；Administration time, method of administration and the excretion rate of the particular compound used；Control
Treat the duration；It is applied in combination or medicine used at the same time with the particular compound that is used；And it is similar known to medical field
Factor.For example, the way of this area is, the dosage of compound is opened from the level required less than therapeutic effect needed for obtaining
Begin, gradually incremental dose, until obtaining required effect.It is, in general, that the compound of the present invention is particularly for mammal
The dosage of people can between 0.001-1000mg/kg body weight/days, such as between 0.01-100mg/kg body weight/days, for example between
0.01-10mg/kg body weight/days.
It can effectively prevent and/or treat various diseases of the present invention or illness according to the compound of the present invention.
In the present invention, term " C1-6Alkyl " refers to the straight or branched alkyl with 1-6 carbon atom, such as methyl,
Ethyl, propyl group, isopropyl, normal-butyl, sec-butyl, the tert-butyl group, amyl group, 2- amyl groups, isopentyl, neopentyl, hexyl, 2- hexyls,
3- hexyls, 3- methyl amyls etc..
Term " C1-6Alkoxy ", refers to the straight or branched alkoxyl with 1-6 carbon atom, such as methoxyl group, ethoxy
Base, propoxyl group, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, amoxy, 2- oxygen amyl group, different oxygen amyl group, new penta oxygen
Base, hexyloxy, 2- hexyloxies, 3- oxygen hexyl, 3- methyl amoxys etc..
Term " C1-6Alkyl amino ", refers to C1-6Contain one or more amino on any carbon potential or many carbon potentials on alkyl.
C1-4Alkyl amino or C1-3Alkyl amino can also do similar understanding.
Term " C6-12Aryl " term " C5-20The example of aryl " includes phenyl, benzyl, phenethyl, phenylpropyl, etc..This
A little aryl can be by alkyl (such as C1-6Alkyl) or alkoxy (such as C1-6Alkoxy) or halogen atom substitution.Substituent can be with
In the ortho position of phenyl ring, meta or contraposition.
Term " C6-12The example of aryloxy group " is including benzyloxy etc..These aryloxy group can be by one or more alkoxies
(such as C1-6Alkoxy) or alkyl (such as C1-6Alkyl) or halogen atom substitution.Substituent can the ortho position of phenyl ring, meta,
Or contraposition.
The beneficial effect of invention
The compound of the present invention can effectively adjust CLA-1 activity and/or level, and cardiovascular and cerebrovascular is prevented and treated with being used as
Disease (such as atherosclerosis), anti-inflammatory, the prospect of body weight control (lose weight, maintain body weight) or antineoplastic.
Brief description of the drawings
Fig. 1：The influence that compound is expressed CLA-1 in HepG2 cells.Fig. 1 (A)：Compound 7 is to CLA-1mRNA levels
Influence；Fig. 1 (B)：Influence of the Flow Cytometry detection compound 7 to CLA-1 protein expressions；Fig. 1 (C)：Western
Influence of the Blot detection compounds 7 to CLA-1 protein expressions；Fig. 1 (D)：Western Blot detection compounds 7 are to CLA-1 eggs
The quantification result of white expression influence.
Fig. 2：Compound absorbs the influence of ability to HepG2 cells DiI-HDL.Fig. 2 (A)：0.3 μM of compound 7 is to HepG2
The influence of cellular uptake DiI-HDL abilities；Fig. 2 (B)：Shadow of 0.75 μM of compound 7 to HepG2 cellular uptake DiI-HDL abilities
Ring；Fig. 2 (C)：Influence of 1.5 μM of compounds 7 to HepG2 cellular uptake DiI-HDL abilities；Fig. 2 (D)：0.3 μM SAHA pairs
The influence of HepG2 cellular uptake DiI-HDL abilities；Fig. 2 (E)：0.6 μM of SAHA is to HepG2 cellular uptake DiI-HDL abilities
Influence；Fig. 2 (F)：Compound 7 and SAHA absorb the quantification result of ability to HepG2 cells DiI-HDL.
Fig. 3：Influence of the compound to mouse weight.
