CN112194697B - Novel triterpenoid and application thereof in preparation of medicine for treating cardiovascular diseases - Google Patents

Novel triterpenoid and application thereof in preparation of medicine for treating cardiovascular diseases Download PDF

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CN112194697B
CN112194697B CN201910611991.XA CN201910611991A CN112194697B CN 112194697 B CN112194697 B CN 112194697B CN 201910611991 A CN201910611991 A CN 201910611991A CN 112194697 B CN112194697 B CN 112194697B
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叶淼
许文
徐伟
林羽
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Fujian University of Traditional Chinese Medicine
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Abstract

The invention provides a compound shown as a formula I, or a pharmaceutically acceptable salt, an optical isomer, a stereoisomer or a solvate thereof. The compound of the invention has novel structure, can obviously improve the heart failure index and the thrombus index of heart failure zebra fish, and has obviously better improvement effect than that of a contrast medicament.The compound can be used as a lead compound for improving structural heart diseases and cardiac preload and afterload, and has a very good application prospect in the preparation of medicaments for preventing and/or treating heart failure and thrombus.
Figure DDA0002122639490000011

Description

Novel triterpenoid and application thereof in preparation of medicine for treating cardiovascular diseases
Technical Field
The invention belongs to the field of medicine preparation, and particularly relates to a novel triterpenoid and application thereof in preparing a medicine for treating cardiovascular diseases.
Background
Coronary heart disease has been one of the most common cardiovascular diseases in recent 17 years, seriously threatening human health. At present, the treatment drugs for coronary heart disease have various limitations, and the research and development of the drugs for coronary heart disease are underway. In the process of searching for new drugs, natural products are receiving much attention. According to records in Kaibao materia medica, the bark of the tree root of the traditional Chinese medicine Rhus chinensis Mill (Rhus chinensis Mill.) has the effects of breaking blood and stopping bleeding, and the rhizome can activate blood and resolve stasis. The clinical curative effect of the Shuguantong syrup (Chinese medicine standard Z35020635) for treating coronary heart disease is definite. In 1973 to 1978, more than ten units in the country verify the clinical effect of Shuguantong syrup, and 346 cases of coronary heart disease are treated, and the total clinical effective rate reaches more than 80%. Pharmacological research shows that the Rhus chinensis Mill extract can obviously improve the blood rheological property of an animal model with coronary heart disease, and the Rhus chinensis Mill extract is adopted to inject an experimental dog intravenously, so that the coronary blood flow can be increased by 59.7%, the vascular resistance can be reduced by 51%, and the myocardial oxygen consumption can be reduced by 24.2%.
However, the basis of the drug effect substance of rhus chinensis for radically treating coronary heart disease is not clear up till now. To date, scholars both at home and abroad have also been short-studied about the chemical composition of Rhus chinensis roots, with only 12 triterpenes being reported in addition to flavones, phenolic acids, tannins (e.g., kim GS, jeong TS, kim YO, baek NI, cha SW, lee JW, song ks. Human acyl-CoA: cholesterol acyl transfer enzyme-inhibiting dammarane triterpenes from Rhus chinensis chips. J Korean Soc for Appl Biol Chem 2010.
Therefore, the research on chemical components in the rhus chinensis root and the search of a medicine capable of effectively treating coronary heart disease have very important significance.
Disclosure of Invention
The object of the present invention is to provide a novel compound which is effective for the treatment of cardiovascular diseases.
The invention provides a compound shown in formula I, or a pharmaceutically acceptable salt, an optical isomer, a stereoisomer or a solvate thereof:
Figure GDA0003947029270000011
wherein R is 1 Selected from the group consisting of from 0 to 4 of R 1x Substituted alkyl, substituted by 0-4R 1x Substituted alkenyl, substituted with 0-4R 1x Substituted alkynyl, halogen, hydroxy, carboxy, H;
R 1x selected from halogen, -L-OH, carboxyl, H, by 0-4R a Substituted saturated or unsaturated cycloalkyl radicals, substituted by 0 to 4R a Substituted saturated or unsaturated heterocyclic radical, substituted by 0-4R a Substituted, saturated or unsaturated cyclic keto groups containing 0 to 4 heteroatoms, substituted by 0 to 4R a Substituted C1-5 alkyl, substituted by 0-4R a Substituted C2-5 alkenyl, substituted by 0-4R a Substituted C2-5 alkynyl; r a Selected from H, -L-OH, carboxyl, halogen, C1-5 alkyl, C1-5 alkoxy; l is 0 to 5 methylene groups;
R 2 、R 3 、R 4 、R 5 、R 6 、R a1 、R a2 、R a3 each independently selected from H, C1-10 alkyl, C1-10 alkoxy, C2-10 alkenyl, C2-10 alkynyl, hydroxyl, carboxyl, amino, halogen;
Figure GDA0003947029270000021
represents a single bond or a double bond.
Further, the structure of the compound is shown as formula II:
Figure GDA0003947029270000022
wherein R is 2 、R 3 、R 4 、R 5 、R 6 Each independently selected from H, hydroxy, carboxy, halogen, C1-3 alkyl;
R 1 selected from the group consisting of 0 to 3R 1x Substituted alkyl, by 0-3R 1x Substituted alkenyl, halogen, hydroxy, carboxy, H;
R 1x selected from halogen, -L-OH, carboxyl, H, by 0-3R a Substituted, unsaturated cyclic keto groups containing 1 to 2 heteroatoms, substituted with 0 to 3R a Substituted C1-5 alkyl, substituted by 0-3R a Substituted C2-5 alkenyl; r a Selected from H, -L-OH, carboxyl, halogen, C1-5 alkyl, C1-5 alkoxy; l is 0 to 3 methylene groups;
Figure GDA0003947029270000023
represents a single bond or a double bond.
