WO2016192631A1

WO2016192631A1 - Abietane-type diterpene compound having lipid-lowering activity, method for preparing same, and use of same

Info

Publication number: WO2016192631A1
Application number: PCT/CN2016/084358
Authority: WO
Inventors: 叶阳; 王逸平; 姚胜; 赵晶; 唐春萍; 徐文伟; 柯昌强; 席聪
Original assignee: 中国科学院上海药物研究所
Priority date: 2015-06-01
Filing date: 2016-06-01
Publication date: 2016-12-08
Also published as: CN106279200B; CN106279200A

Abstract

The present invention provides an abietane-type diterpene compound having lipid-lowering activity, a method for preparing same, and use of same. Specifically, the compound has the structure shown in formula I. The definitions of the groups are discussed in the specification. The compound of the present invention has activity of increasing in vivo or in vitro ingestion of low-density lipoprotein, and has a potential to be used as a novel lipid-lowering drug.

Description

Rosin type diterpenoid compound having hypolipidemic activity, preparation method and use thereof

Technical field

The invention belongs to the field of medicinal chemistry, and more particularly relates to a novel class of rosin-type diterpenoids having hypolipidemic activity, a preparation method thereof and use thereof for drugs for lowering blood fat and atherosclerosis.

Background technique

Atherosclerosis (AS) refers to the deposition of lipids (mainly cholesterol and cholesterol) in the intima and intima of the arterial wall of arteries and their branches, accompanied by the migration of mesothelial smooth muscle cells to subendocardial hyperplasia. A yellow or gray-yellow plaque, such as an atheroma, is formed, so that the arterial wall thickens and hardens, loses elasticity, and the lumen becomes smaller. AS is the most common and important disease common in arteriosclerotic vascular disease and has been the leading cause of death in Western developed countries. In recent years, with the improvement of the living standards of Chinese people and changes in eating habits, the disease has also become the main cause of death in China. The incidence rate in China is over 79.9% among people over 60 years old.

Numerous studies have shown that hyperlipidemia is a major risk factor for human atherosclerotic disease. Direct damage to blood in the cholesterol (TC) and / or triglyceride (TG) or high density lipoprotein cholesterol (HDL-C) (hypoplastic dyslipidemia in modern medicine) can accelerate systemic atherosclerosis, Because the vital organs of the whole body rely on arterial blood supply and oxygen supply, once the artery is blocked by atherosclerotic plaque, it will lead to serious consequences.

Cholesterol plays an important role in metabolic syndrome and atherosclerosis. 70% of cholesterol in the blood is carried by low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL), 90% of which pass LDL through low-density lipids. The protein receptor (LDLR) pathway is cleared. LDLR is the main receptor for the recovery and uptake of LDL by the liver. It plays an important role in the lipoprotein metabolism of the sputum tissues of the liver and adrenal cortex, testis, ovary, etc. Its main function is to participate in the metabolism of LDL. Mutations in the LDLR gene are one of the leading causes of hereditary hyperlipidemia.

Hypolipidemic is the most effective treatment for atherosclerosis. Statins are currently the most widely used and most potent lipid-lowering drugs in clinical practice. As a star drug on the market for lowering blood fat, it can competitively inhibit the activity of the rate-limiting enzyme hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase in the process of cholesterol synthesis, and reduce intracellular free cholesterol. The effect is to up-regulate the number of low-density lipoprotein (LDL) receptors on the cell surface, accelerate the catabolism of LDL in plasma, and then regulate the body's blood lipid levels. With the wide application of statins, the adverse reactions and interactions with other drugs have gradually attracted the attention of clinical medical personnel, especially after the Bestin incident has caused the safety of statin lipid-lowering drugs. Great concern. Adverse reactions to statins have been reported to include hepatotoxicity, muscle toxicity (rhabdomyolysis), elevated blood glucose levels, osteoarthritis, and joint pain. Statins are not effective in all patients with a high risk of hyperlipidemia and high atherosclerosis. Clinical studies have shown that pravastatin (pravastatin) or atorvastatin is used to intensively treat coronary heart disease patients after an average of 24 months. LDL cholesterol levels are reduced to varying degrees, but there is still a high incidence of cardiovascular disease. In addition, a large proportion of patients are not sensitive to statin responses and cannot rely on statins to prevent the progression of atherosclerosis. Therefore, the task of developing new lipid-lowering drugs is imminent.

In summary, there is an urgent need in the art to provide new compounds having hypolipidemic activity.

Summary of the invention

It is an object of the present invention to provide a class of compounds having hypolipidemic activity.

In a first aspect of the invention there is provided a use of a compound of formula I, a dimer thereof, or a ring-opening product thereof, or a pharmaceutically acceptable salt thereof,

among them,

Ra, Rb, Rc, and Rd are each independently selected from the group consisting of H, halogen, -OH, -OMe, O, -OC ₁ -C ₆ alkyl, -CHO, -OC ₁ -C ₆ acyl;

X is selected from the group consisting of CHRe, OC(O), NRe, O, C=Re, C-Re, N; wherein Re is selected from the group consisting of H, -CHO, -COOH, -OH, - OMe, =O, -OC ₁ -C ₆ alkyl, -OC ₁ -C ₆ acyl, -OC ₂ -C ₃₀ acyl;

M is selected from the group consisting of CHRf, NRf, O, C=Rf, C-Rf, N; wherein the Rf is selected from the group consisting of H, -CHO, -COOH, -OH, -OMe, =O, -OC ₁ -C ₆ alkyl, -OC ₁ -C ₆ acyl, -OC ₂ -C ₃₀ acyl;

Or any one or two of Re and Rf are substituents selected from the group consisting of:

Or Re, Rf together constitute a structure selected from the group consisting of: -O-, -C ₁ -C ₆ alkylene-, -C ₁ -C ₆ alkylene-O-, -OC ₁ -C ₆ alkylene -O-, or -C ₁ -C ₆ alkylene-OC ₁ -C ₆ alkylene-,

Or one of Re and Rf together with one of Ri or Rg constitutes a substituted or unsubstituted -C ₁ -C ₆ alkylene-, substituted or unsubstituted -C ₁ -C ₆ alkylene-O-, -C(O)-O-; wherein said substitution means that one or more hydrogen atoms on the group are substituted by =0;

Or X, M and a chemical bond together constitute a group selected from the group consisting of CH-OR', wherein R' is selected from the group consisting of H, C ₁ -C ₆ alkyl;

Rg, Rh are each independently selected from the group consisting of H, -COOH, substituted or unsubstituted C ₁ -C ₆ alkyl, -OH, substituted or unsubstituted C ₁ -C ₆ alkoxy, -COO-substituted Or unsubstituted C ₁ -C ₆ alkyl, -COO-substituted or unsubstituted C ₆ -C ₁₀ aryl, -COO-substituted or unsubstituted C ₁ -C ₁₀ heteroaryl, -COO-substituted or An unsubstituted C ₁ -C ₆ alkoxy group; or Rg and Rh together form =0; wherein said substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, -OH, -COOH;

Ri is selected from the group consisting of H, -COOH, -OH, -Me; or Ra and Ri together form -C(O)-O-;

Rj is one or more substituents on ring A, and said Rj are each independently selected from the group consisting of H, =O, substituted or unsubstituted C ₁ -C ₆ alkyl, -OH, -COOH, -COO-substituted or unsubstituted C ₁ -C ₆ alkyl, -COO-substituted or unsubstituted C ₆ -C ₁₀ aryl, -COO-substituted or unsubstituted C ₁ -C ₁₀ heteroaryl, wherein Said substitution is substituted by one or more substituents selected from the group consisting of halogen, -OH, -COOH;

Rk is selected from the group consisting of H, halogen, C1-C6 alkyl, -CH ₂ OH, -CH ₂ OCOOR, -COOR; or together with Rc to form a 5-9 membered epoxy ring or lactone ring;

R" is selected from the group consisting of H, -COOH, -OH, -Me;

Unless stated otherwise, "substituted" means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of a carboxy group, a C ₁ -C ₆ alkyl group, a phenyl group, a C ₃ -C ₆ ring. An alkyl group, a C ₁ -C ₁₀ ester group, a halogen, a C ₁ -C ₁₀ alkyl-oxy group, a C ₂ -C ₁₀ acyl group, a hydroxyl group, a hydroxy-C ₁ -C ₁₀ alkylene group;

The dotted line is a single bond or a double bond;

And

a substituted or unsubstituted aromatic ring (benzene ring or benzoquinone);

Characterized in that the compound is used in one or more uses selected from the group consisting of:

a) preparing a pharmaceutical composition for lowering blood fat;

b) preparing a pharmaceutical composition for lowering the content of low density lipoprotein (LDL);

c) preparing a pharmaceutical composition for stabilizing the stability of the LDLR gene;

d) preparing a pharmaceutical composition for upregulating LDLR gene expression;

e) preparing a pharmaceutical composition for increasing the amount of LDLR receptors on the surface of hepatocytes;

f) preparing a pharmaceutical composition for reducing degradation of the LDLR receptor;

g) preparing a pharmaceutical composition for reducing the concentration of TC and/or TG in the blood;

h) preparing a pharmaceutical composition for increasing the concentration of high density lipoprotein (HDL) in the blood;

i) Preparation of a pharmaceutical composition for improving liver function damage.

In another preferred embodiment, the ring opening product is the product of ring opening of the A ring or the B ring.

In another preferred embodiment, the number of carbon atoms of the ring-opening product remains unchanged before and after ring opening.

In another preferred embodiment, the dimer of the compound of formula I has the structure shown in formula Ia below:

In the formula,

Ra, Rb, Rc, and Rd are each independently selected from the group consisting of H, halogen, -OH, -OMe, -OC ₁ -C ₆ alkyl, -CHO, -OC ₁ -C ₆ acyl;

The definitions of the remaining groups are as described in the first aspect of the invention.

In another preferred embodiment, X is selected from the group consisting of CHRe, O, C=Re, C-Re; wherein Re is selected from the group consisting of H, -CHO, -COOH, -OH, -OMe, =O, -OC ₁ -C ₆ alkyl, -OC ₁ -C ₆ acyl;

M is selected from the group consisting of CHRf, O, C=Rf, C-Rf; wherein said Rf is selected from the group consisting of H, -CHO, -COOH, -OH, -OMe, =O, -OC ₁ - C ₆ alkyl, -OC ₁ -C ₆ acyl;

Or Re, Rf together constitute a structure selected from the group consisting of: -O-, -C ₁ -C ₆ alkylene-, -C ₁ -C ₆ alkylene-O-, -OC ₁ -C ₆ alkylene -O-, or -C ₁ -C ₆ alkylene-OC ₁ -C ₆ alkylene-;

Or one of Re and Rf together with Ri constitutes a substituted or unsubstituted -C ₁ -C ₆ alkylene-, substituted or unsubstituted -C ₁ -C ₆ alkylene-O-; wherein Substituting one or more hydrogen atoms on a group for substitution with =0;

Rg, Rh are each independently selected from the group consisting of H, -COOH, substituted or unsubstituted C ₁ -C ₆ alkyl, -OH, substituted or unsubstituted C ₁ -C ₆ alkoxy, -COO-substituted Or an unsubstituted C ₁ -C ₆ alkyl group, a -COO-substituted or unsubstituted C ₁ -C ₆ alkoxy group; or Rg and Rh together form =0; wherein the substituent refers to a group on the group Or a plurality of hydrogen atoms are substituted with a substituent selected from the group consisting of halogen, -OH, -COOH;

Ri is selected from the group consisting of H, -COOH, -Me; or Ra and Ri together form -C(O)-O-;

The remaining groups are as defined above.

In another preferred embodiment, Rc is H.

In another preferred embodiment, Ra, Rb, Rc, Rd are each independently selected from the group consisting of H, -OH, -OMe;

X is selected from the group consisting of CHRe, O, C=Re, C-Re; wherein Re is selected from the group consisting of H, -CHO, -COOH, -OH, =O;

M is selected from the group consisting of CHRf, O, C=Rf, C-Rf; wherein the Rf is selected from the group consisting of H, -CHO, -COOH, -OH, =O;

And when X and M are different, it is O;

Rg, Rh are each independently selected from the group consisting of H, -COOH, substituted or unsubstituted C ₁ -C ₃ alkyl, -OH; wherein the substituent refers to one or more hydrogen atoms on the group a substituent selected from the group consisting of halogen, -OH, -COOH;

Rj is H.

In another preferred embodiment, the compound of formula I is a rosinane type diterpenoid.

In another preferred embodiment, the compound of formula I is a plant extract selected from the group consisting of cedar bark extract, cedar bark extract, cedar fruit extract, fir bark extract, rat Oxalic acid, carnosol.

Preferred Ra, Rb, Rc, Rd, Re, Rf, X, M, Rg, Rh, Ri, Rj, Rk, R" are each independently the corresponding group corresponding to the specific compound in the examples.

In another preferred embodiment, the pharmaceutical composition is further for use in a group selected from the group consisting of:

j) (non-therapeutic in vitro) increase the uptake rate of LDL by hepatocytes;

k) (non-therapeutic in vitro) upregulate the number of LDLR receptors on the surface of hepatocytes.

In another preferred embodiment, the effective amount of the compound of formula I in the pharmaceutical composition is from 0.1 to 50 mg/kg body weight, preferably from 1 to 20 mg/kg body weight.

In another preferred embodiment, the pharmaceutical composition is a dosage form selected from the group consisting of an oral dosage form and an injectable dosage form.

According to a second aspect of the invention, there is provided a kit, characterized in that the kit comprises:

(i) a first container, and the active ingredient (a) a compound of formula I contained in the first container; or a drug containing the active ingredient (a);

(ii) a second container, and the active ingredient contained in the second container (b) a statin, or a pharmaceutically acceptable salt thereof; or a drug containing the active ingredient (b);

(iii) A description of the description of the combination of the active ingredient (a) and the active ingredient (b) to reduce the low-density lipoprotein content in the subject.

In a third aspect of the invention, there is provided a compound of formula I, or a dimer thereof:

among them,

X is selected from the group consisting of CHRe, NRe, O, C=Re, C-Re, N;

M is selected from the group consisting of CHRf, NRf, O, C=Rf, C-Rf, N; wherein, Re and Rf are each independently a substituent selected from the group consisting of:

Or Re, Rf together constitute a structure selected from the group consisting of: -C ₁ -C ₆ alkylene-O-, -OC ₁ -C ₆ alkylene-O-, or -C ₁ -C ₆ alkylene- OC ₁ -C ₆ alkylene-,

Rk is selected from the group consisting of H, halogen, C1-C6 alkyl, -CH ₂ OH, -CH ₂ OCOOR, -COOR; or together with Rc forms a 5-9 membered oxygen ring (preferably an epoxy ring or a lactone) ring);

R" is selected from the group consisting of H, -COOH, -OH, -Me;

The dotted line is a single bond or a double bond;

And

A substituted or unsubstituted aromatic ring (benzene ring or benzoquinone).

In a fourth aspect of the invention, there is provided a compound of formula I, or a dimer thereof:

among them,

X is O;

Or the Rf is a substituent selected from the group consisting of:

Or Rf together with one of Ri or Rg constitutes a substituted or unsubstituted -C ₁ -C ₆ alkylene-, substituted or unsubstituted -C ₁ -C ₆ alkylene-O-; wherein Substituting one or more hydrogen atoms on a group for substitution with =0;

R" is selected from the group consisting of H, -COOH, -OH, -Me;

The dotted line is a single bond or a double bond;

And

A substituted or unsubstituted aromatic ring (benzene ring or benzoquinone).

According to a fifth aspect of the invention, there is provided a compound of formula I, or a dimer thereof:

among them,

Or the Re and Rf are each independently a substituent selected from the group consisting of:

Or one of Re, Rf and one of Ri or Rg together constitute a substituted or unsubstituted -C ₁ -C ₆ alkylene-, substituted or unsubstituted -C ₁ -C ₆ alkylene-O-; Wherein said substitution means that one or more hydrogen atoms on the group are substituted by =0;

Rg is selected from the group consisting of H, -COOH, substituted or unsubstituted C ₁ -C ₆ alkyl, -OH, substituted or unsubstituted C ₁ -C ₆ alkoxy, -COO-substituted or unsubstituted C _1- C ₆ alkyl, -COO-substituted or unsubstituted C ₆ -C ₁₀ aryl, -COO-substituted or unsubstituted C ₁ -C ₁₀ heteroaryl, -COO-substituted or unsubstituted C ₁ a C ₆ alkoxy group; wherein said substituent means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, -OH, -COOH;

Rh is a water-soluble improving group, preferably selected from the group consisting of -COOH, -OH, substituted or unsubstituted C ₁ -C ₆ alkylene-OH, substituted or unsubstituted C ₁ -C ₆ alkylene- COOH, -COO-substituted or unsubstituted C ₁ -C ₆ alkyl, -COO-substituted or unsubstituted C ₆ -C ₁₀ aryl, -COO-substituted or unsubstituted C ₁ -C ₁₀ heteroaryl a -COO-substituted or unsubstituted C ₁ -C ₆ alkoxy group; wherein said substituent means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, -OH, -COOH;

R" is selected from the group consisting of H, -COOH, -OH, -Me;

The dotted line is a single bond or a double bond;

And

A substituted or unsubstituted aromatic ring (benzene ring or benzoquinone).

