CN111592520A - 4, 5-disubstituted piperine derivatives, and preparation method and application thereof - Google Patents
4, 5-disubstituted piperine derivatives, and preparation method and application thereof Download PDFInfo
- Publication number
- CN111592520A CN111592520A CN202010407352.4A CN202010407352A CN111592520A CN 111592520 A CN111592520 A CN 111592520A CN 202010407352 A CN202010407352 A CN 202010407352A CN 111592520 A CN111592520 A CN 111592520A
- Authority
- CN
- China
- Prior art keywords
- piperine
- compound
- disubstituted
- derivative
- substrate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
- MXXWOMGUGJBKIW-YPCIICBESA-N piperine Chemical class C=1C=C2OCOC2=CC=1/C=C/C=C/C(=O)N1CCCCC1 MXXWOMGUGJBKIW-YPCIICBESA-N 0.000 title claims abstract description 99
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 44
- 239000003814 drug Substances 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 10
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 4
- 230000015572 biosynthetic process Effects 0.000 claims abstract 2
- WVWHRXVVAYXKDE-UHFFFAOYSA-N piperine Natural products O=C(C=CC=Cc1ccc2OCOc2c1)C3CCCCN3 WVWHRXVVAYXKDE-UHFFFAOYSA-N 0.000 claims description 56
- 235000019100 piperine Nutrition 0.000 claims description 56
- 229940075559 piperine Drugs 0.000 claims description 54
- 238000006243 chemical reaction Methods 0.000 claims description 51
- 150000001875 compounds Chemical class 0.000 claims description 22
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
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- 239000002904 solvent Substances 0.000 claims description 18
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 13
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 12
- -1 potassium ferricyanide Chemical compound 0.000 claims description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 claims description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- DGODWNOPHMXOTR-UHFFFAOYSA-N dipotassium;dioxido(dioxo)osmium;dihydrate Chemical compound O.O.[K+].[K+].[O-][Os]([O-])(=O)=O DGODWNOPHMXOTR-UHFFFAOYSA-N 0.000 claims description 6
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- OTLNPYWUJOZPPA-UHFFFAOYSA-N 4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-N 0.000 claims description 5
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 5
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- YUCBLVFHJWOYDN-HVLQGHBFSA-N 1,4-bis[(s)-[(2r,4s,5r)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methoxy]phthalazine Chemical compound C1=C(OC)C=C2C([C@H](OC=3C4=CC=CC=C4C(O[C@H]([C@@H]4N5CC[C@H]([C@H](C5)CC)C4)C=4C5=CC(OC)=CC=C5N=CC=4)=NN=3)[C@H]3C[C@@H]4CCN3C[C@@H]4CC)=CC=NC2=C1 YUCBLVFHJWOYDN-HVLQGHBFSA-N 0.000 claims description 3
- YUCBLVFHJWOYDN-PPIALRKJSA-N 4-[(r)-[(2r,4s,5r)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methoxy]-1-[(r)-[(2r,4r,5s)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methoxy]phthalazine Chemical group C1=C(OC)C=C2C([C@@H](OC=3C4=CC=CC=C4C(O[C@@H]([C@@H]4N5CC[C@@H]([C@@H](C5)CC)C4)C=4C5=CC(OC)=CC=C5N=CC=4)=NN=3)[C@H]3C[C@@H]4CCN3C[C@@H]4CC)=CC=NC2=C1 YUCBLVFHJWOYDN-PPIALRKJSA-N 0.000 claims description 3
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
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Abstract
The invention discloses a preparation method and application of a 4, 5-disubstituted piperine derivative serving as a medicament for treating senile dementia. In particular to an asymmetric synthesis method of a medicament for treating senile dementia, which respectively prepares (4R,5R), (4S,5S), (4S,5R) or (4R,5S)4, 5-disubstituted piperine isomer derivatives according to different synthesis routes. The derivatives have good activity for treating senile dementia, do not show acute toxicity, and can be clinically applied in oral administration, intravenous injection, intramuscular injection and other modes.
Description
Technical Field
The invention relates to the field of organic synthesis and medicinal chemistry, in particular to a synthesis method of a 4, 5-disubstituted piperine derivative and application thereof in medicaments for treating and preventing Alzheimer disease.
Background
Alzheimer's Disease (AD), also known as senile dementia, is a progressive degenerative disease of the nervous system with occult disease. The clinical manifestations are progressive hypomnesis, cognitive dysfunction, abnormal daily behaviors and the like, which seriously affect social, occupational and life functions, and the etiology of AD is unknown so far. In recent years, various pathogenesis hypotheses such as an Abeta hypothesis, a tau hypothesis, a neurotransmitter imbalance hypothesis, a chronic inflammation hypothesis and the like are proposed by a plurality of researchers at home and abroad. Based on these hypotheses, researchers developed different drugs. The target of action of the drugs is mainly acetylcholinesterase (such as tacrine and huperzine A) butyrylcholinesterase (such as rivastigmine and galantamine) and N-methyl-D-aspartic acid (such as memantine), wherein cholinesterase is an important target against AD. However, because the pathogenesis of AD is extremely complex, the existing AD treatment drugs have the defects of large side effect, unobvious curative effect and the like. Therefore, there is a great need to find new active molecules for the treatment or prevention of AD.