Further, the structure of the compound is shown as a formula III-1:
Figure GDA0003947029270000024
wherein R is 7 Is selected from
Figure GDA0003947029270000025
m, n and a are independently selected from integers of 0-2;
R 13 、R 14 n R a4 Each independently selected from H, -L-OH, carboxyl, halogen, C1-5 alkyl, C1-5 alkoxy, L is 0-1 methylene;
m is selected from O, S, CY 2 NY, Y is selected from H, hydroxyl, carboxyl, halogen, C1-5 alkyl and C1-5 alkoxy;
or, the structure of the compound is shown as formula III-2:
Figure GDA0003947029270000031
wherein R is 8 Is selected from
Figure GDA0003947029270000032
a is an integer of 0 to 2;
R 13 、R 14 、R 9 each independently selected from H, -L-OH, carboxyl, halogen, C1-5 alkyl, C1-5 alkoxy, L is 0-1 methylene;
or, the structure of the compound is shown as the formula III-3:
Figure GDA0003947029270000033
wherein R is 10 Is selected from
Figure GDA0003947029270000034
a is an integer of 0 to 2;
R 13 、R 14 、R 11 、R 12 each independently selected from H, -L-OH, carboxyl, halogen, C1-5 alkyl, C1-5 alkoxy, L is 0-1 methylene.
Further, the structure of the formula III-1 is shown as a formula III-1a or III-1 b:
Figure GDA0003947029270000035
wherein R is 13 、R 14 、R a4 Each independently selected from H, -L-OH, C1-3 alkyl, L is 0-1 methylene.
Further, said R 13 、R 14 、R a4 、R 11 、R 12 Each independently selected from H, hydroxy, -CH 2 OH and methyl.
Further, the structure of the compound is one of the following structures:
Figure GDA0003947029270000041
further, the structure of the compound is one of the following structures:
Figure GDA0003947029270000042
the invention also provides application of the compound in preparing a medicament for preventing and/or treating cardiovascular diseases.
Further, the cardiovascular disease is selected from heart failure, thrombosis, coronary heart disease.
In the present invention, fr. means fraction, meaning a component.
The prefix C x-y represents any group containing "from any to" any carbon atom. Thus, for example, C1-5 alkyl refers to an alkyl group containing any straight or branched chain of 1 to 5 carbon atoms.
"substituted" means that 1,2 or more hydrogen atoms in a molecule are replaced by a different atom or molecule, including 1,2 or more substitutions on the same or different atoms in the molecule.
"Cycloketo" means having
Figure GDA0003947029270000043
Cyclic groups of the structure include substituted or unsubstituted, saturated or unsaturated cyclic ketone groups with or without heteroatoms.
"cycloalkyl" means that the backbone atoms making up the ring are all carbon atoms; "Heterocyclyl" means that the backbone atoms making up the ring contain at least one heteroatom.
Heteroatom means an atom other than carbon and hydrogen, and includes O, S, N, and the like.
The method adopts mass spectrum guided separation and applies modern spectrum technology (NMR and MS) combined with ECD, DFT density pan-function calculation method and the like to prepare a novel compound with a rare structure. Unlike conventional dammarane-type triterpenes, the compounds of the invention are unique dammarane-type triterpenes with a 17 α -side chain.
The proportions of the mixed solvents used in the present invention are volume ratios.
Experimental results show that the compound can obviously improve the heart failure index and the thrombus index of the heart failure zebra fish, and the improvement effect of the compound is obviously superior to that of a control medicament. The compound can be used as a lead compound for improving structural heart diseases and cardiac preload and afterload, and has very good application prospect in the preparation of medicaments for preventing and/or treating heart failure and thrombus.
It will be apparent that various other modifications, substitutions and alterations can be made in the present invention without departing from the basic technical concept of the invention as described above, according to the common technical knowledge and common practice in the field.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1. Spatial distance experimental values (calculated from NOE integrated intensity, green) and theoretical values (calculated from DFT, red) for Compound 1.
FIG. 2.A calculated ECD patterns (red, gray) for the experimental ECD patterns (blue), (3S, 5S,8R,9S,10R,13R,14R,17R, 22S) -1a and (3S, 5S,8R,9S,10R,13R,14R,17R, 22R) -1 b; experimental ECD spectra for compounds 1 and 7.
FIG. 3 is a phenotypic graph of zebrafish heart enlargement and venous sinus blood stasis area improvement after 4.5 hours of sample treatment (heart and venous sinus blood stasis sites are marked by red and yellow dotted frames, respectively): (A) a blank control; (B) a model control group; (C) a positive control group (0.8. Mu.g/mL); (I-L) administration group [ Compound 7-10 at a concentration of its Maximum Tolerated Concentration (MTC) in zebrafish ]; and heart area (N) and venous sinus blood stasis area (O) of the zebra fish after the test sample is treated at the MTC concentration; comparison with model control group: * P <0.05, P <0.01, P <0.001.
FIG. 4 Zebra fish cardiac output (A), blood flow rate (B) and heart rate (C) after treatment at concentrations of their MTC in each experimental group; comparison with model control group: * P <0.05, P <0.01, P <0.001.
FIG. 5 is a graph showing the quantitative evaluation of the staining intensity of red blood cells of the heart after 18 hours of treatment of zebrafish in each experimental group (yellow-labeled zebrafish heart): (A) a blank control; (B) model control group; (C) a positive control group (45. Mu.g/mL); (I-L) administration group. (N) quantitatively evaluating the heart red blood cell staining intensity of each experimental group after treating the zebra fish for 18 hours; comparison with model control group: * P <0.05, P <0.01, P <0.001.
FIG. 6 high resolution mass spectrum of Compound 7 of the present invention.