Fig. 4：Influence of the compound to mouse aorta patch (* represents P ＜ 0.05).Fig. 4 (A)：High fat diet control
(HFC) mouse aorta patch formational situation；Fig. 4 (B)：Protection situation of the compound 7 (25mg/Kg) to mouse aorta；
Fig. 4 (C)：The quantitative result (n=4) of mouse aorta plaque area.
Embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.It is unreceipted specific in embodiment
Condition person, the condition advised according to normal condition or manufacturer is carried out.Agents useful for same or the unreceipted production firm person of instrument, be
Can be by the conventional products of acquisition purchased in market.
Embodiment 1：The preparation of adipyl aniline hydroxamic acid (compound 1)
1) preparation of 5- anilino-s formyl-methyl valerate.
Monoethyl adipatee (3.20g, 20.0mmol) is dissolved in CH2Cl2In (20.0ml), it is cooled to -5 DEG C, adds EDC.HCl
(3.84g, 20.0mmol), is then added dropwise to aniline (1.86g, 20.0mmol) CH2Cl2(10.0ml) solution, reaction solution is natural
It is warmed to room temperature, is stirred overnight.
Add 1mol/L HCl (30ml) in reaction solution to wash, 5%Na2HCO3(30ml) is washed, saturated common salt washing.Organic phase
Use anhydrous sodium sulfate drying.It is concentrated to give crude product, yield about 60%.It need not purify, be directly used in the next step.
2) preparation of adipyl aniline hydroxamic acid (compound 1)
5- anilino-s formyl-methyl valerate (1.18g, 5.0mmol) is dissolved in methanol (50mL), adds hydroxylamine hydrochloride
(1.40g, 20.0mmol) is cooled to 0 DEG C, is added dropwise to 8mol/L NaOH (10mL) solution, is stirred at room temperature 1-2 hours.
1mol/L HCl (50mL) being added dropwise into solution at 0 DEG C and adjusting Ph=7-8, MCI GEL are crossed in solution decompression concentration
20Y posts (water/methanol) are purified, and obtain yellow solid 698mg, yield:59.2%；m.p.180-181.5℃.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：Compound 2-9 preparation
Embodiment 2-9 is prepared for compound 2-9 respectively.Compound 2-9 preparation process and compound 1 in embodiment 1
Preparation process it is identical, except raw materials used otherwise varied.Difference is as shown in Table 3 below：
Table 3：Compound 2-9 preparation process and the difference of embodiment 1
Embodiment 10：The preparation of N- hydroxyls -4- { [anilino- carbamoylmethyl] methyl } benzamide (compound 10)
1) preparation of acetobromanilide
Bromoacetic acid (2.78g, 20.0mmol) is dissolved in CH2Cl2In (20.0ml), be cooled to -5 DEG C, add EDC.HCl (3.84g,
20.0mmol), then it is added dropwise to aniline (1.86g, 20.0mmol) CH2Cl2(10.0ml) solution, reaction solution rises to room naturally
Temperature, is stirred overnight.
Add 1mol/L HCl (30ml) in reaction solution to wash, 5%Na2HCO3(30ml) is washed, saturated common salt washing.Organic phase
Use anhydrous sodium sulfate drying.It is concentrated to give crude product, yield about 60%.It need not purify, be directly used in the next step.
2) preparation of 4- [(benzoyl methylamino)-methyl]-methyl benzoate
5- anilino-s formyl-methyl valerate (1.18g, 5.0mmol) is dissolved in methanol (50mL), adds hydroxylamine hydrochloride
(1.40g, 20.0mmol) is cooled to 0 DEG C, is added dropwise to 8mol/L NaOH (10mL) solution, is stirred at room temperature 1-2 hours.
1mol/L HCl (50mL) being added dropwise into solution at 0 DEG C and adjusting Ph=7-8, MCI GEL are crossed in solution decompression concentration
20Y posts (water/methanol) are purified, and obtain yellow solid.
Acetobromanilide (10.0mmol), 4- (amine methyl) benzoate hydrochloride (2.02g, 10.0mmol) and carbonic acid
Hydrogen potassium (1.50g, 15.0mmol) is dissolved in acetonitrile (100ml), solution return stirring 3-4 hours.
