CN105037252A - N-substituted-3,5-bis(2-trifluoromethyl)benzal)piperidine-4-one derivative, preparation method and application thereof - Google Patents
N-substituted-3,5-bis(2-trifluoromethyl)benzal)piperidine-4-one derivative, preparation method and application thereof Download PDFInfo
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- CN105037252A CN105037252A CN201510261550.3A CN201510261550A CN105037252A CN 105037252 A CN105037252 A CN 105037252A CN 201510261550 A CN201510261550 A CN 201510261550A CN 105037252 A CN105037252 A CN 105037252A
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- 0 *N(CC1)CCC1=O Chemical compound *N(CC1)CCC1=O 0.000 description 1
- ZDVRPKUWYQVVDX-UHFFFAOYSA-N O=Cc1c(C(F)(F)F)cccc1 Chemical compound O=Cc1c(C(F)(F)F)cccc1 ZDVRPKUWYQVVDX-UHFFFAOYSA-N 0.000 description 1
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract
The invention discloses an N-substituted-3,5-bis(2-trifluoromethyl)benzal)piperidine-4-one derivative used for resisting inflammation, a preparation method and an application thereof and belongs to the field of medicinal chemistry. In the method, the target compound, N-substituted-3,5-bis(2-trifluoromethyl)benzal)piperidine-4-one derivative, is synthesized through a condensation reaction with N-substituted piperidone and o-trifluoromethyl benzaldehyde and the like as raw materials. The N-substituted-3,5-bis(2-trifluoromethyl)benzal)piperidine-4-one derivative has a certain inhibition effect on an experiment cell and shows an excellent anti-inflammation activity.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to a kind of N-acting on anti-inflammatory and replace-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-derivative and preparation method thereof and application.
Background technology
Inflammation refers to the reaction that body tissue and cell occur when being subject to biological factor, physical factor, chemical factor or antigenicity factor equivalent damage, and being the Rational Unified Process of damage and antibody Monoclonal, is a kind of important defensive reaction of body.In inflammatory process, cause tissue injury and airframe systems to open the strength being formed between antibody Monoclonal and resist mutually for a pair, the power of two sides directly affects the direction of inflammatory development.Body produces inflammation, can cause substance metabolism obstacle, cytopathy and necrosis.In recent years, research finds that body inflammatory is under the impact of some factor, also can bring out the disease of the serious harm such as cardiovascular disorder and cancer health of people.
The safran crystallization that curcumine (1,7-bis-(4-hydroxy-5-methyl oxygen base) phenyl-1,6-heptadiene-3,5-diketone) is zingiberaceous plant turmeric, curcuma zedoary, the block root of root tuber of aromatic turmeric or rhizome Hydrolysis kinetics obtain or powder.Have anti-inflammatory, antibacterial, anti-oxidant, anti-cancer, anticancer, the effect such as atherosclerosis, reducing blood-fat, has good DEVELOPMENT PROSPECT.But curcumine also has its insoluble problem, namely it shows obvious unstable in vitro with in solution state.((2E, 6E)-2,6-bis-(2-trifluoromethyl benzylidene pimelinketone) is synthetic to C66
novelcurcumin analogue, have another name called o-trifluoromethyl cyclopentanone curcumin analogue, a kind of curcumin analogue of symmetrical configuration of the composition optimizes according to curcumine, synthesis, containing bis trifluoromethyl, diolefin and ketone group in its structure, these potential sites be combined with biomacromolecule.Its pharmaceutical research shows; C66 can suppress the inflammation factor; as the expression of TNF-α, IL-6, IL-1 β etc.; studies have found that curcumin analogue C66 can protect the kidney injury of diabetes-induced by the hyperglycemia suppressing renal inflammation reaction and macrophages infiltration to cause, these evidences all show its obviously anti-inflammatory activity.
Summary of the invention
The invention provides a kind of N-and replace-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-derivative and preparation method thereof and application, this N-replaces-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-derivative has good anti-inflammatory activity, has the potentiality as anti-inflammatory drug.
