CN109160927B - Novel amide compounds in moringa seeds and application thereof - Google Patents

Novel amide compounds in moringa seeds and application thereof Download PDF

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CN109160927B
CN109160927B CN201810206497.0A CN201810206497A CN109160927B CN 109160927 B CN109160927 B CN 109160927B CN 201810206497 A CN201810206497 A CN 201810206497A CN 109160927 B CN109160927 B CN 109160927B
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CN109160927A (en
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叶文才
范春林
王英
刘辉
李满妹
刘俊珊
黄晓君
张晓琦
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Jinan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/20—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C07H1/08—Separation; Purification from natural products

Abstract

The invention relates to 6 novel amide compounds extracted and separated from moringa seeds and application of the amide compounds in preparing medicaments for treating diabetes, depression and senile dementia. Experiments show that the compound has better effects of reducing blood sugar, resisting depression and resisting senile dementia. The compound has the characteristics of clear activity mechanism, low toxicity, safety and the like, and has wide application prospect.

Description

Novel amide compounds in moringa seeds and application thereof
Technical Field
The invention relates to a novel amide compound separated from moringa seeds and application thereof in preparing medicaments for treating diabetes, depression and senile dementia.
Background
Moringa oleifera (A), (B), (CMoringaoleiferaLam.) is a plant of the genus moringa, a perennial tropical deciduous tree, native to arid and semiarid regions of the tropical and southern subtropics, and now widely distributed in tropical marine climatic regions such as africa, arabia, southeast asia, pacific islands (Anwar F,et al.PhytotherRes, 2007, 21(1): 17-25). After 60 s of the last century, large-area planting (Dongzaoying, etc.) was carried out in Yunnan, Hainan, Guangdong, Guangxi, etc. of China.Guangdong feed, 2008, 17(9):39-41.). Moringa oleifera is a multipurpose fast-growing tree which can blossom and bear fruits after being planted for 6 months, and the root, stem, leaf, flower and seed of the moringa oleifera can be used as medicines: (Chinese plant, 1984: 34(1): 6). The main chemical components in the moringa oleifera include phenols and glycosides thereof, flavones and glycosides thereof, sterols and glycosides thereof, polysaccharides, amino acids, vitamins and the like. Modern pharmacological research shows that the moringa oleifera has the activities of reducing blood sugar, reducing blood fat, protecting liver injury, protecting nervous system, resisting tumor, resisting inflammation, inhibiting bacteria, relieving pain, relieving spasm and the like (YanuYu and the like).Tianjin Pharmaceutical preparations2015, 27(2): 57-59, permissive for allergy, etc.Science of food, 2016, 37(23): 291-301). However, the pharmacological activities are all researches on aqueous extracts or alcohol extracts of moringa oleifera, and no related activity report of monomer components is found.
According to the invention, a series of amide compounds are discovered from moringa seeds, wherein the amide compounds comprise 9 new compounds, and the amide compounds are discovered to have the effects of treating diabetes, resisting depression and senile dementia for the first time through research.
Disclosure of Invention
The invention relates to a novel amide compound separated from moringa seeds and application thereof in preparing medicaments for treating diabetes, depression and senile dementia.
The chemical general formula of the amide compound and the derivative thereof is as follows:
Figure 707796DEST_PATH_IMAGE001
wherein R is1Is hydrogen or a sugar radical; r2Is a hydrocarbyl group. The amide is preferably formamide, acetamide, propionamide, butyramide, hexadecanamide, octadecylamide, eicosanamide; the glycosyl is preferably six-carbon (glucose, mannose, rhamnose) pyranose, and six-carbon furanose, and the acylated saccharide is preferably six-carbon (glucose, mannose, rhamnose) pyranose, and six-carbon furanose. Or an acyl sugar (acetyl, propionyl, benzoyl). Preferred substituents and names of compounds according to the invention are shown in table 1.
Figure 135366DEST_PATH_IMAGE002
Figure 931284DEST_PATH_IMAGE003
Figure 418897DEST_PATH_IMAGE004
When the compound of the present invention is used as a medicament, it may be used as it is or in the form of a pharmaceutical composition. Comprises at least one compound of formula (I) as an active ingredient in combination with one or more pharmaceutically acceptable carriers and excipients which are non-toxic and inert to humans.
The carriers and excipients used are one or more of solid, semi-solid and liquid diluents, fillers and pharmaceutical adjuvants. The pharmaceutical composition of the invention is prepared into various dosage forms, such as liquid preparations (suspension, syrup, oral liquid or injection, and the like), solid preparations (tablets, capsules or granules, and the like), sprays, and the like by adopting a method accepted in the pharmaceutical field. The above medicine can be administered by oral administration, sublingual administration, or injection (intravenous injection, intramuscular injection, subcutaneous injection, etc.).