It is concentrated under reduced pressure, residue adds in water and ethyl acetate point liquid, organic phase and adds HCl solution (1mol/L), separates out
Precipitation, filtering, solid is washed with water, and obtains crude product, yield about 50%.It need not purify, be directly used in the next step.
3) preparation of N- hydroxyls -4- { [anilino- carbamoylmethyl] methyl } benzamide
4- [(benzoyl methylamino)-methyl]-methyl benzoate (149mg, 0.5mmol) is dissolved in methanol (5mL), is added
Hydroxylamine hydrochloride (140mg, 2.0mmol) is cooled to 0 DEG C, is added dropwise to 8mol/L NaOH (1mL) solution, 1-2 is stirred at room temperature small
When.
1mol/L HCl (50mL) being added dropwise into solution at 0 DEG C and adjusting Ph=7-8, MCI GEL are crossed in solution decompression concentration
20Y posts (water/methanol) are purified, and obtain white solid 71.3mg, yield:47.7%；m.p.124-126℃.1HNMR(DMSO-
d6,400MHz,δppm)3.26(2H,s,CH2CO),3.77(2H,s,NHCH2),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 C16H18N3O3,334.0953；
found,334.0952。
Embodiment 11-24：Compound 11-24 preparation
Embodiment 11-24 is prepared for compound 11-24 respectively.In compound 11-24 preparation process and embodiment 10
The preparation process of compound 10 is identical, except raw materials used otherwise varied.Difference is as shown in Table 4 below：
Table 4：Compound 11-24 preparation process and the difference of embodiment 10
Embodiment 25：Compound 1-24 structure verification
As shown in Table 5 below.
Embodiment 26：CLA-1 promoter activities up-regulation experiment in liver cell HepG2
1. reagent and material
Test specimen：Compound 1-24.
Positive control：SAHA and TSA (being purchased from Sigma companies).
The compound of all tests is all screened by HPLC, and purity is more than 95%, and experimental concentration is 10 μ g/mL.
CLAP-Luc HepG2 cells are the luciferase reporter gene for the promoter containing CLA-1 that this laboratory is built
HepG2 cells (method that construction method can be known using those skilled in the art, for example, may be referred to Liu Xiaohui, Hong Bin, Wang Li
It is non-, Yang Yuan, Si Shuyi, Li Yuan；Foundation [J] the Chinese medicines section of human high-density lipoprotein receptor expression up regulating agent screening model
Institute's journal, 2004,26 (4)：354-358.).
2. experimental method and step
Influence of the detection compound to CLA-1 promoter (CLA-1promoter, CLAP) activity.
By CLAP-Luc HepG2 cells with 5 × 104Individual/hole is inoculated in 96 porocyte culture plates, and about 6h treats that cell is pasted
After wall, it is changed to respectively containing the serum-free medium that concentration is 10 μ g/ml compounds 1-24.Separately set 0.1%DMSO containing final concentration (molten
Agent) hole of culture medium does blank control.Continue at 37 DEG C, 5%CO2Under the conditions of culture 18h after, by determining at each compound group
The luciferase expression activity of cell is managed, average up-regulation multiple of the compound to CLA-1 promoters is calculated.It is obvious to up-regulation multiple
Compound carry out quantitative dose-effect relationship, analyzing the compound concentration be serially diluted, (luciferase expression is lived with promoter activity
Property) between relation, calculate EC50.Concrete operation step refers to Luciferase Assay System (Promega) explanation
Book.
3. experimental result
As a result as shown in following table 6 and table 7.
Table 6：Average up-regulation multiples of the compound 1-24 to CLA-1 promoter activities
Table 7：Maximum up-regulation multiples and EC of the compound 1-9 to CLA-1 promoter activities50
The result of table 6 and table 7 shows that compound of the invention can effectively raise CLA-1 activity/level.
Embodiment 27：Compound 7 is to liver cell HepG2 HDL receptors CLA-1 expression and the influence of function
First, reagent and material
Test specimen：Compound 7 (is also referred to as " Cpd- sometimes in heptanedioyl 3- chloroaniline hydroxamic acid, the present invention
7”)。
Positive control：SAHA and TSA (being purchased from Sigma companies).