A kind of N-replaces-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-derivative, and structure is as shown in formula I:
In formula I, R is selected from C
1~ C
4one in alkyl, replacement or unsubstituted benzyl, replacement or unsubstituted benzoyl group;
Substituting group on described benzyl
independentbe selected from halogen ,-CF
3, C
1~ C
4one or more in alkoxyl group and nitro;
Substituting group on described benzoyl group
independentbe selected from halogen, C
1~ C
4alkyl and C
1~ C
4one or more in alkoxyl group.
Test-results shows, compare with curcumin analogue C66, it is higher that N-of the present invention replaces-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-derivative inhibiting rate to inflammatory factor, there is better anti-inflammatory activity, there are the potentiality as anti-inflammatory drug.
As preferably, described N-replaces-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-derivative, and structure is as shown in the one in formula II ~ (IV):
In formula II, R
1for-CH
3,-CH
2cH
3or-CH
2cH
2cH
3;
In formula III, R
2for F, Cl, Br ,-CF
3,-OCH
3or-NO
2;
In formula IV, R
3for-CH
3,-OCH
3, F or Cl.
As preferably, compound shown in formula II is the one in N1 ~ N3, compound shown in formula III is the one in N4 ~ N11, and the compound shown in formula IV is the one in N12 ~ N18, substituent kind and position
as table 1shown in.
table 1: the substituent kind of N1 ~ N18 and position
One as further preferred, described N-replacement-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-derivative is in following particular compound:
N-methyl-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-, chemical structure is as follows:
N-(3,5-dimethoxy-benzyl)-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-, chemical structure is as follows:
N-(4-chlorobenzene formacyl)-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-, chemical structure is as follows:
Present invention also offers the preparation method that a kind of described N-replaces-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-derivative, comprise the following steps:
Under the effect of basic catalyst, 2-(Trifluoromethyl) benzaldehyde and N-substituted piperidine ketone carry out condensation reaction, after reaction terminates, obtain described N-through aftertreatment and replace-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-derivative;
Described R is selected from C
1~ C
4alkyl, replacement or unsubstituted benzyl.
The structure of described N-substituted piperidine ketone is such as formula shown in (V):
As preferably, described basic catalyst is sodium hydroxide, and described condensation reaction is carried out in dehydrated alcohol.
It is C that this preparation method is applicable to R
1~ C
4the product of alkyl, replacement or unsubstituted benzyl.When R is C
1~ C
4during alkyl, N-substituted piperidine ketone generally can directly be buied from the market.
For N1, concrete preparation process is as follows:
The 2-(Trifluoromethyl) benzaldehyde of 5mmol is dissolved in 15-50mL dehydrated alcohol, then adds the N-methylpiperidone of 2.5mmol, add 3-5 and drip 40%NaOH as catalyzer, control temperature of reaction below 8 DEG C, with the carrying out of TLC monitoring reaction.After having reacted, carry out suction filtration to solid, use 50% ethanol, water washing precipitates, vacuum-drying, if do not have solid to separate out, regulates PH to neutral, then operate as stated above with 10%HCl.The sterling obtaining N-methyl-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-is purified with silica gel column chromatography (with chloroform: methyl alcohol or sherwood oil: the mixed solvent of ethyl acetate is eluent) or recrystallization method.
When R is for replacing or unsubstituted benzyl, raw material N-substituted piperidine ketone is prepared by the following method:
Under the effect of mineral alkali, piperidone and replacement or unsubstituted benzyl bromine carry out substitution reaction in organic solvent, after reaction terminates, obtain described N-substituted piperidine ketone through aftertreatment.