FIG. 7 shows UV spectrum of inventive compound 7.
FIG. 8 shows an IR spectrum of Compound 7 of the present invention.
FIG. 9 Compound 7 of the present invention 1 H-NMR(500MHz,CDCl3)。
FIG. 10 Compound 7 of the present invention 13 C-NMR(125MHz,CDCl3)。
FIG. 11. Compound 7 DEPT135 of the present invention (125MHz, CDCl 3 )。
FIG. 12 Compound 7 of the present invention 1 H- 1 H COSY(500MHz,CDCl 3 )。
FIG. 13. Compound 7 HSQC (500MHz, CDCl) of the present invention 3 )。
FIG. 14. Compound 7 HMBC (500MHz, CDCl) of the present invention 3 )。
FIG. 15. Compound 7 NOESY (500MHz, CDCl) of the present invention 3 )。
FIG. 16.A NOE cross-peak volume of H-21b/Me-30 refers to the volume of H-12 β/H-13 β in Compound 7 of the present invention; B-Experimental dynamic distance of H-21B/Me-30 for Compound 7 of the present invention was calculated from the NOE intensity (red).
FIG. 17 high resolution Mass Spectrometry of Compound 8 of the present invention.
FIG. 18 shows an IR spectrum of Compound 8 according to the invention.
FIG. 19. Compound 8 of the present invention 1 H-NMR(500MHz,CDCl3)。
FIG. 20 Compound 8 of the present invention 13 C-NMR(125MHz,CDCl3)。
FIG. 21 Compound 8 DEPT135 (125MHz, CDCl) of the present invention 3 )。
FIG. 22. Compound 8 HSQC (500MHz, CDCl) of the present invention 3 )。
FIG. 23. Compound 8 HMBC (500MHz, CDCl) of the present invention 3 )。
FIG. 24. Compound 8 NOESY (500MHz, CDCl) of the present invention 3 )。
FIG. 25.A NOE cross-peak volume of H-21b/Me-30 refers to the volume of H-12 β/H-13 β in Compound 8 of the present invention; B-Experimental dynamic distance of H-21B/Me-30 for Compound 8 of the present invention was calculated from the NOE intensity (red).
FIG. 26 high resolution Mass Spectrometry of Compound 9 of the present invention.
FIG. 27 is an IR spectrum of Compound 9 of the present invention.
FIG. 28 Compound 9 of the present invention 1 H-NMR(500MHz,CDCl3)。
FIG. 29 Compound 9 of the present invention 13 C-NMR(125MHz,CDCl3)。
FIG. 30 Compound 9 DEPT135 (125MHz, CDCl) of the present invention 3 )。
FIG. 31. Compound 9 HSQC (500MHz, CDCl) of the present invention 3 )。
FIG. 32. Compound 9 HMBC (500MHz, CDCl) of the present invention 3 )。
FIG. 33 shows Compound 9 NOESY (500MHz, CDCl) of the present invention 3 )。
FIG. 34 high resolution Mass Spectrometry of Compound 10 of the present invention.
FIG. 35 is an IR spectrum of Compound 10 of the present invention.
FIG. 36 Compound 10 of the present invention 1 H-NMR(500MHz,CDCl3)。
FIG. 37. Compound 10 of the present invention 13 C-NMR(125MHz,CDCl3)。
FIG. 38 Compound 10 DEPT135 (125) of the present inventionMHz,CDCl 3 )。
FIG. 39 Compound 10 of the present invention 1 H- 1 H COSY(500MHz,CDCl 3 )。
FIG. 40. Compound 10 HSQC (500MHz, CDCl) of the present invention 3 )。
FIG. 41. Compound 10 HMBC (500MHz, CDCl) of the present invention 3 )。
FIG. 42. Compound 10 NOESY (500MHz, CDCl) of the present invention 3 )。
Detailed Description
The raw materials and equipment used in the invention are known products and are obtained by purchasing commercial products.
1 test reagent
Column chromatography silica gel (100-200 mesh, 200-300 mesh, qingdao ocean chemical plant); MCI filler (75-150 μm, mitsubishi chemical Co., ltd., japan); ODS reverse phase silica gel (50 μm, silica, canada); thin layer chromatography plate (GF 254,0.20-0.25mm, qingdao ocean plant); methanol, ethanol, acetone, dichloromethane, ethyl acetate, petroleum ether (analytically pure, national chemical group, chemical reagents, ltd.); acetonitrile, methanol (chromatographically pure, MERCK, germany); milli-Q ultrapure water (Millipore, USA).
2 laboratory instruments
High resolution triple quadrupole LC MS (waters, USA); LC-20A analysis was performed with a semi-preparative high performance liquid chromatograph (Shimadzu, japan); ELSD-LT II evaporative light Scattering Detector (Shimadzu, japan); agilent XDB C18 column (250X 4.6mm,5 μm); 2545Autopurification System (waters, USA); WFH-203B three-purpose ultraviolet analyzer (Shanghai Jingke industries, ltd.); an Autopol IV automatic polarimeter; hitachi U-2900E ultraviolet visible spectrophotometer; avatar 360ESP FTIR Infrared Spectroscopy; JASCO-810 spectropolarimeter; DRX-500MHz NMR spectrometer (Bruker, germany); daltonics microOTOF-QII high resolution mass spectrometer (Bruker, germany); DBS-160F computer Automation parts gatherer (Shanghai Seiko industries, ltd.); multifunctional extraction and concentration equipment (Shanghai Shunji science and technology Co., ltd.); RE-2000A rotary evaporator (Shanghai Yangrong Biochemical Instrument factory); RV 10 rotary evaporator (IKA, germany); medium-sized rotary evaporators (Nanjing beidi laboratory instruments Co., ltd.); one in ten thousand electronic balance (sidoris scientific instruments ltd); KQ-500E desk ultrasonic cleaner (Kunshan ultrasonic instruments Co., ltd.).
