LU502069B1 - Resveratrol a-ring n(ch3)2-based derivative res4 and preparation method and application thereof - Google Patents

Resveratrol a-ring n(ch3)2-based derivative res4 and preparation method and application thereof Download PDF

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Publication number
LU502069B1
LU502069B1 LU502069A LU502069A LU502069B1 LU 502069 B1 LU502069 B1 LU 502069B1 LU 502069 A LU502069 A LU 502069A LU 502069 A LU502069 A LU 502069A LU 502069 B1 LU502069 B1 LU 502069B1
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res4
compound
formula
preparation
pasmcs
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LU502069A
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German (de)
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tiantian Zhu
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Univ Xinxiang Medical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups

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  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present disclosure provides a resveratrol A-ring N(CH3)2-based derivative Res4 and a preparation method and application thereof, belonging to the technical field of medicine. The present disclosure provides a resveratrol A-ring N(CH3)2-based derivative Res4, the synthesis method is mild in condition, the raw material cost is low, and the total yield reaches 70% or above. It is found in in-vitro cell experiments and animal experiments that, compared with traditional Chinese medicine, the Res4 has the advantages of obviously inhibiting PASMCs proliferation and effectively preventing low-oxygen PH pulmonary vascular remodeling and right ventricular remodeling, and has the advantage of being capable of effectively preventing the occurrence and development of PH.

Description

RESVERATROL A-RING N(CH;)-BASED DERIVATIVE RES4 AND LU502069
PREPARATION METHOD AND APPLICATION THEREOF
TECHNICAL FIELD
[0001] The present disclosure belongs to the technical field of medicine, and particularly relates to a resveratrol A-ring N(CHs):-based derivative Res4 and a preparation method and application thereof.
BACKGROUND ART
[0002] Pulmonary hypertension (PH) is a group of chronic progressive cardiopulmonary diseases that can eventually lead to right heart failure and death, affecting approximately 1% of the global populations. Pathological features of PH include progressive adventitial and medial thickening, eccentric or concentric intimal thickening, arterial occlusion and recanalization, and plexiform lesions; of which, proliferation of pulmonary artery smooth muscle cells (PASMCs) can lead to pulmonary artery medial thickening, which is an important cause of pulmonary arterial remodeling.
At present, the targeted drugs approved by the FDA for the treatment of PH mainly target the three signaling pathways of NO/sGC/cGMP pathway, prostacyclin pathway and endothelin pathway, but such strategies cannot prevent or reverse the progression of
PH, and it is prone to drug resistance after use for a long time; in addition, side effects of systemic hypotension occur due to relaxation of peripheral blood vessels. In view of the current drug treatment, PH is still a fatal disease, so there is an urgent need to develop a new drug for PH caused by the proliferation of PASMCs, to overcome the drawback of effective reversal of PH in the markets.
SUMMARY
[0003] In view of this, an object of the present disclosure is to provide a resveratrol
A-ring N(CH4)»-based derivative Res4 and a preparation method thereof] the resveratrol
A-ring N(CHz)»-based derivative Res4 can inhibit hypoxia PASMCs proliferation and activity increase, inhibit hypoxia pulmonary vascular remodeling, and effectively prevent and control occurrence and development of PH.
[0004] The present disclosure provides a Res4 which has a structure shown in the formula I: on OCH;
Er FN
NS OH
[0005]
[0006] Formula I.
[0007] The present disclosure provides a method for preparing the Res4, which comprises the following steps: 1
[0008] 1) diethyl phosphite and 4-methoxybenzyl bromide are subjected to LU502069 nucleophilic substitution reaction in ice bath under the action of NaH, and then are separated to obtain a compound 1 having a structure shown as formula IT; paie ne NE ®
[0009]
[0010] Formula II
[0011] 2) 4-(dimethylamino)salicylaldehyde, methyl chloromethyl ether and diisopropylethylamine are subjected to electrophilic substitution reaction, and then are separated to obtain a compound 2 having a structure shown as formula III; = = x A 253 a,
[0012]
[0013] Formula III
[0014] 3) the compound 1 and the compound 2 are subjected to condensation reaction in oil bath under the action of NaH, and then are separated to obtain a compound 3 having a structure shown as formula IV; and
RG, Le Ï ht À JL ESS -
NTE
[0015]
[0016] Formula IV
[0017] 4) the compound 3 and pyridinium toluenesulfonate are subjected to deprotection reaction in oil bath, and then are separated to obtain the Res4.