Piperine (piperine) is a natural amide compound extracted from pepper, and has wide biological activities of resisting infection, resisting oxidation, regulating immunity and the like. Currently, the research on the activity of piperine and its derivatives mainly lies in the aspects of anti-tumor, anti-depression, lipid lowering and the like, such as: 5- (3',4' -methylenedioxyphenyl) -pentenoylpropylamine has an antidepressant action superior to that of piperine. However, there is no document or patent report that 4, 5-disubstituted piperine derivatives have the effect of treating or preventing senile dementia.
Recently, we have a topic of separating a new derivative of piperine, 4, 5-disubstituted piperine, from the dried leaves of piper pseudopiper longum of the genus piper. Meanwhile, the novel asymmetric synthesis of four derivatives with different configurations of (4R,5R), (4S,5S), (4S,5R) and (4R,5S) -disubstituted piperine is completed by using piperine as a substrate and through Sharpless asymmetric disubstituted reaction, Mitsunobu reaction and the like. The screening of cholinesterase activity and the screening of the compound-induced senile dementia zebra fish in vivo indicates that only 4R, 5S-disubstituted piperine can obviously improve the cognitive ability and the reaction ability of the senile dementia zebra fish, and does not inhibit the activity of cholinesterase, and the research result indicates that the 4R, 5S-disubstituted piperine has a new anti-AD action mechanism.
In conclusion, the innovation of the invention is that the 4, 5-disubstituted piperine derivative is a brand new compound separated from a natural product for the first time, and four configurations of 4, 5-disubstituted piperine (4R,5R), (4S,5S), (4S,5R) and (4R,5S) are synthesized for the first time by an asymmetric synthesis method, so that the piperine is further proved to have no AD resistance activity, and the 4, 5-disubstituted piperine is a key activity center of the derivative. The invention has the advantages that the 4, 5-disubstituted piperine does not act on cholinesterase which is a recognized target spot of AD, and the 4R, 5S-disubstituted piperine has excellent anti-AD activity in animals without acute toxicity, which suggests that the 4R, 5S-disubstituted piperine may have a new anti-AD action mechanism.
Disclosure of Invention
The invention aims to synthesize a series of piperine compounds containing different substituents and configurations at 4-position and 5-position by breaking the 4-position double bond of piperine to form 4-position and 5-position dihydroxy and replacing the 4-position and 5-position hydroxyl groups with bioisosteres.
Another objective of the invention is to provide a method for synthesizing a series of piperine compounds with different substituents and configurations at positions 4 and 5.
The invention also aims to provide application of the piperine derivatives containing different 4-position and 5-position substituents and configurations in preparation of medicaments for preventing senile dementia.
The piperine derivatives containing different substituents and configurations at 4 and 5 positions have the specific structure shown in the general formula I:
wherein,
R1is an aromatic ring/aromatic heterocycle
R2is-OH, -NH2，-SH
R3is-OH, -NH2，-SH
The invention provides a preparation method of the piperine derivatives containing different 4-position and 5-position substituents and configurations. The method comprises the following steps:
taking piperine as a substrate, and carrying out addition and disconnection on a 4-site double bond under the action of potassium ferricyanide, potassium carbonate, potassium osmate dihydrate and cinchona alkaloid derivatives to generate a compound I; wherein the cinchona alkaloid derivative is (DHQ)2PHAL or (DHQD)2 PHAL; the solvent is water: mixed solution of tert-butanol 1: 1.
The compound I generates a compound II under the action of a substrate I, triphenylphosphine and diethyl azodicarboxylate, wherein the substrate I is p-nitrobenzoic acid or imino dicarbonate 1- (1, 1-1-dimethylethyl) ester and thioacetic acid, and the solvent is dichloromethane and tetrahydrofuran.
And (3) generating a compound III by the compound II under the action of a substrate II, wherein the substrate II is potassium carbonate or trifluoroacetic acid and lithium aluminum hydride, and the solvent is tetrahydrofuran and diethyl ether.
Wherein the generated compound I is a 4, 5-dihydroxy piperine derivative with (4R,5R) and (4S,5S) configurations, and the 4, 5-dihydroxy piperine derivative with (4S,5R) and (4R,5S) configurations is generated by converting the configurations under the action of p-nitrobenzoic acid, triphenylphosphine and diethyl azodicarboxylate.
The invention synthesizes a series of piperine derivatives containing different substituents at 4-position and 5-position according to the conditions that the 4-position double bond of the piperine is added and broken to form 4-position and 5-position dihydroxy, and 4-position and 5-position hydroxyl groups are replaced by biological electron isosteres.