For N4, concrete preparation process is as follows:
Get the piperidone hydrochloride of 1mmol, the various of 1mmol have the benzyl bromine of 3,5-dimethoxy replacement and the anhydrous K of 2mmol
2cO
3be dissolved in the acetonitrile of 10ml, TLC monitors reaction, and reaction terminates, and be spin-dried for acetonitrile, the stirring that adds water is spent the night, and is extracted with ethyl acetate to obtain N-3,5-dimethoxy piperidone.The 2-(Trifluoromethyl) benzaldehyde of 5mmol is dissolved in 15-50mL dehydrated alcohol, add the N-3 of 2.5mmol again, 5-dimethoxy piperidone, add 3-5 and drip the sodium hydroxide of 40% as catalyzer, control temperature of reaction below 8 DEG C, with the carrying out of TLC monitoring reaction.After having reacted, carry out suction filtration to solid, use 50% ethanol, water washing precipitates, vacuum-drying, if do not have solid to wash out, regulates pH to neutral, then operate as stated above with 10%HCl.Purify with silica gel column chromatography (with chloroform: methyl alcohol or sherwood oil: the mixed solvent of ethyl acetate is eluent) or recrystallization method and obtain N-(3,5-dimethoxy-benzyl) sterling of-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidone.
The N-that present invention also offers described in another replaces the preparation method of-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-derivative, comprises the following steps:
(1) under the effect of basic catalyst, 2-(Trifluoromethyl) benzaldehyde and piperidone hydrochloride carry out condensation reaction, after reaction terminates, obtain described 3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-through aftertreatment;
(2) step (1) obtain 3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-compound and replacement or unsubstituted benzoyl chloride generation acylation reaction, obtain described N-through process later after reaction terminates and replace-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-derivative;
This preparation method is applicable to the product that R is replacement or unsubstituted benzoyl group.
As preferably, in step (1), described basic catalyst is sodium hydroxide, and described condensation reaction is carried out in dehydrated alcohol.
As preferably, in step (2), described acylation reaction is carried out in methylene dichloride under the catalysis of DMAP.
For N15, concrete preparation process is as follows:
(1) 2-(Trifluoromethyl) benzaldehyde of 5mmol is dissolved in 15-50mL dehydrated alcohol, then adds the piperidone hydrochloride of 2.5mmol, add 3-5 and drip 40%NaOH as catalyzer, control temperature of reaction below 8 DEG C, with the carrying out of TLC monitoring reaction.After having reacted, carry out suction filtration to solid, use 50% ethanol, water washing precipitates, vacuum-drying, if do not have solid to separate out, regulates PH to neutral, then operate as stated above with 10%HCl.The sterling obtaining 3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-is purified with silica gel column chromatography (with chloroform: methyl alcohol or sherwood oil: the mixed solvent of ethyl acetate is eluent) or recrystallization method.
(2) 3 of 0.3mmol are got, after 5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-compound, DMAP, 5ml triethylamine of 3mg, 10ml methylene dichloride are placed in flask ice bath 30min, drip the various benzoyl chlorides that there is 4-chlorine and replace of 0.6mmol.With the carrying out of TLC monitoring reaction.After having reacted; successively with dilute hydrochloric acid, saturated sodium bicarbonate, saturated sodium-chloride washing; vacuum-drying; the sterling obtaining N-(4-chlorobenzene formacyl)-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-is purified with silica gel column chromatography (chloroform: methyl alcohol or sherwood oil: the mixed solvent of ethyl acetate is eluent) or recrystallization method.
Present invention also offers a kind of described N-replacement-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-derivative and prepare the application in anti-inflammatory drug.
As preferably, the N-that described anti-inflammatory drug comprises treatment significant quantity replaces-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-derivative and pharmaceutical excipients;
The dosage form of described anti-inflammatory drug comprises: injection, tablet, capsule, aerosol, suppository, film, pill, ointment, control-released agent, sustained release dosage or nanometer formulation.