In another preferred embodiment, the dimer is a dimer formed from the same or different compounds of formula I, preferably a dimer formed from the same compound of formula I.

In another preferred embodiment, Ra, Rb, Rc, and Rd are each independently selected from the group consisting of H, -OH, O, -OC ₁ -C ₆ alkyl, -OC ₁ -C ₆ acyl.

In another preferred embodiment, at least one of Ra and Rb is -OH and the other is -OC ₁ -C ₆ alkyl.

In another aspect of the present invention, there is provided a rosin-type diterpenoid or a ring-opening product thereof, wherein the rosin-type diterpenoid or a ring-opening product thereof is selected from the group consisting of

It is to be understood that within the scope of the present invention, the various technical features of the present invention and the various technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here.

DRAWINGS

Figure 1 shows the effect of compounds LSP-6-1 to LSP-6-6 on hepatocyte low density lipoprotein uptake in Example 2;

Figure 2 Effect of compound LSP-6-6 on hepatocyte low density lipoprotein uptake at different concentrations in Example 2;

Figure 3 shows the results of the test of the low density lipoprotein receptor (LDLR) expression level of the compound in Example 3;

Figure 4 Effect of oral administration of compound LSP-6-6 on total cholesterol levels in high fat model golden hamsters; Figure 4A: TC (serum total cholesterol) levels, Figure 4B: TG (triglyceride) levels, Figure 4C: LDL Level; *P<0.05, **P<0.01 vs normal control group, #P<0.05, ##P<0.01 vs high-fat control group.

detailed description

After long-term and in-depth research, the inventors have unexpectedly discovered that rosin-type diterpenoids have a good blood drop. It has lipid activity and is superior to the existing general lipid-lowering compound statins. The compounds can reduce total cholesterol, triglycerides, low density lipoprotein concentrations, and increase high density lipoprotein concentrations in vivo or in vitro, in a time- and dose-dependent manner. Based on the above findings, the inventors completed the present invention.

the term

The term "C ₁ -C ₆ alkyl" or "C ₁ -C ₁₀ alkyl" as used herein refers to a straight or branched alkyl group having from 1 to 6 or 1 to 10 carbon atoms, such as methyl, Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.

The term "C ₃ -C ₆ cycloalkyl" refers to a cycloalkyl group having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, or the like.

The term "C ₂ -C ₁₀ acyl" or "C ₂ -C ₄ acyl" as used herein refers to a straight or branched alkyl/cycloalkyl group having the form of 0 to 9 or 0 to 3 carbon atoms. Substituents for the /aryl-carbonyl" structure, such as acetyl, propionyl, butyryl, or the like.

The term "C ₂ -C ₃₀ ester group" refers to a group of the structure shown by -OOC-R' wherein R' is a group selected from the group consisting of 1 to 9 carbon atoms: A substituent of a linear or branched alkyl, cycloalkyl, alkenyl, alkynyl, aryl or heteroaryl structure, such as an acetyl group, a propionyl group, a butyryl group, or the like. Wherein, said R' may further be substituted, for example, by one or more substituents selected from the group consisting of halogen, -OH, -COOH, -COO (C ₁ -C ₆ alkyl), or halo-substituted phenyl, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C ₂ -C ₆ acyl group, an unsubstituted or halogenated C ₁ -C ₆ alkyl - hydroxy.

The term "C ₁ -C ₄ alkylene" refers to a group formed after the C1 to C4 alkyl group has lost a hydrogen atom as described above, for example, -CH ₂ -, -CH ₂ -CH ₂ -, or the like. .

The term "halogen" refers to F, Cl, Br and I.

The term "C ₆ -C ₁₀ aryl" refers to an aryl group having 6 to 10 carbon atoms, such as phenyl, naphthyl and the like.

The term "C ₁ -C ₁₀ heteroaryl" refers to a heteroaryl group having from 1 to 10 carbon atoms and one or more heteroatoms selected from O, S and/or N.

In the present invention, the terms "containing", "comprising" or "including" mean that the various ingredients may be used together in the mixture or composition of the present invention. Therefore, the terms "consisting essentially of" and "consisting of" are encompassed by the term "contains."

In the present invention, the term "pharmaceutically acceptable" ingredient means a substance which is suitable for use in humans and/or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reaction), that is, a reasonable benefit/risk ratio.

In the present invention, the term "effective amount" means an amount of a therapeutic agent that treats, alleviates or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or prophylactic effect. The precise effective amount for a subject will depend on the size and health of the subject, the nature and extent of the condition, and the combination of therapeutic and/or therapeutic agents selected for administration. Therefore, it is useless to specify an accurate effective amount in advance. However, for a given condition, routine experimentation can be used to determine the effective amount that the clinician can determine.

As used herein, unless otherwise specified, the term "substituted" means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, unsubstituted or halogenated C1-C6 alkyl, unsubstituted. Substituted or halogenated C ₂ -C ₆ acyl, unsubstituted or halogenated C1-C6 alkyl-hydroxy.

Unless otherwise stated, all compounds appearing in the present invention are meant to include all possible optical isomers, such as a single chiral compound, or a mixture of various chiral compounds (i.e., racemates). Among all the compounds of the present invention, each of the chiral carbon atoms may be optionally in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.

The term "compound of the invention" as used herein refers to a compound of formula I. The term also encompasses various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula I.

As used herein, the term "pharmaceutically acceptable salt" refers to a salt of the compound of the invention formed with an acid or base suitable for use as a medicament. Pharmaceutically acceptable salts include inorganic and organic salts. A preferred class of salts are the salts of the compounds of the invention with acids. Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzoic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

As used herein, the term "dimer" refers to the rosin-type diterpene itself or to other rosin-type diterpenes (including rosin-type diterpenes re-cyclized after ring opening or ring opening of A, B) through COC, Or CC, or a dimer formed by COC and CC at the same time.

Rosin-type diterpenoid

As a defensive component in plants, rosin-type diterpenoids are abundant in nature and widely distributed, mainly in higher plants such as cedar, pine, and cypress. Such diterpenes are known in the art to have antiviral, antitumor, antiulcer, antibacterial, antimalarial and the like activities. However, the inventors unexpectedly found in the screening process of natural product activity that the LDL phagocytosis test of HepG2 cells in vitro showed that some rosin-type diterpenoids had significant hypolipidemic activity at 5 μM concentration, and the compound LSP-6-6 showed Significant dose-dependent hypolipidemic activity. The activity was comparable at 10 μM, 20 μM compared to the positive control berberine. In animal models, compound LSP-6-6 was administered intraperitoneally at 30 mg/kg/day, and total cholesterol (TC), total triglyceride (TG) and LDL levels in the blood of high-fat-fed golden hamsters decreased after 20 days. 75%, 72%, and 58% (relative to the high-fat feeding model group), and no significant adverse effects were observed.

As a most preferred embodiment of the present invention, the rosin-type diterpenoid has a structure selected from the group consisting of:

In another preferred embodiment of the present invention, the rosin-type diterpenoid has a structure selected from the group consisting of:

In other embodiments of the invention, the rosin-type diterpenoid has a structure selected from the group consisting of:

Rosin-type diterpenoids in cedar (bark):

Rosin-type diterpenoids in the bark of cedar:

Rosin type diterpenoids in cedar fruit:

Rosin-type diterpenoids in fir bark:

Based on derivatives of carnosic acid (CA-1):

Pharmaceutical composition and method of administration

Since the compound of the present invention has an excellent activity for lowering the LDL content in blood, the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the present invention are mainly The pharmaceutical composition of the active ingredient can be used for the treatment, prevention, and alleviation of diseases caused by excessive levels of LDL in the blood, such as fatty liver.

The pharmaceutical compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. By "safe and effective amount" it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. In general, the pharmaceutical compositions contain from 1 to 30,000 (active dose range 3-30 mg/kg) mg of the compound/agent of the invention, more preferably from 10 to 2000 mg of the compound/agent of the invention. Preferably, the "one dose" is a capsule or tablet.

"Pharmaceutically acceptable carrier" means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By "compatibility" it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid). , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as

), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.

The mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. .

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients Mixing: (a) a filler or compatibilizer, for example, starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) a binder, for example, hydroxymethylcellulose, alginate, gelatin, polyvinyl Pyrrolidone, sucrose and gum arabic; (c) humectant, for example, glycerin; (d) disintegrant, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate (e) a slow solvent such as paraffin; (f) an absorption accelerator such as a quaternary amine compound; (g) a wetting agent such as cetyl alcohol and glyceryl monostearate; (h) an adsorbent such as kaolin And (i) a lubricant such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or a mixture thereof. In capsules, tablets and pills, the dosage form may also contain a buffer.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.

In addition to these inert diluents, the compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.

In addition to the active compound, the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.

Compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion. Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.

Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants. The active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.

The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

When a pharmaceutical composition is used, a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight, The dose to be administered is usually from 1 to 2000 mg, preferably from 6 to 600 mg. Of course, specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.

The main advantages of the present invention over the prior art include:

1. The present invention finds for the first time that the rosin-type diterpenoid has good hypolipidemic activity; the in vitro activity is equivalent to berberine at the same concentration; and the activity of some compounds at 5 μM is much higher than that of the bamboo cyanolide;

2. It was found that the hypolipidemic activity of rosin-type diterpenoids was significantly dose-dependent;

3. The mechanism of hypolipidemic action of rosin-type diterpenoids was first discovered, that is, the effect of clearing LDL was achieved by up-regulating the number of LDLR receptors on the surface of hepatocytes;

4. It was found that rosin-type diterpenoids showed hypolipidemic activity in vitro and in vivo, and showed hypolipidemic effect at doses as low as 30 mg/kg, far lower than reported pravastatin and sputum. The effective dose of the base drug;

5. In addition to lowering LDL, the rosin-type diterpenoids provided by the present invention can also lower the concentration of TC and TG in blood.

The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

In each of the examples, the structure of the comparative compound ZBM30 (Nagilactone B (7)) is as follows:

1, instruments and equipment

In addition, the spectrum UV: SHIMADIU UV-2550 and Beckman DU-7 UV-Vis spectrometer;

Infrared spectroscopy IR: Perkin-Elmer 577 infrared spectrophotometer;

Low resolution mass spectrometry LR-EIMS: Finnigan MAT-95;

High resolution mass spectrometry HR-EIMS: Kratos 1H spectrometer;

Nuclear magnetic resonance spectrum: Varian INOVA 600 nuclear magnetic resonance spectrometer, Bruker AM-500, AM-400, AM-300 nuclear magnetic resonance spectrometer, δ (ppm), with TMS as internal standard;

LC-MS: Agilent 1100 liquid phase coupled Bruker esquire mass spectrometer;

Analytical HPLC: Waters 2690 Separate Model, Waters PDA 996 detector coupled to Alltch ELSD2000 detector, Millennium 2000 operating system, Waters RP18 column (5.0 x 125 mm, 5 μm, Waters), flow rate 1.0 ml/min, CH3CN (Merck, Germany), H2O (Rapex); Jasco HPLC (Chiralcel IA column, 5m, 150 × 4.6mm), flow rate 0.6ml / min, hexane / ethanol (7:3).

HPLC-MS: Waters 2695 Separate Model, Waters PDA 2998 detector coupled Alltch ELSD 2424 detector, 3100 Ms detector, SunFireTM C-18 column (4.6 x 100 mm, 3.5 μm, Waters), flow rate 1.0 ml/min, CH3CN (Merck, Germany ), H2O (Rapex); Jasco HPLC (Chiralcel IA column, 5m, 150 × 4.6mm), flow rate 0.6ml / min, hexane / ethanol (7:3).

Preparative HPLC: Varian SD1 instrument, Varians 320 single wavelength detector, C18 column (220 x 25 nm, 10 μm, Waters), flow rate 15 ml/min, CH3CN (Merck, Germany), H2O (Rapex);

SpectraMax M2 ^e multi-function microplate reader (Molecular Instrument Company, USA);

Electrophoresis apparatus and semi-dry transfer tank (Bio-Rad Laboratories, Hercules, CA);

PCR instrument (Bio-Rad Laboratories, Hercules, CA);

Desktop refrigerated centrifuge (Hettich, Germany);

752C ultraviolet visible spectrophotometer (Shanghai third analytical instrument);

DK-8B electric thermostatic water tank (Shanghai Jinghong Experimental Equipment Co., Ltd.);

REVCO carbon dioxide incubator (REVCO, USA);

2, reagents and materials

Column chromatography silica gel: 100-200 mesh, 200-300 mesh silica gel and silica gel H are produced by Qingdao Ocean Chemical Plant;

TLC thin layer preparation board: HSGF254 is produced by Yantai Chemical Plant.

MCI resin: CHP20P (75-150μm) is produced by Mitsubishi Corporation;

Sephadex LH-20: Pharmacia Biotech AB, Uppsala, Sweden.

Color developer: 10% sulfuric acid-vanillin solution, iodine;

Plant materials: cedar, cedar, and Chinese fir were collected in Qixian County, Anhui Province, and Suining, Hunan Province. They were collected and identified by Associate Professor Shen Jingui from the Shanghai Institute of Materia Medica. The specimens were kept in the specimen room.

DMEM, fetal bovine serum (FBS) was purchased from Gibco-BRL (Grand Island, NY); DiI was purchased from biotuim (Hayward, CA); β-actin antibody was purchased from Cell Signaling Technology (Beverly, MA); LDLR Antibodies were purchased from Abeam (Cambridge, United Kingdom); protease inhibitor Cocktail was purchased from Calbiochem (San Diego, CA); Immobilon-P transfer transfer membrane (PVDF) was purchased from Millipore Corporation (Bedford, MA); Enhanced Chemiluminescence Reagent (Enhanced Chemiluminescence) Reagents, ECL) were purchased from Pierce (Rockford, IL); medical X-ray film was purchased from China Biyuntian Company; Golden Hamster High Fat Feed (0.12% cholesterol, 10% coconut oil) was purchased from Shanghai Slex Company. The protein assay kit was purchased from China Biyuntian Company; the liver tissue triglyceride TG and the total cholesterol TC content determination kit were purchased from Shanghai Rongsheng Biotechnology Co., Ltd. Blood index (total cholesterol TC, triglyceride TG, high density lipoprotein HDL, low density lipoprotein LDL, alanine aminotransferase ALT, aspartate aminotransferase AST) assay kit was purchased from Sichuan Mike Bio Company . Other reagents were purchased from Shanghai Sinopharm Group unless otherwise stated.

The experimental animals were male Syrian golden hamsters weighing 100±10 g and purchased from Shanghai Experimental Animal Center of Chinese Academy of Sciences. The animals were placed in the SPF animal room of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences (temperature 23 ± 1 ° C; humidity 60%), natural day/night cycle, and fed with standard food and water. (Experiment approval number: SIMM-AE-2010-10-WYP-01)

Method for extracting and separating compound LS 41-76 of Example 1

The 9.5 Kg of cedar bark was dried and pulverized, soaked in acetone 60 L at room temperature for 20 days, repeated 3 times, and the extracts were combined and concentrated under reduced pressure to obtain 860 g of total extract. The total extract was suspended in 5 L of water, and extracted with petroleum ether, dichloromethane, and ethyl acetate in that order, and the organic solvent was evaporated under reduced pressure to give a petroleum ether portion (500 g), methylene chloride portion (120 g), and ethyl acetate portion (160 g). Take 120g of dichloromethane and mix with 100-200 mesh silica gel (240g), 200-300 mesh silica gel (2kg), use petroleum ether: acetone system 100:2,100:5,10:1,5:1 , 3:1, 2:1, 1:1, acetone elution, combined with TLC to obtain 10 fractions. Fraction 2 was subjected to silica gel column chromatography (petroleum ether: ethyl acetate 10:1 to 2:1) and Sephadex LH-20 (chloroform-methanol = 6:4) to give the compound LS-61 (10 mg) and LS. -75 (65 mg). The fraction 3 was subjected to silica gel column chromatography (petroleum ether: ethyl acetate: 8:1 to 1:1), and purified by gel column chromatography (chloroform-methanol = 1:1) to give compound LS-41 (68 mg) , 43 (23 mg), 51 (40 mg), 53 (42 mg), 60 (50 mg), 63 (3.4 g), 67 (46 m), 72 (35 mg), 74 (2.0 g), 79 (3 mg), 80 ( 5mg). The fraction 4 was subjected to silica gel column chromatography (petroleum ether: acetone 12:1 to 3:1), and Sephadex LH-20 column chromatography (chloroform-methanol = 1:1) to obtain the compound LS-42 (24 mg), 52 (28 mg) ), 54 (14 mg), 66 (13 mg), 68 (49 mg), 70 (38 mg), 76 (34 mg). Fraction 5 was subjected to silica gel column chromatography (petroleum ether: acetone 4:1) eluting to afford compound LS-64 (160 mg) and 65 (62 mg). After passing through MCI column chromatography (60% methanol/water solution-pure methanol), fraction 6 was subjected to silica gel column chromatography (petroleum ether: acetone 4:1) to obtain LS-69 (30 mg) and 71 (14 mg). ), 73 (10 mg). Fraction 7 was subjected to a gradient of Sephadex LH-20 column chromatography (chloroform-methanol = 1:1) and silica gel column chromatography (dichloromethane: acetone 20:1) to give compound LS-46 (37 mg), 62 ( 28mg). After passing through MCI column chromatography (60% methanol/water solution-pure methanol), fraction 8 was subjected to silica gel column chromatography (dichloromethane: acetone 20:1-2:1) and then passed through Sephadex LH-20. Column chromatography (methanol) gave compound LS-44 (19 mg), 45 (29 mg), 48 (19 mg), 49 (29 mg), 55 (25 mg), 58 (30 mg). Fraction 9 was purified by silica gel column chromatography (dichloromethane: acetone: 10:1 to 1:1) and purified by EtOAc (EtOAc) (4mg). The fraction 10 was subjected to MCI column chromatography (50% methanol/water-purified methanol), and then subjected to silica gel column chromatography (dichloromethane: acetone: 8:1 to 1:1), and then passed through Sephadex LH-20. Purification by column chromatography (methanol) gave compound LS-50 (13mg), 56 (73mg), 57 (85mg), 77 (12mg), 78 (9 mg), LS-79 (3 mg) LS-80 (2 mg), LS-81 (12 mg) LS-82 (24 mg).