[0018] The present disclosure provides an application of the Res4 in preparation of a medicine for preventing and treating PH.
[0019] The present disclosure provides an application of the Res4 in preparation of a medicine for inhibiting PASMCs proliferation and activity.
[0020] The present disclosure provides an application of a reagent for inhibiting
PASMCs proliferation and activity in preparation of a medicine for preventing and treating PH, and the reagent is the Res4.
[0021] The present disclosure provides an application of the Res4 in preparation of a medicine for preventing and treating PH pulmonary vascular remodeling and/or right ventricular remodeling.
[0022] In the present disclosure, the Res4 is synthesized, the synthesis method is mild in condition, the raw material cost is low, and the total yield reaches 70% or above. It can be found in in-vitro cell experiments and animal experiments that compared with traditional Chinese medicine, the Res4 has the advantages of obviously inhibiting
PASMCs proliferation and effectively preventing low-oxygen PH pulmonary vascular 2 remodeling and right ventricular remodeling, and has the advantages of being capable of LU502069 effectively preventing PH and obvious in effect.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIG. 1 is Res4 synthetic route chart;
[0024] FIG. 2 is the Res4 'H NMR pattern;
[0025] FIG. 3 is the Res4 *C NMR pattern;
[0026] FIG. 4 is the HPLC of Res4:
[0027] FIG. 5 shows the results of culture and identification of primary mouse
PASMCs, wherein, primary mouse PASMCs are isolated by tissue block method (40%),
B. a-SMA immunofluorescence identification of PASMCs (200%);
[0028] FIG. 6 shows the effect of Res4 treatment on the proliferation of hypoxic
PASMCs, wherein, A: PASMCs proliferation; B: PCNA protein expression; data are mean + SEM, n=3; *"P<0.01 vs control, *P <0.01 vs hypoxia,
[0029] FIG. 7 shows the effect of Res4 on body weight, right ventricular systolic blood pressure and right heart remodeling index in hypoxic PH mice, wherein, A: Body weight; B: RVSP (right ventricular systolic blood pressure); C: RV/tibial length (right ventricle/tibial length); D: RV/(LV+S) (right ventricle/(left ventricle + interventricular septum)). Data are mean + SEM, n=6; "’P<0.01 vs control, *P<0.05, *#P<0.01 vs hypoxia,
[0030] FIG. 8 shows the hemodynamics and cardiac morphology of PH model detected by thoracic echocardiography, wherein, A: PH model hemodynamics, B: cardiac morphology; n=6;
[0031] FIG. 9 shows the morphological staining of lung tissues, wherein, A: HE staining, scale: 50 um; B: Masson staining, scale: 100 um, n=6.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0032] The present disclosure provides a Res4 which has a structure shown in the formula I:
Le, CH
LA
SNE oH
[0033]
[0034] Formula I.
[0035] The present disclosure provides a method for preparing the Res4, as shown in
FIG. 1, which comprises the following steps: 1) diethyl phosphite and 4-methoxybenzyl bromide are subjected to nucleophilic substitution reaction in ice bath under the action of NaH, and then are separated to obtain a compound 1 having a structure shown as formula IT; 3 a AN A
Ra SE 3
[0036]
[0037] Formula II
[0038] 2) 4-(dimethylamino)salicylaldehyde, methyl chloromethyl ether and diisopropylethylamine are subjected to electrophilic substitution reaction, and then are separated to obtain a compound 2 having a structure shown as formula III;
A 15 SNR Ry
ON
[0039]
[0040] Formula III
[0041] 3) the compound 1 and the compound 2 are subjected to condensation reaction in oil bath under the action of NaH, and then are separated to obtain a compound 3 having a structure shown as formula IV; and a CH
De AA, Tea
[0042]
[0043] Formula IV
[0044] 4) the compound 3 and pyridinium toluenesulfonate are subjected to deprotection reaction in oil bath, and then are separated to obtain the Res4.