Compared with the existing technology, beneficial effect of the present invention is embodied in:
N-of the present invention replaces-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-derivative has certain restraining effect to test cell, shows certain anti-inflammatory activity.Synthesis compound N 1-N18 to the inhibiting rate of inflammatory factor generally higher than positive control drug C66, so this compounds has good anti-inflammatory action.Wherein compound N 1, N2, N10, N12, N13, N14, N15, N16, N17, N18 are to the inhibiting rate of TNF-a and IL-6 higher than C66, and N2, N12, N13, N16, N17, N18 wherein has exceeded 50% to the inhibiting rate of two kinds of inflammatory factors.The inhibiting rate of derivative to inflammatory factor TNF-a and IL-6 of the N position replacement 3-methyl benzoyl of compound N 17 reaches 72.97% and 82.50%; (research and development of 2-(trifluoromethyl) benzylidene to anti-inflammatory drug have certain potentiality to preliminary deduction N-(3-methyl benzoyl)-3,5-bis-.
Accompanying drawing explanation
fig. 1for in prior art to the mode that the structure of curcumine is optimized;
fig. 2for all target compounds of the present invention act on the signal of the inhibiting rate of the inflammation-inhibiting factor
figure.
Embodiment
Below in conjunction with
accompanying drawingthe present invention will be further described with embodiment.It should be noted that the combination of technical characteristic or the technical characteristic described in following embodiment should not be considered to isolated, they can mutually be combined thus be reached better technique effect.
One, the synthesis of compound
The synthetic route of 1.1 compounds
The synthesis of embodiment 1 ~ 3N1-N3
The 2-(Trifluoromethyl) benzaldehyde of 5mmol is dissolved in 15-50mL dehydrated alcohol, then containing R on the N adding 2.5mmol
1the piperidone replaced, adds 3-5 and drips 40%NaOH as catalyzer, controls temperature of reaction below 8 DEG C, with the carrying out of TLC monitoring reaction.After having reacted, suction filtration is carried out to solid, with 50% ethanol, water washing precipitation, vacuum-drying, if do not have solid to separate out, regulate PH to neutral with 10%HCl, then operate as stated above.The sterling obtaining N1-N3 compound is purified with silica gel column chromatography (with chloroform: methyl alcohol or sherwood oil: the mixed solvent of ethyl acetate is eluent) or recrystallization method.Reaction result and product characters are shown in
table 2, Characterization of The Products data are shown in
table3.
Reaction formula is as follows:
The synthesis of embodiment 4 ~ 11N4-N11
Get the piperidone hydrochloride of 1mmol, the various of 1mmol have the benzyl bromine of substituting group (R2) and the anhydrous K of 2mmol
2cO
3be dissolved in the acetonitrile of 10ml, TLC monitors reaction, and reaction terminates, and be spin-dried for acetonitrile, the stirring that adds water is spent the night, and is extracted with ethyl acetate N is upper contains R
2the piperidone replaced.The 2-(Trifluoromethyl) benzaldehyde of 5mmol is dissolved in 15-50mL dehydrated alcohol, then containing R on the N adding 2.5mmol
2the piperidone replaced, adds 3-5 and drips the sodium hydroxide of 40% as catalyzer, controls temperature of reaction below 8 DEG C, with the carrying out of TLC monitoring reaction.After having reacted, carry out suction filtration to solid, use 50% ethanol, water washing precipitates, vacuum-drying, if do not have solid to wash out, regulates pH to neutral, then operate as stated above with 10%HCl.The sterling obtaining N4-N11 compound is purified with silica gel column chromatography (with chloroform: methyl alcohol or sherwood oil: the mixed solvent of ethyl acetate is eluent) or recrystallization method.Reaction result and product characters are shown in
table 2, Characterization of The Products data are shown in
table 3.
Reaction formula is as follows:
The synthesis of embodiment 12 ~ 18N12-N18
The 2-(Trifluoromethyl) benzaldehyde of 5mmol is dissolved in 15-50mL dehydrated alcohol, then adds the piperidone hydrochloride of 2.5mmol, add 3-5 and drip 40%NaOH as catalyzer, control temperature of reaction below 8 DEG C, with the carrying out of TLC monitoring reaction.After having reacted, carry out suction filtration to solid, use 50% ethanol, water washing precipitates, vacuum-drying, if do not have solid to separate out, regulates pH to neutral, then operate as stated above with 10%HCl.The sterling obtaining 3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-compound is purified with silica gel column chromatography (with chloroform: methyl alcohol or sherwood oil: the mixed solvent of ethyl acetate is eluent) or recrystallization method.