3 Experimental drugs
The Rhus chinensis medicinal material is collected from Tengchong city of Yunnan province in 2017 months, is identified as the dry root of Rhus chinensis Mill (Rhus chinensis Mill) of Rhus genus of Anacardiaceae by Rooibos squarroschem of Yunnan province, and a voucher specimen (No. 20170310002) is stored in a specimen room of the college of pharmacy of Fujian Chinese medicinal university.
4 quantum chemical calculation method
Confab was used to search for low energy conformations. Further using PM7 (MOPAC 2016) ] The method is optimized. An energy window of 4kcal/mol was selected and further optimized using the Density Functional Theory (DFT) method, which combines the B3LYP method with the 6-31G basis set. Carbon spectrum data based on 13 C NMR was calculated on
Figure GDA0003947029270000071
The B97x-D method combines the 6-31G-base group and in the gaseous state. ECD calculations were based on B3LYP theoretical binding/6-311G basis group, treated with SpecDis v1.71 software. The calculated values of the carbon spectrum, ECD and atomic space distance are all Boltzmann averages based on Gibbs free energy. All DFT calculations are processed using Gaussian09 software.
EXAMPLE 1 preparation of Compounds 7-10 of the invention
Drying and pulverizing Rhus chinensis Mill root (43.03 kg), extracting with 95% methanol at 70 deg.C under reflux for 6 hr for 4 times, and concentrating under reduced pressure to obtain methanol total extract (6.61 kg). Suspending the methanol extract with water, extracting with petroleum ether, selecting a petroleum ether part extract (1.62 kg), and performing gradient elution with a silica gel column (100-200 mesh, 120cm × 15cm) by using dichloromethane/methanol (70. The resulting TLC system was analyzed and judged in a comprehensive manner, and the collected solutions were combined to obtain 13 subfractions (Fr.1-13). Based on the TLC combined HPLC-DAD/ELSD/MS compound detection method constructed by us and the LC-MS chemical profile analysis of each sub-component, the target component required to be separated is determined according to the determination result.
(1) Preparation of Compounds 7, 8, 9
From fr.5 (35.65 g, silica gel column dichloromethane/methanol 15 elution site), silica gel column was first used, and gradient elution was performed using dichloromethane/methanol (70-0. From fr.5b (18.2 g, silica gel column dichloromethane/methanol 30 elution portion) was separated and purified by means of a silica gel column (200 to 300 mesh), and a petroleum ether/acetone system (5. From Fr.5B-8 (570.0 mg, silica gel column petroleum ether/acetone 3, elution site 1) was passed through an MCI column (i.e., a small pore resin gel column) and subjected to further fine separation, and a methanol/water system (70-100).
Fr.5B-8-1 (50.3mg, MCI column 70% methanol/water elution part) is taken to be rapidly prepared by semi-preparative HPLC (chromatographic condition: 84% methanol/water system), and the compound 9 (44.2mg, t) of the invention is obtained R 34.8min)
Fr.5B-8-9 (46.7mg, MCI column 100% methanol/water elution part) was subjected to semi-preparative HPLC (chromatography conditions: 83% methanol/water system) to prepare rapidly the compound of the present invention, compound 8 (37.20mg, t. R 37.0min)。
Fr.5B-8-10 (18.6 mg, MCI column 100% methanol/water elution part) is taken to be rapidly prepared by semi-preparative HPLC (chromatographic condition: 83% methanol/water system), and the compound 7 (5.2mg, t) is obtained R 37.6min)。
(3) Preparation of Compound 10
From Fr.5B-7 (2.3 g, silica gel column petroleum ether/acetone 3.5 elution site), further separation and purification were performed by means of silica gel column (200 to 300 mesh), and gradient elution was performed by selecting a petroleum ether/acetone system (5. Fr.5G-10 (863.0 mg, silica gel column petroleum ether/acetone 31-Fr.5G-10-5). Fr.5g-10-2 (245.2mg, 95% methanol/water elution site on spe column) was taken, and finally prepared rapidly by semi-preparative HPLC under methanol/water (82) isocratic conditions to give compound 10 (36.02mg, t R 41.3min)。
Structural confirmation of the compounds of the invention:
compound 7: white amorphous solid.