[0045] In the present disclosure, the molar ratio of diethyl phosphite to NaH to 4-methoxybenzyl bromide in the step 1) was preferably 2: 3: 3. A solvent of diethyl phosphite was preferably DMF. Diethyl phosphite and NaH were pre-mixed for 0.5 h and then mixed with 4-methoxybenzyl bromide to react for 1 h. After the reaction, reaction quenching was performed with a saturated ammonium chloride solution, extracting was performed with dichloromethane, and column chromatography purification was performed after reduced pressure distillation (petroleum ether and ethyl acetate in volume ratio of 1: 1). The yield of the compound 1 was 90%.
[0046] In the present disclosure, the molar ratio of 4-(dimethylamino)salicylaldehyde to methyl chloromethyl ether to diisopropylethylamine in the step 2) was preferably 2: 3: 3, and the reaction time was preferably 2 h. After the reaction ended, a saturated ammonium chloride solution was used for quenching the reaction, dichloromethane was sequentially used for extraction, and column chromatography purification was performed after reduced pressure distillation (petroleum ether and ethyl acetate in volume ratio of 5: 1). The conversion rate of the compound 2 was 98%.
[0047] In the present disclosure, the molar ratio of the compound 1 to NaH to the compound 2 in the step 3) was preferably 1: 1.5: 1.5. A solvent of the compound 1 was 4 preferably DMF. The compound 1 and NaH were preferably mixed for 0.5 h, and then LU502069 mixed with the compound 2 for reaction for 1 h. The temperature of the oil bath was preferably 100°C. After the reaction ended, the product was cooled to room temperature, a saturated ammonium chloride solution was added for quenching the reaction, dichloromethane was used for extraction, and column chromatography purification was carried out after reduced pressure distillation (petroleum ether and ethyl acetate in volume ratio of 10: 1). The yield of the compound 3 was 95%.
[0048] In the present disclosure, the molar ratio of the compound 3 to pyridinium toluenesulfonate in step 4) was preferably 1: 2. The temperature of the oil bath was preferably 95°C. After the reaction ended, the product was cooled to room temperature, preferably water was added for quenching the reaction, dichloromethane was used for extraction, and column chromatography purification was carried out after reduced pressure distillation (petroleum ether and ethyl acetate in volume ratio of 3: 1). The yield of the compound 4 was 84%. Through hydrogen spectrum, carbon spectrum and high performance liquid chromatography detection, the compound 4 was Res4.
[0049] Studies have shown that, hypoxia (3% Oz) could promote proliferation and activity of primary PASMCs, and 10 pM Res4 could significantly inhibit hypoxia-induced cell proliferation and activity increase and had no influence on normal cell proliferation and activity. Therefore, the present disclosure provided the application of the Res4 in preparation of drugs for inhibiting the proliferation and activity of the
PASMCs.
[0050] In the present disclosure, the proliferation of PASMCs was an important reason for pulmonary artery reconstruction, which caused pulmonary artery mesolamella thickening, and simultaneously, hypoxia (3% Oz) could promote the proliferation and the activity of primary PASMCs. Therefore, in the present disclosure, a hypoxia (10% Oz) induced construction of hypoxia PH mouse model, the weight of a mouse was reduced, and the systolic pressure and the right cardiac hypertrophy index of the right ventricle were obviously increased; the pulmonary artery blood flow acceleration time/ejection time was changed, and the wall thickness of the right ventricle in a diastole was increased; and the pulmonary vascular remodeling and the pulmonary vascular collagen deposition were carried out. Res4 at a dose of 50 mg. kg! could increase the body weight of the mouse, reduce the systolic pressure and the right cardiac hypertrophy index of the right ventricle, increase the ratio of the pulmonary artery blood flow acceleration time/ejection time, reduce the wall thickness of the right ventricle in the diastole and inhibit the pulmonary vascular remodeling and the pulmonary vascular collagen deposition without obvious influence on the indexes of a normal mouse. The present disclosure could inhibit the proliferation and the activity increase of the hypoxia PASMCs and the hypoxia pulmonary vascular remodeling and effectively prevent the occurrence and the development of PH of the mouse. Therefore, the present disclosure provided the application of the Res4 in preparing a medicament for preventing and treating PH pulmonary vascular remodeling and/or right ventricle reconstruction. Meanwhile, the present disclosure also provided the application of a reagent for inhibiting the proliferation and the activity of the PASMCs in preparing the medicament for preventing and treating PH, wherein the reagent was the Res4.