Description of the drawings:
FIG. 1 is an ESI-MS diagram of Compound 1
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of Compound 1
FIG. 3 is a nuclear magnetic resonance carbon spectrum of Compound 1
FIG. 4 is an ESI-MS diagram of Compound 2
FIG. 5 is a NMR spectrum of Compound 2
FIG. 6 is a NMR carbon spectrum of Compound 2
FIG. 7 is an ESI-MS diagram of Compound 3
FIG. 8 is a NMR spectrum of Compound 3
FIG. 9 is a NMR carbon spectrum of Compound 3
FIG. 10 is an ESI-MS diagram of Compound 4
FIG. 11 is a NMR spectrum of Compound 4
FIG. 12 is a NMR carbon spectrum of Compound 4
FIG. 13 is an ESI-MS diagram of Compound 5
FIG. 14 is a NMR spectrum of Compound 5
FIG. 15 is a NMR carbon spectrum of Compound 5
FIG. 16 is an ESI-MS diagram of Compound 6
FIG. 17 is a NMR hydrogen spectrum of Compound 6
FIG. 18 is a NMR carbon spectrum of Compound 6
FIG. 19 is an ESI-MS diagram of Compound 7
FIG. 20 is a NMR hydrogen spectrum of Compound 7
FIG. 21 is a NMR carbon spectrum of Compound 7
FIG. 22 is an ESI-MS diagram of Compound 8
FIG. 23 is a NMR hydrogen spectrum of Compound 8
FIG. 24 is a NMR carbon spectrum of Compound 8
Fourth, detailed description of the invention
The invention will be more readily understood by reference to the following examples, which are given to illustrate the invention, but are not intended to limit the scope thereof.
Example 1 isolation and structural characterization of novel compounds:
pulverizing Moringa seed 15 kg, percolating with 10 times of 50% ethanol for three times (each for 24 hr), mixing extractive solutions, concentrating, filtering, adsorbing the filtrate with HP-20 macroporous resin column, eluting with water and 10% ethanol sequentially to remove impurities, eluting with 80% ethanol 100L, recovering 80% ethanol eluate, concentrating, and drying under reduced pressure to obtain total extract. And (3) performing silica gel column chromatography on 550 g of the total extract, performing gradient elution by using a cyclohexane-ethyl acetate system (the volume ratio of cyclohexane to ethyl acetate is from 100:0 to 1: 1), recovering the solvent in each gradient, and combining to obtain fractions Fr.1-Fr.10. Fr.2 (22 g) was subjected to ODS (reverse octadecyl bonded silica) column chromatography with gradient elution (methanol to water volume ratio from 2:8 to 1: 0) from methanol-water system to give 6 fractions, Fr.3a-Fr.3f, in which Fr.3b (1.2 g) was subjected to preparative HPLC using 70% methanol-water as the mobile phase, to give Compound 8 (106 mg). Fr.3d (0.9 g) was subjected to preparative HPLC using 68% methanol-water as the mobile phase to give compound 6 (510 mg). Fr.3e (1.5 g) was subjected to preparative HPLC using 65% methanol-water as the mobile phase to give compound 5 (78 mg). Fr.3f (2.3 g) prepared by preparative HPLC with 65% methanol-water as the mobile phase, giving compounds 7 (655 mg) and 3 (575 mg). Fr.6 (25 g) was subjected to ODS column chromatography and gradient elution with a methanol-water system (methanol to water volume ratio from 15:85 to 1: 0) to give 5 fractions, Fr.6a-Fr.6e, in which Fr.6a (0.8 g) was subjected to preparative HPLC using 30% methanol-water as the mobile phase, to give Compound 1 (427 mg). Fr.6c (1.3 g) was subjected to preparative HPLC using 35% methanol-water as the mobile phase to give compound 4 (603 mg). Fr.6d (1.1 g) was subjected to preparative HPLC using 40% methanol-water as the mobile phase to give Compound 2 (537 mg).
Compound 1 is a yellow amorphous powder with the chemical formula:
Figure 300266DEST_PATH_IMAGE005
the spectral data are as follows: ESI-MSm/z:342.1203 [M+HCOO]-. ESI-MS is shown in FIG. 1.1H-NMR (D2O)：7.32 (2H, d,JH-2 and H-6), 7.13 (1H, d,J= 8.5 Hz, H-3 and H-5), 5.57(1H, d,J= 1.5Hz, H-1ʹ)，4.41 (2H, s, H-7)，4.18 (1H, m, H-2ʹ)，4.02 (1H, dd,J= 9.5, 3.5 Hz, H-3ʹ)，3.81 (1H, m, H-5ʹ)，3.53 (1H, t,J= 9.5 Hz, H-4ʹ)，1.23(3H, d,Jh-6 ʹ at 6.5 Hz). The hydrogen nuclear magnetic resonance spectrum is shown in FIG. 2.13C-NMR (D2O): 164.2 (C-9), 154.5 (C-4), 132.1 (C-1), 128.8 (C-2 and C-6), 117.4 (C-3 and C-5), 98.2 (C-1 ʹ), 72.0(C-4 ʹ), 70.1 (C-3 ʹ), 70.0 (C-2 ʹ), 69.4 (C-5 ʹ), 41.1 (C-7), 16.6 (C-6 ʹ). The NMR spectrum is shown in FIG. 3.
Hydrolyzing compound 1 with acid to obtain aglycone and sugar part, performing derivatization reaction on sugar, and performing HPLC liquid phase analysis on the derivative and standard sugar derivativeControl, identifying the sugar as L-rhamnose, C-3-C-5 binding to rhamnose13C chemical shift values identify the glycosyl asα-L-rhamnosyl.