[ M + Na ] according to HRESIMS] + Peak: m/z 475.3176, deducing the molecular formula as C 30 H 44 O 3 The unsaturation degree was 9. The carbon spectrum and DEPT spectrum of Compound 7 showed 5 sp in the structure of Compound 7 3 Singlet and 1 sp 3 Double-bonded methyl of, 1 sp 2 And 9 sp 3 Hybridized methylene group, 1 sp 2 And 5 sp 3 Hybrid methine (including 1 vicinal oxymethylene), 8 quaternary carbons (including 1 ketocarbonyl, 1 ester carbonyl, and 1 alkene carbon). By comprehensively analyzing the hydrogen spectrum, the carbon spectrum and the DEPT spectrum of the compound 7 (Table 1, 2), the structure of the compound of the invention contains 1 keto group (delta 218.2); 1 α, β -unsaturated- δ -lactone ring (δ 81.1, 29.1,139.3,128.6,17.2, 166.2), 1 exocyclic double bond (δ 113.7, 149.3) and 5 singlet and 1 alkenylmethyl groups. According to C-3 and H 2 -1/H 2 -2/H-5/H 3 -28/H 3 HMBC correlation of-29, it can be determined that the keto carbonyl group is located on C-3; the molecular structure of the molecular structure is shown by H-23a/C-22, C-24 and C-25 in an HMBC spectrum; H-24/C-22,23,25,26,27 and H 3 The presence of the α, β -unsaturated- δ -lactone ring is confirmed by the correlation peak of-26/C-24,25,27; h-17 and C-13/C-20/C-21; h 2 -21 correlation with HMBC at C-20 determines that the exocyclic double bond is at C20 (21); all of the above groups satisfied 5 degrees of unsaturation, indicating that the compound is a tetracyclic triterpene with 1 side chain forming a ring. The control literature (Kim GS et al, J Korean Soc for Appl Biol Chem 2010, 53, 417-21, sung CK, et al, chem Soc Chem Commun 1980, 909-10.) found that the hydrogen and carbon spectra data of compound 7 are very similar to semialcactone and rhallactone isolated from Rhus chinensis reported, except that the hemiacetal structure is replaced by a keto group. However, the relative configuration of the two C-17 is opposite, semialactone is 17 beta side chain, and rhusalactone is 17 alpha side chain. Compound 7Was analyzed by comparison with compound 1 isolated from the plant at the same time as the subject group. The NOESY spectrum of Compound 1 shows a significant H-21/H 3 -30 correlation peaks. Therefore, we can follow the formula H-21/H 3 Calculation of H-21b/H from the integrated area of the NOE correlation peak of-30 3 A spatial distance of-30 (Wang WX et al, J Nat Prod,2016 79. Based on the conformational optimisation of B3LYP/6-31G theory, we calculated H-21/H in the 17 α and 17 β side chain configurations (1a, 1c) of Compound 1 3 Boltzmann mean distance of-30, 2.05 and
Figure GDA0003947029270000081
(Table 3). Integration of NOE-related peaks by H-1 β (δ 2.18)/H-19 b (δ 3.72) located within the rigid structural loop and their atomic distance->
Figure GDA0003947029270000082
For reference, according to the formula: [ r ] of H-21/Me-30 ＝r ref (a ref /a H-21/Me-30 ) 1/6 ] 1/6 (Wang WX et al, J Nat Prod,2016; 704-10.) to calculate H-21/H 3 An experimental distance of ` 30>
Figure GDA0003947029270000083
(FIG. 1). It was concluded that the experimental values of the spatial distance H-21/Me-30 were consistent with the theoretical values for the (3S, 5S,8R,9S,10R,13R,14R,17R, 22S) -1a, i.e., the 17 α side chain configuration, and deviated significantly from the 1c, i.e., 17 β side chain configuration. Thus, it was confirmed that the relative configuration of the side chain attached to C-17 was α. To further determine the absolute configuration of C-17, a determination is made on the basis of->
Figure GDA0003947029270000084
The B97 x-D/6-31G// B3LPY/6-31G method calculates the 4C-17 and C-22 diastereoisomeric carbon spectra data (1 a-1D) for Compound 1 using literature reported parameters (Kutateladze AG et al, J Org Chem 2017, 82. Calculation of sDP4 for the four C-17 and C-22 diastereomers (1 a-1 d) + Probability (table 4). As a result, the probability of sDP4+ of 17R is farGreater than 17S. Thus, the absolute configuration of C-17 is identified as R. However, sDP4 of 1a with its 22R epimer 1b + The probability difference is small, and the absolute configuration of C-22 cannot be judged according to the probability difference. To further confirm the absolute configuration of C-22, ECD calculations were performed on 1a and 1 b. As shown in FIG. 2, the calculated ECD curves for (3S, 5S,8R,9S,10R,13R,14R,17R, 22S) -1a were highly matched with the experimental curves, demonstrating that the absolute configuration of C-22 is S. Compound 1 was finally identified as rhuslactone (1) (Sung CK, et al, chem Soc Chem Commun 1980, 909-10.) consistent with the structure of 1 a.
Figure GDA0003947029270000091
From FIG. 16, it can be seen that the spatial distance between H-21 and Me-30 of Compound 7 is
Figure GDA0003947029270000092
The absolute configuration of 17R was thus determined. From the high similarity of the ECD spectrum of compound 7 shown in FIG. 2 to that of compound 1, the absolute configuration of C-22 of compound 7 was determined to be S. Thus, compound 7 of the present invention is (17R, 22S) -3-oxodamar-20, 24-dien-27,22-lactone, having the structure:
Figure GDA0003947029270000093
compound 8: white amorphous solid.
HRESIMS (m/z 479.3495M + Na) according to compound 8] + ) Calculated value of 479.3501 (C) 30 H 48 O 3 Na), its molecular formula is deduced to be C 30 H 48 O 3 The unsaturation degree was 7. Carbon and DEPT spectra of 8 (Table 1, 2) showed that the structure of Compound 8 contained 5 sp 3 Methyl, 1 sp 2 And 12 sp 3 Hybridized methylene group (including 2 oxo methylene groups), 1 sp 2 And 4 sp 3 Hybridized methine, 7 quaternary carbons (including 1 ketocarbonyl). By comprehensively analyzing the hydrogen, carbon and DEPT spectra of 7 (tables 1, 2), the junction of 8 can be deducedThe structure contains 1 ketocarbonyl group (delta 218.4), 1 trisubstituted double bond, 1 exocyclic double bond, 2 vicinal oxymethylene groups and 5 unimodal methyl groups. Based on the degree of unsaturation of 8, 8 tetracyclic triterpenes can be identified as 1 tetracyclic triterpene. According to C-3 and H 2 -1/H 2 -2/H-5/H 3 -28/H 3 HMBC correlation of-29, it can be determined that the ketocarbonyl is located on C-3; according to the H-17 and C-13/C-20 in the HMBC spectrum 2 A correlation peak between 21/C-20, which infers the double bond at C-20; at the same time, the HMBC spectrum shows a clear H 2 -21/C-22；H 2 -22/C-20；H-24/C-22,23,26,27；H 2 -26/C-24,25,27；H 2 Correlation of-27/C-25,26, from which it was deduced that the planar structure of 8 was 26,27-dihydroxy-dammara-20,24-diene-3-one. The NOESY spectrum shows a clear H-21b/H 3 -30 correlation peaks, so we can follow from H-21b/H 3 Calculation of H-21/H from the integrated area of NOE correlation peaks of-30 3 A spatial distance of-30 (Wang WX et al, J Nat Prod,2016 79. Based on the conformational optimisation of B3LYP/6-31G theory, we calculated H-21/H for compound 8 in both 17 α and 17 β side chain configurations respectively 3 Boltzmann mean distance of-30, 2.26 and
Figure GDA0003947029270000102
(Table 5). Integration of NOE-related peaks by H-12 beta/H-13 beta located within a rigid structural loop and their atomic distance->
Figure GDA0003947029270000103
For reference, according to the formula: [ r ] of H-21/Me-30 ＝r ref (a ref /a H-21/Me-30 ) 1/6 ] 1/6 Calculating H-21/H 3 An experimental distance of-30 @>
Figure GDA0003947029270000104
(FIG. 25), which is consistent with the theoretical value of the 17. Alpha. Side chain configuration, the deviation from the 17. Beta. Side chain configuration is large. Thus, it was confirmed that the relative configuration of the side chain attached to C-17 was α.