MEM-EBSS culture mediums (Hyclone companies) (contain 10% standard hyclone<Hyclone companies>) thin for liver
Born of the same parents HepG2 (being purchased from American Type Culture collecting center, ATCC) culture.
2nd, experimental method and experimental result
1. influences of the real-time quantitative RT-PCR technique study Cpd-7 to CLA-1 transcriptional levels
(1) extraction of cell total rna
Human liver cell HepG2 is with 5 × 105Individual inoculation 60mm Tissue Culture Plates, 37 DEG C, 5%CO2Under the conditions of cultivate 24 hours
Afterwards, ice-cold PBS rinsing cell 2 times, be separately added into containing 0.75,1.5 μM of (DMSO contents are 0.1%) Cpd-7 without blood
Clear MEM-EBSS culture mediums, positive control adds the TSA containing 0.6 μM (containing 0.1%DMSO).37 DEG C, 5%CO2Under the conditions of cultivate
After 24 hours, the extraction of cell total rna is carried out with Trizol reagents (Invitrogen companies), and (concrete operation step is according to reagent
The specification of box is carried out) and determine extracted RNA concentration.
(2) reverse transcription reaction -- cDNA synthesis
Using ThermoScriptTMRT-PCR System kits (Invitrogen companies) are carried out, concrete operations step
Suddenly according to described in kit specification.Each 4 μ g of template ribonucleic acid respectively with ThermoScriptTMWith primer RT Oligo (dT)20It is mixed
Close, 55 DEG C of insulation 60min carry out reverse transcription reaction, reaction terminates to heat 5min after 85 DEG C with terminating reaction.Gained cDNA can
Preserved in -20 DEG C or continue the following PCR reactions of row.
(3) Real-time PCR are detected
The cDNA samples of acquisition are prepared by Real-Time PCR using SYBR Green PCR Master Mix respectively anti-
Answer system.System configurations are as follows：
The μ l of 2 × PCR Master Mix buffer solutions 12.5；Each 2.5 μ l of upstream and downstream primer (2 μM)；The μ l of template 7.5；It is overall
25 μ l of product.Solution is mixed, the of short duration centrifugations of 5000rpm.
PCR reaction solutions are placed in Real-time PCR instruments, performing PCR reaction is entered by following reaction condition：
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, every five seconds for example raises 1 DEG C, 81 cycle detection solubility curves
(Melting Curve)。
The target gene and housekeeping gene GAPD (GAPDH, internal reference) of each sample carry out Real- respectively
Time PCR react.The relative amount of target gene is calculated using △ △ Ct methods in each sample, 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 genes in HepG2 cells, 0.75 μM
And 1.5 μM Cpd-7 effect after, its up-regulation rate is respectively 89.6% and 74.4%.
2. the influence using flow cytomery Cpd-7 to CLA-1 protein levels
(1) HepG2 cells press 5 × 105Individual/hole is inoculated with 6 orifice plates；
(2) 37 DEG C, 5%CO2Under the conditions of after culture 24h with PBS rinsing cells 2 times, be separately added into and trained with serum-free per hole
The compound 7 and SAHA and TSA of the respective concentration of base dilution are supported, while doing no compound control；
(3) each hole cell, PBS rinsings cell 1 time are digested with pancreatin after 24h；
(4) (prepared with 4% (w/v) paraformaldehyde with PBS, 65 DEG C of water-baths are stirred continuously to being completely dissolved, 0.22 μm of filter membrane
Filtering, 4 DEG C of preservations, in 2 weeks effectively) 2ml, 4 DEG C of fixed cell pellet overnights or room temperature fix 40min；
(5) fix after terminating, 1000rpm centrifugation 5min, abandon paraformaldehyde, and cell is rinsed 1 time with PBS；
(6) cell, 4 DEG C of placement 15min is resuspended with PBSs of the 1ml containing 5%FBS；
(7) 1ml PBS wash cell 1 time, and cell is divided into two parts；
(8) primary antibody is incubated (1 ﹕ 50 dilutes)：Corresponding control tube is not added with primary antibody dilution, only adds the PBS of same volume,
Mix, 4 DEG C are placed after 50min, and 1ml PBS wash cell 2 times；
(9) secondary antibody is incubated (FITC marks, 1:100-1:150 dilutions)：Cell is mixed after adding secondary antibody dilution, 4 DEG C
Place after 50min, 1ml PBS rinsings cell 2 times；
(10) often pipe sample adds 0.5ml PBS and cell, 300 mesh nylon membrane filtrations, flow cytomery is resuspended.