The characterization of each compound is as follows:

Fortunin A (LS-41)

White solid. EIMS: m/z 344 [M] ⁺ , MF: C ₂₂ H ₃₂ O ₃ , ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.48 (s, 1H, H-14), 6.82 (s, 1H, H- 11), 4.86 (dd, J = 8.6, 8.6 Hz, 1H, H-7), 2.89 (sept, J = 7.0 Hz, 1H, H-15), 2.84 (m, 2H, H-7), 1.39and 2.15 (m, each 1H, H-1), 1.41 and 1.51 (m, each 1H, H-2), 1.65 and 1.75 (m, each 1H, H-3), 1.39 (m, 1H, H-5) ), 1.70and 2.27(m,each 1H,H-6),1.20and 1.22(sept,J=6.8Hz,6H,H-16/17),0.93,0.96,1.25(s,each 3H,H-18 /19/ ₂₀ ), 2.32 (s, 3H, 12-CH ₃ CO).

Fortunin B (LS-42)

White solid. EIMS: m/z 402 [M] ⁺ , MF: C ₂₄ H ₃₄ O ₅ , ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.36 (s, 1H, H-14), 6.84 (s, 1H, H- 11), 5.63 (dd, J = 5.3, 11.7 Hz, 1H, H-6), 4.69 (brd, J = 5.3 Hz, 1H, H-7), 2.95 (sept, J = 6.8 Hz, 1H, H- 15), 1.46 and 2.14 (m, each 1H, H-1), 1.53 (m, 2H, H-2), 1.61 and 1.68 (m, each 1H, H-3), 1.75 (d, J = 11.7) Hz, 1H, H-5), 1.19 and 1.21 (sept, J=6.8Hz, 6H, H-16/17), 1.02, 1.08, 1.23 (s, each 3H, H-18/19/20), 2.32 (s, 3H, 12-CH ₃ CO), 2.18 (s, 3H, 6-CH ₃ CO.

Fortunin C (LS-43)

White solid. EIMS: m/z 362 [M] ⁺ , MF: C ₂₂ H ₃₂ O ₄ , ¹ H NMR (600 MHz, CDCl ₃ ) δ 6.85 (s, 1H, H-14), 4.25 (dd, J = 8.8, 11.1 Hz, 1H, H-6), 4.47 (d, J = 8.6 Hz, 1H, H-7), 3.20 (sept, J = 6.8 Hz, 1H, H-15), 1.34 and 3.07 (m, each 1H) , H-1), 1.51 and 1.68 (m, each 1H, H-2), 1.28 and 1.48 (m, each 1H, H-3), 1.53 (d, J = 11.1 Hz, 1H, H-5), 1.24 (sept, J = 6.8 Hz, 6H, H-16/17), 1.21, 1.23, 1.43 (s, each 3H, H-18/19/20), 3.76 (s, 3H, 12-OMe), 3.26 (s, 3H, 7-OMe)

Fortunin D (LS-44)

White solid. EIMS: m/z 362 [M] ⁺ , MF: C ₂₂ H ₃₄ O ₄ , ¹ H NMR (600 MHz, CDCl ₃ ) δ 6.71 (s, 1H, H-14), 4.19 (brd, J = 10.3 Hz) , 1H, H-6), 4.15 (d, J = 3.8 Hz, 1H, H-7), 3.22 (sept, J = 7.0 Hz, 1H, H-15), 1.31 and 3.01 (m, each 1H, H -1), 1.49 and 1.56 (m, each 1H, H-2), 1.54 and 1.72 (m, each1H, H-3), 1.86 (d, J = 10.3 Hz, 1H, H-5), 1.25 (sept , J = 6.8 Hz, 6H, H-16/17), 1.18, 1.20, 1.35 (s, each 3H, H-18/19/20), 3.76 (s, 3H, 12-OMe), 3.61 (s, 3H, 7-OMe).

Fortunin E (LS-45)

White solid. EIMS: m/z 332 [M] ⁺ , MF: C ₂₀ H ₂₈ O ₄ , ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.93 (s, 1H, H-14), 6.74 (s, 1H, H- 11), 4.50 (d, J = 12.7 Hz, 1H, H-6), 3.19 (sept, J = 7.5 Hz, 1H, H-15), 1.36 and 2.17 (m, each 1H, H-1), 1.81 (m, 2H, H-2), 1.47 and 1.67 (m, each 1H, H-3), 2.04 (d, J = 12.7 Hz, 1H, H-5), 1.23 and 1.25 (sept, J = 7.5 Hz) , 6H, H-16/17), 1.16, 1.32 (s, each 3H, H-18/20), 3.26 and 3.56 (d, J = 11.6 Hz, each 1H, H-19).

Fortunin F (LS-46)

Light yellow solid. EIMS: m/z 330 [M] ⁺ , MF: C ₂₀ H ₂₆ O ₄ , ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.02 (s, 1H, H-14), 6.88 (s, 1H, H- 11), 3.16 (sept, J = 7.0 Hz, 1H, H-15), 1.54 and 2.24 (m, each 1H, H-1), 1.75 (m, 2H, H-2), 1.86 and 1.96 (m, Each 1H, H-3), 1.28and 1.30 (sept, J=7.0Hz, 6H, H-16/17), 1.28, 1.50 (s, each 3H, H-18/20), 3.35 and 4.25 (d, J=11.5Hz, each 1H, H-19).

Fortunin G (LS-47)

White solid. ESIMS: m / z 438.2 [M + Na] +, MF: C 26 H 36 O 7, 1 H NMR (300MHz, CDCl 3) δ7.38 (s, 1H, H-14), 6.84 (s, 1H, H-11), 5.39 (dd, J = 5.2, 11.8 Hz, 1H, H-6), 4.64 (d, J = 5.2 Hz, 1H, H-7), 2.94 (sept, J = 6.4 Hz, 1H, H-15), 1.52 and 1.74 (m, each 1H, H-1), 1.68 (m, 2H, H-2), 1.42 and 1.58 (m, each 1H, H-3), 2.13 (d, J = 11.8Hz, 1H, H-5), 1.20and 1.21 (sept, J=6.4Hz, 6H, H-16/17), 1.00, 1.37 (s, each 3H, H-18/20), 3.67 and 4.13 ( d, J=11.6Hz, each 1H, H-19).

Fortunin H (LS-48)

White solid. EIMS: m/z 316 [M] ⁺ , MF: C ₂₀ H ₂₈ O ₃ , ¹ H NMR (600MHz, CDCl ₃ ) δ 8.08 (s, 1H, H-14), 7.03 (s, 1H, H- 11), 4.38 (dd, J = 7.0, 12.7 Hz, 1H, H-6), 5.10 (d, J = 7.0 Hz, 1H, H-7), 3.69 (sept, J = 7.3 Hz, 1H, H- 15), 1.29 and 1.98 (m, each 1H, H-1), 1.51 (m, 2H, H-2), 1.56 and 1.63 (m, each 1H, H-3), 1.68 (d, J = 12.7 Hz) , 1H, H-5), 1.36 and 1.37 (sept, J = 7.3 Hz, 6H, H-16/17), 1.07, 1.11 (s, each 3H, H-18/20), 3.47 and 3.74 (d, J=7.4Hz, each 1H, H-19).

Fortunin I (LS-49)

Light yellow solid. EIMS: m/z 330 [M] ⁺ , MF: C ₂₁ H ₃₀ O ₃ , ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.05 (s, 1H, H-14), 6.57 (s, 1H, H- 11), 4.17 (dd, J = 3.8, 12.2 Hz, 1H, H-6), 4.46 (d, J = 3.8 Hz, 1H, H-7), 3.15 (sept, J = 6.3 Hz, 1H, H- 15), 1.44 and 2.03 (m, each 1H, H-1), 1.75 (m, 2H, H-2), 1.30 and 1.82 (m, each 1H, H-3), 2.14 (d, J = 12.2) Hz, 1H, H-5), 1.25 and 1.26 (sept, J = 6.3 Hz, 6H, H-16/17), 1.17, 1.11 (s, each 3H, H-18/20), 3.51 and 3.77 (d , J = 6.7 Hz, each 1H, H-19).

Fortunin J (LS-50)

Light yellow solid. EIMS: m/z 318 [M] ⁺ , MF: C ₂₀ H ₃₀ O ₃ , ¹ H NMR (600MHz, CDCl ₃ ) δ 6.76 (s, 1H, H-14), 6.66 (s, 1H, H- 11), 1.16 and 1.18 (m, each 1H, H-6), 2.51 (dd, J = 4.7, 5.2 Hz, 1H, H-7), 3.18 (sept, J = 6.4 Hz, 1H, H-15) , 1.26 and 2.61 (m, each 1H, H-1), 4.04 (m, 1H, H-2), 1.47 and 1.68 (m, each 1H, H-3), 1.65 (d, J = 4.7, 11.0) Hz, 1H, H-5), 1.17 and 1.18 (sept, J = 6.4 Hz, 6H, H-16/17), 0.89, 1.22 (s, each 3H, H-18/20), 3.13 and 3.44 (d , J = 10.8 Hz, each 1H, H-19).

Fortunin K (LS-51)

Light yellow solid. EIMS: m/z 302 [M] ⁺ , MF: C ₁₉ H ₂₆ O ₃ , ¹ H NMR (300 MHz, CD ₃ OD) δ 7.55 (s, 1H, H-14), 6.88 (s, 1H, H) -11), 3.09 (sept, J = 6.8 Hz, 1H, H-15), 1.52 and 2.46 (m, each 1H, H-1), 2.00 and 2.13 (m, each 1H, H-2), 1.68 ( m, 2H, H-3), 1.21 and 1.23 (sept, J = 6.8 Hz, 6H, H-16/17), 1.27, 1.30, 1.63 (s, each 3H, H-18/19/20), 9.67 (s, 1H, CHO).

Fortunin L (LS-52)

Light yellow solid. EIMS: m/z 304 [M] ⁺ , MF: C ₁₉ H ₂₈ O ₃ , ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.36 (s, 1H, H-14), 6.84 (s, 1H, H- 11), 1.40 and 2.14 (m, each 1H, H-1), 1.56 (m, 2H, H-2), 1.60 (m, 2H, H-3), 1.25 and 1.26 (sept, J = 6.8 Hz, 6H, H-16/17), 0.46, 0.88, 1.44 (s, each 3H, H-18/19/20).

Fortunin M (LS-53)

Light yellow solid. EIMS: m/z 318 [M] ⁺ , MF: C ₂₀ H ₃₀ O ₃ , ¹ H NMR (600MHz, CDCl ₃ ) δ 6.72 (s, 1H, H-14), 6.46 (s, 1H, H- 11), 5.03 (d, J = 7.4 Hz, 1H, H-6), 1.35 (d, J = 7.4 Hz, 1H, H-5), 3.12 (sept, J = 6.8 Hz, 1H, H-15) , 1.26 and 2.61 (m, each 1H, H-1), 4.04 (m, 1H, H-2), 1.47 and 1.68 (m, each 1H, H-3), 1.65 (d, J = 4.7, 11.0 Hz) , 1H, H-5), 1.22 (sept, J = 6.4 Hz, 6H, H-16/17), 0.92, 1.12, 1.23 (s, each 3H, H-18/19/20).

Fortunin N (LS-54)

Light yellow solid. ESIMS: m/z 333.4 [M+H] ⁺ , MF: C ₂₀ H ₂₈ O ₄ , ¹ H NMR (400 MHz, CD ₃ OD) δ 7.81 (s, 1H, H-14), 7.01 (s, 1H) , H-11), 3.11 (s, 1H, H-5), 3.20 (sept, J = 6.9 Hz, 1H, H-15), 1.63-2.15 (m, 6H, H-1/2/3), 1.20 (sept, J = 6.4 Hz, 6H, H-16/17), 0.37, 0.89, 1.43 (s, each 3H, H-18/19/20), 10.59 (s, 1H, CHO).

Fortunin O (LS-55)

Light yellow solid. ESIMS: m / z 319.4 [M + H] +, MF: C 19 H 26 O 4, 1 H NMR (400MHz, CDCl 3) δ7.93 (s, 1H, H-14), 6.77 (s, 1H, H-11), 3.17 (sept, J=6.9Hz, 1H, H-15), 2.12–1.85 (m, 1H), 1.79–1.58 (m, 3H), 1.57–1.39 (m, 2H), 1.25and 1.26 (d, J = 6.9 Hz, each 3H, H-16/17), 0.68, 1.14, 1.33 (s, each 3H, H-18/19/20).

3-hydroxysugiol (LS-56)

White solid. ESIMS: m/z 317.2 [M+H] ⁺ , MF: C ₂₀ H ₂₈ O ₃ , ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.90 (s, 1H, H-14), 6.68 (s, 1H, H-11), 3.33 (dd, J = 11.0, 4.8 Hz, 1H, H-3), 3.16 (sept, J = 6.9 Hz, 1H, H-15), 2.70 - 2.66 (m, 2H, H-6) ), 1.69and 2.25(m,each 1H,H-1),1.80-1.94(m,3H,H-2/5),1.25and 1.23(d,J=6.9Hz,each 3H,H-16/17 ), 1.21, 1.04, 0.95 (s, each 3H, H-18/19/20).

Cryptojaponol (LS-57)

Light yellow solid. EIMS: m/z 330 [M] ⁺ , MF: C ₂₁ H ₃₀ O ₃ , ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.60 (s, 1H, H-14), 3.18 (sept, J = 6.9 Hz) ,1H,H-15), 1.39and 3.23(m,each 1H,H-1),1.57and 1.75(m,each1H,H-2),1.26-1.48(m,each 1H,H-3),1.85 (m, 1H, H-5), 2.54 and 2.64 (m, each 1H, H-6), 1.22 and 1.24 (d, J = 6.9 Hz, each 3H, H-16/17), 0.92, 0.96, 1.32 (s, each 3H, H-18/19/20).

Fortunin P (LS-58)

Light yellow solid. ESIMS: m / z 317.4 [M + H] +, MF: C 20 H 28 O 3, 1 H NMR (400MHz, CDCl 3) δ7.46 (s, 1H, H-14), 6.57 (s, 1H, H-11), 4.69 (d, J = 7.7 Hz, 1H, H-7), 3.97 (dd, J = 12.6, 7.7 Hz, 1H, H-6), 3.13 (sept, J = 6.9 Hz, 1H) , 2.12 - 2.05 (m, 1H, H-5), 1.33 - 2.04 (m, 6H), 1.25 and 1.27 (d, J = 6.9 Hz, each 3H, H-16/17), 1.19 and 1.21 (s, Each 3H, H-18/20), 3.47 and 3.76 (d, J = 7.3 Hz, each 1H, H-19), 3.65 (s, 3H, 7-OMe).

Fortunin Q (LS-59)

Light yellow solid. ESIMS: m/z 333.2 [M+H] ⁺ , MF: C ₂₀ H ₂₈ O ₃ , ¹ H NMR (400 MHz, CD ₃ OD) δ 10.59 (s, 1H, CHO), 7.81 (s, 1H, H -14), 7.01 (s, 1H, H-11), 3.20 (sept, J = 6.9 Hz, 1H, H-15), 3.11 (s, 1H, H-5), 1.80-2.15 (m, 5H) , 1.63 (dt, J = 14.0, 4.2 Hz, 1H, H-1a), 1.20 (d, J = 6.9 Hz, 6H, H-16/17), 0.37, 0.89, 1.43 (s, each 3H, H- 18/19/20).

6β-hydroxyferruginol (LS-60)

White solid, HREIMS: m/z 302.2247, MF: C ₂₀ H ₃₀ O ₂ . ¹ H-NMR (300MHz, CDCl ₃ ) δ 6.82 (s, 1H), 6.66 (s, 1H), 4.65 (brs, 1H) ), 3.10 (sept, J = 6.8 Hz, 1H), 3.08 (dd, J = 4.5, 17.0 Hz, 1H), 2.83 (brd, J = 17.0 Hz, 1H), 2.06 (brd, J = 12.6 Hz, 1H) ), 1.37 (brs, 1H), 1.52 (s, 3H), 1.25 (s, 3H), 1.22 and 1.21 (d, J = 6.8 Hz, each 3H), 1.02 (s, 3H).