Based on the analysis of the data, the compound 8 of the invention is determined to be (17R) -26,27-dihydroxy-dammara-20 and 24-diene-3-one, and the structure is as follows:
Figure GDA0003947029270000101
compound 9: white amorphous powder.
HRESIMS shows that the peak of its molecular ion is m/z 479.3495[ M ] +Na ]] + Calculated value is 479.3501 (C) 30 H 48 O 3 Na), compounds 9 and 8 are a pair of isomers. By analysis of 1 H-NMR、 13 The results of C-NMR, DEPT135 (Table 1, 2) showed that Compound 9 contained 1 ketocarbonyl (. Delta.218.2), 1 trisubstituted double bond, 1 tetrasubstituted double bond, 5 monomodal methyl groups, 1 methylene group attached to the alkenyl group and 2 vicinal oxymethylene groups. Meanwhile, when the carbon spectrum data of 9 is compared with 8, the A-C rings are highly similar, and the D ring is different from the side chain. Indicating that there is a high possibility that the side chain structures of the two are different. By the reaction of H-13,H 2 -16,H 2 -21,H 2 -22 and C-17; h 2 -21,H 2 -22 and C-20 and H-13,H 2 Correlation of-21 with HMBC at C-22, it was determined that the tetrasubstituted double bond is located at C-17 and C-20, while passing through H 2 -23/C-22, C-24; H-24/C-26, C-27 and H 3 -26,H 2 HMBC correlation at-27/C-25 infers that the trisubstituted double bond is at C-24 and either C-26 or C-27 is attached to the hydroxyl group. Further according to H-24/H 3 NOE correlation between-26, confirming a cis double bond at C-24. Thus, compound 9 of the present invention was identified as 21,27-dihydrorydammar-17 (20), 24 (Z) -dien-3-one, having the structure:
Figure GDA0003947029270000111
compound 10: white powder.
According to the molecular ion peak (m/z 481.3688[ M ] +Na) in HRESIMS spectrum] + ) The molecular formula of Compound 10 is identified as C 30 H 50 O 3 The unsaturation degree was 6. The hydrogen, carbon and DEPT spectra (Table 1, 2) show that the structures of compounds 10 and 9 are highly similar. The difference between the two is that in 10The exocyclic double bond disappeared and there was only one oxymethylene group, while there were 1 more oxygenated quaternary carbon in 10 and 1 unimodal methyl group as compared to 9. According to H 2 -11/H 2 -12/H-13/H-17 1 H- 1 H COSY related and H-17 with C-13, C-16, C-20, C-22 and H 3 -21 and H 2 The correlation of-22 with HMBC at C-20 demonstrates that the hydroxyl group is attached to C-20. Furthermore, from H 2 -23/C-22, C-24; H-24/C-26, C-27 and H 3 -26,H 2 HMBC correlation of-27/C-25 infers that the trisubstituted double bond is located at C-24 and either C-26 or C-27 is attached to the hydroxyl group as represented by H-24/H 3 NOE correlation of-26 determined that the double bond was cis. Unlike Compound 8, the NOESY spectrum of Compound 10 showed significant H-17/H 3 30 alpha, thereby determining the relative configuration of H-17 as alpha. Thus, compound 10 is a common β -side chain substituted dammarane-type triterpene. Whereas the absolute configuration of C-20 was determined by comparison of the literature (Asakawa J et al, tetrahedron 1977 33, 1935-9.) the chemical shifts of C-17, C-21, and C-22 of Compound 10 were 50.76, 26.60, and 42.64, respectively, which are highly aligned with the chemical shifts of dammarane-type triterpenes in the literature where the absolute configuration of C-20 is S, thereby determining the absolute configuration of C-20 as S. Thus, compound 10 of the present invention was identified as 20,27-dihydroxy-24 (Z) -dammaren-3-one, having the structure:
Figure GDA0003947029270000112
TABLE 1 Hydrogen spectra data (500 MHz) of the compounds of the invention
Figure GDA0003947029270000113
/>
Figure GDA0003947029270000121
TABLE 2 carbon spectra data (125 MHz) of the compounds of the invention
Figure GDA0003947029270000122
H-21 and H in (3S, 5S,8R,9S,10R,13R,14R,17R, 22S) -1a and its 17S-epimer (1 c) 3 -a calculation of the boltzmann mean distance of 30.