Experimental result is shown in Fig. 1 (B), and compound 7 can raise CLA-1 protein levels in HepG2 cells, 0.3 μM of Cpd-7
After effect, up-regulation rate is 224.6%, is better than 0.3 μM of SAHA (63.5%) and TSA (135.4%).
3. the influence using Western Blot detections Cpd-7 to CLA-1 protein levels
(1) human hepatoma HepG2 cell is with 6 × 1056 orifice plates of individual inoculation, 37 DEG C, 5%CO2Under the conditions of culture 24h after, use PBS
Rinse cell 2 times, be separately added into the Cpd-7 and TSA of compound containing respective concentration serum-free MEM culture medium 1ml, while compareing ware
Add the serum-free MEM culture mediums containing 0.1%DMSO.37 DEG C, 5%CO2Under the conditions of cultivate 24h~48h；
(2) the PBS rinsings cell of ice precooling 2 times, trypsin digestion cell；
(3) with the effect in the MEM culture mediums containing 10% serum with pancreatin, cell suspension is transferred to 1.5ml EP pipes
In；
(4) 4 DEG C, 800rpm centrifugation 5min abandon nutrient solution, collect cell, ice-cold PBS rinses cell 1 time, again
Cell is collected by centrifugation；
(5) often pipe adds 100 μ l RIPA cell pyrolysis liquids (50mM Tris-HCL, pH7.4,150mM NaCl, 1%
NP40,0.1%SDS), in cell lysis 20min on ice.Every 5min vortex mixeds 30s；
(6) 4 DEG C, 12,000rpm centrifugation 5min.Supernatant is transferred in new centrifuge tube, produces total protein of cell product.
It is stored in -70 DEG C；
(7) protein quantification is carried out to supernatant with BCA kits, each group protein sample is adjusted to same concentration.Take one
Quantitatively carry out protein electrophoresis.Transferring film reaction (0.45 μm of pvdf membrane) is carried out after the completion of electrophoresis；
(8) room temperature closing transfer film 1h, the pvdf membrane of corresponding target protein is incubated overnight with respective primary antibody (1 ﹕ 1000)；
(9) film is washed with TBST three times, each 10min.It is incubated at room temperature after washing with the secondary antibody of each self-corresponding HRP marks
1h；
(10) fully it is imaged after washing using enhanced luminescent detection system (Millipore Products), and will
The gray value standardization of respective scan stripes band is calculated to the gray value of respective internal reference albumen.
Experimental result is shown in Fig. 1 (C) and 1 (D), and compound 7 can dose-dependently raise the egg of CLA-1 in HepG2 cells
White expression, after 0.75 μM and 1.5 μM of Cpd-7 effects, its up-regulation rate is respectively 91.2% and 119.6%.
4. the influence using flow cytomery Cpd-7 to cellular uptake DiI-HDL
1,1 '-bis- octadecanes -3,3,3 ', 3 '-tetramethyl indoles carbocyanine-perchlorate (1,1 '-dioctadecyl-3,
3,3 ', 3 '-tetramethylindocarbocyanine perchlorate, referred to as DiI) it is that a kind of aubergine fluorescence shows
Track coloring matter, belongs to lipophilicity carbonyl cyanine dye.It is utilized to mark HDL, can be by detecting that the fluorescence signal of intracellular is strong
Spend to study intake ability of the cell to HDL-C.