Combining the above information, compound 1 was identified asN-benzylcarboxamide-4-O- α -L-rhamnoside, a new compound.
Compound 2 is a yellow amorphous powder with the chemical formula:
Figure 531527DEST_PATH_IMAGE006
the spectral data are as follows: ESI-MSm/z:356.1339 [M+HCOO]-. ESI-MS is shown in FIG. 4.1H-NMR(DMSO-d 6 )：7.18 (2H, d,JH-2 and H-6), 6.98 (1H, d,J= 8.5 Hz, H-3 and H-5), 5.33 (1H, d,J= 1.5Hz, H-1ʹ)，4.18 (2H, d,J= 5.9 Hz, H-7)，3.82 (1H, m,H-2ʹ)，3.63 (1H, dd,J= 9.3, 3.5 Hz, H-3ʹ)，3.47 (1H, m, H-5ʹ)，3.27 (1H, t,J= 9.3 Hz, H-4ʹ)，1.85 (3H, s, H-9)，1.10(3H, d,Jh-6 ʹ at 6.2 Hz). The hydrogen nuclear magnetic resonance spectrum is shown in FIG. 5.13C-NMR (DMSO): 168.9 (C-8), 154.9 (C-4), 132.9 (C-1), 128.6 (C-2 and C-6), 116.3 (C-3 and C-5), 98.4 (C-1 ʹ), 71.8 (C-4 ʹ), 70.4 (C-2 ʹ), 70.2 (C-3 ʹ), 69.4 (C-5 ʹ), 41.6 (C-7), 22.6 (C-9), 17.9 (C-6 ʹ). The NMR spectrum is shown in FIG. 6.
Hydrolyzing compound 2 with acid to obtain aglycone and sugar part, performing derivatization reaction on sugar, and comparing with standard sugar derivative by HPLC liquid phase analysis to identify sugar as L-rhamnose combined with C-3-C-5 of rhamnose13C chemical shift values identify the glycosyl asα-L-rhamnosyl.
Combining the above information, compound 2 was identified asN-benzyl-acetamide-4-O- α -L-rhamnoside, a new compound.
Compound 3 is a yellow amorphous powder with the chemical formula:
Figure 414907DEST_PATH_IMAGE007
the spectral data are as follows: ESI-MSm/z:566.3692 [M-H]-. ESI-MS is shown in FIG. 7.1H-NMR (CD3OD)：7.21 (2H, d,JH-2 and H-6), 7.02 (1H, d,Jh-3 and H-5), 5.40(1H, d,J= 1.5Hz, H-1ʹ)，2.22 (2H, t,J= 7.5 Hz, H-9)，4.30 (2H, s, H-7)，3.99(1H, m, H-2ʹ)，3.83 (1H, dd,J= 9.5, 3.4 Hz, H-3ʹ)，3.62 (1H, m, H-5ʹ)，3.45(1H, t,J= 9.5 Hz, H-4ʹ)，3.38(1H, br s, H-16)，3.37(1H, br s, H-17)，1.63-2.20(28H, overlapped)，1.22(3H, d,J= 6.2 Hz, H-25)，0.90(3H, t,Jh-6 ʹ at 7.0 Hz). The hydrogen nuclear magnetic resonance spectrum is shown in FIG. 8.13C-NMR (CD3OD): 176.1 (C-8), 157.0 (C-4), 133.8 (C-1), 129.9 (C-2 and C-6), 117.6 (C-3 and C-5), 99.9 (C-1 ʹ), 75.3 (C-16), 75.3 (C-17), 73.8(C-4 ʹ), 72.2(C-2 ʹ), 72.1 (C-3 ʹ), 70.6 (C-5 ʹ), 43.5 (C-7), 37.1(C-9), 33.94, 33.91, 33.1, 30.8, 30.7, 30.6, 30.4, 30.3, 30.2, 27.09, 27.05, 27.0, 23.7, 18.0 (C-6 ʹ), 14.4 (C-25). The NMR spectrum is shown in FIG. 9. By comparison of Compound 31H、13C nuclear magnetism and MS data, it can be concluded that the compound is an amide compound containing 18 carbon long aliphatic chains. The two hydroxyl groups can be judged to be at the C-16 and C-17 positions respectively by mass spectrum fragments m/z 112.9885, 142.1215 and 171.1385. According to C-16 (H3.37,C75.3 )，C-17 (H3.38,C75.3) compared with the literature, the absolute configuration of C-16 and C-17 can be determined to be 16R,17S。
Hydrolyzing compound 3 with acid to obtain aglycone and sugar part, performing derivatization reaction on sugar, and comparing with standard sugar derivative by HPLC liquid phase analysis to identify sugar as L-rhamnose combined with C-3-C-5 of rhamnose13C chemical shift values identify the glycosyl asα-L-rhamnosyl.
Combining the above information, compound 3 was identified asN-benzyl- (16)R, 17S-dihydroxy) -octadecaneAmide-4-O- α -L-rhamnoside, a new compound.