The compound I generates a compound II under the action of imino dicarbonate 1- (1, 1-dimethylethyl) ester, triphenylphosphine and azodicarboxylic acid diethyl ester, and a solvent is tetrahydrofuran; and (3) generating a compound III which is 4, 5-diamino piperine containing four configurations by the compound II under the action of trifluoroacetic acid, wherein the solvent is dichloromethane.
Generating a compound II by the compound I under the action of thioacetic acid, triphenylphosphine and azodicarboxylic acid diethyl ester, wherein a solvent is tetrahydrofuran; and (3) generating a compound III which is 4, 5-dimercapto piperine containing four configurations by the compound II under the action of lithium aluminum hydride, wherein the solvent is diethyl ether.
Further, in the synthesis reaction of the compound I, the reaction temperature is room temperature, and the reaction time is 12-24 hours. Wherein the ratio of piperine to potassium ferricyanide, potassium carbonate, potassium osmate dihydrate and cinchonine derivative is 1-2: 2.5-4.5: 2.5-4.5: 0.01-0.1: 0.05 to 0.1;
further, in the reaction of the compound I to generate the compound II under the action of the substrate I, triphenylphosphine and diethyl azodicarboxylate, the reaction temperature is 40-60 ℃, and the reaction time is 4-6 hours. Wherein the mass ratio of the compound I to the substrate I, triphenylphosphine and azodicarboxylic acid diethyl ester is 1-2: 1-2: 1-2: 1 to 2.
Further, in the reaction of the compound II to generate the compound III under the action of the substrate II, the reaction temperature is 40-55 ℃, and the reaction time is 8-10 hours.
The invention also provides application of the derivative containing the 4, 5-disubstituted piperine in preparing a medicament for treating or preventing Alzheimer disease.
The derivatives of the invention have good activity of resisting senile dementia, and can be any one of tablets, pills, capsules, granules, micro-capsule tablets, suspensions, dripping pills, oral liquid, injections, aerosols, inhalants, suppositories or subcutaneous administration dosage forms in clinic.
Further, the derivative of the 4, 5-disubstituted piperine is a 4R, 5S-disubstituted piperine derivative or a 4S, 5R-disubstituted piperine derivative.
The invention has the beneficial effects that: the invention provides a preparation method of a novel piperine derivative containing different 4-and 5-substituted groups, and finds out the novel application of 4R, 5S-disubstituted piperine in medicines or health products with activity in senile dementia of experimental animals for the first time. Compared with the existing medicine for treating senile dementia, the 4, 5-disubstituted piperine does not inhibit cholinesterase, but the 4R, 5S-disubstituted piperine shows excellent activity in an anti-senile dementia experiment of zebra fish, so that the 4R, 5S-disubstituted piperine has a brand-new action mechanism in the anti-senile dementia, and can be used for preparing the medicine for preventing or treating senile dementia.
Drawings
FIG. 1 is a schematic representation of the locomotion speed of senile dementia recovering zebrafish with piperine and four configurations of 4,5 dihydroxy piperine.
FIG. 2 is a schematic representation of the ability of piperine and four configurations of 4,5 dihydroxy piperine to restore the reactivity of Alzheimer's disease zebrafish;
Detailed Description
The inventor of the application finds that the 4, 5-disubstituted pepper can not obviously inhibit cholinesterase when being applied to animals, but can obviously improve the cognitive ability and the reaction ability of the senile dementia zebra fish in a compound-induced senile dementia zebra fish model. That is, 4, 5-disubstituted pepper does not exert the anti-alzheimer effect through cholinesterase, but acts on other targets, which means that 4, 5-disubstituted pepper has a new anti-AD mechanism for treating/relieving symptoms related to brain function and its disorder diseases without completely inhibiting all activities and without toxic and side effects.
The novel piperine derivatives having different substituents at the 4-and 5-positions and the preparation method thereof according to the present invention are described in more detail in the following examples, which are not intended to limit the present invention, and any modifications or substitutions based on the present invention are within the scope of the present invention.