(1) human liver cell HepG2 is with 5 × 10424 porocyte culture plates of individual inoculation, 37 DEG C, 5%CO2Under the conditions of culture it is 24 small
When；
(2) ice-cold PBS rinsing cell 2 times, are separately added into containing 0.3,0.75,1.5 μM (DMSO contents are 0.1%)
Cpd-7 serum-free MEM-EBSS culture mediums, while control wells add the corresponding culture medium containing 0.1%DMSO.37 DEG C, 5%CO2
Under the conditions of cultivate 24 hours；
(3) 2 μ g/ml DiI-HDL, 37 DEG C of incubation 4h are added per hole；
(4) cell is rinsed 1 time with cold PBS, each hole is separately added into the PBS that 1ml contains 0.5%BSA and 2mM EDTA, in 4
DEG C place 1h；
(5) gently blow and beat and cell dispersion, cell suspension is in 4 DEG C, 800g centrifugations 3min；
(6) collect cell to be resuspended in 0.5ml PBS, cross after 300 mesh nylon wires through flow cytomery fluorescent value.
Experimental result is shown in Fig. 2, and compound 7 has certain up-regulation effect to the ability of HepG2 cellular uptake cholesterol
(A)-(C), 0.3 μM, 0.75 μM and 1.5 μM of Cpd-7 raised 62.5% to HepG2 cellular uptakes DiI-HDL respectively,
60.3% and 132.9%, see Fig. 2 (F).Effects of wherein 0.3 μM of the Cpd-7 to cellular uptake DiI-HDL is better than 0.3 μM
SAHA (Fig. 2 (E), 24.1%) effect.
Embodiment 28：Influence of the compound to Apo E deficient mices body weight, blood lipid level and atherosclerosis
1. reagent and material
Test specimen：Compound 7 (Cpd-7).
Positive control：Simvastatin (purchased from friendship pharmaceuticals of Hisense in medicine-feeding group).
Testing compound detects that purity is more than 95%, and administration concentration is defined as 25mg/kg through toxicity trial test by HPLC
And 100mg/kg.
Apo E deficient mices (Apo E-/-), male, eight week old, 22~25g of body weight, purchased from Department Of Medicine, Peking University
Experimental animal portion.
Blood lipids index detection is measured using Beijing Zhong Shengbei kits for controlling bio-engineering corporation.
2. experimental method and step
Apo E-/-Mouse is randomly divided into four groups, 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) and positive controls (Simvastatin, 5mg/
Kg), every group 5.Raise with high lipid food (containing 20% lard and 0.15% cholesterol), while gastric infusion 8 weeks, high fat is compareed
Group gives isometric physiological saline.Weigh body weight once within every three days.
Raise after expiring, fasting (can't help water) 12h, mouse orbit venous blood collection.After separated plasma, T-CHOL (TC),
Triglycerides (TG), HDL-C (HDL-C) and LDL-C (LDL-C) are with the type of Hitachi 7060
Automatic biochemical analyzer is determined.Separating mouse sustainer peels off outer-layer fat, O pairs of oil red from the arch of aorta to pubis bifurcated section
The fat of Wall of Artery patch is dyed.Sustainer is half-and-half splitted under stereomicroscope, en face (anteposition) points is carried out
Analysis.
3. experimental result
When experiment starts, each group body weight is without marked difference.Hereafter, each group the weight of animals it is slow as time went on
Rise.Each group is administered due to the effect of medicine, ApoE can be substantially controlled-/-The growth of mouse weight, wherein compound group (high agent
Measure compound group and low dose compounds group) with high fat control group significant difference (P ＜ 0.01), Fig. 3 display administrations each group is all
It is lower than high fat control group body weight, and the effect of compound 7 is better than positive control Simvastatin, present between high low dosage dosage according to
Lai Xing.
Table 8：Influence (mean ± SD) of the compound to ApoE deficient mice blood lipid levels
Compared with high fat control group, * represents P ＜ 0.01
The result of table 8 shows that the compound drug therapy of 7 eight weeks can make the Apo E that high lipid food is fed-/-The total courage of mouse
Sterol (TC) level is remarkably decreased 25%-30%, and drug effect is better than Simvastatin group, has obvious system compared with high fat control group
Meter learns difference (P ＜ 0.01).There is also downward trend with high fat control group for the Other blood lipids index of administration group.