Compound 4 is a yellow amorphous powder with the chemical formula:
Figure 339001DEST_PATH_IMAGE008
the spectral data are as follows: ESI-MSm/z:550.3396 [M+COOH]-. ESI-MS is shown in FIG. 10.1H-NMR(CD3OD)：7.21 (2H, d,JH-2 and H-6), 7.02 (1H, d,Jh-3 and H-5), 5.40(1H, d,J= 1.5Hz, H-1ʹ)，5.34 (1H, H-16)，5.34 (1H, H-17)，4.30 (2H, s,H-7)，3.99 (1H, m, H-2ʹ)，3.84 (1H, dd,J= 9.5, 3.4 Hz, H-3ʹ)，3.62 (1H, m, H-5ʹ)，3.45 (1H, t,J= 9.5 Hz, H-4ʹ)，1.30-2.22 (24H, overlapped)，1.20 (3H, d,J= 6.2 Hz,H-23)，0.90(3H, t,Jh-6 ʹ at 7.0 Hz). The hydrogen nuclear magnetic resonance spectrum is shown in FIG. 11.13C-NMR(MeOD): 176.1 (C-8), 157.0 (C-4), 133.8 (C-1), 129.9 (C-2 and C-6), 117.6 (C-3 and C-5), 130.9 (C-16), 130.8(C-17), 99.9 (C-1 ʹ), 73.8(C-4 ʹ), 72.2(C-2 ʹ), 72.1 (C-3 ʹ), 70.6 (C-5 ʹ), 43.5 (C-7), 37.1(C-9), 32.9, 30.8, 30.7, 30.3, 30.2, 30.1, 30.0, 28.15, 28.12, 27.0, 18.0 (C-6 ʹ), 14.4 (C-22). The nuclear magnetic resonance carbon spectrum is shown in FIG. 12. By comparison of Compound 41H、13C nuclear magnetism and MS data can conclude that the compound is an amide compound containing 16 carbene long aliphatic chains. The double bond is positioned at the C-16 position according to mass spectrum fragments m/z 71.0512, 138.0520, and the chemical shifts of two adjacent methylene carbons of the double bond are respectively28.15, 28.12 can judge the configuration of the double bond is cis.
Hydrolyzing compound 4 with acid to obtain aglycone and sugar part, performing derivatization reaction on sugar, and comparing with standard sugar derivative by HPLC liquid phase analysis to identify sugar as L-rhamnose combined with C-3-C-5 of rhamnose13C chemical shift values identify the glycosyl asα-L-rhamnosyl.
Combining the above information, compound 4 was identified asN-benzyl- (16)Z) -hexadecenamide-4-O- α -L-rhamnoside, a new compound.
Compound 5 is a yellow amorphous powder with the chemical formula:
Figure 910927DEST_PATH_IMAGE009
the spectral data are as follows: ESI-MSm/z:552.3542 [M+COOH]-. ESI-MS is shown in FIG. 13.1H-NMR(CD3OD)：7.21 (2H, d,JH-2 and H-6), 7.02 (1H, d,Jh-3 and H-5), 5.40(1H, d,J= 1.5Hz, H-1ʹ)，4.30 (2H, s, H-7)，3.99 (1H, m, H-2ʹ)，3.84(1H, dd,J= 9.5, 3.4 Hz, H-3ʹ)，3.62 (1H, m, H-5ʹ)，3.45 (1H, t,J= 9.5 Hz,H-4ʹ)，1.30-2.22 (20H, overlapped)，1.20 (3H, d,J= 6.2 Hz,H-23)，0.90(3H, t,Jh-6 ʹ at 7.0 Hz). The hydrogen nuclear magnetic resonance spectrum is shown in FIG. 14.13C-NMR (CD3OD): 176.1 (C-8), 157.0 (C-4), 133.8 (C-1), 129.9 (C-2 and C-6), 117.6 (C-3 and C-5), 99.9 (C-1 ʹ), 73.8(C-4 ʹ), 72.2(C-2 ʹ), 72.1 (C-3 ʹ), 70.6 (C-5 ʹ), 43.5 (C-7), 37.1(C-9), 33.1, 30.8, 30.77, 30.76, 30.75, 30.69, 30.62, 30.47, 30.40, 30.3, 27.1, 23.7, 18.0 (C-6 ʹ), 14.4 (C-22). The NMR spectrum is shown in FIG. 15. By comparison of Compound 51H、13C nuclear magnetism and MS data, it can be concluded that the compound is an amide compound containing a long aliphatic chain of 16 carbons.
Hydrolyzing compound 5 with acid to obtain aglycone and sugar part, performing derivatization reaction on sugar, and comparing with standard sugar derivative by HPLC liquid phase analysis to identify sugar as L-rhamnose combined with C-3-C-5 of rhamnose13C chemical shift values identify the glycosyl asα-L-rhamnosyl.
Combining the above information, compound 5 was identified asN-benzylhexadecenamide-4-O- α -L-rhamnoside, a new compound.
