阅读说明：本技术 一类4,5-二取代基胡椒碱衍生物及其制备方法和应用 (4, 5-disubstituted piperine derivatives, and preparation method and application thereof ) 是由 许敏 罗佳 袁浩洋 伍俊琪 于 2020-05-14 设计创作，主要内容包括：本发明公开了一种具有治疗老年痴呆症药物4,5-二取代基胡椒碱衍生物的制备方法和应用。具体涉及具有治疗老年痴呆症药物的不对称合成方法,本方法按不同的合成路线分别制备(4R,5R)、(4S,5S)、(4S,5R)或(4R,5S)4,5-二取代基胡椒碱异构体类衍生物。其中,本发明的一类衍生物具有良好的治疗老年痴呆症的活性,且未显示急性毒性,在临床上可进行口服、静脉注射、肌肉注射等方式应用。(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.)

1. The derivatives containing 4, 5-disubstituted piperine are characterized by having a structure shown in a general formula I:

wherein the content of the first and second substances,

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.

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 the content of the first and second substances,

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.