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CN-121974882-A - Amide alkaloid compound, preparation method and application

CN121974882ACN 121974882 ACN121974882 ACN 121974882ACN-121974882-A

Abstract

The invention belongs to the technical field of medicines, and particularly discloses an amide alkaloid compound, a preparation method and application thereof, wherein the amide alkaloid compound is extracted and extracted from fruits of long pepper by adopting an organic solvent, then separated by three to four methods of normal phase silica gel column chromatography, reverse phase silica gel column chromatography, gel column chromatography and chiral high performance liquid chromatography to obtain fourteen novel amide alkaloid monomer compounds, and the fourteen novel amide alkaloid monomer compounds are determined to be novel amide alkaloid compounds by high resolution mass spectrum, nuclear magnetic resonance spectrum, circular dichroism spectrum and quantum chemical means thereof, and are subjected to structural identification. In addition, the activity measurement of in vitro blood sugar reduction, anti-tumor and anti-inflammatory is carried out on the fourteen amide alkaloid compounds, and the results show that the amide alkaloid compounds have the activity of blood sugar reduction, anti-tumor and anti-inflammatory and can be used for blood sugar reduction, anti-tumor and anti-inflammatory drugs.

Inventors

  • LI JUN
  • GOU GUANGHUI
  • BAO WENLI
  • LIU LIU
  • TANG DAN
  • Agui Iqbal Isa

Assignees

  • 中国科学院新疆理化技术研究所

Dates

Publication Date
20260505
Application Date
20260123

Claims (9)