Compound 6 is a yellow amorphous powder with the chemical formula:
Figure 945879DEST_PATH_IMAGE010
the spectral data are as follows: ESI-MSm/z:578.3664 [M+COOH]-. ESI-MS is shown in FIG. 16.1H-NMR(CD3OD)：7.21 (2H, d,JH-2 and H-6), 7.02 (1H, d,Jh-3 and H-5), 5.40(1H, d,J= 1.5Hz, H-1ʹ)，5.34 (1H, H-19)，5.34 (1H, H-20)，4.30 (2H, s,H-7)，3.99 (1H, m, H-2ʹ)，3.84 (1H, dd,J= 9.5, 3.4 Hz, H-3ʹ)，3.62 (1H, m, H-5ʹ)，3.45 (1H, t,J= 9.5 Hz, H-4ʹ)，1.30-2.22 (28H, overlapped)，1.20 (3H, d,J= 6.2 Hz,H-25)，0.90(3H, t,Jh-6 ʹ at 7.0 Hz). The hydrogen nuclear magnetic resonance spectrum is shown in FIG. 17.13C-NMR(CD3OD): 174.7 (C-8), 155.6 (C-4), 132.4 (C-1), 128.5 (C-2 and C-6), 116.1 (C-3 and C-5), 129.4(C-19), 129.4 (C-20), 98.4 (C-1 ʹ), 72.4 (C-4 ʹ), 70.8 (C-2 ʹ), 70.6 (C-3 ʹ), 69.2 (C-5 ʹ), 42.1 (C-7), 35.7 (C-9), 35.7, 31.5, 29.4, 29.1, 29.0, 28.9, 28.8, 28.7, 28.6, 26.7, 26.6, 25.6, 22.3, 16.6 (C-6 ʹ), 13.0 (C-22). The nuclear magnetic resonance carbon spectrum is shown in FIG. 18. By comparison of Compound 61H、13C nuclear magnetism and MS data can conclude that the compound is an amide compound containing 18 carbon alkene long aliphatic chains. The double bond is judged to be positioned at the C-19 position through mass spectrum fragments m/z 58.0310, 111.0100 and 121.1299, and the chemical shifts of two adjacent methylene carbons of the double bond are respectively28.88, 28.86 can judge the configuration of the double bond is cis.
Hydrolyzing compound 6 with acid to obtain aglycone and sugar part, performing derivatization reaction on sugar, and comparing with standard sugar derivative by HPLC liquid phase analysis to identify sugar as L-rhamnose combined with C-3-C-5 of rhamnose13C chemical shift values identify the glycosyl asα-L-rhamnosyl.
Combining the above information, compound 6 was identified asN-benzyl- (19)Z) -octadecenamide-4-O- α -L-rhamnoside, a new compound.
Compound 7 is a yellow amorphous powder with the chemical formula:
Figure 450810DEST_PATH_IMAGE011
the spectral data are as follows: ESI-MSm/z:578.3664 [M+COOH]-. ESI-MS is shown in FIG. 19.1H-NMR(CD3OD)：7.21 (2H, d,JH-2 and H-6), 7.02 (1H, d,Jh-3 and H-5), 5.40(1H, d,J= 1.5Hz, H-1ʹ)，5.34 (1H, H-18)，5.34 (1H, H-19)，4.30 (2H, s,H-7)，3.99 (1H, m, H-2ʹ)，3.84 (1H, dd,J= 9.5, 3.4 Hz, H-3ʹ)，3.62 (1H, m, H-5ʹ)，3.45 (1H, t,J= 9.5 Hz, H-4ʹ)，1.30-2.22 (28H, overlapped)，1.20 (3H, d,J= 6.2 Hz,H-25)，0.90(3H, t,Jh-6 ʹ at 7.0 Hz). The hydrogen nuclear magnetic resonance spectrum is shown in FIG. 20.13C-NMR(CD3OD): 174.7 (C-8), 155.6 (C-4), 132.4 (C-1), 128.5 (C-2 and C-6), 116.1 (C-3 and C-5), 129.4 (C-18), 129.4(C-19), 98.4 (C-1 ʹ), 72.4 (C-4 ʹ), 70.8 (C-2 ʹ), 70.6 (C-3 ʹ), 69.2 (C-5 ʹ), 42.1 (C-7), 35.7 (C-9), 35.7, 31.5, 29.4, 29.1, 29.0, 28.9, 28.8, 28.7, 28.6, 26.7, 26.6, 25.6, 22.33, 16.6 (C-6 ʹ), 13.0 (C-22). The nuclear magnetic resonance carbon spectrum is shown in FIG. 21. By comparison of Compound 71H、13C nuclear magnetism and MS data can conclude that the compound is an amide compound containing 18 carbon alkene long aliphatic chains. The double bond is judged to be positioned at the C-18 position through mass spectrum fragments m/z 70.0314, 123.0385 and 155.1523, and the chemical shifts of two adjacent methylene carbons of the double bond are respectively28.88, 28.86 can judge the configuration of the double bond is cis.
Hydrolyzing compound 7 with acid to obtain aglycone and sugar part, performing derivatization reaction on sugar, and comparing with standard sugar derivative by HPLC liquid phase analysis to identify sugar as L-rhamnose combined with C-3-C-5 of rhamnose13C chemical shift values identify the glycosyl asα-L-rhamnosyl.
Combining the above information, compound 7 was identified asN-benzyl- (18)Z) -octadecenamide-4-O- α -L-rhamnoside, a new compound.