Pass through Apo E-/-Mouse en face sustainer lipidosis staining analysis, finds the high whole sustainer of fat control group
All there is obvious plaque, in arch of aorta position and its three big branch (truncus brachiocephalicus, left common carotid artery and left locks of upper limb
Artery under bone) there are a large amount of lipid accumulations, see Fig. 4 (A), plaque lesions area percentage is 10.2 ± 2.2%；It is fresh with this formation
Bright contrast, compound group (Cpd-7,25mg/Kg) mouse lesion degree is lighter, sees Fig. 4 (B), and Aortic Plaque area is bright
Aobvious to reduce (P ＜ 0.05), percentage is 4.5 ± 2.6%.Illustrate that compound can play a positive role to artery sclerosis treatment.
Above result of study shows that compound of the invention can be effectively reduced total plasma cholesterol, and effect is cut down with pungent
Statin group drug effect is similar, and can substantially reduce Apo E-/-The plaque area of Atherosclerosis Model mouse, with anti-artery congee
Sample induration.
Although the embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that root
According to disclosed all teachings, various modifications and replacement can be carried out to those details, these change the guarantor in the present invention
Within the scope of shield.The four corner of the present invention is provided by appended claims and its any equivalent.
Claims (6)
1. the compound shown in formula II, or its officinal salt,
Wherein,
R ' is selected from the benzene of phenyl, benzyl, the benzyl of substitution, phenethyl, the phenethyl of substitution, phenylpropyl and the substitution of substitution
Propyl group；
M is 1,2 or 3；
Ortho position, meta or contraposition of the substituent on phenyl ring；
Described substitution, which is each independently, to be selected from chlorine atom, methoxy or ethoxy, dimethylamino or lignocaine and is taken
Generation.
2. compound according to claim 1, or its officinal salt, it is selected from following compound:
N- hydroxyls -4- { [2- chloroanilino formoxyls methylamino] methyl } benzamide,
N- hydroxyls -4- { [3- chloroanilino formoxyls methylamino] methyl } benzamide,
N- hydroxyls -4- { [4- chloroanilino formoxyls methylamino] methyl } benzamide,
N- hydroxyls -4- { [2- methoxybenzene amido formoxyls methylamino] methyl } benzamide,
N- hydroxyls -4- { [3,4- dimethoxy benzene amido formoxyl methylamino] methyl } benzamide,
N- hydroxyls -4- { [4- Dimethylaminobenzene amido formacyls methylamino] methyl } benzamide,
N- hydroxyls -4- { [2- chloroanilino formoxyls ethylamino] methyl } benzamide,
N- hydroxyls -4- { [4- chloroanilino formoxyls ethylamino] methyl } benzamide,
N- hydroxyls -4- { [4- methoxybenzene amido formoxyls ethylamino] methyl } benzamide,
N- hydroxyls -4- { [3,4- dimethoxy benzene amido formoxyl ethylamino] methyl } benzamide, and
N- hydroxyls -4- { [4- methoxyphenethylamine base formoxyls ethylamino] methyl } benzamide；
Or its officinal salt.
3. the preparation method of any described compound of claim 1 or 2, comprises the steps：
Wherein, a represents 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides, the amine chemical combination corresponding with product
Thing, CH2Cl2；B represents NH2OHHCl, NaOH, MeOH；C represents NaHCO3, the aminated compounds corresponding with product, CH3CN,
Backflow；R ', m are respectively as described in claim 1 or 2.
4. a kind of pharmaceutical composition, it is comprising the compound or pharmaceutically acceptable salt thereof described in any one of claim 1 or 2 and pharmaceutically
Acceptable carrier or auxiliary material.
5. the compound or pharmaceutically acceptable salt thereof described in any one of claim 1 or 2 is preparing regulation CLA-1 activity or CLA-1 water
Purposes in flat medicine or regulation blood lipid level or the medicine of total cholesterol level.
6. the compound or pharmaceutically acceptable salt thereof described in any one of claim 1 or 2 is preparing treatment and/or prevention and/or aided in
Treat the purposes in the medicine of cardiovascular and cerebrovascular disease；The cardiovascular and cerebrovascular disease is selected from atherosclerosis, hyperlipemia, high courage
Sterol mass formed by blood stasis, acute myocardial infarction AMI, cerebral apoplexy and coronary heart disease.
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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 |
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| CN101209974A (en) * | 2006-12-31 | 2008-07-02 | 天津药物研究院 | Hydroxamic acids derivatives and use thereof |
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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 |
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