Get 3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-compound of 0.3mmol, after DMAP, 5ml triethylamine of 3mg, 10ml methylene dichloride be placed in flask ice bath 30min, drip the various of 0.6mmol and there is R
3the benzoyl chloride replaced.With the carrying out of TLC monitoring reaction.After having reacted, successively with dilute hydrochloric acid, saturated sodium bicarbonate, saturated sodium-chloride washing, vacuum-drying, purifies with silica gel column chromatography (chloroform: methyl alcohol or sherwood oil: the mixed solvent of ethyl acetate is eluent) or recrystallization method the sterling obtaining N12-N18 compound.Reaction result and product characters are shown in
table 2, Characterization of The Products data are shown in
table 3.
Reaction formula is as follows:
table 2the structure of compound N 1-N18 and physical data
table 3the IR of target compound N1-N18 and
1h-NMR data
Proterties and the solvability thereof of target compound synthesized by the present invention are as follows:
Compound N 1-N18 is yellow, light yellow or white solid.Compound N 1-N18 is soluble in DMSO, DMF, ethyl acetate, ethanol, methylene dichloride, methyl alcohol, acetonitrile; Be insoluble to sherwood oil, water.
Compound synthesized by the present invention, carries out mass spectrometric measurement, and positive pole all shows [M+1]
+, and signal is comparatively strong, part of compounds also show [M+Na]
+.Compound synthesized by the present invention, carries out infrared test, target compound all containing carbonyl, C-N key, C=C double bond etc., IR
figurespectrum can obviously see that it exists, the compound synthesized by the present invention, carry out
1h-NMR tests, from
1h-NMR
figurespectrum can be clearly seen that the hydrogen signal of compound and residing chemical shift thereof.
Two, compound anti-inflammatory activity data
1, MPM (huge bite) cell is obtained, cultivate Monocytes/Macrophages strain, with LPS (lipopolysaccharides), the inductions such as IFN-γ, can a large amount of scavenger cell be produced, and produce a large amount of inflammatory factors, mainly with TNF-α, IL-6 is main, and anti-inflammatory drug is played a role by the generation of these two kinds of factors in T suppression cell.
Working method:
1) meat soup is prepared---stimulate mouse to produce a large amount of scavenger cell
Take extractum carnis 0.15g, peptone 0.5g, NaCl0.25g, Zulkovsky starch 3g, meat soup is boiled to thoroughly
light colour, being down to room temperature just can abdominal injection.
2) to injected in mice meat soup 2mL, cell (compound can be prepared during this, dissolve with DMSO) after three days, is carried.
3) carry plating cells: mouse is plucked eye, bloodletting reduces red corpuscle in abdominal cavity, and rear disconnected marrow is put to death, and health 75% alcohol disinfecting, faces upward position and fix on foam, fixed head, four limbs, tail.At thorax median line meta place, pick up barrier film with curved tweezer, with syringe to intraperitoneal injection RPMI-1640 substratum (not containing FBS) 3 ~ 4ml, gently rub belly, scavenger cell and substratum are mixed.Pick up medial septum with curved tweezer, with operating scissors (vertical direction is taken), cut off barrier film, hand over intraperitoneal liquid to pick up with liquid-transfering gun, move in 15ml centrifuge tube, centrifugal 1100r, 5min, abandon supernatant.In centrifugal cell, the substratum added containing FBS is about 2ml, repeatedly blows and beats into cell suspension gently.Cell counting (20 μ L/ hole), assigns to cell on six orifice plate 1ml and cultivates (5 × 10
5/ hole) in 37 DEG C, 5%CO
2cultivate.After 4 ~ 6h, take out and wash with PBS, change liquid.