Compound 8 is a yellow amorphous powder with the chemical formula:
Figure 784620DEST_PATH_IMAGE012
the spectral data are as follows: ESI-MSm/z:578.3664 [M+COOH]-. ESI-MS is shown in FIG. 22.1H-NMR(CD3OD)：7.21 (2H, d,JH-2 and H-6), 7.02 (1H, d,Jh-3 and H-5), 5.40(1H, d,J= 1.5Hz, H-1ʹ)，5.38 (1H, H-18)，5.38 (1H, H-19)，4.30 (2H, s,H-7)，3.99 (1H, m, H-2ʹ)，3.84 (1H, dd,J= 9.5, 3.4 Hz, H-3ʹ)，3.62 (1H, m, H-5ʹ)，3.45 (1H, t,J= 9.5 Hz, H-4ʹ)，1.30-2.22 (28H, overlapped)，1.20 (3H, d,J= 6.2 Hz,H-25)，0.90(3H, t,Jh-6 ʹ at 7.0 Hz). The hydrogen nuclear magnetic resonance spectrum is shown in FIG. 23.13C-NMR(CD3OD): 176.1 (C-8), 155.9 (C-4), 133.8 (C-1), 129.9 (C-2 and C-6), 117.5 (C-3 and C-5), 131.4 (C-18), 131.5(C-19), 99.8 (C-1 ʹ), 73.8(C-4 ʹ), 72.2(C-2 ʹ), 72.1 (C-3 ʹ), 70.7 (C-5 ʹ), 43.5 (C-7), 37.1(C-9), 33.6, 33.5, 33.1, 33.1, 30.8, 30.7, 30.6, 30.5, 30.2, 30.1, 30.0, 27.1, 23.7, 18.0 (C-6 ʹ), 14.5 (C-22). The nuclear magnetic resonance carbon spectrum is shown in FIG. 24. By comparison of Compound 81H、13C nuclear magnetism and MS data can conclude that the compound is an amide compound containing 18 carbon alkene long aliphatic chains. The double bond is judged to be positioned at the C-18 position through mass spectrum fragments m/z 70.0348, 123.0499 and 137.0199, and the chemical shifts of two adjacent methylene carbons of the double bond are respectively33.5, 33.6 can judge the configuration of the double bond is trans.
Hydrolyzing the compound 8 with acid to obtain aglycone and sugar part, performing derivatization reaction on sugar, and comparing with standard sugar derivative by HPLC liquid phase analysis to identify that the sugar is L-rhamnose and is combined with C-3-C-5 of rhamnose13C chemical shift values identify the glycosyl asα-L-rhamnosyl.
Combining the above information, compound 8 was identified asN-benzyl- (18)E) -octadecenamide-4-O- α -L-rhamnoside, a new compound.
EXAMPLE 2 injection
Taking 10 parts by weight of the compound or the derivative thereof obtained in the example 1, 8.5 g of sodium chloride and 1000 parts by weight of water for injection, mixing and dissolving, stirring, adding 2 parts by weight of activated carbon, stirring for 30 min, filtering the solution through a microporous filter membrane (0.22 mu m), subpackaging into 5 ml of ampoule, sterilizing, checking to be qualified and preparing into 50 mg of water injection per ampoule. Other examination items should meet the requirements under the injection item of pharmacopoeia of the people's republic of China (2015 edition).
EXAMPLE 3 lyophilized powder for injection
Taking 10 parts by weight of the compound or the derivative thereof obtained in the example 1, dissolving the compound or the derivative thereof in 1000 parts by weight of water for injection containing 1% of mannitol, adding 5 parts by weight of activated carbon, stirring for 20 min, filtering the solution through a microporous membrane (0.22 mu m) to obtain a clear solution, subpackaging the clear solution in 10 ml penicillin bottles with 2 ml each, and freeze-drying to prepare freeze-dried powder injection containing 20 mg each. Other examination items should meet the requirements under the injection item of pharmacopoeia of the people's republic of China (2015 edition).
EXAMPLE 4 tablets
Taking 20 parts by weight of the compound or the derivative thereof obtained in the example 1, 30 parts by weight of starch as a filling agent, 5 parts by weight of hydroxypropyl methyl cellulose as a binding agent and 10 parts by weight of microcrystalline cellulose as a disintegrating agent; and 0.5 part of magnesium stearate is selected as a lubricant, mixed, added with a proper amount of 50% ethanol for granulation, dried and tabletted to obtain the tablet. Other examination items should meet the requirements under the item of tablets in pharmacopoeia of the people's republic of China (2015 edition).
Example 5 hypoglycemic Activity of amides in Moringa seed
(1) Principle of experiment
A mouse diabetes model induced by High Fat Diet (HFD) and Streptozotocin (STZ) is adopted, different compounds are respectively used for intragastric administration, the influence of the amide compounds on the blood sugar and the body weight of a diabetic mouse is observed, and the effect of the moringa seed amide compounds on treating diabetes is evaluated.
(2) Experimental Material
Kunming mice; 1-8 parts of moringa seed amide compound; streptozotocin; lard oil; blood glucose test paper and glucometer; sodium citrate buffer (pH 4.4); a glove; a mouse box; and (4) distilled water.
(3) Experiment grouping
Experimental group of new amide compounds; normal group (distilled water); model set (HFD + STZ).