Iguestol (LS-61)

Light yellow solid, HREISM m/z 332.2343.MF: C ₂₁ H ₃₂ O ₃ . ¹ H NMR (500MHz, CDCl ₃ ) δ 1.13 (s, 3H, H-18), 1.16 (s, 3H, H-19 ), 1.18 (d, J = 7 Hz, 3H, H-16), 1.20 (d, J = 7 Hz, 3H, H-17), 1.25 (td, J = 13, 3.3 Hz, 1H, H-3β), 1.33 (s, 3H, H-20), 1.39 (d, 1H, J = 9 Hz, H-5), 1.45 (dt, J = 13.0, 4.0 Hz, 1H, H-3α), 1.53 (m, 2H, H-1R/H-2), 1.70 (m, 1H, H-2), 2.74 (dd, J = 15.7, 7.6 Hz, 1H, H-7), 2.99 (dt, J = 13.0, 4.0 Hz, 1H) , H-1α), 3.14 (m, 2H, H-7/15), 3.72 (s, 3H-OMe), 4.21 (1H, brs, J = 18 Hz, H-6), 5.98 (s, 1H, OH ), 6.45 (s, 1H, H-14).

2-dehydroxy-15-hydroxy iguestol (LS-62)

Light yellow solid, EISM m/z 332 [M] ⁺ .MF: C ₂₁ H ₃₂ O ₃ . ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.64, 1.62, 1.37, 0.98, 0.94 (s, each 3H, H -16/17/18/19/20), 1.70-1.85 (m, 3H), 1.20-1.54 (m, 4H), 2.48-2.69 (m, 2H), 3.23 (m, 1H), 3.92 (s, 3H,12-OMe), 5.97 (s, 1H, 11-OH), 7.66 (s, 1H, H-14).

(+)-Sugiol (LS-63)

White powder, EIMS m/z 300(M) ⁺ , MF: C ₂₀ H ₂₈ O ₂ , [α] _D ²⁵ : + 28.3° (c 1.0, CHCl ₃ ), ¹ H NMR (300 MHz CDCl ₃ ): δ0 .99, 1.00, 1.19 (each 3H, s, H-18/19/20), 1.20 (3H, d, J = 7.0 Hz, H-16), 1.24 (3H, d, J = 7.0 Hz, H- 17), 1.83 (dd, J = 4.5, 13.0 Hz, H-5), 2.18 (dd, J = 13.0, 18.0 Hz, H-6β), 2.62 (1H, dd, J = 4.5, 1.8 Hz, H- 6α), 3.13 (1H, sept, J = 7.0 Hz, H-15), 6.68 (1H, s, H-11), 7.89 (1H, s, H-14).

11-hydroxysugiol (LS-64)

Light yellow powder, EIMS m/z 316 (M) ⁺ , MF: C ₂₀ H ₂₈ O ₃ , ¹ H NMR (300 MHz CDCl ₃ ): δ 0.92, 0.97, 1.40 (each 3H, s, H-18/19 /20), 1.22 and 1.24 (each 3H, d, J = 7.0 Hz, H-16/17), 1.87 (dd, J = 3.2, 14.2 Hz, H-5), 2.53 (dd, J = 14.2, 17.4 Hz, H-6β), 2.62 (1H, dd, J = 14.2, 17.4 Hz, H-6α), 1.28 and 1.50 (each 1H, m, H-3), 1.78 and 1.61 (each 1H, m, H -2), 1.51 and 3.11 (each 1H, m, H-1), 3.13 (1H, sept, J = 7.0 Hz, H-15), 5.81 and 6.13 (2H, brs, 11/12-OH), 7.63 (1H, s, H-14).

Hypagenin B (LS-65)

Light yellow powder, EIMS m/z 316 (M) ⁺ , MF: C ₂₀ H ₂₈ O ₃ , ¹ H NMR (300 MHz CDCl ₃ ): δ 7.58 (s, lH, H-14), 6.47 (s, 1H) , H-11), 3.0 (m, 1H, H-6b) 2.8 (br d, J = 12 Hz, 1H, H-1a), 2.4 (dd, J = 4, 12 Hz, 1H, H-6a), 1.4 -2.4 (m, 6H), 1.40, 1.35, 1.12, 1.10, 1.08 (s, each 3H, H-16/17/18/19/20).

5,6-dehydrosugiol(LS-66)

Light yellow powder, HREIMS: 298.1933 [M+H] ⁺ , MF: C ₂₀ H ₂₆ O ₂ , ¹ H NMR (400 MHz, CDCl ₃ ): δ=8.01 (s, 1H), 7.15 (s, 1H), 6.84 (s, 1H), 5.24 (s, 1H), 3.17 (sept, J = 6.8 Hz, 1H), 2.33 - 2.27 (m, 1H), 1.97-1.87 (m, 2H), 1.81-1.70 (m, 2H) ), 1.51, 1.43, 1.43 (s, each 3H), 1.31 and 1.28 (d, J = 6.8 Hz, each 3H), 1.25-1.23 (m, 1H).

6-hydroxy-5,6-dehydrosugiol(LS-67)

Light yellow powder, EIMS: 314 [M] ⁺ , MF: C ₂₀ H ₂₆ O ₃ , ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.16 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H), 1.19 (s, 3H), 1.29 (s, 3H), 1.42 (s, 3H), 1.31 - 2.30 (m, 6H), 3.16 (sept., J = 6.8 Hz, 1H) , 6.23 (s, 1H), 6.94 (s, 1H), 7.71 (s, 1H), 10.20 (s, 1H).

14-Deoxycoleon U (LS-68)

Light yellow powder, EIMS: 330 [M] ⁺ , MF: C ₂₀ H ₂₆ O ₄ , 1H NMR (500 MHz, CDCl ₃ ) δ 1.27 and 1.30 (each 3H, d, J = 6.8 Hz, H-16/17) , 1.41 (1H, m, H-3α), 1.43 and 1.44 (each 3H, s, H-18/19), 1.61 and 1.86 (each 1H, m, H-2), 1.71 and 2.93 (each 1H, m , H-1), 2.01 (1H, td, J = 13, 5 Hz, H-3β), 3.04 (1H, sept, J = 6.8 Hz, H-15), 7.09 (1H, s, 6-OH), 7.70 (1H, s, H-14).

12-O-Acetylhinokiol (LS-69)

Light yellow powder, EIMS: 344 [M] ⁺ , MF: C ₂₂ H ₃₂ O ₃ , ¹ H NMR (500 MHz, CDCl ₃ ) δ 1.11 and 1.36 (3H, m), 1.58-1.93 (5H, m), 1.18 , 1.05 and 0.89 (each 3H, s, H-18/19/20), 2.20 (1H, m), 2.30 (3H, s, OMe), 2.90 (1H, sept, J = 6.8 Hz, H-15) , 3.28 (1H, m, H-3), 6.81 (1H, s, H-11), 6.95 (1H, s, H-14).

3β-Acetoxyabieta-8,11,13-trien-12-ol(LS-70)

Light yellow solid, EIMS m/z 344 [M ⁺ ], MF: C ₂₂ H ₃₂ O ₃ , ¹ H NMR (CDCl ₃ , 400 MHz) δ 6.81 (1H, s, H-14), 6.58 (1H, s , H-11), 5.03 (1H, brs, OH), 4.51 (1H, dd, J = 11.1, 4.9 Hz, H-3), 3.09 (1H, sept, J = 6.8 Hz, H-15), 2.83 (1H, ddd, J = 12.6, 4.0, 1.5 Hz, Hα-7), 2.75 (1H, ddd, J = 12.6, 11.3, 3.5 Hz, Hβ-7), 2.17 (1H, ddd, J = 13.2, 3.3 , 3.3 Hz, Hα-1), 2.05 (3H, s, OAc), 1.60 (1H, ddd, J = 13.2, 11.0, 3.0 Hz, Hβ-1), 1.36 (1H, dd, J = 12.0, 2.1 Hz) , H-5), 1.21, 1.20 (3H each, d, J = 6.8 Hz, H-16/17), 1.18 (3H, s, H-20), 0.94 (3H, s, H-19), 0.92 (3H, s, H-18).

Salviviridinol (LS-71)

A pale solid, EIMS m/z 348 [M ⁺ ], MF: C ₂₁ H ₃₂ O ₄ , ¹ H NMR (CDCl ₃ , 400 MHz) δ 6.99 (1H, s, H-14), 4.49 (1H, d , J=9.5Hz, H-7), 3.98 (1H, d, J=9.5, 13.0Hz, H-6), 3.20 (1H, sept, J=6.8Hz, H-15), 3.08and 1.70(each 1H, m, H-1), 1.40 and 1.60 (each 1H, m, H-2), 1.60 and 1.80 (each 1H, m, H-3), 1.52 (1H, d, J = 13.0 Hz, H- 5), 1.17 (6H, d, J = 6.8 Hz, H-16/17), 1.10, 1.24, 1.04 (each 3H, s, H-18/19/20), 3.80 (3H, s, OMe).

Sugikurojin D (LS-72)

White solid, EIMS m/z 390 [M ⁺ ], MF: C ₂₃ H ₃₄ O ₅ , ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.03 (1H, s, H-14), 4.6149 (1H, d, J=8.5 Hz, H-7), 5.42 (1H, d, J=8.5, 12.0 Hz, H-6), 3.19 (1H, sept, J=7.0 Hz, H-15), 3.15 and 1.32 (each 1H , m, H-1), 1.51 and 1.68 (each 1H, m, H-2), 1.28 and 1.45 (each1H, m, H-3), 1.73 (1H, d, J = 12.0 Hz, H-5) , 1.24and 1.21(each 3H,d,J=7.0Hz,H-16/17), 1.15,0.99, 1.49(each 3H,s,H-18/19/20),3.76(3H,s,OMe) , 2.19 (3H, s, Ac).

18-Hydroxyferruginol (LS-73)

White solid, EIMS m/z 302 [M ⁺ ], MF: C ₂₀ H ₃₀ O ₂ , ¹ H NMR (600 MHz, CDCl ₃ ) δ 0.86 (3H, s, H-19), 1.18 (3H, s, H-20), 1.21 (3H, d, H-16), 1.22 (3H, d, H-17), 1.36 (1H, m, H-1α), 1.42 (1H, m, H-3), 1.59 (1H, m, H-5), 1.64 (1H, m, H-6), 1.71 (1H, m, H-2), 2.16 (1H, m, H-1β), 2.80 (2H, m, H) -7), 3.09 (1H, m, H-15), 3.21 (1H, d, J = 10.9 Hz, H-18α), 3.45 (1H, d, J = 11.0 Hz, H-18β), 6.61 (1H) , s, H-11), 6.81 (1H, s, H-14).

12-hydroxy-6,7-seco-abieta-8,11,13-triene-6,7-dial(LS-74)

White solid, HREIMS m/z 316.2038, MF: C ₂₀ H ₂₈ O ₃ , ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.47 (s, 1H), 9.86 (d, J = 3.8 Hz, 1H), 7.84 ( s, 1H), 6.96 (s, 1H), 6.34 (br s, 1H), 3.18 (sept, J = 6.9 Hz, 1H), 3.13 (d, J = 3.8 Hz, 1H), 2.28 - 2.34 (m, 1H), 1.50–1.83 (m, 5H), 1.50 (s, 3H), 1.27 and 1.26 (d, J=6.9 Hz, each 3H), 1.01 and 0.70 (s, each 3H).

Cupresol (LS-75)

White solid, EIMS m/z 318 [M] ⁺ , MF: C ₁₉ H ₂₆ O ₄ , ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.96 (s, 1H, H-14), 6.76 (s, 1H, H-11), 5.82-5.99 (br s, 2H, OH), 3.18 (sept, J = 6.9 Hz, 1H, H-15), 3.13 (m, 1H, H-1a), 1.39 - 2.08 (m, 5H), 1.27and 1.26 (d, J = 6.9 Hz, each 3H, H-16/17), 1.33, 1.14 and 0.70 (s, each 3H).

7β-hydroxydeoxy-cryptojaponol (LS-76)

Pale white solid, EIMS m/z 332 [M] ⁺ , MF: C ₂₁ H ₃₂ O ₃ , ¹ H NMR (300MHz, CDCl ₃ ) δ 6.63 (s, 1H, H-14), 4.41 (1H, m , H-7), 1.55 and 5.72 (br s, 2H, OH), 2.96 (sept, J = 6.9 Hz, 1H, H-15), 3.13 (m, 1H, H-1a), 1.31 - 2.07 (m , 6H), 1.27and 1.15 (d, J = 6.9 Hz, each 3H, H-16/17), 0.93, 0.93 and 1.35 (s, each 3H, H-18/19/20), 3.58 (s, 3H) , OMe).

Fortunin R (LS-77)

White solid. ESIMS: m/z 349.4 [M+H] +, MF: C ₂₀ H ₂₈ O ₅ , 1H NMR (400 MHz, CD ₃ OD) δ 8.06 (s, 1H, H-14), 6.36 (S, 1H, H-11), 3.69 (dd, J = 10.3, 5.7 Hz, 1H, H-16a), 3.54 (dd, J = 11.7, 4.9 Hz, 1H, H-1), 3.48 (dd, J = 10.2, 7.4 Hz, 1H, H-16b), 3.14 (m, 1H, H-15), 2.66 (m, 2H, H-7), 2.21 (dt, J = 13.2, 3.5 Hz, 1H, H-3a), 2.07 (m, 1H, H-2α), 2.05 (m, 2H, H-6), 1.70 (dt, 1H, J = 13.6, 3.6 Hz, H-3b), 1.25 (s, 3H, H-19), 1.24 (d, J = 6.8 Hz, 3H, H-17), 1.18 (m, 1H, H-3b), 1.13 (s, 3H, H-20).

Fortunin S (LS-78)

White solid. ESIMS: m/z 349.4 [M+H] +, MF: C ₂₀ H ₂₈ O ₅ , 1H NMR (400 MHz, CD ₃ OD) δ 6.71 (s, 1H, H-14), 6.65 (s, 1H, H-11), 4.05 (brs, 1H, H-3), 3.68 (dd, J = 10.5, 5.8 Hz, 1H, H-16a), 3.49 (dd, J = 10.4, 7.4 Hz, 1H, H-16b ), 3.16 (m, 1H, H-15), 2.73 (m, 2H, H-7), 2.30 (m, 1H, H-2a), 2.00 (m, 2H, H-2α), 1.90 (m, 1H, H-5), 1.89 (m, 1H, H-1a), 1.74 (m, 1H, H-1b), 1.70 (m, 1H, H-2b), 1.31 (s, 3H, H-19) , 1.21 (d, J = 6.8 Hz, 3H, H-17), 1.09 (s, 3H, H-20).

Fortunin T (LS-79)

White solid. EIMS: m/z 330[M]+, MF: C ₂₁ H ₃₀ O ₃ , 1H NMR (400MHz, CDCl3) δ 9.81 (s, 1H, CHO-), 7.14 (s, 1H, H-14), 6.48 (s, 1H, H-11), 5.30 (s, 1H, OH-Ar), 4.70 (s, 1H, H-7), 3.52 (s, 3H, 7-OMe), 3.19 (sept, J = 6.8 Hz, 1H, H-15), 1.23 (d, J = 6.8 Hz, 6H, H-16/17), 1.43-1.96 (m, 6H, H-1/2/3), 1.25, 1.11, 0.53 (s, each 3H, H-20/19/18).

Fortunin U (LS-80)

White solid. EIMS: m/z 304 [M]+, MF: C ₁₉ H ₂₈ O ₃ , 1H NMR (400 MHz, Acetone-d6) δ 7.94 (s, 1H, OH-Ar), 7.13 (s, 1H, H- 14), 6.54 (s, 1H, H-11), 5.12 (d, J = 7.2 Hz, 1H, H-7), 4.19 (d, J = 7.2 Hz, 1H, 7-OH), 3.24 (sept, J = 6.8 Hz, 1H, H-15), 3.16 (s, 1H, 5-OH), 1.65 - 1.20 (m, 6H, H-1/2/3), 1.16 and 1.18 (d, J = 6.8 Hz) , 3H, H-16/17), 1.36, 1.10, 1.01 (s, each3H, H-20/19/18).