4) the synthetic compound 1 μ l of 10 μm of ol concentration is added, add LPS (0.5 μ g/ul) 1 μ l after 30min to stimulate, be divided into three groups: different sorts medicine+LPS, LPS (stimulating group), con (control group only has cell and DMSO).
5) above-mentioned be disposed after put into incubator again and carry out hatching >24h.
2, experimentation
Working method:
1) bag quilt: get primary antibodie (capureantibody250 ×) 40ul, aqua sterilisa 9ml, coatingbuffer (10 ×) 1ml, piping and druming mixing, then add 100 μ L/ holes in elisa plate, wrap with preservative film, 4 DEG C are spent the night.Join PBST:PBS1000ml, 500ul polysorbas20, for subsequent use.
2) add AD to close: within second day, wash three times with PBST, 250 μ L/ holes, each 1 ~ 2min, turns around for the last time, puts on paper and pats dry, and adds AD (1 ×) 200 μ L/ hole, wraps with preservative film, 1h closed by shaking table.Close and washed three times with PBST, 250 μ L/ holes, each 1 ~ 2min.Supernatant samples can be taken out in above-mentioned closed process and thaw.
3) application of sample: 100 μ L/ holes (sample 5%, AD95%) are wrapped with preservative film, and shaking table hatches 2h.
4) add two to resist: (two resist: AD=1000:4), and get two anti-(Detectionantibody) 40 μ L, AD100mL, piping and druming mixing, adds 100 μ L/ holes in above-mentioned elisa plate, wrap, shaking table hatches 1h with preservative film.
5) enzyme-added HRP: wash three times with PBST, 250 μ L/ holes, each 1 ~ 2min, enzyme-added HRP (250 × → 1 ×), 100 μ L/ holes, wrap with preservative film, shaking table hatch 30min.
6) add TMP: wash five times with PBST, 250 μ L/ holes, each 1 ~ 2min, lucifuge adds TMP (1 ×), 100 μ L/ holes, colour developing → blue.
7) stop: add H
2sO
4(2mol) 50 μ L/ holes.
8) OD value (λ=450nm) is surveyed: the anti-inflammatory activity IL-6 to two kinds of inflammatory factors of our survey here, TNF-α, calculate respectively: IL-6:(sample/LPS group) × 100%, TNF-α: (sample/LPS group) × 100%.
3, experimental result
3.1 anti-inflammatory activity primary dcreening operation results
fig. 2for all target compounds of the present invention act on the signal of the inhibiting rate of the inflammation-inhibiting factor
figure.From
fig. 2can find out:
1) result display, the compound N 1-18 of synthesis to the inhibiting rate of inflammatory factor generally higher than positive control drug C66, so this compounds has good anti-inflammatory action.
2) shown by the comparison of this inhibiting rate: wherein compound N 1, N2, N10, N12, N13, N14, N15, N16, N17, N18 are to the inhibiting rate of TNF-a and IL-6 higher than C66, and N2, N12, N13, N16, N17, N18 wherein has exceeded 50% to the inhibiting rate of two kinds of inflammatory factors.
4) can be found by comparison object compound and positive control drug: the inhibiting rate of derivative to inflammatory factor TNF-a and IL-6 of the N position replacement 3-methyl benzoyl of compound N 17 reaches 72.97%; 82.50%; (research and development of 2-(trifluoromethyl) benzylidene to anti-inflammatory drug have certain potentiality to preliminary deduction N-(3-methyl benzoyl)-3,5-bis-.
Claims (10)
1. a N-replaces-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-derivative, and it is characterized in that, structure is as shown in formula I:
In formula I, R is selected from C
1~ C
4one in alkyl, replacement or unsubstituted benzyl, replacement or unsubstituted benzoyl group;
Substituting group independent selected from halo on described benzyl ,-CF
3, C
1~ C
4one or more in alkoxyl group and nitro;
Substituting group independent selected from halo on described benzoyl group, C
1~ C
4alkyl and C
1~ C
4one or more in alkoxyl group.