(4) Preparation and treatment of the model
3 male Kunming mice are placed in a cage, the room temperature is 22 +/-3 ℃, the relative humidity is 60 +/-10%, the illumination is carried out for 12 hours every day, and the mice can be freely eaten and drunk. After 1 week of adaptive feeding, randomized into groups of 10: normal group was fed with normal diet, high-fat diet diabetes (HFD + STZ) group was fed with high-fat diet, and after 3 weeks, mice were fasted for 12 hours without water deprivation, (HFD + STZ) mice and STZ solution were administered with intraperitoneal injection of 100mg/kg, and normal group mice were intraperitoneally injected with citric acid-sodium citrate buffer at the same dose. After the STZ injection, the mice were kept on the same diet, and the mice were kept on the same diet. The tail vein blood was taken one or two weeks after administration and was checked with a glucometer. 10 mice with common feed are control groups, and 90 successfully molded diabetic mice are randomly divided into 9 groups. The administration was according to the following groups: the new moringa seed amide compound group is 20 mg/kg, the model group and the normal group are 0.3-0.4 ml/day of distilled water, and the administration is carried out in a gastric perfusion mode for 1 time per day.
(5) Detailed Experimental procedures
After 2 weeks of administration, the conditions of ingestion, drinking, body mass, mental state, hair color and the like are observed; measurement: blood sugar level and body weight.
(6) Results of the experiment
General observation
After the model is made, the mice have the symptoms of polydipsia, polyphagia, polyuria, weight loss, slow response, disorder and lightless fur and the like, and the symptoms of the mice in each group are improved to different degrees after the new compound is administrated, so the response is more flexible, and the fur is flat and glossy.
② the influence of the new moringa seed amide compound on the blood sugar content of HFD + STZ diabetic mice
From the results (table 2) it can be seen that: the mean blood sugar of the HFD + STZ-induced diabetic mice is obviously increased and has obvious difference compared with the normal group (P<0.001). The blood sugar of the new moringa seed amide compound group is obviously reduced compared with that of the model group mice (1)P<0.05，P<0.01）。
③ Effect of novel Moringa seed amides on the body weight of HFD + STZ diabetic mice As can be seen from the results (Table 3), the body weight of mice in the diabetic model group is significantly increased compared with the body weight of mice in the normal group: (P<0.01，P<0.001), the weight of the novel amide compound is remarkably reduced compared with that of a model group (P<0.05，P<0.01）。
Figure 640581DEST_PATH_IMAGE013
Figure 948066DEST_PATH_IMAGE014
EXAMPLE 6 antidepressant Activity of amides in Moringa seed
(1) Principle of experiment
The Forced Swimming Test (FST) system is mainly used for research of antidepressant, sedative and analgesic drugs. By placing the experimental animal in a confined environment (such as water) where the animal struggles to struggle to try to escape and fail to escape, a non-avoidable stressed environment is provided in which the animal exhibits a typical "immobility" after a period of experimentation, reflecting a condition known as "behavioral despair", and a series of parameters are recorded during the process in which the animal in the environment develops the desired immobility. The immobility time of the mouse is an index for judging the action of the depression drug, and the shorter the immobility time is, the stronger the antidepressant action is. Mouse Tail Suspension Test (TST): is a classic method for rapidly evaluating the drug effects of antidepressant drugs, stimulants and sedatives. The principle is that the mouse tries to escape after hanging the tail but cannot escape, so that struggle is abandoned and the special depression immobility state is entered, the animal immobility time is recorded in the experimental process to reflect the depression state, and antidepressant drugs and exciting drugs can obviously shorten and change the state.
(2) Experimental Material
C57BL/6 mice; 1-8 parts of amide compounds in moringa seeds; fluoxetine hydrochloride; a glove; a mouse box; deionized water; an organic glass water tank; a camera; gavage needle for No. 12 mice.
(3) Experiment grouping
The experimental group of the novel moringa seed amide compounds comprises 10 moringa seed amide compounds; group of positive drugs (fluoxetine hydrochloride): 10, 20 mg/kg; blank (deionized water), 10 pieces.
(5) Detailed Experimental procedures
Forced swimming experiment: mice were taken, fasted and kept without water for 12h, and transferred to the laboratory 1h before the experiment to adapt to the environment. After the gavage for 1h, the mice are respectively placed in glass jar water for swimming, the first 2min is taken as adaptation time, and the cumulative time of floating and immobility of the mice stopping swimming within 4min is recorded. The low-dose multi-administration group is administered at 9-10 am every day for 6 days and 7 days, the fasting is advanced for 1h before administration, the mice are respectively placed in glass jar for swimming after the intragastric administration for 1h, the first 2min is taken as the adaptation time, and the cumulative time of floating and standing which stops swimming within 4min after the recording.
Tail suspension test: 1h after the last administration, fixing the part of the tail of the mouse, which is 2 cm away from the root, on a self-made tail suspension bracket, enabling the head of the mouse to be in an inverted hanging state about 5 cm away from the table top, and separating the two sides of each animal by using plates to shield the sight of the animals so as not to interfere with each other. The cumulative immobility time of each group of animals within 5min after tail suspension within 6 min was observed.
(6) The experimental results are as follows:
Figure 573082DEST_PATH_IMAGE015
compared with a model group, the novel amide compounds in the moringa seeds can obviously shorten the accumulated immobility time in forced swimming of mice（P<0.05，P<0.01), the results are shown in Table 4.