Fortunin V (LS-81)

White solid. EIMS: m/z 316 [M] ⁺ , MF: C ₂₀ H ₂₈ O ₃ , ¹ H NMR (CDCl ₃ , 500 MHz): δ 6.90 (s, 1H, H-14), 6.74 (s, 1H, H -11), 3.15 (sept, 6.9 Hz, 1H, H-15), 2.60-2.57 (m, 2H, H-6), 1.45 (s, 3H, H-20), 1.23 (d, 6.9 Hz, 3H) , H-17), 1.22 (d, 6.9 Hz, 3H, H-16), 1.10 (s, 3H, H-18), 0.87 (s, 3H, H-19)

¹³ C NMR (CDCl ₃ , 125 MHz): δ 38.8 (C-1), 18.8 (C-2), 41.2 (C-3), 36.1 (C-4), 55.1 (C-5), 31.9 (C) -6), 174.2 (C-7), 145.0 (C-8), 138.9 (C-9), 39.6 (C-10), 111.6 (C-11), 150.3 (C-12), 133.6 (C- 13), 118.6 (C-14), 26.9 (C-15), 22.4 (C-16), 22.6 (C-17), 21.4 (C-18), 33.2 (C-19), 20.4 (C-20) )

Fortunin W (LS-82)

White solid. EIMS: m/z 388 [M] ⁺ , MF: C ₂₅ H ₄₀ O ₃ , ¹ H NMR (CDCl ₃ , 500 MHz): δ 6.97 (s, 1H, H-14), 4.46 (dd, 10.9, 6.5 Hz, 1H, H-7), 3.73 (s, 3H, - OME), 3.19 (m, 1H, H-15), 2.16 (dd, 12.2, 6.5 Hz, 1H, H-6), 1.24 (d, 7.2 Hz, 3H, H-16), 1.25 (d, 7.2 Hz, 3H, H-17)

¹³ C NMR (CDCl ₃ , 125 MHz): δ 36.4 (C-1), 19.3 (C-2), 41.5 (C-3), 33.6 (C-4), 50.0 (C-5), 25.0 (C) -6), 79.2 (C-7), 134.5 (C-8), 133.4 (C-9), 40.0 (C-10), 146.3 (C-11), 143.6 (C-12), 138.0 (C- 13), 116.3 (C-14), 26.4 (C-15), 23.7 (C-16), 23.9 (C-17), 22.1 (C-18), 33.6 (C-19), 19.7 (C-20) ), 67.2 (C-21), 32.5 (C-22), 19.7 (C-23), 14.1 (C-24), 61.8 (-OME)

1.2. Separation of rosin-type diterpenoids from the bark of cedar

The cedar bark (27Kg) collected from Yiyang, Hunan Province, was pulverized, soaked three times with industrial acetone at room temperature for 7 days, and the extracts were combined, concentrated under reduced pressure to remove acetone, and dissolved in 10 L of 35 ° C distilled water, respectively, using petroleum ether. Each of dichloromethane and ethyl acetate was extracted three times, and concentrated under reduced pressure to give a petroleum ether portion (118 g, m. The methylene chloride is subjected to normal phase silica gel (100-200 mesh, 200-300 mesh, silica gel H, etc.), elution conditions: petroleum ether/acetone, chloroform/acetone, chloroform/methanol), Sephadex LH-20 (chloroform/methanol) =1:1, methanol), MCI resin (methanol/water, ethanol/water), preparative thin layer and preparative high performance liquid chromatography for separation, co-separation and identification Twenty-two compounds, 13 of which are new compounds, including three rosin-type diterpenoids Taxodascen A (7,18 mg), Taxodascen B (10,13 mg), Taxodascen C (11,31 mg) and one B-ring cracked rosin Alkane Taxodascen D (12, 25 mg), 3 A-ring-cracked rosin-type diterpenoids Nortaxodascen A (13, 20 mg), Nortaxodascen B (15, 35 mg), Nortaxodascen C (16, 51 mg), 6 rosin 2 Bismuth dimer Bitaxodascen A (17,50 mg), Bitaxodascen B (18,12 mg), Bitaxodascen C (19,8 mg), Bitaxodascen D (20,27 mg), Bitaxodascen E (21,85 mg), Bitaxodascen F (22, 70mg). 9 known compounds Ferrucinol (1,85 mg), Abieta-8, 11, 13-trien-12, 19-diol (2,80 mg), 6,7-dehydroferruginol (3,126 mg), 19-hydroxy-6,7 -Dehydroferruginol (4,12 mg), sugiol (5,1.7 g), 6α-hydroxy-7-oxoferruginol (6,65 mg), Fortunin E (8,14 mg), 6,12-dihydroxyabieta-5,8,11,13 -tetraen-7-one (9,141 mg), 20 (10->5) abeo-4,5-secoabieta-5 (10), 6,8,11,13-pentaene-3,4,12-triol (14 , 34mg).

The characteristics of each compound are as follows:

Ferruginol(1)

Light yellow gum-like solid. ESIMS: m/z 287.0 [M+H] ⁺ , MF: C ₂₀ H ₃₀ O, ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.83 (s, 1H, H-14), 6.63 (s, 1H, H) -11), 4.55 (s, 1H, 12-OH), 3.11 (sept, J = 7.0 Hz, 1H, H-15), 2.84 (m, 2H, H-7), 1.90-1.80 (m, 1H) , 1.78-1.70 (m, 1H), 1.69-1.63 (m, 1H), 1.64-1.55 (m, 2H), 1.50-1.43 (m, 1H), 1.40 (dd, J = 13.0, 3.9 Hz, 1H) , 1.35 - 1.28 (m, 1H), 1.23 (t, J = 6.8 Hz, 6H, H-16/17), 1.17 (s, 3H, H-20), 0.94 (s, 3H, H-18), 0.92 (s, 3H, H-19).

Abieta-8,11,13-trien-12,19-diol(2)

Yellow amorphous powder. ESIMS: m/z 300.9 [MH] ^- , MF: C ₂₀ H ₃₀ O ₂ , ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.82 (s, 1H), 6.63 (s, 1H), 3.86 (d, J) =11.0 Hz, 1H), 3.55 (d, J = 11.0 Hz, 1H), 3.11 (sept, J = 6.9 Hz, 1H), 2.90-2.69 (m, 2H), 2.04-1.82 (m, 2H), 1.75 -1.55 (m, 3H), 1.52-1.35 (m, 2H), 1.23 (t, J = 6.6 Hz, 6H), 1.16 (s, 3H), 1.05 (s, 3H).

6,7-dehydroferruginol(3)

Light yellow gum-like solid. ESIMS: m/z 283.0 [MH] ^- , MF: C20H28O, ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.89 (d, J = 8.0 Hz, 1H), 6.58 (s, 1H), 6.49 (dd, J = 9.6, 3.1 Hz, 1H), 5.87 (dd, J = 9.6, 2.7 Hz, 1H), 4.84 (s, 1H), 3.12 (sept, J = 6.9 Hz, 1H), 2.07 (dd, J = 6.0, 3.1 Hz, 2H), 1.66-1.57 (m, 3H), 1.54-1.47 (m, 2H), 1.27 (dd, J = 6.9 Hz, 4H), 1.22 (dd, J = 6.9 Hz, 3H), 1.04 ( s, 3H), 1.01 (s, 3H), 0.96 (s, 3H).

19-hydroxy-6,7-dehydroferruginol(4)

Light yellow powdery solid. ESIMS: m/z 298.9 301.0 [M+H] ⁺ , MF: C ₂₀ H ₂₈ O ₂ , ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.88 (s, 1H), 6.59 (s, 1H), 6.48 ( Dd, J = 9.6, 3.0 Hz, 1H), 5.96 (dd, J = 9.6, 2.3 Hz, 1H), 3.85 (d, J = 11.2 Hz, 1H), 3.73 (d, J = 11.3 Hz, 1H), 3.15 (sept, J=6.9 Hz, 1H), 2.24 (s, 1H), 2.10 (d, J = 11.6 Hz, 1H), 1.88 (d, J = 13.9 Hz, 2H), 1.25 (d, J = 6.9) Hz, 4H), 1.22 (d, J = 6.9 Hz, 3H), 1.06 (s, 4H), 0.98 (s, 3H).

Sugiol(5)

Light yellow granular crystals, slightly soluble in organic solvents such as chloroform, acetone, and methanol. ESIMS: m/z 301.3 [M+H] ⁺ , MF: C ₂₀ H ₂₈ O ₂ , ¹ H NMR (300 MHz, DMSO-d6) δ10.25 (s, 1H), 7.66 (s, 1H), 6.80 ( s, 1H), 3.14 (sept, J = 6.9 Hz, 1H), 2.23 - 2.05 (m, 1H), 1.75 (dd, J = 13.0, 4.1 Hz, 2H), 1.63 (t, J = 14.4 Hz, 1H) ), 1.43 (t, J = 15.6 Hz, 2H), 1.34 - 1.21 (m, 1H), 1.16 (overlap, 9H), 0.95 (s, 3H), 0.89 (s, 3H).

6α-hydroxy-7-oxoferruginol(6)

Light yellow gum-like solid, slightly soluble in organic solvents such as chloroform, acetone, methanol. ESIMS: 316.94 [M+H] ⁺ , MF: C ₂₀ H ₂₈ O ₃ , ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 6.72 (s, 1H), 5.71 (s, 1H) , 4.65 (dd, J = 12.8, 1.6 Hz, 1H), 3.95 (d, J = 1.8 Hz, 1H), 3.17 (sept, J = 6.9 Hz, 1H), 2.20 (t, J = 5.3 Hz, 1H) , 1.85 (d, J = 12.8 Hz, 1H), 1.77 (tt, J = 13.4, 3.1 Hz, 1H), 1.64 (dt, J = 14.0, 3.7 Hz, 2H), 1.56 - 1.48 (m, 2H), 1.38 (s, 3H), 1.28 (t, J = 6.9 Hz, 6H), 1.25 (s, 3H), 1.22 (s, 3H).

Taxodascen A(7)

Light yellow gelatinous solid. ESIMS: m/z 315.3 [M+H] ⁺ , MF: C ₂₀ H ₂₆ O ₃ , ¹ H NMR (300 MHz, acetone-d ₆ ) δ 8.00 (s, 1H), 6.91 (s, 1H), 6.46 (s, 1H), 3.90 (d, J = 11.5 Hz, 1H), 3.57 (d, J = 11.5 Hz, 1H), 3.22 (sept, J = 6.9 Hz, 1H), 2.31 (m, 1H), 1.90 (m, 1H), 1.83 (m, 1H), 1.68 (m, 1H), 1.62 (m, 1H), 1.51 (s, 3H), 1.36 (m, 1H), 1.42 (s, 3H), 1.24 ( s, 3H), 1.26 (dd, J = 6.9 Hz, 6H).

Fortunin E(8)

Yellow granular solid. ESIMS: m/z 331.0 [M+H] +, MF: C ₂₀ H ₂₆ O ₄ , ¹ H NMR (300 MHz, acetone-d ₆ ) δ 7.92 (s, 1H), 7.09 (s, 1H), 4.15 (d, J = 10.5 Hz, 1H), 3.59 (d, J = 10.5 Hz, 1H), 3.31 (sept, J = 6.9 Hz, 1H), 2.48 - 2.24 (m, 2H), 1.51 (s, 3H) , 1.35 (s, 3H), 1.26 (dd, J = 6.9 Hz, 6H).

6,12-dihydroxyabieta-5,8,11,13-tetraen-7-one(9)

Light yellow powdery solid. ESIMS: m/z 314.9 [M+H] ⁺ , MF: C ₂₀ H ₂₆ O ₃ , ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.01 (s, 1H, H-14), 7.15 (s, 1H) , 6.86 (s, 1H, H-11), 3.18 (sept, J = 7.0 Hz, 1H H-15,), 2.27 (dd, J = 13.9, 5.9 Hz, 1H, H-1β), 2.00–1.82 ( m, 2H), 1.80–1.67 (m, 2H), 1.49 (s, 3H, H-20), 1.43 (s, 6H, H-18 and H-19), 1.28 (d, J = 6.9 Hz, 3H) , H-16), 1.26 (d, J = 6.9 Hz, 3H, H-17).

Taxodascen B(10)

Light yellow solid powder. MF: C20H28O4, ESIMS: m / z 331.0 [MH] -, [α] 22 D 52.3 (c 0.13, MeOH) 1 H NMR (400MHz, CDCl 3) δ6.79 (s, 1H, H-11),. 6.77 (s, 1H, H-14), 4.20 (t, J = 11.4, 4.4 Hz, 1H, H-2), 3.20 (sept, J = 7.0 Hz, 1H, H-15), 2.79 (dd, J =16.3, 4.3 Hz, 1H, H-7a), 2.68 (m, 1H, H-7b), 2.49 (m, 1H, H-1a), 2.47 (m, 1H, H-3a), 2.17 (m, 1H, H-6a), 1.97 (m, 1H, H-6b), 1.24 (m, 1H, H-1b), 1.33 (s, 3H, H-18), 1.16 (d, 3H, J = 6.8 Hz) , H-16), 1.18 (d, 3H, J = 6.8 Hz, H-17), 1.08 (s, 3H, H-20).

Taxodascen C(11)

Light yellow gelatinous solid. MF: C ₂₀ H ₂₆ O ₄ , ESI MS: m/z 328.9 [MH] ^- , ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.52 (s, 1H, H-11), 6.60 (s, 1H, H- 14), 5.16 (d, J = 3.2 Hz, 1H, H-7), 4.85 (dd, J = 5.8, 3.2 Hz, 1H, H-6), 3.19 (sept, J = 7.0 Hz, 1H, H- 15), 2.26 (dd, J = 14.5, 6.0 Hz, 1H, H-3a), 1.46 (dd, J = 13.3, 8.8 Hz, 1H, H-3b), 1.96 (m, 1H, H-1a), 1.61 (m, 1H, H-1b), 1.81 (m, 1H, H-2a), 1.68 (m, 1H, H-2b), 1.81 (d, J = 5.8 Hz, 1H, H-5), 1.28 (s, 3H, H-18), 1.26 (d, 3H, J = 6.8 Hz, H-16), 1.23 (d, 3H, J = 6.8 Hz, H-17), 1.02 (s, 3H, H-) 20).

Taxodascen D(12)

Pale yellow gelatinous solid. MF: C ₂₀ H ₂₈ O ₄ , ESI MS: m/z 330.9 [MH] ^- . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.88 (s, 1H, H-11), 7.15 (s, 1H, H-14), 10.70 (s, 1H, H-7), 3.28 (sept, J = 7.0 Hz, 1H, H-15), 3.20 (s, 1H, H-5), 2.01 ( m, 1H, H-3a), 1.16 (m, 1H, H-3b), 2.11 (m, 1H, H-1a), 1.98 (m, 1H, H-1b), 1.84 (m, 1H, H- 2a), 1.62 (m, 1H, H-2b), 0.93 (s, 3H, H-18), 1.24 (d, 3H, J = 6.9 Hz, H-16), 1.23 (d, 3H, J = 6.9) Hz, H-17), 0.43 (s, 3H, H-19), 1.02 (s, 3H, H-20).

Nortaxodascen A(13)

Light red gelatinous solid. HRESIMS m/z 271.1304 [MH]-, MF: C ₁₇ H ₂₀ O ₃ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.59 (s, 1H, H-11), 7.29 (s, 1H, H-14 ), 7.54 (d, J = 8.3 Hz, 1H, H-7), 7.11 (d, J = 8.3 Hz, 1H, H-6), 3.37 (sept, J = 7.0 Hz, 1H, H-15), 3.20 (s, 1H, H-5), 3.34 (m, 1H, H-1), 2.66 (m, 1H, H-2), 1.34 (d, 6H, J = 6.9 Hz, H-16, 17) , 2.46 (s, 3H, H-20).

20(10->5)abeo-4,5-secoabieta-5(10),6,8,11,13-pentaene-3,4,12-triol(14)

Orange-red powdery solid. ESIMS: m/z 314.9 [MH]-, MF: C ₂₀ H ₂₈ O ₃ , ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.58 (s, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.43(s,1H), 7.09 (dd, J=8.2, 2.7 Hz, 1H), 3.69–3.61 (m, 1H), 3.46–3.26 (m, 2H), 3.03–2.89 (m, 1H), 2.44 ( s, 3H), 1.74 (m, 2H), 1.34 (d, J = 6.9 Hz, 6H), 1.24 (s, 3H), 1.17 (s, 3H).

Nortaxodascen B(15)

An orange-colored powdery solid. MF: C ₂₀ H ₂₈ O _{3 .} ESI MS: m/z 314.9 [MH]-, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56 (s, 1H, H-11), 7.50 (d, J = 8.3 Hz, 1H, H-7), 7.30 (s, 1H, H-14), 7.08 (d, J = 8.3, 1H, H-6), 3.38 (sept, J = 6.9 Hz, 1H, H-15), 3.52 (d, J = 11.4 Hz, H-18a), 3.44 (d, J = 11.4 Hz, H-18b), 2.91 (t, J = 7.9 Hz, 2H, H-1) , 167 (m, 2H, H-2), 1.76 (m, 2H, H-3), 1.32 (d, J = 6.8 Hz, 6H, H-16, 17), 1.11 (s, 3H, H-19 ), 2.41 (s, 3H, H-20).

Nortaxodascen C(16)

Orange-colored gummy solid. MF: C ₂₀ H ₂₆ O _{3 .} ESI MS: m/z 312.9 [MH] ^- , ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56 (s, 1H, H-11), 7.50 (d, J = 8.3 Hz , 1H, H-7), 7.24 (s, 1H, H-14), 7.10 (d, J = 8.3, 1H, H-6), 3.35 (sept, J = 6.9 Hz, 1H, H-15), 3.02 (m, 1H, H-1a), 2.90 (m, 1H, H-1b), 1.67 (m, 2H, H-2b), 1.90 (m, 1H, H-3a), 1.68 (m, 1H, H-3b), 2.45 (m, 1H, H-4), 1.33 (d, J = 6.8 Hz, 6H, H-16, 17), 1.22 (d, J = 6.8 Hz, 3H, H-18), 2.42 (s, 3H, H-20).