2. N-according to claim 1 replaces-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-derivative, and it is characterized in that, structure is as shown in the one in formula II ~ (IV):
In formula II, R
1for-CH
3,-CH
2cH
3or-CH
2cH
2cH
3;
In formula III, R
2for F, Cl, Br ,-CF
3,-OCH
3or-NO
2;
In formula IV, R
3for-CH
3,-OCH
3, F or Cl.
3. N-according to claim 2 replaces-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-derivative, it is characterized in that, the one in following particular compound:
N-methyl-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-, chemical structure is as follows:
N-(3,5-dimethoxy-benzyl)-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-, chemical structure is as follows:
N-(4-chlorobenzene formacyl)-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-, chemical structure is as follows:
4. the preparation method of N-replacement-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-derivative as described in any one of claims 1 to 3, is characterized in that, comprise the following steps:
Under the effect of basic catalyst, 2-(Trifluoromethyl) benzaldehyde and N-substituted piperidine ketone carry out condensation reaction, after reaction terminates, obtain described N-through aftertreatment and replace-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-derivative;
Described R is selected from C
1~ C
4alkyl, replacement or unsubstituted benzyl.
5. N-according to claim 4 replaces-3, the preparation method of 5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-derivative, it is characterized in that, described basic catalyst is sodium hydroxide, and described condensation reaction is carried out in dehydrated alcohol.
6. the preparation method of N-replacement-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-derivative as described in any one of claims 1 to 3, is characterized in that, comprise the following steps:
(1) under the effect of basic catalyst, 2-(Trifluoromethyl) benzaldehyde and piperidone hydrochloride carry out condensation reaction, after reaction terminates, obtain described 3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-through aftertreatment;
(2) step (1) obtain 3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-compound and replacement or unsubstituted benzoyl chloride generation acylation reaction, obtain described N-through process later after reaction terminates and replace-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-derivative;
Described R is for replacing or unsubstituted benzoyl group.
7. N-according to claim 6 replaces-3, the preparation method of 5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-derivative, it is characterized in that, in step (1), described basic catalyst is sodium hydroxide, and described condensation reaction is carried out in dehydrated alcohol.
8. N-according to claim 6 replaces-3; the preparation method of 5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-derivative; it is characterized in that, in step (2), described acylation reaction is carried out in methylene dichloride under the catalysis of DMAP.
9. the N-as described in any one of claim 1-3 replaces-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-derivative and is preparing the application in anti-inflammatory drug.
10. N-according to claim 9 replaces-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-derivative is preparing the application in anti-inflammatory drug, it is characterized in that, the N-that described anti-inflammatory drug comprises treatment significant quantity replaces-3,5-bis-(2-(trifluoromethyl) benzylidene) piperidin-4-one-derivative and pharmaceutical excipients;
The dosage form of described anti-inflammatory drug comprises: injection, tablet, capsule, aerosol, suppository, film, pill, ointment, control-released agent, sustained release dosage or nanometer formulation.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108191751A (en) * | 2018-01-08 | 2018-06-22 | 滨州医学院 | Bis- aryl methylene -4- piperidines ketone compounds of 3,5- of 4- fluorophenylsulphonyls substitution and preparation method thereof |