Example 1
Preparation of 4R, 5R-dihydroxy piperine (Compound 1):
5mL of water and 5mL of t-butanol were taken and stirred well as a solvent to the mixed solvent was added potassium ferricyanide (807.7mg,2.45mmol), potassium carbonate (339.1mg,2.45mmol), potassium osmate dihydrate (1.3mg, 3.5. mu. mol), (DHQ)2PHAL (5.4mg,0.701mmol) and reacted at room temperature for 20min, piperine (200mg,0.701mmol) was then added, the mixture was stirred at room temperature for 24h, anhydrous sodium sulfite (1.5443mg,12.3mmol) was added to the mixture and stirred at room temperature for 12h to terminate the reaction, the reaction solution was added to 25mL of water, extracted with ethyl acetate (25 × 3mL), the combined organic phases were concentrated in vacuo to give a crude product, which was purified by flash column chromatography (silica gel, DCM: M)eOH ═ 35:1) to give the corresponding 4R, 5R-dihydroxypiperine as a clear oil in 44.5% yield (99.8 mg);1H NMR(600MHz,MeOD)6.88(d,J＝1.5Hz,1H),6.80(dd,J＝7.9,1.5Hz,1H),6.76(d,J＝7.9Hz,1H),6.51(dd,J＝15.3,4.9Hz,1H),6.43(dd,J＝15.3,1.5Hz,1H),5.91(dd,J＝5.3,1.2Hz,2H),4.45(d,J＝6.7Hz,1H),4.31(ddd,J＝6.7,4.9,1.5Hz,1H),3.58–3.47(m,2H),3.43-3.37(m,2H),1.68–1.62(m,2H),1.55–1.46(m,4H)。
example 2
Preparation of 4S, 5S-dihydroxy piperine (compound 2):
5mL of water and 5mL of tert-butanol were taken and stirred uniformly as a solvent, potassium ferricyanide (807.7mg,2.45mmol), potassium carbonate (339.1mg,2.45mmol), potassium osmate dihydrate (1.3mg, 3.5. mu. mol), (DHQD)2PHAL (5.4mg,0.701mmol) were added to the mixed solvent, followed by reaction at room temperature for 20min, piperine (200mg,0.701mmol) was then added, the mixture was stirred at room temperature for 24h, anhydrous sodium sulfite (1.5443mg,12.3mmol) was added to the mixture and stirred at room temperature for 12h, the reaction solution was added to 25mL of water, extracted with ethyl acetate (25 × 3mL), and the combined organic phases were concentrated in vacuo to give a crude product, which was purified by DCM flash column chromatography (silica gel, MeOH: 35:1) to give the corresponding 4S, 5S-dihydroxypiperine as a transparent oil in 44.4% yield (99.4 mg);1H NMR(600MHz,MeOD)6.90(d,J＝1.5Hz,1H),6.83(dd,J＝7.9,1.5Hz,1H),6.78(d,J＝7.9Hz,1H),6.53(dd,J＝15.3,4.9Hz,1H),6.45(dd,J＝15.3,1.5Hz,1H),5.93(dd,J＝4.9,1.5Hz,2H),4.47(d,J＝6.7Hz,1H),4.34(ddd,J＝6.7,4.9,1.5Hz,1H),3.61–3.50(m,2H),3.46–3.40(m,2H),1.70–1.65(m,2H),1.57–1.49(m,4H).
example 3
Preparation of 4S, 5R-dihydroxy piperine (Compound 3):
dissolving Compound 1(285mg,0.893mmol) in 4.5mL of THF, placing p-nitrobenzoic acid (149.2mg,0.893mmol) and triphenylphosphine (234.2mg,0.893mmol) in a 10mL reaction tube, stirring, exhausting the air in the reaction tube, placing the reaction tube in an ice-water bath (0 deg.C), and after 5min, dropwise adding diethyl azodiacetate (141) into the reaction tube under the condition of ice-water bathμ L,0.893mmol) was stirred well and the reaction tube was placed under N2Placing the mixture in an oil bath pan at 45 ℃ under protection and stirring for 5 hours. The reaction was concentrated in vacuo and purified by flash column chromatography (silica gel, P: EtOAc 1:1+. 0.1% HOAc) to give the crude product. The resulting crude product was purified by semipreparative liquid chromatography (COSMUSIL 5 SL-ii, n-hexane: EtOAc ═ 10% to 100%) to give compound 1a as a white solid in 5.5% yield (22.9 mg).
Dissolve Compound 1a (9.3mg, 19.9. mu. mol) in 250. mu.L of THF in a 5mL reaction tube, add 50. mu. L H to the reaction tube2O, then stirring uniformly, then adding potassium carbonate (13.7mg,99.3 mu mol) into a reaction tube, stirring uniformly, placing the mixture into an oil bath kettle at 45 ℃ for reaction for 10h, then dropwise adding 1M HCl into the reaction solution to adjust the pH value of the reaction solution to subacidity, extracting with ethyl acetate (3 × 3mL), combining organic phases, and concentrating in vacuum to obtain a crude product, purifying the obtained crude product by flash column chromatography (silica gel, petroleum ether: EtOAc ═ 1:1) to obtain a compound 3(4S, 5R-dihydroxy piperine) which is a transparent oily substance with the yield of 41.2% (2.6 mg);1H NMR(600MHz,MeOD)6.81(d,J＝1.5Hz,1H),6.73(dd,J＝7.9,1.5Hz,1H),6.67(d,J＝8.0Hz,1H,6.68–6.64(m,1H,overLap),6.38(dd,J＝15.3,1.5Hz,1H),5.82(dd,J＝2.1,1.1Hz,2H),4.47(d,J＝5.5Hz,1H),4.23(td,J＝5.3,1.5Hz,1H),3.47(t,5.5,2H),3.39(t,5.5,2H),1.61–1.56(m,2H),1.48–1.43(m,4H).