Bitaxodascen A(17)

Light yellow granular crystals. [α] ²² _D 90.0 (c 0.08, MeOH), ESIMS: m/z 629 [MH] ^- , ¹ H NMR (600 MHz, CDCl ₃ ) δ 1.55 and 1.28 (m, each 1H, H-1), 1.61 ( m, 2H, H-2), 1.88 and 1.09 (m, each 1H, H-3), 1.71 (d, J = 8.6 Hz, 1H, H-5), 5.35 (d, J = 8.6 Hz, 1H, H-6), 3.97 (s, H-7), 6.87 (s, 1H, H-11), 6.96 (s, 1H, H-14), 3.17 (sept, J = 6.9 Hz, H-15), 1.16and 1.20 (d, J = 6.9 Hz, each 3H, H-16, 17), 1.02 and 1.40 (s, each 3H, H-18, 20), 3.89 (m, 2H, H-19), 3.14 ( s, 3H, 7-OMe); 2.27 and 1.69 (m, each 1H, H-1"), 1.69 and 1.80 (m, each 1H, H-2"), 1.03 and 2.02 (m, each 1H, H- 3"), 2.21 (dd, J = 3.0, 3.0 Hz, 1H, H-5"), 6.05 (dd, J = 9.6, 3.0 Hz, 1H, H-6"), 6.51 (dd, J = 9.6, 3.0 Hz, 1H, H-7"), 7.11 (s, 1H, H-11"), 6.96 (s, 1H, H-14"), 3.27 (sept, J = 6.9 Hz, 1H, H-15" ), 1.03 and 1.08 (d, J = 6.9 Hz, each 3H, H-16", 17"), 1.06 (s, 6H, H-18", 20"), 3.63 and 3.84 (d, J = 10.8 Hz) , H-19"a, 19"b).

Bitaxodascen B(18)

Light yellow powdery crystals. MF: C ₄₀ H ₅₆ O ₅ , ESIMS: m/z 615.43 [MH] ^- , ¹ H NMR (600 MHz, CDCl ₃ ) δ 1.59 and 2.16 (m, each 1H, H-1), 1.59 and 1.74 (m, Each 1H, H-2), 1.05 and 1.97 (m, each 1H, H-3), 1.77 (d, J = 9.1 Hz, 1H, H-5), 5.25 (d, J = 9.1 Hz, 1H, H -6), 4.59 (s, H-7), 6.81 (s, 1H, H-11), 6.97 (s, 1H, H-14), 3.23 (sept, J = 6.8 Hz, H-15), 1.16 And 1.14 (d, J = 6.8 Hz, each 3H, H-16, 17), 1.04 and 1.47 (s, each 3H, H-18, 20), 3.82 and 3.98 (d, J = 10.7 Hz, each 1H, H-19); 2.34 and 1.66 (m, each 1H, H-1"), 1.64 and 1.80 (m, each 1H, H-2"), 1.02 and 1.99 (m, each 1H, H-3"), 2.20 (dd, J=3.0, 3.0 Hz, 1H, H-5"), 6.03 (dd, J = 9.6, 3.0 Hz, 1H, H-6"), 6.50 (dd, J = 9.6, 3.0 Hz, 1H , H-7"), 7.26 (s, 1H, H-11"), 6.94 (s, 1H, H-14"), 3.23 (sept, J = 6.9 Hz, 1H, H-15"), 1.06and 1.10 (d, J = 6.9 Hz, each 3H, H-16", 17"), 1.03 and 1.05 (s, each 3H, H-18", 20"), 3.61 and 3.85 (d, J = 10.9 Hz, H-19"a,19"b).

Bitaxodascen C (19)

Light yellow gelatinous solid. [α] ²² _D 211.4 (c 0.07, MeOH), ESIMS m/z 627.10 [MH] ^- .1H NMR (600 MHz, CDCl ₃ ) δ 1.71 and 2.28 (m, each 1H, H-1), 1.81 and 1.95 (m, each 1H, H-2), 1.19 and 1.85 (m, each 1H, H-3), 2.36 (d, J = 11.3 Hz, 1H, H-5), 6.03 (d, J = 11.3 Hz, 1H, H-6), 4.59 (s, H-7), 6.97 (s, 1H, H-11), 7.69 (s, 1H, H-14), 3.27 (sept, J = 6.9 Hz, H-15) ), 1.20and 1.21 (d, J = 6.8 Hz, each 3H, H-16, 17), 1.14 and 1.42 (s, each 3H, H-18, 20), 3.81 and 3.94 (m, each 1H, H- 19); 2.54 and 1.85 (m, each 1H, H-1"), 1.62 and 1.70 (m, each 1H, H-2"), 1.38 and 1.89 (m, each 1H, H-3"), 6.31 ( s, 1H, H-6"), 7.48 (s, 1H, H-11"), 7.92 (s, 1H, H-14"), 3.39 (sept, J = 6.9 Hz, 1H, H-15") , 1.17and 1.22(d, J=6.9Hz, each 3H, H-16", 17"), 1.24and 1.51(s,each 3H,H-18",20"),3.63and 3.83(m,each 1H , H-19"a, 19"b).

Bitaxodascen D(20)

Yellow powdery solid, [α] ²² _D 128.6 (c 0.08, MeOH). MF: C ₄₀ H ₅₂ O ₄ .ESIMS: m/z 595.1 [MH] ^- , ¹ H NMR (600MHz, CDCl ₃ ) δ1.66and 2.17(m,each 1H,H-1), 1.72(m,2H,H-2),1.10and 1.94(m,each 1H,H-3),1.77(d,J=7.6Hz,1H,H- 5), 5.20 (dd, J = 7.6, 7.3 Hz, 1H, H-6), 4.87 (d, J = 7.4 Hz, 1H, H-7), 6.66 (s, 1H, H-11), 6.69 ( s, 1H, H-14), 2.92 (sept, J=6.9Hz, H-15), 1.14and1.18 (d, J=6.8Hz, each 3H, H-16, 17), 1.21and 1.28(s ,each 3H,H-18,20),3.87and 4.01(d,J=11.0Hz,each 1H,H-19);6.32(s,1H,H-1"),2.08and 2.24(m,each 1H , H-2"), 1.43 and 1.66 (m, each 1H, H-3"), 6.06 (s, 1H, H-6"), 6.31 (s, 1H, H-7"), 6.73 (s, 1H, H-14"), 2.97 (sept, J = 6.9 Hz, 1H, H-15"), 1.17 (d, J = 6.9 Hz, 6H, H-16", 17"), 1.04 and 1.40 (s , each 3H, H-18", 20"), 3.63 and 3.83 (d, J = 11.0 Hz, each 1H, H-19"a, 19"b).

Bitaxodascen E (21)

As a pale yellow powdered ^{_{solid, [α] 22 D 245.7 (}} c 0.07, MeOH), MF: C 40 H 54 O 5 .ESIMS:. M / z 613.2 [MH] - 1 H NMR (600MHz, CDCl 3) δ1. 48 and 2.14 (m, each 1H, H-1), 1.66 and 1.71 (m, each 1H, H-2), 1.14 and 1.82 (m, each 1H, H-3), 1.89 (d, J = 7.4 Hz, 1H, H-5), 5.53 (dd, J = 7.4, 7.8 Hz, 1H, H-6), 4.72 (d, J = 7.4 Hz, 1H, H-7), 6.64 (s, 1H, H-11) ), 6.51 (s, 1H, H-14), 2.89 (sept, J = 6.8 Hz, H-15), 0.70 and 0.85 (d, J = 6.8 Hz, each 3H, H-16, 17), 1.25 and 1.34(s,each 3H,H-18,20),3.87and4.01(d,J=11.0Hz,each 1H,H-19);2.84and 2.99(m,each 1H,H-1"),1.47 And 1.66(m,each 1H,H-2"), 1.47and 2.15(m,each 1H,H-3"),7.13(d,J=8.4Hz,1H,H-6"),7.57(d, J = 8.4 Hz, 1H, H-7"), 7.48 (s, 1H, H-14"), 3.11 (sept, J = 6.9 Hz, 1H, H-15"), 1.26 and 1.27 (d, J = 6.9Hz, each3H, H-16", 17"), 1.03, 2.47and 3.33(s,each 3H,H-18",19",20").

Bitaxodascen F(22)

Yellow amorphous powder. MF: C ₄₀ H ₅₂ O ₄ , [α] ²² _D 213.3 (c 0.07, MeOH), ESIMS: m/z 594.92 [MH] ^- . ¹ H NMR (600 MHz, CDCl ₃ ) δ 1.70 and 2.21 (m, each 1H, H-1), 1.71 and 1.79 (m, each 1H, H-2), 1.72 and 2.19 (m, each 1H, H-3), 1.93 (d, J = 7.8 Hz, 1H, H-5) , 5.48 (t, J = 7.8 Hz, 1H, H-6), 4.81 (d, J = 7.8 Hz, 1H, H-7), 6.68 (s, 1H, H-11), 6.57 (s, 1H, H-14), 2.91 (sept, J=6.8Hz, H-15), 0.74and 0.89 (d, J=6.8Hz, each 3H, H-16, 17), 1.31and 1.32(s,each 3H,H -18, 20), 4.00 and 4.04 (d, J = 10.8 Hz, each 1H, H-19); 2.97 and 3.09 (m, each 1H, H-1"), 2.27 (m, 2H, H-2" ), 5.39 (t, J = 6.6 Hz, 1H, H-3"), 7.18 (d, J = 8.3 Hz, 1H, H-6"), 7.62 (d, J = 8.3 Hz, 1H, H-7) "), 7.52 (s, 1H, H-14"), 3.16 (sept, J = 6.9 Hz, 1H, H-15"), 1.29 and 1.30 (d, J = 6.9 Hz, each 3H, H-16" , 17"), 1.60, 2.52 and 3.93 (s, each 3H, H-18", 19", 20").

1.3. Separation of rosin-type diterpenoids from cedar fruit

The cedar fruit (25Kg) collected from Qixian County, Anhui Province was pulverized, soaked in 95% industrial ethanol three times for 7 days at a time, the extracts were combined, concentrated under reduced pressure to remove ethanol, and after adding 12 L of suspension, respectively, using petroleum ether, Dichloromethane and ethyl acetate were extracted three times, and concentrated under reduced pressure to give a petroleum ether portion 120 g, methylene chloride, 200 g, ethyl acetate Part 47g. The dichloromethane fraction was eluted with MCI resin 30%, 60%, 80%, 95% ethanol solution and acetone, and the obtained fraction was passed through normal phase silica gel (100-200 mesh, 200-300 mesh, silica gel H, etc.). Elution conditions: petroleum ether / acetone, chloroform / acetone, chloroform / methanol), Sephadex LH-20 (chloroform / methanol = 1:1, methanol), MCI resin (methanol / water), preparation of thin layers and preparation of high-efficiency liquid Separate column chromatography for separation and identification of 14 compounds, 9 of which are known rosin-type diterpenes, 6-oxo-abieta-8, 11, 13-triene-11, 12-diol (CS -23, 12 mg), Taxodone (CS-24, 26 mg), 11, 12, 14-trihydroxyabieta-8, 11, 13-trien-7-one (CS-25, 29 mg), 6α-hydroxydemethyl cryptojaponol (CS-26 , 38mg), 6,7-dioxo-abieta-8,11,13-triene-11,12-diol (CS-27,15mg),hypargenin C(CS-28,7mg),6,7-dehydroroyleanone(CS -29,10 mg), 14-deoxycoleon U (CS-30, 12 mg), 7,7"-bistaxodione (CS-31 36 mg); 5 are new rosin-type diterpenes, respectively, two B-ring cracking products Taxodascens E (CS-32, 28 mg) and F (CS-33, 4 mg), and 3 normal rosin-type diterpenoids Taxodascens G (CS-34, 21 mg), H ( CS-35, 11 mg), I (CS-36, 7 mg), J (CS-37, 11 mg).

The characteristics of each compound are as follows:

6-oxo-abieta-8,11,13-triene-11,12-diol(23)

Light yellow powder, MF: C ₂₀ H ₂₈ O ₃ , EI-MS m/z 316 (100%, M ⁺ ), ¹ H-NMR (CDCl ₃ , 400 MHz): δ 6.40 (1H, s), 5.93 ( 1H, br), 5.02 (1H, br), 3.70 (1H, d, J = 20.0 Hz), 3.37 (1H, d, J = 20.0 Hz), 3.24 - 3.16 (1H, m), 3.03 (1H, sept , J = 6.8 Hz), 2.65 (1H, s), 1.81-1.53 (5H, m), 1.35 (3H, s), 1.25 (3H, s), 1.23 (3H, d, J = 6.8 Hz), 1.08 (3H, d, J = 6.8 Hz), 1.02 (3H, s).

Taxodone(24)

Orange-red amorphous powder, MF: C ₂₀ H ₂₈ O ₃ , EI-MS m/z: 316 (26%, M ⁺ ), ¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.11 (3H, d, J = 6.8 Hz), 1.13 (3H, d, J = 6.8 Hz), 1.13 (3H, s), 1.19 (3H, s), 1.19 (3H, s), 1.40 (2H, m), 1.43 (2H, m,), 1.54 (1H, m), 1.55 (2H, m), 1.63 (2H, m), 1.65 (2H, m), 2.89 (2H, m), 3.04 (1H, Sept, J = 6.8 Hz) , 4.67 (1H, br d, J = 10.0 Hz), 6.52 (1H, d, J = 2.7 Hz), 6.79 (1H, s), 7.46 (1H, s).

11,12,14-trihydroxyabieta-8,11,13-trien-7-one(25)

Yellow amorphous powder, MF: C ₂₀ H ₂₈ O ₄ , HR-EI-MS m/z 332.1996 [M] ⁺ , ¹ H-NMR (CDCl ₃ ): δ 12.16 (1H, br s), 6.33 (1H Br s), 4.83 (1H, br s), 3.42 (1H, sept, J = 6.8 Hz), 2.98 (1H, br d, J = 12.4 Hz), 2.57 (1H, m), 1.78 (1H, overlap) , 1.42-1.72 (2H, m), 1.24-1.44 (2H, m), 1.53 (1H, m), 1.32 (6H, d, J = 6.8 Hz), 1.34 (3H, s), 0.94 (3H, s ), 0.92 (3H, s).

6α-Hydroxydemethylcryptojaponol(26)

Light yellow solid, MF: C ₂₀ H ₂₈ O ₄ , EIMS m/z: 332 [M] ⁺ (58), 317 (25), 303 (100), 299 (17), 285 (7), 271 (6 ), 247(46), 235(29), 231(13), 219(23); ¹ H NMR (500MHz, CDCl ₃ ): δ 1.19 (3H, s), 1.24 (3H, s), 1.27and 1.29(each 3H,d,J=6.9Hz)7Hz),1.30and 1.51(each 1H,m),1.54(3H,s),1.53(1H,m),1.72(1H,m),1.82(1H, d, J = 13 Hz), 2.97 (1H, m), 3.00 (1H, sept, J = 6.9 Hz), 3.87 (1H, d, J = 2.5 Hz), 4.59 (1H, dd, J = 13, 2.5 Hz) ), 5.64 and 5.68 (each1H, br s), 7.58 (1H, s).

6,7-dioxo-abieta-8,11,13-triene-11,12-diol(27)

Light yellow solid, MF: C ₂₀ H ₂₆ O ₄ , EI MS: m/z 330 (100%, M ⁺ ), ¹ H-NMR (CDCl ₃ , 400 MHz): δ 7.63 (1H, s), 6.60 ( 1H, s), 3.14 - 2.84 (2H, m), 2.71 (1H, s), 1.2-1.8 (5H, m), 1.41 (3H, s), 1.27 (3H, s), 1.08 (3H, d, J = 6.5 Hz), 1.07 (3H, d, J = 6.5 Hz), 1.05 (3H, s).

Hypargenin C (28)

White amorphous powder, MF: C ₂₀ H ₂₆ O _{3 .} EI MS: m/z 314 (50%, M ⁺ ), ¹ H NMR (CDCl ₃ , 400 MHz): δ 1.12 (3H, s), 1.12 (3H, s), 1.32 (3H, s), 1.18 (3H, d, J = 7 Hz), 1.20 (3H, d, J = 7 Hz), 1.0-1.8 (m), 2.60 (1H, s), 2.8 (1H, dd, J = 3, 12 Hz), 3.08 (1H, m), 6.24 (1H, s), 6.90 (1H, s), 7.58 (1H, s).

6,7-Dehydroroyleanone(29)

Red needle crystal, mp: 171 ° C, MF: C ₂₀ H ₂₆ O ₃ ; EI MS: m/z 314 (79%, M ⁺ ), ¹ H-NMR (CDCl ₃ , 400 MHz): δ 0.98 (3H) , s), 1.01 (3H, s), 1.03 (3H, s), 1.21 (3H, d, J = 7.1 Hz), 1.22 (3H, d, J = 7.2 Hz), 1.25 (2H, m), 1.43 (2H, td, J = 13.3 Hz), 1.51 (2H, m), 1.62 (2H, m), 1.71 (2H, m), 2.14 (1H, t, J = 3.1 Hz), 2.89 (2H, d, J = 3.4 Hz), 3.17 (1H, hept, J = 7.1 Hz), 6.46 (1H, dd, J = 3.0 Hz), 6.81 (1H, dd, J = 3.1 Hz), 7.34 (1H, s).