Figure GDA0003947029270000131
TABLE 4 Experimental values of carbon spectra for Compound 1 and calculated values of carbon spectra for 4C-17, C-22 diastereomers (1 a-1 d) of Compound 1
Figure GDA0003947029270000132
/>
Figure GDA0003947029270000141
TABLE 5. In the case of compound 8 having alpha and beta side chains at position 17, respectively, H-21 and H 3 -a calculation of the boltzmann mean distance of 30.
Figure GDA0003947029270000142
/>
Figure GDA0003947029270000151
The advantageous effects of the compounds of the present invention are demonstrated below by experimental examples.
1 laboratory instrumental dissecting microscope (SZX 7, OLYMPUS, japan); a camera (TK-C1481 EC) connected to the microscope; precision electronic balances (CP 214, OHAUS, america); six-well microplates (Nest Biotech, shanghai, china); heartbeat blood flow analysis system (zebralab 3.3 (PB 2084C).
2 experimental reagents with the drug methylcellulose (Aladdin, shanghai, china); dimethyl sulfoxide (DMSO, sigma, batch: BCBN 0845V); verapamil hydrochloride (batch No. L1303078, shanghai Jing pure industries, ltd.); digoxin (batch No. K1417048, shanghai Jing pure industries, ltd.); o-dianisidine (Sigma, batch: MKBG 4648V); ponatinib (batch number: 13771, medchemexpress); aspirin (batch No. 059K0199, shanghai crystal pure industry Co., ltd.) compound was prepared into 50mg/mL mother liquor with DMSO and stored at-20 deg.C; the DMSO concentration in the final working solution is 0.1% after dilution with DMSO as required.
In which LCZ696 is a dual-effect angiotensin receptor-enkephalinase inhibitor (ARNI) and can enhance the protective neuroendocrine system (NP system, natriuretic peptide system) of heart and inhibit the harmful system (RAAS system, renin-angiotensin-aldosterone system). In the historically largest PARADIGM PARADIGM-HF study, LCZ696 was shown to be significantly more efficacious than the standard therapeutic enalapril in clinical studies. Approved by FDA in the United states in 2015 and approved by NMPA in China in 2017 to be marketed. Enalapril is an angiotensin converting enzyme inhibitor; digoxin is Na + /K + ATPase inhibitors, being cardiac inotropic drugs; hydrochlorothiazide is a diuretic; metoprolol is a selective β 1 adrenoceptor antagonist (Yang BF et al, pharmacology: people's Medical Publishing House,2018, p.232-5). Irbesartan is an angiotensin receptor antagonist (Yang BF et al, pharmacology: peoples' Medical Publishing House,2018, p.207). The medicines are first-line medicines for treating heart failure at present.
3 Experimental animals
Zebrafish share over 71% homology with the human gene. Zebrafish have a very high similarity to humans in signaling pathways and response to drugs. In addition, other characteristics of zebrafish, such as: strong in vitro fertilization, reproductive capacity, rapid development and the like, so that the model becomes a popular cardiovascular and cerebrovascular drug screening model. After the zebra fish is induced by 200 mu M verapamil for 0.5 hour, the zebra fish has the symptoms of pericardial edema, venous blood stasis, bradycardia, blood circulation obstruction and the like; and after the zebrafish is treated by 4 mu g/mL ponatinib for 18 hours, the zebrafish generates thrombus. The symptoms are almost consistent with the clinical symptoms of patients with coronary heart disease, and the disease state of coronary heart disease can be well simulated.
The wild AB line zebra fish adopted by the invention is carried out in a natural pairing mating breeding mode. The total number of the fertilized eggs is 1500, and the age is 2 days after fertilization. The zebra fish are all raised in water for fish culture at 28 deg.C (water quality: 200mg of instant sea salt is added to 1L of reverse osmosis water, conductivity is 480-510 μ S/cm, pH is 6.9-7.2, hardness is 53.7-71.6 mg/L CaCO) 3 ) The license number for experimental animals is as follows: SYXK (Zhe) 2012-0171. The feeding management meets the requirements of international AAALAC certification.
4 Experimental methods
Adult AB strain zebrafish is provided by huntington girt biotechnology limited. The selected compounds were dissolved in 100% DMSO to prepare a stock solution, and the stock solution was diluted with water for fish culture at the time of administration, whereby the DMSO concentration in the final working solution was 0.1% w/v. Treating zebrafish with verapamil hydrochloride of 200 mu M for 0.5 hour to induce a zebrafish heart failure model; zebrafish were treated with 4 μ g/mL ponatinib for 18 hours to induce a zebrafish thrombus model. 0.1% DMSO-treated experimental group as a normal control group. Digoxin (0.8 mug/mL) and aspirin (45 mug/mL) which are clinical routine heart failure treatment medicines are adopted as positive control medicines. And six clinical common heart failure drugs LCZ696, enalapril, digoxin, hydrochlorothiazide, irbesartan and metoprolol which are reported in other documents are adopted as contrast drugs.
The experimental methods for the evaluation of the prevention of heart failure of zebrafish are fully referred to the literature (Zhu XY, wu SQ, guo SY, yang H, xia B, li P, li CQ. A zebrafish failure model for the assessment of therapeutic agents. Zebrafish 2018. First, the MTC of the compounds was determined. Next, the prophylactic effect of the concentration of the tested compound on the heart failure of zebrafish at its MTC was evaluated. After the treatment with the drug according to the literature method, the area of cardiac dilatation (A1) and the area of venous sinus haemostasis (A2), cardiac Output (CO), blood flow rate (BFV) and Heart Rate (HR) were analyzed and counted for each experimental group. Evaluation of prevention of zebrafish heart failure experimental methods several modifications were made on the basis of literature methods (Zhu XY, liu HC, guo SY, xia B, song RS, lao QC, xuan YX, li cq.a zebraphis model for assessing anti-inflammatory drugs.zebrafish 2016).