example 4
Preparation of 4R, 5S-dihydroxy piperine (compound 4):
dissolving compound 2(245mg,0.767mmol) in 4.5mL of THF in a 10mL reaction tube, sequentially adding P-nitrobenzoic acid (128.5mg,0.767mmol) and triphenylphosphine P (201.3mg,0.76mmol) into the reaction tube, stirring uniformly, exhausting the air in the reaction tube, placing the reaction tube in an ice-water bath (0 ℃), dropwise adding diethyl azodiacetate (134 μ L,0.767mmol) into the reaction tube under the condition of the ice-water bath after 5min, stirring uniformly, and placing the reaction tube in an N reaction tube2Placing the mixture in an oil bath pan at 45 ℃ under protection and stirring for 5 hours. The reaction was concentrated in vacuo and purified by flash column chromatography (silica gel, P: EtOAc 1:1+. 0.1% HOAc) to give the crude product. The resulting crude material was purified by semi-preparative liquid chromatography (COSMUSIL 5 SL-ii, n-hexane: EtOAc 10% -100%)The product was obtained as compound 2a as a white solid in 5.0% yield (17.8 mg).
Dissolve Compound 2a (8.7mg, 18.6. mu. mol) in 250. mu.L of THF in a 5mL reaction tube, add 50. mu. L H to the reaction tube2O, then stirring uniformly, adding potassium carbonate (12.9mg,92.9 mu mol) into a reaction tube, stirring uniformly, placing the mixture into an oil bath kettle at 45 ℃ for reaction for 10h, then dropwise adding 1M HCl into the reaction solution to adjust the pH value of the reaction solution to subacidity, extracting with ethyl acetate (3 × 3mL), combining organic phases, and concentrating in vacuum to obtain a crude product, purifying the obtained crude product by flash column chromatography (silica gel, petroleum ether: EtOAc ═ 1:1) to obtain a compound 4(4R, 5S-dihydroxy piperine) which is a transparent oily substance with the yield of 40.4% (2.4 mg);1H NMR(600MHz,MeOD)6.81(d,J＝1.5Hz,1H),6.73(dd,J＝7.9,1.5Hz,1H),6.67(d,J＝7.9Hz,1H),6.68–6.64(m,1H,overLap),6.38(dd,J＝15.3,1.5Hz,1H),5.82(dd,J＝2.1,1.1Hz,2H),4.47(d,J＝5.5Hz,1H),4.23(td,J＝5.5,1.5Hz,1H),3.47(t,5.5,2H),3.39(t,5.5,2H),1.60–1.56(m,2H),1.48–1.43(m,4H).
example 5
The anti-acetylcholinesterase activity test was carried out using 4R, 5R-dihydroxy piperine, 4S, 5S-dihydroxy piperine, 4R, 5S-dihydroxy piperine, 4S, 5R-dihydroxy piperine and piperine prepared in examples 1 to 4 as test substances:
taking NaH2PO4·2H2O3.121 g is dissolved in water, and the solution is settled to 100mL to obtain 0.2mol/L NaH2PO4；Na2HPO4·12H2O71.64 g was dissolved in water to obtain a solution of 0.2mol/L Na in 1000mL2HPO4. 26.5mL of NaH prepared as described above was taken2PO4And 473.5mL Na2HPO4After thorough mixing, 0.2mol/L of PBS pH 8.0 was obtained, and this solution was diluted 1-fold to obtain 0.1mol/L of PBS pH 8.0; b. 39mL of NaH prepared as described above was taken2PO4And 61mL Na2HPO4After thorough mixing, 0.2mol/L of PBS pH 7.0 was obtained, and this solution was diluted 1-fold to obtain 0.1mol/L of PBS pH 7.0.
Preparing a mother solution of 1000U/mL acetylcholinesterase (AchE) by PBS (pH 8.0), and then preparing the mother solutionThe stock solution is diluted to 4U/mL and stored at the temperature of 80 ℃ below zero, and the stock solution is diluted to 0.4U/mL of acetylcholine esterase solution during the experiment. Accurately weighing 8.8mg of ATCI (thioacetylcholine iodide), dissolving in deionized water, dissolving to 50mL, and standing at 4 deg.C (for use in preparation); 0.6mmol/LDTNB [5,5' -dithiobis (2-nitrobenzoic acid) ]]The preparation of (1): accurately weighed 11.9mg DTNB and 0.75g NaHCO3Dissolved in PBS at pH 7.0, and dissolved to 50mL, and stored away from light (ready for use). The positive medicine huperzine A is prepared into 10mg/mL initial concentration by chromatographic grade methanol, and the substance to be detected is prepared into 100mg/mL initial concentration by chromatographic grade methanol. In the experiment, the positive control and the object to be tested are diluted to 5 concentrations (the positive control: 100, 10, 1, 0.1, 0.01 mg/mL; the object to be tested: 100, 50, 25, 12.5, 6.25mg/mL), and each concentration is subjected to 3 groups of parallel experiments. The test is divided into the following groups: experimental groups: mu.L of PBS (pH 8.0), 10. mu.L of the analyte, 10. mu.L of 0.4U/mL AchE solution, 20. mu.L of 0.6mmol/L DTNB were sequentially added to a 96-well plate, preincubated at 37 ℃ for 10min, then 20. mu.L of 0.6mmol/L ATCI was added thereto, and the reaction was terminated by adding 50. mu.L of absolute ethanol thereto at 37 ℃ for 30 min. Experiment control group: mu.L PBS (pH 8.0), 10. mu.L analyte, 10. mu.L PBS (pH 8.0), 20. mu.L 0.6mmol/L DTNB were sequentially added to a 96-well plate, preincubated at 37 ℃ for 10min, then 20. mu.L 0.6mmol/L ATCI was added thereto, and the reaction was terminated at 37 ℃ for 30min, and then 50. mu.L absolute ethanol was added thereto. Blank group: mu.L of PBS (pH 8.0), 10. mu.L of methanol, 10. mu.L of 0.4U/mL AchE solution, 20. mu.L of 0.6mmol/L DTNB were sequentially added to a 96-well plate, preincubated at 37 ℃ for 10min, then 20. mu.L of 0.6mmol/L ATCI was added thereto, and the reaction was terminated by adding 50. mu.L of absolute ethanol thereto at 37 ℃ for 30 min. Blank control group: mu.L of PBS (pH 8.0), 10. mu.L of methanol, PBS (pH 8.0), 20. mu.L of 0.6mmol/L of DTNB were sequentially added to a 96-well plate, preincubated at 37 ℃ for 10min, then 20. mu.L of 0.6mmol/L of ATCI was added thereto, and the reaction was terminated at 37 ℃ for 30min, followed by addition of 50. mu.L of absolute ethanol.