| CN108997311A (en) * | 2018-08-06 | 2018-12-14 | 滨州医学院 | Bis- aryl methylene -4- the piperidones of 3,5- and preparation method thereof that asymmetric 4- pyridine replaces |
| CN109608388A (en) * | 2018-12-27 | 2019-04-12 | 温州医科大学 | A kind of double carbonyl curcumin derivatives and its application |
| CN114853630A (en) * | 2022-06-07 | 2022-08-05 | 温州医科大学 | 2, 6-diphenylmethylene cyclohexanone oxime compound and preparation method and application thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001040188A1 (en) * | 1999-12-03 | 2001-06-07 | Emory University | Curcumin analogues for treating cancer |
| CN102381951A (en) * | 2007-01-22 | 2012-03-21 | 温州医学院生物与天然药物开发中心有限公司 | Cyclohexanone-contained mono-carbonyl analogues of curcumin and usage thereof |
| CN102863376A (en) * | 2012-09-27 | 2013-01-09 | 上海师范大学 | N-substituted methyl-3,5-disubstituted benzylidene base-4-piperidone and preparation method and application thereof |
| CN103181922A (en) * | 2013-04-02 | 2013-07-03 | 温州医学院 | Application of piperidone-containing single-carbonyl curcumin compound in preparation of anti-inflammatory drug |
| CN103919778A (en) * | 2013-12-19 | 2014-07-16 | 温州医科大学 | Application of curcumin analog S1 containing piperidone structure in preparation of anti-inflammation drugs |
-
2015
- 2015-05-21 CN CN201510261550.3A patent/CN105037252B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001040188A1 (en) * | 1999-12-03 | 2001-06-07 | Emory University | Curcumin analogues for treating cancer |
| CN102381951A (en) * | 2007-01-22 | 2012-03-21 | 温州医学院生物与天然药物开发中心有限公司 | Cyclohexanone-contained mono-carbonyl analogues of curcumin and usage thereof |
| CN102863376A (en) * | 2012-09-27 | 2013-01-09 | 上海师范大学 | N-substituted methyl-3,5-disubstituted benzylidene base-4-piperidone and preparation method and application thereof |
| CN103181922A (en) * | 2013-04-02 | 2013-07-03 | 温州医学院 | Application of piperidone-containing single-carbonyl curcumin compound in preparation of anti-inflammatory drug |
| CN103919778A (en) * | 2013-12-19 | 2014-07-16 | 温州医科大学 | Application of curcumin analog S1 containing piperidone structure in preparation of anti-inflammation drugs |
Non-Patent Citations (3)
| Title |
|---|
| JIANZHANG WU等: "Discovery and evaluation of piperid-4-one-containing mono-carbonyl analogs of curcumin as anti-inflammatory agents", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| YONG PAN等: "Inhibition of high glucoseinduced inflammatory response and macrophage infiltration by a novel curcumin derivative prevents renal injury in diabetic rats", 《BRITISH JOURNAL OF PHARMACOLOGY》 * |
| 肖笛: "新型单羰基姜黄素类似物的研究", 《上海师范大学硕士学位论文》 * |
Cited By (7)
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|---|---|---|---|---|
| CN108191751A (en) * | 2018-01-08 | 2018-06-22 | 滨州医学院 | Bis- aryl methylene -4- piperidines ketone compounds of 3,5- of 4- fluorophenylsulphonyls substitution and preparation method thereof |
| CN108191751B (en) * | 2018-01-08 | 2023-06-27 | 滨州医学院 | 4-fluorobenzenesulfonyl substituted 3, 5-diarylmethylene-4-piperidone compound and preparation method thereof |
| CN108997311A (en) * | 2018-08-06 | 2018-12-14 | 滨州医学院 | Bis- aryl methylene -4- the piperidones of 3,5- and preparation method thereof that asymmetric 4- pyridine replaces |
| CN108997311B (en) * | 2018-08-06 | 2023-06-23 | 滨州医学院 | Asymmetric 4-pyridine substituted 3, 5-diarylmethylene-4-piperidone and preparation method thereof |
| CN109608388A (en) * | 2018-12-27 | 2019-04-12 | 温州医科大学 | A kind of double carbonyl curcumin derivatives and its application |
| CN109608388B (en) * | 2018-12-27 | 2020-08-25 | 温州医科大学 | Dicarbonylcurcumin derivative and application thereof |
| CN114853630A (en) * | 2022-06-07 | 2022-08-05 | 温州医科大学 | 2, 6-diphenylmethylene cyclohexanone oxime compound and preparation method and application thereof |
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