Figure 838978DEST_PATH_IMAGE016
Figure 651076DEST_PATH_IMAGE017
Figure 27831DEST_PATH_IMAGE018
Compared with a model group, the amide compounds in the moringa seeds can obviously shorten the accumulated immobility time of tail-suspended mice (P<0.05), the results are shown in table 5.
(7) And (4) experimental conclusion:
experimental results show that the amide compounds in the moringa seeds prepared by the invention can shorten the immobility time of mice in forced swimming experiments and tail suspension experiments. Shows that: the amide compounds in the moringa seeds prepared by a certain extraction and separation method have good anti-depression effect, and can be used for preparing and developing anti-depression preparations.
Example 7 anti-senile dementia Activity of Moringa seed amides
(1) Principle of experiment
The A β deposition is one of the most typical pathological features of senile dementia, and has a key role in the occurrence and development process of senile dementia, the accuracy rate of senile dementia diagnosis according to the A β deposition condition can reach 80%, and the study shows that the A β deposition in the brain can reach 80%40And A β42The Morris water maze test is a classic method for evaluating space learning and memory ability and an objective index for evaluating the replication result of a dementia animal model, in recent years, the dementia animal model becomes an important means for researching senile dementia, and SD rats are adopted to prepare A β1-42And (3) injecting a dementia-causing model in a cerebral ventricle, respectively administering the amide compounds and normal saline in the moringa seeds of the test group and the control group, and evaluating the improvement condition of the amide compounds in the moringa seeds on the learning and memory capacity of the senile dementia rats through a Morris water maze experiment.
(2) Experimental Material
SPF SD male rat, amide compound 1-9 in moringa seed, amyloid fragment (A β)1-42) (ii) a DW-5 rat brain stereotaxic instrument; WMT-100 Morris water maze video analysis system; a glove; a mouse box; deionized water; an organic glass water tank; a camera; and (5) performing gastric lavage.
(3) Experiment grouping
Control group (saline); model group (saline); the experimental group of urea new compounds in the moringa seeds comprises 10 urea new compounds in each group.
(4) Dosage and frequency of administration
The new amide compound group in moringa seeds is 20 mg/kg, and is administrated in a gastric lavage manner 1 time a day for 7 days continuously.
(5) Detailed Experimental procedures
Figure 740310DEST_PATH_IMAGE015
Model preparation comprises anesthetizing SD rat with 10% urethane, fixing skull, positioning in bregma 3.4 mm, lateral opening of the right and left of the midline of the brain 2.0 mm, and injecting 5 μ L of condensed A β slowly at uniform speed at a depth of 2.7 mm below the surface of skull1-42The model A β control group was injected with isotonic saline at equal volume and the Morris water maze behavioural test was performed 1 week after molding.
Figure 645949DEST_PATH_IMAGE018
Morris water maze behavioural test: the test is carried out in quiet, dark and constant-temperature environments, and different patterns can be properly pasted on the wall of the laboratory to help the animal to determine the direction. Before the experiment, a bucket is filled with clear water to a preset height (about 40 cm), a proper amount of white pigment is added to enable the water to be opaque milky white liquid, and a heater is used for heating the water to 25 ℃. The platform was placed in the center of the fourth quadrant, approximately 1.5 cm below the water surface, and the platform position remained unchanged throughout the experiment. Positioning navigation test: the positioning voyage test lasted four days. The platform was placed in the center of the second quadrant, rats entered the water from the four quadrant surfaces in sequence towards the pool wall, and the record was taken of how well the rats found the platform within 120sI.e. the Escape Latency (EL). If the rat does not find the platform within 120s, the escape latency is 120s, and the rat should be guided to mount the platform. All rats climbing on the platform should stay on the platform for 15s, so that the rats can know that the underwater platform is an escape point and memorize the spatial position of the platform. The mean escape latency, i.e. the mean escape latency, was calculated for each group of rats in the four quadrants per day. The length of the Average Escape Latency (AEL) reflects the learning and memory ability of the rat, and the shorter the AEL, the faster the spatial position learning and cognition of the rat on the underwater platform. Space search test: and performing a space search test 24h after the positioning navigation test is finished. The specific method is to remove the platform, to make the rat search the platform by memory under the condition of no platform, and to record the platform crossing times of the rat in 120s, the swimming distance in each quadrant and the total distance. The position of the reference, including the experimenter, around the basin should be fixed throughout the test.
(6) Results of the experiment
As shown in Table 6, the average escape latency of the moringa seed amides was significantly reduced in the localized voyage test compared with the model group (P<0.05). In a space search test, compared with a model group, the cross-platform times and the distance of the moringa seed amide compounds are obviously improved (P<0.05，P<0.01) (table 7). The above results show that: the moringa seed amide compound has the effect of improving the dysmnesia of rats with senile dementia.
Figure 945343DEST_PATH_IMAGE019
Figure 860210DEST_PATH_IMAGE020
It should be noted that the above-mentioned embodiments are only for illustrating the technical concept and features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the content of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.

Claims (2)

1. The amide compound in the moringa seeds is characterized by comprising the following compounds, and the specific structure is as follows:
Figure 210468DEST_PATH_IMAGE001
。
2. the use of amides of claim 1 for the preparation of medicaments for the treatment of diabetes, antidepressant and senile dementia.
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