The detection wavelength is measured at 412nm by a microplate reader, and the inhibition rate is calculated according to the following formula:
the results show (table 1) that all piperines tested and 4, 5-dihydroxy piperine of the four configurations did not have significant acetylcholinesterase inhibiting effect.
Table 1: acetylcholinesterase inhibitory Activity assay
Example 6
The test for activity against butyrylcholinesterase was carried out using 4R, 5R-dihydroxy piperine, 4S, 5S-dihydroxy piperine, 4R, 5S-dihydroxy piperine, 4S, 5R-dihydroxy piperine and piperine prepared in examples 1 to 4 as test substances:
taking NaH2PO4·2H2O3.121 g is dissolved in water, and the solution is settled to 100mL to obtain 0.2mol/L NaH2PO4；Na2HPO4·12H2O71.64 g was dissolved in water to obtain a solution of 0.2mol/L Na in 1000mL2HPO4. 26.5mL of NaH prepared as described above was taken2PO4And 473.5mL Na2HPO4After thorough mixing, 0.2mol/L of PBS pH 8.0 was obtained, and this solution was diluted 1-fold to obtain 0.1mol/L of PBS pH 8.0; b. 39mL of NaH prepared as described above was taken2PO4And 61mL Na2HPO4After thorough mixing, 0.2mol/L of PBS pH 7.0 was obtained, and this solution was diluted 1-fold to obtain 0.1mol/L of PBS pH 7.0.
The stock solution of butyrylcholinesterase (BchE) with pH 8.0 PBS is prepared into 1000U/mL stock solution, then diluted into 4U/mL stock solution, stored at-80 ℃, and then diluted into 0.4U/mL butyrylcholinesterase solution during the experiment. Accurately weighing 2.5mg BTCI (thiobutyrylcholine iodide), dissolving in deionized water, dissolving to 50mL, and standing at 4 deg.C (for use in preparation); sufficiently dissolving butyrylcholinesterase (BChE) powder with PBS (phosphate buffer solution) with the pH value of 8.0 to prepare 500U/mL mother liquor, diluting the mother liquor into 8U/mL stock solution, preserving the stock solution at the temperature of 80 ℃, and diluting the stock solution into 0.8U/mL butyrylcholinesterase solution during experiments; the DTNB configuration method is the same as above. The positive drug tacrine is prepared into 10 mu M initial concentration by chromatographic grade methanol, 5 gradients are diluted during the experiment, and 3 groups of parallel experiments are carried out on each concentration. The test is divided into the following groups: experimental groups: mu.L of PBS (pH 8.0), 10. mu.L of the analyte, 10. mu.L of 0.4U/mL BchE solution, 20. mu.L of 0.6mmol/L DTNB were sequentially added to a 96-well plate, preincubated at 37 ℃ for 10min, then 20. mu.L of 0.6mmol/LATCI was added thereto, and the reaction was terminated by adding 50. mu.L of absolute ethanol thereto at 37 ℃ for 30 min. Experiment control group: mu.L of PBS (pH 8.0), 10. mu.L of the analyte, 10. mu.L of PBS (pH 8.0), 20. mu.L of 0.6mmol/L of DTNB were sequentially added to a 96-well plate, preincubated at 37 ℃ for 10min, then 20. mu.L of 0.6mmol/L of ATCI was added thereto, and the reaction was terminated at 37 ℃ for 30min, and then 50. mu.L of absolute ethanol was added thereto. Blank group: mu.L of PBS (pH 8.0), 10. mu.L of methanol, 10. mu.L of 0.4U/mL BchE solution, 20. mu.L of 0.6mmol/L DTNB were sequentially added to a 96-well plate, preincubated at 37 ℃ for 10min, 20. mu.L of 0.6mmol/L ATCI was further added thereto, and the reaction was terminated by adding 50. mu.L of absolute ethanol thereto at 37 ℃ for 30 min. Blank control group: mu.L of PBS (pH 8.0), 10. mu.L of methanol, PBS (pH 8.0), 20. mu.L of 0.6mmol/L of DTNB were sequentially added to a 96-well plate, preincubated at 37 ℃ for 10min, then 20. mu.L of 0.6mmol/L of ATCI was added thereto, and the reaction was terminated at 37 ℃ for 30min, and then 50. mu.L of absolute ethanol was added thereto.