30 AB line zebra fishes of 5 days after fertilization were randomly selected and placed in a six-well plate, and after being treated with 4. Mu.g/mL ponatinib and a compound for 18 hours, the thrombus formation of each experimental zebra fish was quantitatively analyzed by a literature method (patent No. 201110126427). The preventive effect of the test article on thrombosis was quantitatively evaluated in the statistical significance of the staining intensity of heart erythrocytes (described as S in the calculation). Each experiment was repeated three times using one-way analysis of variance, followed by Ttest testing. p <0.05 means statistically significant.
The test article is used for calculating the improving effects of the test article on heart enlargement, venous sinus blood stasis, cardiac output, blood flow velocity and heart rate and the preventing effect on thrombosis by using formula-1-6 respectively. formula-1 (2) cardiac enlargement improvement (%) = [ A ] 1(2) (model group) -A 1(2) (Compound group)]/[A 1(2) (model group) -A 1(2) (blank group)]X 100%; formula-3 cardiac output increasing action (%) = [ CO (Compound group) -CO (model group)]/[ CO (blank group) -CO (model group)]X is 100%; formula-4 blood flow rate increasing effect (%) = [ BFV (Compound group) -BFV (model group)]/[ BFV (blank group) -BFV (model group)]X is 100%; formula-5 heart rate increase (%) = [ HR (Compound group) -HR (model group)]/[ HR (blank group) -HR (model group)]X is 100%; formula-6 thrombosis prevention (%) = [ S (Compound group) -S (model group)]/[ S (blank group) -S (model group)]×100％。
Experimental example 1 preventive Effect of the Compound of the present invention on Heart failure of Zebra Fish
First, the Maximum Tolerated Concentration (MTC) of the compounds of the invention in both models of zebrafish heart failure and thrombosis was tested, with 0.5. Mu.g/mL for compounds 7, 10, 25. Mu.g/mL for 8, and 5. Mu.g/mL for 9. Subsequently, the preventive effect on heart failure and thrombosis in zebrafish was evaluated at each compound concentration as its MTC.
As can be seen from Table 3, compounds 7-10 all exhibited significant prophylactic effects on zebrafish heart failure at their MTC (P <0.05, P-woven cloth 0.01, P-woven cloth 0.001). The concrete points are as follows: has effects in improving heart enlargement and venous sinus blood stasis area (figure 2), and increasing heart output (CO, A in figure 3), zebra fish back aorta blood flow velocity (BFV, B in figure 3) and heart rate (HR, C in figure 3). In particular, the compounds of the present invention all significantly improved the five indices of heart failure above, especially compound 7 (p < 0.001), compared to the model group. CO, as an important index for evaluating the function of cardiac ejection, is affected by structural heart disease and overload of the heart. This indicates that the compounds of the invention are likely to be lead compounds for the improvement of structural cardiac pathology and cardiac preload and afterload.
In order to better evaluate the improvement effect of the compound of the invention on the heart failure of the zebrafish, a positive control drug digoxin (0.8 mug/mL) for clinically and routinely treating the heart failure and six clinically and commonly used heart failure drugs LCZ696, enalapril, digoxin, hydrochlorothiazide, irbesartan and metoprolol reported in the literature are compared with the experimental compound in the improvement effect of the zebrafish heart failure at the same concentration (0.5 mug/mL) or higher concentration (10 mug/mL) (Table 3).
The results show that the compound of the invention, especially the compound 7 is obviously superior to the control drugs of enalapril (10 mug/mL), metoprolol and irbesartan (0.5 mug/mL) and the positive control drug of digoxin in the increase effect on BFV. The compound of the invention can play a significant role in preventing and/or treating the development of zebra fish heart failure.
TABLE 6 comparison of prevention effects of each compound, positive control drug and clinical conventional drug for resisting heart failure on heart failure and thrombus of zebra fish
Figure GDA0003947029270000171
Compared with the model group, P <0.05, P <0.01, P <0.001.
Experimental example 2 preventive Effect of the Compound of the present invention on thrombosis of Zebra Fish
According to the Hangzhou Huanti Biotechnology GmbH (patent No. 201110126427), the cardiac red blood cell staining intensity (RBC) is inversely related to the severity of thrombus formation, so that the RBC can be used for quantitatively evaluating the prevention effect of the test sample on the thrombus formation induced by ponatinib. The intensity of cardiac red blood cell staining after treatment with each compound was counted as described in the "experimental methods" above.
As shown in Table 3 and FIG. 4, the compounds 7 to 9 of the present invention showed a significant increase in RBC and a decrease in thrombogenesis in zebrafish at MTC concentrations. Among them, compound 7 (0.5. Mu.g/mL) had the strongest effect of preventing thrombosis, 62% (p < 0.001). The compound can obviously prevent and/or treat the formation of the thrombus of the zebra fish.
In conclusion, the invention provides the triterpenoid with a novel structure, the triterpenoid can obviously improve the heart failure index of heart failure zebra fish and the compounds 7-9 can obviously improve the thrombus index of the zebra fish, and the triterpenoid can be used as a lead compound for improving structural heart lesion and heart preload and afterload and has a very good application prospect in preparing medicaments for preventing and/or treating heart failure and thrombus.

Claims (3)

1. A compound, or a pharmaceutically acceptable salt thereof, characterized by: the structure of the compound is one of the following structures:
Figure DEST_PATH_IMAGE002
Figure DEST_PATH_IMAGE004
。
2. use of a compound according to claim 1 for the preparation of a medicament for the prophylaxis and/or treatment of cardiovascular diseases.
3. Use according to claim 2, characterized in that: the cardiovascular disease is selected from heart failure, thrombosis, coronary heart disease.
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