[0051] The Res4 and a preparation method and application thereof provided in the LU502069 present disclosure will be described in detail with reference to embodiments, but they should not be construed as limiting the protection scope of the present disclosure.
[0052] Material description
[0053] Experimental animals: C57 male mice about 8 weeks old, purchased from SPF (Beijing) Biotechnology Co., Ltd. (license number: SCXK (Jing) 2019-0010), the rearing and handling of mice strictly followed the guidelines of animal experimental procedures of the National Institute of Health Guidelines.
[0054] Cells: Primary mouse PASMCs.
[0055] Reagents: purchased from conventional purchase channels.
[0056] Equipment: purchased from the channels of ordinary commodities.
[0057] Example 1
[0058] Synthesis of Res4
[0059] (1) Diethyl phosphite (10 mmol, 1.38 g) was dissolved into DMF (8 mL),
NaH (15 mmol, 0.36 g) was added under the condition of ice-water bath and reacted for 0.5 h, then 4-methoxybenzyl bromide (15 mmol, 3.02 g) was added to perform nucleophilic substitution reaction, and reacting was continued for 1 h. After the reaction ended, a saturated ammonium chloride solution was added to quench the reaction, extracting was performed by using dichloromethane, column chromatography purification was carried out after reduced pressure distillation (petroleum ether and ethyl acetate in volume ratio (v/v) of 1: 1) to obtain a compound 1, wherein the yield was 90%;
[0060] (2) 4-(dimethylamino)salicylaldehyde (10 mmol, 1.65 g) was dissolved in dichloromethane (40 mL), chloromethyl methyl ether (15 mmol, 1.21 g) and diisopropylethylamine (15 mmol, 1.94 g) were added under the condition of ice-water bath to perform electrophilic substitution reaction for 2 h. A saturated ammonium chloride solution was added to quench the reaction, extracting was carried out by using dichloromethane, column chromatography purification was carried out after reduced pressure distillation (petroleum ether and ethyl acetate in volume ratio (v/v) of 5: 1) to obtain a compound 2, wherein the conversion rate was 98%;
[0061] (3) The compound 1 (3 mmol, 0.774 g) was dissolved in DMF (4 mL), NaH (4.5 mmol, 0.11 g) was added under the condition of ice-water bath and reacted for half an hour, then the compound 2 (4.5 mmol, 0.94 g) was added, and condensation reaction was performed in an oil bath at the temperature of 100°C for 1 h. After the reaction ended, the product was cooled to room temperature, a saturated ammonium chloride solution was added to quench the reaction, extracting was carried out with dichloromethane, column chromatography purification was carried out after reduced pressure distillation (petroleum ether and ethyl acetate in volume ratio (v/v) of 10: 1) to obtain a compound 3, wherein the yield was 95%; and
[0062] (4) the compound 3 (1 mmol, 0.313 g) was dissolved in tert-butyl alcohol (4 mL), pyridinium p-toluenesulfonate (2 mmol, 0.502 g) was added, and heating and refluxing were performed in an oil bath at the temperature of 95°C for 1 h. After the reaction ended, the product was cooled to room temperature, water was added for quenching reaction, extracting was performed by using dichloromethane, column 6 chromatography purification was carried out after reduced pressure distillation LU502069 (petroleum ether and ethyl acetate in volume ratio (v/v) of 3: 1) to obtain a target compound 4, wherein the yield was 84%.