The detection wavelength is measured at 412nm by a microplate reader, and the inhibition rate is calculated according to the following formula:
the results show that (table 2) all the piperines tested and 4, 5-dihydroxy piperine of the four configurations have no significant effect on inhibiting butyrylcholinesterase.
Table 2: butyrylcholinesterase inhibitory Activity assay
Example 7
In vivo anti-senile dementia activity tests were carried out using 4R, 5R-dihydroxy piperine, 4S, 5S-dihydroxy piperine, 4R, 5S-dihydroxy piperine, 4S, 5R-dihydroxy piperine and piperine prepared in examples 1 to 4 as test substances:
1) laboratory animal
The experimental zebra fish juvenile fish is formed by naturally incubating the embryo produced by the zebra fish. Water quality for fish culture: adding 200mg of instant sea salt into every 1L of reverse osmosis water, wherein the conductivity is 480-510 mu S/cm; the pH value is 6.9-7.2; the hardness of the CaCO is 53.7-71.6 mg/L3. After completion of the experiment, zebrafish at various stages of development were euthanized with 0.25mg/mL tricaine methanesulfonic acid. The procedures for anesthesia sacrifice meet the regulatory requirements of the American veterinary Association (AVMA) for anesthesia sacrifice in animals.
2) Design of experiments
In the study, 5 groups of experiments are set, and each group of experiments comprises 1 blank control group, 1 solvent control group, 1 senile dementia model group, 1 positive control group (donepezil), 1 piperine and 4, 5-dihydroxy piperine. The concentration of piperine and 4, 5-dihydroxy piperine in the primary screening was 30. mu.M, and if death or deformity occurred, 3. mu.M was selected and tested. The zebra fish treated by the aluminum trichloride is an senile dementia model group; the zebra fish treated by the aluminum trichloride and the DPZ are taken as a positive control group; the zebra fish processed by the aluminum trichloride and the compound to be detected together is a compound group to be detected; 0.1% DMSO-treated zebrafish was a negative control group (solvent control group); untreated zebrafish were blank control groups, and 30 zebrafish were treated per experimental group. The motion trail of the zebra fish within 60min is recorded by a behavior analyzer, three light-dark periods are divided by light-dark periodic change, namely dark 10min, light 10min and 60min, and then the motion speed (motion dysfunction) and light-dark periodic speed change (reaction capacity) of the zebra fish are statistically analyzed.
The activity test result meets the quality control standard: firstly, no zebra fish death or deformity occurs in all experimental groups in the whole experimental process; the model group and the solvent control group have statistical difference (p is less than 0.001); (iii) there was no statistical difference between the blank control group and the solvent control group in all experiments (p > 0.05); comparison of the positive control group (donepezil, DPZ) with the model group showed statistical differences (p < 0.05).
3) Recovery effect on senile dementia zebra fish dyskinesia
The zebra fish movement speed of all experimental senile dementia model groups is obviously reduced, and the zebra fish movement speed has statistical significance (p is less than 0.001) compared with a solvent control group; the zebrafish movement speed of the positive Drug (DPZ) group is remarkably increased, and the zebrafish movement speed has statistical significance compared with the model group (p <0.01 or p < 0.001). The zebra fish has regular, periodic and stable movement speed in a light and dark period of 60 min. Compared with a model group, the movement speed of AD zebra fish treated by the 4R, 5S-dihydroxy piperine prepared in the example 4 is remarkably improved (p is less than 0.05, p is less than 0.01 or p is less than 0.001), and the movement speed of Alzheimer disease zebra fish is remarkably recovered (Table 3 and figure 1).