14-Deoxycoleon U(30)

Light yellow powder, MF: C ₂₀ H ₂₆ O ₄ , EI MS: m/z 330 [M] ⁺ (49), 315 (11), 287 (13), 274 (11), 260 (100), 248 ( 17), 245 (16), 233 (11), 217 (9), ¹ H NMR (500 MHz, CDCl ₃ ): δ 1.27 and 1.30 (each 3H, d, J = 6.8 Hz), 1.41 (1H, m ), 1.43and 1.44(each 3H,s),1.61and 1.86(each1H,m),1.71and 2.93(each 1H,m),2.01(1H,td,J=13and 5Hz),3.04(1H,quint), 7.09 (1H, s), 7.70 (1H, s).

7,7"-Bistaxodione(31)

Red amorphous powder, MF: C ₄₀ H ₅₀ O ₆ , EI MS: m/z 626 (100%, M ⁺ ), ¹ H-NMR (CDCl3, 400 MHz) δ 7.63 (2H, s), 6.60 (2H) , d, J = 1.2 Hz, H-14), 2.98 (2H, d sept, J = 1.2, 7 Hz), 2.71 (2H, s), 1.08, 1.10 (each 6H, d, J = 7 Hz), 1.41, 1.24, 1.05 (each 6H, s).

Taxodascens E(32)

White solid, MF: C ₁₉ H ₂₄ O ₄ , ESI-MS: m/z 317 [M+H] ⁺ , ¹ H-NMR (CDCl ₃ , 400 MHz): δ 6.37 (1H, d, J = 1.2 Hz ), 3.16-2.95 (1H, m), 2.87 (1H, dd, J = 13.8, 1.6 Hz), 2.31 (1H, s), 1.18-1.76 (m), 1.27 (6H, s), 1.14 (6H, s), 1.12 (3H, d, J = 2.0 Hz).

Taxodascens F(33)

White solid, MF: C ₂₁ H ₃₀ O ₅ , ESI-MS: m/z 363 [M+H] ⁺ , ¹ H-NMR (CDCl ₃ , 400 MHz): δ 7.70 (1H, s), 6.39 (1H) , d, J = 1.3 Hz), 4.31 (1H, d, J = 18.2 Hz), 4.07 (1H, d, J = 18.2 Hz), 3.61 (1H, s), 3.46 (3H, s), 3.03-2.94 (1H, m), 2.55 (1H, d, J = 14.1 Hz), 1.07-1.90 (m), 1.22 (3H, s), 1.16 (3H, d, J = 2.8 Hz), 1.15 (3H, d, J = 2.7 Hz), 0.83 (3H, s), 0.81 (3H, s).

Taxodascens G(34)

a pale yellow amorphous powder, MF: C ₂₆ H ₃₈ O ₆ , ESI-MS: m/z 447 [M+H] ⁺ , ¹ H-NMR (CDCl ₃ , 400 MHz): δ 7.11 (1H, s), 5.20 (1H, dd, J = 12.0, 3.3 Hz), 4.48 (1H, d, J = 3.3 Hz), 3.88 (1H, dt, J = 8.7, 5.8 Hz), 3.59 (1H, dt, J = 8.7, 5.8 Hz), 3.16 (1H, p, J = 7.1 Hz), 2.64 (1H, d, J = 12.6 Hz), 2.15 (3H, s), 0.89-1.70 (m), 1.36 (3H, s), 1.22 (3H, d, J = 7.2 Hz), 1.19 (3H, d, J = 7.1 Hz), 1.17 (3H, s), 0.95 (3H, s).

Taxodascens H(35)

a pale yellow amorphous powder, MF: C ₂₃ H ₃₄ O ₄ , ESI-MS: m/z 372 [M+H] ⁺ , ¹ H-NMR (CDCl ₃ , 400 MHz): δ 6.97 (1H, s), 5.68 (1H, s), 5.06 (1H, d, J = 6.6 Hz), 4.52 (1H, dd, J = 8.9, 6.6 Hz), 3.04 (1H, p, J = 6.9 Hz), 2.84 (1H, d , J = 12.2 Hz), 1.30 - 1.85 (m), 1.54 (1H, d, J = 8.9 Hz), 1.47 (3H, s), 1.43 (3H, s), 1.27 (3H, d, J = 6.8 Hz) ), 1.25 (3H, d, J = 6.8 Hz), 1.24 (3H, s), 1.13 (3H, s), 1.08 (3H, s).

Taxodascens I(36)

Light yellow amorphous powder, MF: C ₂₄ H ₃₆ O ₄ , ESI-MS: m/z 389[M+H] ⁺ , ¹ H-NMR (CDCl ₃ , 400 MHz): δ 6.88 (1H, s) , 4.56 (1H, d, J = 4.8 Hz), 3.91 (1H, d, J = 4.6 Hz), 3.88 (1H, m), 3.59 (1H, m), 2.980-2.86 (1H, m), 2.58 ( 1H, d, J = 12.8 Hz), 2.30 (1H, s), 1.04-1.82 (m), 1.62 (3H, s), 1.56 (3H, s), 1.12 (3H, d, J = 4.0 Hz), 1.10 (3H, d, J = 4.0 Hz), 1.00 (3H, s), 0.99 (3H, t).

Taxodascens J (37)

Yellow a qualitative powder, MF: C ₄₀ H ₅₆ O ₆ , MS (ESI) m/z 632 (M) ⁺ , 1H-NMR (CDCl ₃ , 400 MHz): δ 7.09 (1H, s), 6.86 (1H, s), 4.64 (1H, d, J = 4.5 Hz), 4.58 (1H, d, J = 8.7 Hz), 4.46 (1H, dd, J = 12.4, 4.5 Hz), 3.94 (1H, dd, J = 11.3) , 8.8 Hz), 2.97-3.09 (2H, m), 2.82-2.93 (2H, m), 2.26 (1H, d, J = 12.4 Hz), 1.74 (1H, d, J = 11.1 Hz), 1.15-1.80 (m), 1.52 (3H, s), 1.42 (3H, s), 1.40 (3H, s), 1.31 (3H, s), 1.24-1.28 (15H, m), 1.13 (3H, s);

1.4. Separation of rosin-type diterpenoids from Chinese fir bark

The bark of Cunninghamia lanceolata (13.5 Kg) was pulverized into a coarse powder, which was soaked three times with industrial acetone at room temperature for 7 days, and the extracts were combined and concentrated under reduced pressure to remove acetone. After adding 10 L of 35 ° C distilled water, it was extracted three times with petroleum ether, dichloromethane and ethyl acetate, and concentrated under reduced pressure to obtain 15 g of petroleum ether, 160 g of dichloromethane, and 470 g of ethyl acetate. The methylene chloride is subjected to normal phase silica gel (100-200 mesh, 200-300 mesh, silica gel H, etc.), elution conditions: petroleum ether/acetone, chloroform/acetone, chloroform/methanol), Sephadex LH-20 (chloroform/methanol) =1:1, methanol), MCI resin (methanol/water, ethanol/water), preparative thin layer and preparative high performance liquid chromatography were separated by column chromatography. A total of 24 compounds were isolated and identified, 14 of which were new compounds. It is 12 rosin-type diterpene dimers Picuningine A (27, 25 mg), Bicunningine B (28, 5 mg), Bicunningine C (29, 70 mg), Bicunningine D (30, 6 mg), Bicunningine E (31, 4 mg) , Bicunningine F (32, 14 mg), Bicunningine G (33, 34 mg), Bicunningine H (34, 25 mg), Bicunningine I (35, 25 mg), Bicunningine J (36, 26 mg), Bicunningine K (37, 15 mg), Bicunningine L (38, 5 mg), 2 rosinane diterpenoids Cunningine A (43, 20 mg), Cunningine B (44, 9 mg); two known compounds were identified as: Hinokiol (42) and 6α-hydroxy-7 -oxo-ferruginol (52, same as 6).

The above compounds have the following physicochemical and spectrographic characteristics:

Bicunningine A(27)

White amorphous powder. MF: C ₄₀ H ₅₀ O ₄ , ESIMS: m/z 595.4 [M+H] ⁺ . ¹ H NMR (600 MHz, CDCl ₃ ) δ 2.06 and 2.51 (m, each 1H, H-1), 2.54 and 3.03 ( m, each 1H, H-2), 2.15 (d, J = 7.4 Hz, 1H, H-5), 5.29 (dd, J = 7.4, 8.1 Hz, 1H, H-6), 4.91 (d, J = 8.1 Hz, 1H, H-7), 6.63 (s, 1H, H-11), 6.55 (s, 1H, H-14), 2.88 (sept, J = 6.9 Hz, 1H, H-15), 0.69 and 0.87 (d, J = 6.9 Hz, each 3H, H-16, 17), 1.35, 1.42, 1.55 (s, each 3H, H-18, 19, 20); 2.67 (m, 2H, H-1") , 3.12 and 3.37 (m, each 1H, H-2"), 2.52 (sept, J = 6.9 Hz, 1H, H-4"), 7.17 (d, J = 8.1 Hz, 1H, H-6"), 7.61 (d, J = 8.1 Hz, 1H, H-7"), 7.51 (s, 1H, H-14"), 3.05 (sept, J = 6.9 Hz, 1H, H-15"), 1.27 (d, J=6.9Hz, 6H, H-16", 17"), 1.03and 1.04 (d, J=6.9Hz, each 3H, H-18", 19"), 2.50 (s, 3H, H-20") .

Bicunningine B (28)

White amorphous powder. MF: C ₄₀ H ₅₂ O ₄ , ESIMS: m/z 595.4 [MH] ⁺ . ¹ H NMR (600 MHz, CDCl ₃ ) δ 1.79 and 2.19 (m, each 1H, H-1), 1.93 and 3.11 (m, Each 1H, H-2), 3.41 (m, 1H, H-3), 1.76 (d, J = 8.3 Hz, 1H, H-5), 5.23 (dd, J = 7.8, 8.3 Hz, 1H, H- 6), 4.76 (d, J = 7.8 Hz, 1H, H-7), 6.63 (s, 1H, H-11), 6.50 (s, 1H, H-14), 2.89 (sept, J = 6.9 Hz, 1H, H-15), 0.69 and 0.86 (d, J = 6.9 Hz, each 3H, H-16, 17), 1.17, 1.28, 1.30 (s, each 3H, H-18, 19, 20); 2.66 ( m, 2H, H-1"), 3.11 and 3.35 (m, each 1H, H-2"), 2.51 (sept, J = 6.9 Hz, 1H, H-4"), 7.15 (d, J = 8.2 Hz) , 1H, H-6"), 7.60 (d, J = 8.2 Hz, 1H, H-7"), 7.50 (s, 1H, H-14"), 3.11 (sept, J = 6.9 Hz, 1H, H -15"), 1.27and 1.28 (d, J = 6.9 Hz, each 3H, H-16", 17"), 1.01 and 1.03 (d, J = 6.9 Hz, each 3H, H-18", 19"), 2.48(s,3H,H-20").

Bicunningine C (29)

Light yellow amorphous powder. MF: C ₄₁ H ₅₈ O ₅ , [α] ²² _D 189 (c 0.09, CHCl ₃ ), EIMS: m/z 630 [M] ⁺ , 598, 331, 300, 267, 213, 199, 185, 159. ¹ H NMR (600 MHz, CDCl ₃ ) δ 1.72 and 2.10 ( m,each 1H,H-1), 1.90 (m, 2H, H-2), 3.33 (m, 1H, H-3), 1.66 (d, J = 7.9 Hz, 1H, H-5), 4.93 ( d, J = 7.9 Hz, 1H, H-6), 3.98 (s, 1H, H-7), 6.73 (s, 1H, H-11), 6.88 (s, 1H, H-14), 3.14 (sept , J = 6.8 Hz, H-15), 1.20 and 1.24 (d, J = 6.8 Hz, each 3H, H-16, 17), 1.01, 1.15 and 1.36 (s, each 3H, H-18, 19, 20), 3.13 (s, 3H, 7-OMe); 1.87 and 2.25 (m, each 1H, H-1"), 1.90 (m, 2H, H-2"), 3.41 (m, 1H, H-3) "), 2.16 (dd, J = 3.0, 3.0 Hz, 1H, H-5"), 5.89 (dd, J = 9.7, 3.0 Hz, 1H, H-6"), 6.56 (dd, J = 9.7, 3.0) Hz, 1H, H-7"), 6.98 (s, 1H, H-11"), 6.94 (s, 1H, H-14"), 3.12 (sept, J = 6.9 Hz, 1H, H-15") , 1.03 and 1.04 (d, J = 6.9 Hz, each 3H, H-16", 17"), 1.11, 1.05 and 1.12 (s, each 3H, H-18", 19", 20").

Bicunningine D (30)

Light yellow amorphous powder. MF: C ₄₁ H ₅₈ O ₄ , EIMS: m/z 614 [M] ⁺ , ¹ H NMR (600 MHz, CDCl ₃ ) δ 1.30 and 1.48 (m, each 1H, H-1), 1.67 and 1.83 (m, Each 1H,H-2),1.57and 2.14(m,each 1H,H-3),1.65(d,J=8.4Hz,1H,H-5),4.89(d,J=8.4Hz,1H,H -6), 3.96 (s, 1H, H-7), 6.75 (s, 1H, H-11), 6.88 (s, 1H, H-14), 3.14 (sept, J = 6.9 Hz, H-15) , 1.20 and 1.24 (d, J = 6.9 Hz, each 3H, H-16, 17), 0.92, 1.16 and 1.39 (s, each 3H, H-18, 19, 20), 3.16 (s, 3H, 7- OMe); 1.85 and 2.17 (m, each 1H, H-1"), 1.84 and 1.93 (m, each 1H, H-2"), 3.41 (m, 1H, H-3"), 2.17 (m, 1H) , H-5"), 5.89 (d, J = 9.7 Hz, 1H, H-6"), 6.55 (d, J = 9.7 Hz, 1H, H-7"), 7.01 (s, 1H, H-11) "), 6.95 (s, 1H, H-14"), 3.14 (sept, J = 6.9 Hz, 1H, H-15"), 1.04 and 1.07 (d, J = 6.9 Hz, each 3H, H-16" , 17"), 1.11, 1.07 and 1.12 (s, each 3H, H-18", 19", 20").

Bicunningine E (31)

Light yellow amorphous powder. MF: C ₄₁ H ₅₆ O ₆ , ESIMS: m/z 645 [M+H] ⁺ . ¹ H NMR (600 MHz, CDCl ₃ ) δ 2.09 and 2.13 (m, each 1H, H-1), 1.98 and 2.16 ( m, each 1H, H-2), 3.30 (m, 1H, H-3), 1.66 (m, 1H, H-5), 5.04 (d, J = 8.1 Hz, 1H, H-6), 4.13 ( s, 1H, H-7), 6.89 (s, 1H, H-11), 7.03 (s, 1H, H-14), 3.28 (sept, J = 6.9 Hz, H-15), 1.15 and 1.20 (d , J=6.9Hz, each 3H, H-16, 17), 0.92, 1.10and 1.40 (s, each 3H, H-18, 19, 20), 3.20 (s, 3H, 7-OMe); 1.74 and 2.58 (m, each 1H, H-1"), 1.85 (m, 2H, H-2"), 3.43 (m, 1H, H-3"), 6.42 (s, 1H, H-6"), 7.36 ( s, 1H, H-11"), 7.92 (s, 1H, H-14"), 3.19 (sept, J = 6.9 Hz, 1H, H-15"), 1.02 and 1.14 (d, J = 6.9 Hz, Each 3H,H-16",17"),1.33,1.37and 1.66(s,each 3H,H-18",19",20").

Bicunningine F (32)

Light yellow amorphous powder. MF: C ₄₁ H ₅₈ O ₅ , ESIMS: m/z 629 [M+H] ⁺ . ¹ H NMR (600 MHz, CDCl ₃ ) δ 1.46 and 1.71 (m, each 1H, H-1), 1.73 and 2.52 ( m, each 1H, H-2), 3.35 (m, 1H, H-3), 1.70 (d, J = 8.2 Hz, 1H, H-5), 4.92 (d, J = 8.2 Hz, 1H, H- 6), 4.02 (s, 1H, H-7), 6.75 (s, 1H, H-11), 6.90 (s, 1H, H-14), 3.16 (sept, J = 6.9 Hz, 1H, H-15) ), 1.19 and 1.23 (d, J = 6.9 Hz, each 3H, H-16, 17), 0.96, 1.13 and 1.40 (s, each 3H, H-18, 19, 20), 3.15 (s, 3H, 7) -OMe); 1.74 and 2.16(m,each 1H,H-1"), 1.13and 1.78(m,each 1H,H-2"), 1.38and 1.88(m,each 1H,H-3"),6.49 (s, 1H, H-6"), 7.25 (s, 1H, H-11"), 8.02 (s, 1H, H-14"), 3.16 (sept, J = 6.9 Hz, 1H, H-15" ), 1.05 and 1.14 (d, J = 6.9 Hz, each 3H, H-16", 17"), 1.28, 1.38 and 1.64 (s, each 3H, H-18", 19", 20").