[0063] The synthesis method was mild in condition and low in raw material cost, and a target compound could be obtained with the total yield of 70%.
[0064] The compound 4 was subjected to hydrogen spectrum detection, carbon spectrum detection and high performance liquid chromatography detection respectively.
The results were shown in FIGS. 2 to 4.
[0065] Example 2
[0066] Culture of primary mouse PASMCs
[0067] Primary mouse PASMCs were cultured by adopting a tissue block adherence method, and the 3™ generation of cells were taken for a-smooth muscle actin (a-SMA) cell immunofluorescence assay and analysis, and the result showed that the purity of the cultured PASMCs could reach over 99%. The 39-6" generations of PASMCs were selected for subsequent experiments.
[0068] Experimental groups: a control group: normal cells were cultured for 48 h; an
Res4 group: 10 uM Res4 cells were cultured for 48 h; a hypoxia group: cells were cultured in an incubator containing 92% N2/5% CO» gas mixture for 48 h; a hypoxia + a
Res4 group, 10 uM Res4 was added to a medium to culture for 1, and then the product was treated as the hypoxia group.
[0069] Cell immunofluorescence detection, cell viability detection and western blot experiment were performed on the cells of each group respectively, and the obtained results were subjected to statistical analysis. All data were represented by meant
SEM. Independent-Samples student’s t test was used for comparison of means of two groups, and one-way ANOVA and Newman-Student-Keuls test were used for multiple comparison of means in multiple groups. SPSS 19.0 software was adopted for statistical analysis; the two-sided P < 0.05 was considered statistically significant difference.
[0070] Results
[0071] 1. Culture and identification of primary mouse PASMCs
[0072] The primary PASMCs were cultured by a tissue block method, and the cells were spindle-shaped under light microscope (A in FIG. 5). More than 99% of the cells were positive for anti-a-SMA antibody by immunofluorescence, indicating that the isolated PASMCs were of high purity (B in FIG. 5).
[0073] 2. Effect of Res4 treatment on proliferation of hypoxic PASMCs
[0074] Western blot of MTS and cell proliferation marker PCNA showed that
PASMCs proliferation could be induced by hypoxia, PCNA protein expression was significantly increased, and 10 uM Res4 could significantly inhibit hypoxia-induced
PASMCs activity and PCNA expression (FIG. 6).
[0075] Example 3
[0076] Pharmacological function experiments of Res4
[0077] Establishment of an animal model of Res4 inhibiting hypoxia PH pulmonary vascular remodeling
[0078] C57 mice (n = 24, £25 g) of about 8 weeks years old were selected in the experiment, and the mice were randomly divided into four groups (n = 6): a control 7 group, a Res4 group, a hypoxia group and a hypoxia + Res4 group according to the LU502069 weight after being adaptively fed for one week. The hypoxia group of mice were in hypoxia (10% O2) and induced a PH model for 4 weeks, the control group of mice were normal in oxygen (21% Oz) and served as a control group, and Res4 (50 mg/kg/d) was fed for 4 weeks by gavage. The mice accessed to water and foods freely in the test period.
[0079] After 4 weeks, the body weight was measured, isoflurane gas was used for anesthetizing the mice, and hemodynamics, heart morphology (right ventricular wall thickness) and other related indexes of the PH model were ultrasonically measured. À right cardiac catheter was inserted to measure the systolic pressure of the right ventricle, the right ventricle and left ventricle + ventricular septum weight was measured, and the tibia length was measured. Lung tissue was fixed with paraformaldehyde, and morphological staining was performed subsequently.
[0080] Results
[0081] 1. Effects of Res4 on body weight, the systolic pressure of the right ventricle and the right ventricular remodeling index of hypoxia mice
[0082] Compared with a normal-oxygen group, the body weight of mice in the hypoxia group was reduced, the systolic pressure of the right ventricle was remarkably increased, the right ventricle was obviously thick, and it was indicated that the hypoxia induced PH mouse model was successfully established. Res4 (50 mg/kg) could remarkably increase the body weight of the hypoxia PH mice, reduce the systolic pressure of the right ventricle and relieve the thickness of the right ventricle, and the indexes of the normal mice were not remarkably affected (see FIG. 7).