Table 3: treatment efficiency of movement speed of senile dementia zebra fish
| Name of Compound | Concentration (μ g/mL) | The treatment efficiency is% | p value |
| Positive control group (donepezil) | 3.79 | 22.20 | 3.98E-02 |
| Piperine | 2.85 | 14.73 | 2.13E-01 |
| 4R, 5R-dihydroxy piperine | 3.19 | 3.20 | 7.00E-01 |
| 4S, 5S-dihydroxy piperine | 3.19 | 12.75 | 3.14E-01 |
| 4R, 5S-dihydroxy piperine | 3.19 | 84.41 | 9.34E-08 |
| 4S, 5R-dihydroxy piperine | 3.19 | 23.60 | 1.68E-02 |
4) Influence on the reactivity of Alzheimer's disease zebra fish
In all experiments, the reactivity of the zebra fish in the senile dementia model group is reduced (the speed difference of the light and shade period is obviously reduced), and the zebra fish has statistical significance (p is less than 0.001) compared with a solvent control group; the positive Drug (DPZ) group had partially restored zebrafish response (significant return of light and dark cycle velocity differences) and had statistical significance compared to the model group (p <0.05 or p < 0.001). The reaction ability of the AD zebra fish can be recovered to different degrees after the treatment with the 4R, 5S-dihydroxy piperine prepared in example 4 (the light and dark cycle velocity difference is significantly increased), and compared with the model group, the statistical difference is significant or very significant (p <0.05, p <0.01 or p <0.001) (table 4 and fig. 2).
Table 4: treatment efficiency of Alzheimer's disease zebra fish reaction capability
| Name of Compound | Concentration (μ g/mL) | The treatment efficiency is% | p value |
| Positive control group (donepezil) | 3.79 | 17.53 | 3.98E-02 |
| Piperine | 2.85 | 9.62 | 2.13E-01 |
| 4R, 5R-dihydroxy piperine | 3.19 | 2.60 | 7.00E-01 |
| 4S, 5S-dihydroxy piperine | 3.19 | 7.52 | 3.14E-01 |
| 4R, 5S-dihydroxy piperine | 3.19 | 84.93 | 9.34E-08 |
| 4S, 5R-dihydroxy piperine | 3.19 | 19.02 | 1.68E-02 |
Example 8
Based on the concept of pharmacochemical bioisosteres, that is, if the hydroxyl groups at positions 4 and 5 in examples 1-4 are replaced with groups or substituents having similar physical and chemical properties, a substantially similar or related biological activity will result. Therefore, it is presumed that the 4, 5-hydroxy group is replaced by bioisostere dimercapto, diamino, etc. to synthesize a series of piperine derivatives containing different 4, 5-disubstituted groups, and the piperine derivatives have anti-senile dementia bioactivity related to or similar to that of 4R,5S dihydroxy piperine, and are used as senile dementia drugs.
The above-described embodiments are intended to illustrate rather than to limit the invention, and any modifications and variations of the present invention are within the spirit of the invention and the scope of the claims.
Claims (7)
1. The derivatives containing 4, 5-disubstituted piperine are characterized by having a structure shown in a general formula I:
wherein,
R1is an aromatic ring/aromatic heterocycle.
R2is-OH, -NH2，-SH。
R3is-OH, -NH2，-SH。
The 4, 5-disubstituted piperine derivative comprises four configurations of (4R,5R), (4S,5S), (4S,5R) and (4R, 5S).
2. A method for preparing the derivative containing 4, 5-disubstituted piperine as claimed in claim 1, which comprises the following steps:
taking piperine as a substrate, and carrying out addition and disconnection on a 4-site double bond under the action of potassium ferricyanide, potassium carbonate, potassium osmate dihydrate and cinchona alkaloid derivatives to generate a compound I; wherein the cinchona alkaloid derivative is (DHQ)2PHAL or (DHQD)2 PHAL; the solvent is water: mixed solution of tert-butanol 1: 1.
The compound I generates a compound II under the action of a substrate I, triphenylphosphine and diethyl azodicarboxylate, wherein the substrate I is p-nitrobenzoic acid or imino dicarbonate 1- (1, 1-1-dimethylethyl) ester and thioacetic acid, and the solvent is dichloromethane and tetrahydrofuran.
And (3) generating a compound III by the compound II under the action of a substrate II, wherein the substrate II is potassium carbonate or trifluoroacetic acid and lithium aluminum hydride, and the solvent is tetrahydrofuran and diethyl ether.
3. The process according to claim 2, wherein the reaction temperature is room temperature and the reaction time is 12 to 24 hours in the synthesis of the compound I. Wherein the ratio of piperine to potassium ferricyanide, potassium carbonate, potassium osmate dihydrate and cinchonine derivative is 1-2: 2.5-4.5: 2.5-4.5: 0.01-0.1: 0.05 to 0.1.
4. The process according to claim 2, wherein the compound I is reacted at 40-60 ℃ for 4-6 hours in the presence of the substrate I, triphenylphosphine and diethyl azodicarboxylate to form the compound II. Wherein the mass ratio of the compound I to the substrate I, triphenylphosphine and azodicarboxylic acid diethyl ester is 1-2: 1-2: 1-2: 1 to 2.
5. The preparation method according to claim 2, wherein the reaction of the compound II under the action of the substrate II to form the compound III is carried out at the temperature of 40-55 ℃ for 8-10 hours.
6. The use of the derivative of claim 1, which comprises 4, 5-disubstituted piperine, for the manufacture of a medicament for the treatment or prevention of alzheimer's disease.
7. The use as claimed in claim 6, wherein the derivative of 4, 5-disubstituted piperine is a 4R, 5S-disubstituted piperine derivative or a 4S, 5R-disubstituted piperine derivative.
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