  1. 1. An amide alkaloid compound is characterized by having a structural formula: the compound of formula (1) is (2E, 4E,8S, 9R) -9- (1, 3-benzodioxol-5-yl) -8, 9-dihydroxy-1-piperidin-1-yl-non-2, 4-dien-1-one; The compound of formula (2) is (2E, 4E,8R, 9S) -9- (1, 3-benzodioxol-5-yl) -8, 9-dihydroxy-1-piperidin-1-yl-non-2, 4-dien-1-one; The compound of formula (3) is (2 e,4e,10s,11 s) -11- (1, 3-benzodioxol-5-yl) -10, 11-dihydroxy-1-piperidin-1-yl undec-2, 4-dien-1-one; the compound of formula (4) is (2 e,4e,10r,11 r) -11- (1, 3-benzodioxol-5-yl) -10, 11-dihydroxy-1-piperidin-1-yl undec-2, 4-dien-1-one; The compound of formula (5) is (2E, 8S, 9R) -9- (1, 3-benzodioxol-5-yl) -8-hydroxy-9-methoxy-1-piperidin-1-yl-non-2-en-1-one; The compound of formula (6) is (2E, 8R, 9S) -9- (1, 3-benzodioxol-5-yl) -8-hydroxy-9-methoxy-1-piperidin-1-yl-non-2-en-1-one; the compound of formula (7) is (2E, 4S, 5R) -5- (1, 3-benzodioxol-5-yl) -4-hydroxy-5-methoxy-1-piperidin-1-yl-pent-2-en-1-one; the compound of formula (8) is (2E, 4R, 5S) -5- (1, 3-benzodioxol-5-yl) -4-hydroxy-5-methoxy-1-piperidin-1-yl-pent-2-en-1-one; The compound of formula (9) is (1 r,2s,4ar,8 as) -1- (1, 3-benzodioxol-5-yl) -N-isobutyl-1, 2,4a,5,6,7,8 a-octahydronaphthalene-2-carboxamide; The compound of formula (10) is (1 s,2s,4ar,8 ar) -1- (1, 3-benzodioxol-5-yl) -N-isobutyl-1, 2,4a,5,6,7,8 a-octahydronaphthalene-2-carboxamide; The compound of formula (11) is (1 r,2r,4as,8 as) -1- (1, 3-benzodioxol-5-yl) -N-isobutyl-1, 2,4a,5,6,7,8 a-octahydronaphthalene-2-carboxamide; The compound of formula (12) is (1 r,2r,4as,8 as) -1- (1, 3-benzodioxol-5-yl) -N-piperidinyl-1, 2,4a,5,6,7,8 a-octahydronaphthalene-2-carboxamide; The compound of formula (13) is (3R, 3a, S,4S,7R,7 aR) -4- (1, 3-benzodioxol-5-yl) -2-isobutyl-7- (piperidine-1-carbonyl) -2, 3a,4,7 a-hexahydro-1H-2-isoindol-1-one; the compound of formula (14) is (3 s,3ar,4r, s,7 as) -4- (1, 3-benzodioxol-5-yl) -2-isobutyl-7- (piperidine-1-carbonyl) -2, 3a,4,7 a-hexahydro-1H-2-isoindol-1-one.
  2. 2. The method for preparing an amide alkaloid compound according to claim 1, comprising the steps of: a. pulverizing fructus Piperis Longi fruit, percolating or cold soaking with 5-12 times of 50-100% ethanol water solution or 50-100% methanol water solution at room temperature, evaporating solvent at 45deg.C under reduced pressure to obtain crude extract of fructus Piperis Longi fruit; b. Dispersing the crude extract obtained in the step a with water, adding ethyl acetate, dichloromethane or chloroform for extraction for 3-5 times, and concentrating the ethyl acetate, dichloromethane or chloroform extract to obtain ethyl acetate, dichloromethane or chloroform extract; c. And c, separating the ethyl acetate, dichloromethane or chloroform extract obtained in the step b by three to four separation modes of normal phase silica gel column chromatography, reverse phase silica gel column chromatography, gel column chromatography and chiral high performance liquid chromatography to obtain the compounds of the formulas (1) to (14).
  3. 3. The method for preparing an amide alkaloid compound according to claim 2, wherein three separation modes in the step c are as follows: Subjecting the ethyl acetate, dichloromethane or chloroform extract obtained in the step b to normal phase silica gel column chromatography, performing gradient elution with petroleum ether-acetone or dichloromethane-methanol in a volume ratio of 100:1-0:1 as an eluent, collecting 50:1-10:1 fraction F, subjecting the fraction F to reverse phase silica gel column chromatography, performing gradient elution with 10% -100% methanol-water solution or 10% -100% acetone-water solution to obtain racemate of the compound of formula (1) to formula (14), and performing chiral high performance liquid chromatography on the racemate, and performing gradient elution with n-hexane-isopropanol or n-hexane-ethanol solution in a concentration of 99:1-50:50 to obtain the compound of formula (1) to formula (14).
  4. 4. The method for preparing an amide alkaloid compound according to claim 2, wherein the four separation modes in the step c are as follows: Subjecting the ethyl acetate, dichloromethane or chloroform extract obtained in the step b to normal phase silica gel column chromatography, subjecting the eluent to petroleum ether-ethyl acetate or dichloromethane-methanol gradient elution with the volume ratio of 100:1-0:1, collecting the fraction F with the concentration of 10% -100% of methanol-water solution or 10% -100% of acetone-water solution gradient elution, collecting the fraction F40-90 of 40% -90% of methanol-water solution or acetone-water solution elution, subjecting the fraction F40-90 to gel column chromatography, subjecting the fraction F with the concentration of 50% -100% of methanol-water solution or 50% -100% of dichloromethane-methanol solution gradient elution to obtain the racemate of the compound of the formula (1) to the formula (14), subjecting the racemate to chiral high performance liquid chromatography, and subjecting the racemate to normal hexane-isopropanol gradient elution with the concentration of 99:1-50:50 to the gradient elution to obtain the compound of the formula (1) to the formula (14).
  5. 5. The method for preparing an amide alkaloid compound according to claim 2, wherein in the step c, the normal-phase silica gel column chromatography is normal-pressure or pressurized column chromatography, the filler is normal-phase silica gel, the eluent is petroleum ether or dichloromethane, and the mixture of two solvents of ethyl acetate or methanol is eluted with isocratic elution or gradient.
  6. 6. The method for preparing an amide alkaloid compound according to claim 2, wherein in step c, the reverse phase silica gel column chromatography is normal pressure column chromatography, and the eluent is 10% -100% methanol-water solution or 10% -100% acetone-water solution gradient elution.
  7. 7. The method for preparing an amide alkaloid compound according to claim 2, wherein in the step c, the gel column chromatography is normal pressure column chromatography, the filler is gel Sephadex LH-20, and the eluent is 50% -100% methanol-water solution or 50% -100% dichloromethane-methanol solution.
  8. 8. The method for preparing an amide alkaloid compound according to claim 2, wherein in the step c, the chiral high performance liquid chromatography is pressure column chromatography, and the eluent is n-hexane-isopropanol or n-hexane-ethanol solution with the concentration of 99:1-50:50.
  9. 9. The use of an amide alkaloid compound as defined in claim 1 in the preparation of hypoglycemic, antitumor and anti-inflammatory drugs.