[0083] 2. Effect of Res4 on systolic pulmonary artery frequency spectrum form and diastolic right ventricular wall thickness in hypoxia PH mice
[0084] In PH, the systolic pulmonary artery frequency spectrum form changed: the pulmonary artery blood flow acceleration time (AT)/ejection time (ET) reduced, and the diastolic right ventricular wall thickness increased. Ultrasonic results showed that, compared with the normal-oxygen group, the AT/ET of the mice in the hypoxia group was obviously reduced, the diastolic right ventricular wall thickness increased, Res4 could relieve the systolic pulmonary artery frequency spectrum form and reduce the diastolic right ventricular wall thickness; and no significant influence was caused to the above indexes of the normal mice. (FIG. 8)
[0085] 3. Effect of Res4 on pulmonary vascular remodeling and collagen deposition in hypoxia PH mice
[0086] Pulmonary vascular remodeling was the main feature of PH. HE staining showed that, compared with the normal-oxygen group, pulmonary vessels of the mice in the hypoxia group were obviously thickened; Res4 could relieve pulmonary vascular reconstruction of hypoxia PH mice, and no significant influence was caused on pulmonary vessels of normal mice. (A in FIG. 9)
[0087] Masson staining results showed that accumulation of pulmonary vasculature and peripheral collagen of the mice in the hypoxia group was obviously increased compared with that of the mice in the normal group. Res4 could inhibit accumulation of pulmonary vasculature and peripheral collagen of the mice in the hypoxia group, and no 8 significant influence was caused on pulmonary tissues of the normal mice. (B in FIG. 9) LU502069
[0088] The foregoing description merely describes the preferred embodiments of the present disclosure. It should be noted that for those of ordinary skill in the art, several improvements and modifications can be made without departing from the principle of the present disclosure, and these improvements and modifications shall also fall within the scope of protection of the present disclosure. 9

Claims (7)

WHAT IS CLAIMED IS: LUS02069
1. A resveratrol A-ring N(CH4)»-based derivative Res4, having a structure shown in the formula I: LT NE H 3 77 Re À WON SMS OH . Formula I.
2. A method for preparing the Res4 of claim 1, comprising the following steps: 1) diethyl phosphite and 4-methoxybenzyl bromide are subjected to nucleophilic substitution reaction in ice bath under the action of NaH, and then are separated to obtain a compound 1 having a structure shown as formula II; AB i x Sr hd wed i aout Formula IT 2) 4-(dimethylamino)salicylaldehyde, methyl chloromethyl ether and diisopropylethylamine are subjected to electrophilic substitution reaction, and then are separated to obtain a compound 2 having a structure shown as formula III; A se RS RANGER CO Lu", Formula III 3) the compound 1 and the compound 2 are subjected to condensation reaction in oil bath under the action of NaH, and then are separated to obtain a compound 3 having a structure shown as formula IV; and FA ; eS oe de 2 Formula IV 4) the compound 3 and pyridinium toluenesulfonate are subjected to deprotection reaction in oil bath, and then are separated to obtain the Res4.
3. The method of claim 2, wherein the separation methods in step 1), step 2), step 3)
and step 4) are extraction, reduced pressure distillation and column chromatography LU502069 purification.
4. An application of the Res4 of claim 1 in preparation of a medicine for preventing and treating PH.
5. An application of the Res4 of claim 1 in preparation of a medicine for inhibiting PASMCs proliferation and activity
6. An application of a reagent for inhibiting PASMCs proliferation and activity in preparation of a medicine for preventing and treating PH, wherein the reagent is the Res4 of claim 1.
7. An application of the Res4 of claim 1 in preparation of a medicine for preventing and treating PH pulmonary vascular remodeling and/or right ventricular remodeling. 11
LU502069A 2022-05-11 2022-05-11 Resveratrol a-ring n(ch3)2-based derivative res4 and preparation method and application thereof LU502069B1 (en)

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