Description

Amide alkaloid compound, preparation method and application Technical Field The invention relates to the technical field of medicines, in particular to an amide alkaloid compound, a preparation method and application. Background Piper longum (Piper longum Linn.) is a perennial grass vine of Piper genus of Piperaceae family. Fructus Piperis Longi, also known as fructus Piperis Longi, bi Bo, fructus Piperis Longi pear, fructus Pyri myrobalan, herba SHENSHENG, fructus Piperis Longi, and herba Salvia officinalis etc., is a common medicinal material with homology of medicine and food, and can be widely used in traditional medicine worldwide. The amide alkaloid is a main secondary metabolite in long pepper and piper plants, and has wide pharmacological activity and good application prospect. Diabetes is a chronic disease marked by hyperglycemia, which is caused by absolute or relative insufficient secretion of insulin and utilization disorders, and is largely classified into three types of type 1, type 2 and gestational diabetes. Protein tyrosine phosphatase 1B (PTP 1B) is an enzyme that plays a critical role in cell signaling, particularly in the insulin and leptin signaling pathways. PTP1B is closely related to type 2 diabetes mellitus, and is one of important targets in the development of current diabetes mellitus medicaments. Alpha-glucosidase is a digestive enzyme located at the brush border of the small intestine and is responsible for breaking down complex carbohydrates (e.g. starch, oligosaccharides) into monosaccharides (mainly glucose) for absorption by the intestine. Alpha-glucosidase is an important target for the treatment of type 2 diabetes due to its critical role in postprandial glycemic regulation. In the early stage, a few amide alkaloids in long pepper can effectively inhibit the activities of PTP1B and alpha-glucosidase, thus providing a research basis for the patent. Modern researches show that the amide alkaloid compound is the most main chemical component with the pharmacological activity in long pepper, such as long pepper alkaloid (piperlongumine), and is attracting attention due to the capability of selectively inducing cancer cell apoptosis. With the penetration of modern separation technology and pharmacological research, the compounds are expected to become an important source for developing new drugs. Disclosure of Invention The invention aims to provide an amide alkaloid compound, a preparation method and application thereof, which are used for solving the problems that the preparation of the amide alkaloid compound and the preparation of the amide alkaloid compound are not used for preparing hypoglycemic, antitumor and anti-inflammatory medicaments. In order to achieve the aim, the basic scheme provided by the invention is that an amide alkaloid compound has the structural formula: the compound of formula (1) is (2E, 4E,8S, 9R) -9- (1, 3-benzodioxol-5-yl) -8, 9-dihydroxy-1-piperidin-1-yl-non-2, 4-dien-1-one; The compound of formula (2) is (2E, 4E,8R, 9S) -9- (1, 3-benzodioxol-5-yl) -8, 9-dihydroxy-1-piperidin-1-yl-non-2, 4-dien-1-one; The compound of formula (3) is (2 e,4e,10s,11 s) -11- (1, 3-benzodioxol-5-yl) -10, 11-dihydroxy-1-piperidin-1-yl undec-2, 4-dien-1-one; the compound of formula (4) is (2 e,4e,10r,11 r) -11- (1, 3-benzodioxol-5-yl) -10, 11-dihydroxy-1-piperidin-1-yl undec-2, 4-dien-1-one; The compound of formula (5) is (2E, 8S, 9R) -9- (1, 3-benzodioxol-5-yl) -8-hydroxy-9-methoxy-1-piperidin-1-yl-non-2-en-1-one; The compound of formula (6) is (2E, 8R, 9S) -9- (1, 3-benzodioxol-5-yl) -8-hydroxy-9-methoxy-1-piperidin-1-yl-non-2-en-1-one; the compound of formula (7) is (2E, 4S, 5R) -5- (1, 3-benzodioxol-5-yl) -4-hydroxy-5-methoxy-1-piperidin-1-yl-pent-2-en-1-one; the compound of formula (8) is (2E, 4R, 5S) -5- (1, 3-benzodioxol-5-yl) -4-hydroxy-5-methoxy-1-piperidin-1-yl-pent-2-en-1-one; The compound of formula (9) is (1 r,2s,4ar,8 as) -1- (1, 3-benzodioxol-5-yl) -N-isobutyl-1, 2,4a,5,6,7,8 a-octahydronaphthalene-2-carboxamide; The compound of formula (10) is (1 s,2s,4ar,8 ar) -1- (1, 3-benzodioxol-5-yl) -N-isobutyl-1, 2,4a,5,6,7,8 a-octahydronaphthalene-2-carboxamide; The compound of formula (11) is (1 r,2r,4as,8 as) -1- (1, 3-benzodioxol-5-yl) -N-isobutyl-1, 2,4a,5,6,7,8 a-octahydronaphthalene-2-carboxamide; The compound of formula (12) is (1 r,2r,4as,8 as) -1- (1, 3-benzodioxol-5-yl) -N-piperidinyl-1, 2,4a,5,6,7,8 a-octahydronaphthalene-2-carboxamide; The compound of formula (13) is (3R, 3a, S,4S,7R,7 aR) -4- (1, 3-benzodioxol-5-yl) -2-isobutyl-7- (piperidine-1-carbonyl) -2, 3a,4,7 a-hexahydro-1H-2-isoindol-1-one; the compound of formula (14) is (3 s,3ar,4r, s,7 as) -4- (1, 3-benzodioxol-5-yl) -2-isobutyl-7- (piperidine-1-carbonyl) -2, 3a,4,7 a-hexahydro-1H-2-isoindol-1-one. The preparation method has the beneficial effects that the amide alkaloid compounds are extracted from fruits of long pepper, and then separated in three to four separation modes of normal phase si