Bicunningine G (33)

Light yellow amorphous powder. MF: C ₄₁ H ₅₆ O ₅ , ESI MS: m/z </ s[M+H] ⁺ . ¹ H NMR (600 MHz, CDCl ₃ ) δ 1.58 and 2.12 (m, each 1H, H-1), 1.68 (m, 2H, H-2), 1.30and 1.46 (m, each 1H, H-3), 1.70 (d, J = 8.2 Hz, 1H, H-5), 4.92 (d, J = 8.2 Hz, 1H, H- 6), 4.02 (s, 1H, H-7), 6.77 (s, 1H, H-11), 6.89 (s, 1H, H-14), 3.18 (sept, J = 6.9 Hz, 1H, H-15) ), 1.19 and 1.22 (d, J = 6.9 Hz, each 3H, H-16, 17), 0.87, 1.13 and 1.39 (s, each 3H, H-18, 19, 20), 3.14 (s, 3H, 7) -OMe); 1.78 and 2.52 (m, each 1H, H-1"), 1.41 and 2.02 (m, each 1H, H-2"), 3.45 (dd, J = 11.3, 4.7 Hz, 1H, H-3 "), 6.56 (s, 1H, H-6"), 7.27 (s, 1H, H-11"), 8.01 (s, 1H, H-14"), 3.20 (sept, J = 6.9 Hz, 1H, H-15"), 1.06 and 1.14 (d, J = 6.9 Hz, each 3H, H-16", 17"), 1.33, 1.37 and 1.64 (s, each 3H, H-18", 19", 20" ).

Bicunningine H (34)

Light yellow amorphous powder. MF: C ₄₀ H ₅₂ O ₅ , ESIMS: m/z 623 [M+H] ⁺ . ¹ H NMR (600 MHz, CDCl ₃ ) δ 2.54 and 2.86 (m, each 1H, H-1), 2.09 and 2.49 ( m, each 1H, H-2), 1.77 (s, 1H, H-5), 4.96-4.97 (m, 2H, H-6, 7), 6.65 (s, 1H, H-11), 6.95 (s , 1H, H-14), 2.69 (sept, J = 6.9 Hz, 1H, H-15), 0.89 and 1.21 (d, J = 6.9 Hz, each 3H, H-16, 17), 1.03 and 1.47 ( s,each 3H,H-18,19),3.08and 4.40(d,J=8.4Hz,2H,H-20);1.84and 2.30(m,each 1H,H-1"),1.83and 1.95(m , each 1H, H-2"), 3.42 (dd, J = 10.8, 4.3 Hz, 1H, H-3"), 2.14 (d, J = 3.0 Hz, 1H, H-5"), 5.90 (d, J = 9.6, 3.0 Hz, 1H, H-6"), 6.53 (d, J = 9.6, 3.0 Hz, 1H, H-7"), 6.89 (s, 1H, H-11"), 6.86 (s, 1H, H-14"), 3.19 (sept, J = 6.9 Hz, 1H, H-15"), 0.89 and 1.15 (d, J = 6.9 Hz, each 3H, H-16", 17"), 1.05, 1.10and 1.12(s,each 3H,H-18",19",20").

Bicunningine I(35)

Yellow amorphous powder. MF: C ₄₀ H ₅₀ O ₅ , ESIMS: m/z 611.5 [M+H] ⁺ . ¹ H NMR (600 MHz, CDCl ₃ ) δ 2.50 and 2.90 (m, each 1H, H-1), 2.17 and 2.53 ( m, each 1H, H-2), 1.82 (d, J = 4.3 Hz, 1H, H-5), 5.16 (dd, J = 4.3, 4.0 Hz, 1H, H-6), 5.19 (d, J = 4.0 Hz, 1H, H-7), 6.67 (s, 1H, H-11), 6.88 (s, 1H, H-14), 3.14 (sept, J = 6.9 Hz, 1H, H-15), 1.09and 1.16 (d, J = 6.9 Hz, each 3H, H-16, 17), 1.13 and 1.53 (s, each 3H, H-18, 19), 3.09 and 4.46 (d, J = 8.6 Hz, each 1H, H-20); 2.81 (m, 2H, H-1"), 3.36-3.46 (m, 2H, H-2"), 2.60 (sept, J = 6.9 Hz, 1H, H-4"), 7.17and 7.53 (d, J = 8.3 Hz, each 1H, H-6", 7"), 7.55 (s, 1H, H-11"), 7.50 (s, 1H, H-14"), 3.09 (sept, J =6.9 Hz, 1H, H-15"), 0.90 and 1.01 (d, J = 6.9 Hz, each 3H, H-16", 17"), 1.11 and 1.08 (d, J = 6.9 Hz, each 3H, H -18", 19"), 2.50 (s, 3H.H-20").

Bicunningine J (36)

Yellow amorphous powder. MF: C ₄₀ H ₅₂ O ₄ , ESI MS: m/z 595.4 [MH] ⁺ . ¹ H NMR (600 MHz, CDCl ₃ ) δ 2.78 (m, 2H, H-1), 3.34 (m, 2H, H- 2), 2.63 (sept, J=6.9 Hz, 1H, H-4), 6.79 (s, 1H, H-7), 7.22 (s, 1H, H-11), 7.36 (s, 1H, H-14) ), 3.31 (sept, J = 6.9 Hz, 1H, H-15), 1.29 and 1.30 (d, J = 6.9 Hz, each 3H, H-16, 17), 1.13 (d, J = 6.9 Hz, 6H, H) -18,19); 2.42 (s, 3H, H-20); 1.60 (dt, J = 12.6, 4.7 Hz, 1H, H-1a"), 1.91 (dt, J = 12.6, 2.9 Hz, 1H, H -1b"), 1.77 (m, 2H, H-2"), 3.36 (m, 1H, H-3"), 2.15 (d, J = 2.7 Hz, 1H, H-5"), 5.95 (dd, J=9.7, 2.7 Hz, H-6"), 6.63 (d, J = 9.7, 2.7 Hz, 1H, H-7"), 6.64 (s, 1H, H-11"), 7.07 (s, 1H, H-14"), 3.19 (sept, J = 6.9 Hz, 1H, H-15"), 1.21 and 1.25 (d, J = 6.9 Hz, each 3H, H-16", 17"), 1.11 1.02 and 1.02 ( s,each 3H,H-18",19",20").

Bicunningine K (37)

Yellow amorphous powder. MF: C ₄₀ H ₅₂ O ₄ , ESIMS: m/z 615.3 [M+H] ⁺ . ¹ H NMR (600 MHz, CDCl ₃ ) δ 1.71 and 1.86 (m, each 1H, H-1), 1.73 and 1.88 ( m, each 1H, H-2), 3.31 (dd, J = 10.9, 4.3 Hz, 1H, H-3), 1.73 (d, J = 9.2 Hz, 1H, H-5), 5.04 (d, J = 9.2 Hz, 1H, H-6), 3.58 (s, 1H, H-7), 6.38 (s, 1H, H-11), 5.98 (s, 1H, H-14), 3.00 (sept, J = 6.9) Hz, 1H, H-15), 1.04 and 1.06 (d, J = 6.9 Hz, each 3H, H-16, 17), 1.07 (d, J = 6.9 Hz, 6H, H-18, 19); 1.34 ( s, 3H, H-20); 1.84 and 2.31 (m, each 1H, H-1"), 1.97 and 1.88 (m, each 1H, H-2"), 3.40 (d, J = 10.9, 4.3 Hz, 1H, H-3"), 2.15 (d, J = 2.7 Hz, 1H, H-5"), 5.93 (dd, J = 9.6, 2.7 Hz, H-6"), 6.55 (d, J = 9.6, 2.7 Hz, 1H, H-7"), 6.83 (s, 1H, H-11"), 6.97 (s, 1H, H-14"), 3.25 (sept, J = 6.9 Hz, 1H, H-15" ), 1.13and 1.14(d, J=6.9Hz, each 3H, H-16", 17"), 1.10 1.05and 1.10(s,each 3H,H-18",19",20").

Bicunningine L (38)

Light yellow amorphous powder. MF: C ₄₁ H ₅₆ O ₅ , EIMS: m/z 628 [M] ⁺ , ¹ H NMR (600MHz, CDCl ₃ ) δ 1.77 and 2.17 (m, each 1H, H-1), 1.78 and 1.91 (m, Each 1H, H-2), 3.38 (m, 1H, H-3), 1.73 (d, J = 7.9 Hz, 1H, H-5), 5.04 (d, J = 7.9 Hz, 1H, H-6) , 4.22 (s, 1H, H-7), 6.76 (s, 1H, H-11), 6.88 (s, 1H, H-14), 3.15 (sept, J = 6.8 Hz, H-15), 1.16and 1.21 (d, J = 6.8 Hz, each 3H, H-16, 17), 1.01, 1.14 and 1.41 (s, each 3H, H-18, 19, 20), 3.13 (s, 3H, 7-OMe); 2.73 and 3.04 (m, each 1H, H-1"), 3.38 (m, 2H, H-2"), 2.72 (m, 1H, H-4"), 7.17 (d, J = 8.2 Hz, 1H, H-6"), 7.56 (d, J = 8.2 Hz, 1H, H-7"), 7.56 (s, 1H, H-11"), 7.61 (s, 1H, H-14"), 3.28 (sept , J=6.9Hz, 1H, H-15"), 1.07and 1.22 (d, J=6.9Hz, each 3H, H-16", 17"), 1.15(s,6H,H-18",19" ), 2.49 (s, 3H, H-20").

Hinokiol(39)

Light yellow powdery solid, easily soluble in organic solvents such as chloroform, acetone and methanol. MW: 302, MF: C ₂₀ H ₃₀ O ₂ . ¹ H NMR (300MHz, CDCl ₃ ) δ 0.87 (3H, s, H-18), 1.04 (3H, s, H-19), 1.15 (3H, s, H-20), 1.22 (3H, d, H-16), 1.24 (3H, d, H-17), 2.23 (d, H-5), 2.75 (1H, m, H-7a), 2.86 (1H, dd, J = 16.5, 5.5 Hz, H-7β), 3.08 (1H, m, H-15), 3.27 (1H, dd, J = 11.6, 4.8 Hz, H-3), 6.61 (1H, s, H-11), 6.74 (1H, s, H-14).

Cunningine A (40)

Light yellow powdery solid. _{_{_{MF: C 20 H 24 O 4}}} , ESIMS: m / z 331.2 [M + H] +, 1 H NMR (400MHz, CDCl 3) δ7.90 (s, 1H, H-14), 6.69 (s, 1H, H-11), 4.46 (d, J = 12.8 Hz, 1H, H-6), 3.16 (sept, J = 6.9 Hz, 1H, H-15), 2.47 (d, J = 12.8 Hz, 1H, H- 5), 2.80 and 2.52 (m, each 1H, H-2), 2.33 and 2.17 (m, each 1H, H-1), 1.27 (d, J = 6.9 Hz, 6H, H-16, 17), 1.49 , 1.39, 1.30 (s, each 3H, H-18, 19, 20),

Cunningine B (41)

Light yellow powdery solid. MF: C ₂₀ H ₂₄ O ₄ , ESI MS: m/z 329.2 [M+H] ⁺ , ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.07 (s, 1H, H-14), 6.89 (s, 1H, H-11), 3.22 (sept, J=6.9Hz, 1H, H-15), 2.77 (m, 2H, H-2), 2.41 and 2.07 (m, each 1H, H-1), 1.28 (d, J = 6.9 Hz, 6H, H-16, 17), 1.28, 1.54, 1.58 (s, each 3H, H-18, 19, 20).

1.5. Semi-synthesis and separation of carnosic acid derivatives

1.5.1 Purification of Carnosic Acid (CA-1)

The crude carnosic acid 16g (commercially available, 40%) was dissolved in 25ml of dichloromethane, and 100ml of saturated NaHCO3 solution was added. After no bubbles were generated, it was placed in a separatory funnel and shaken thoroughly to separate the dichloromethane layer. After the aqueous phase was further washed with dichloromethane for three times, the dichloromethane layer was discarded. After the aqueous phase was added to a 2M HCl solution to adjust the pH to acidity, the mixture was extracted three times with 25 ml of dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and decolorized with activated carbon and then distilled under reduced pressure to obtain pure product of carnosic acid.

1.5.2. Synthesis of carnosol (Carnosol, CA-2)

Carnosic acid (6.64 g, 20 mmol) was dissolved in 6 ml of acetic acid, and after adding catalytic equivalent of FeCl ₃ (6 mg), 2 ml of hydrogen peroxide was added at 15 ° C, and the reaction was kept at 15 ° C for 2 hours, then 1 ml of concentrated was added. Hydrochloric acid, reacted overnight. The reaction solution was diluted with water to 400 ml, and extracted with dichloromethane (3 ml), and the mixture was evaporated. 1) Purification to obtain 4.62 g (1.4 mmol, yield: 70%) of carnosol. The physicochemical properties of the compound are as follows:

Carnosol (Car-2), white solid, C ₂₀ H ₂₆ O ₄ , ESI-MS: m/z 331.2 [M+H] ⁺ , ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.86 ( 3H, s, Me-19), 0.90 (3H, s, Me-18), 1.22 (6H, d, J = 7.0 Hz, Me-16/17), 1.31 (1H, dd, J = 3.5, 14.0 Hz) , H-3α), 1.73 (1H, q, H-5), 1.90 (1H, td, H-6β), 1.99 (1H, dt, H-2β), 2.20 (1H, m, H-6α), 2.33, 2.39, 2.46 (1H, td, J = 4.3, 14.0 Hz, H-1α), 2.90 (1H, br d, H-1β), 3.08 (1H, sept, J = 7.0 Hz, H-15), 5.26 (1H, br s, Ar-OH), 5.37 (1H, dd, J = 1.4, 4.0 Hz, H-7), 5.73 (1H, br s, Ar-OH), 6.64 (1H, s, H- 14).

1.5.3. Synthesis of rosinol (CA-3)

The carnosol (CA-2) (52.1 mg, 0.158 mmol) was dissolved in 5 ml of acetone, and 5% NaHCO ₃ (6 ml, 3.57 mmol) was added at room temperature, and the mixture was stirred at room temperature for 12 h and then distilled under reduced pressure. Acetone was removed, and the mixture was acidified with EtOAc EtOAc. The organic phase was combined, washed with saturated brine and dried over anhydrous sodium sulfate, and evaporated and evaporated to remove the residue. The residue was purified by silica gel column chromatography ( petroleum ether: acetone 4:1) to obtain rosmanol (CA-3) ) 36mg, the yield is 70%. ¹ H NMR (400 MHz, Acetone-d ₆ ) δ 0.93 (3H, s, Me-19), 1.03 (3H, s, Me-18), 1.22, 1.23 (each 3H, d, J = 7.0 Hz, Me -16/17), 2.00 (1H, td, H-1α), 2.21 (1H, s, H-5), 3.20 (1H, sept, J = 7.0 Hz, H-15), 3.21 (1H, br d , H-1β), 4.57 (1H, d, J = 3.3 Hz, H-6), 4.74 (1H, d, J = 3.3 Hz, H-7), 6.87 (1H, s, H-14); EIMS m/z 346[M] ⁺ (100).

By using different bases, 7-methoxy rosmarin (CA-4) and 7-ethoxy rosmarin (CA-5), ¹ H NMR and EIMS data were obtained by the same procedure as above. Consistent with the literature (J. Nat. Prod. 2002, 65, 986-989.).

1.5.4. Synthesis of carnosic acid γ-lactone (CA-6)

Carnosic acid (CA-1) (62.8 mg, 0.2 mmol) and 4-dimethylaminopyridine (36.6 mg, 0.3 mmol) were dissolved in 10 ml of dichloromethane, and dicyclohexylcarbodiimide (61.8 mg, 0.3 mmol). The reaction solution was stirred at room temperature overnight, filtered, and dichloromethane was evaporated under reduced pressure. The residue was purified by silica gel column chromatography ( petroleum ether: acetone 5:1) to obtain gamma-lactone (CA-6) 32 mg. The yield is 51%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.09 (3H, s,Me-19), 1.16 (3H, s,Me-18), 1.22 and 1.24 (each 3H, d, J = 7.0 Hz, Me-16 /17), 1.81 and 2.22 (each 1H, m, H-1), 1.71 and 2.00 (each 1H, m, H-2), 1.39 and 2.12 (each 1H, m, H-3), 1.88 (1H, m, H-5), 1.6-1.94 (2H, m, H-6), 3.20 (1H, sept, J = 7.0 Hz, H-15), 2.57 (2H, m, H-7), 6.66 (1H) , s, H-14); ESIMS m/z 315.2 [M+H] ⁺ .

Synthesis of 1.5.5.6,7-dehydroserine dimethyl ether (CA-7)

The carnosol (16.5 mg, 0.05 mmol) was dissolved in 2 ml of acetone, and dimethyl sulfate (CH ₃ ) ₂ SO ₄ (5 ul, 0.11 mmol) was added dropwise to the reaction mixture. After the dropwise addition was completed, the reaction solution was allowed to react at room temperature overnight. The reaction solution was evaporated under reduced pressure to remove the organic solvent, and the residue was subjected to column chromatography of gel, Sephadex LH-20 (chloroform-methanol: 1:1) to obtain 17 mg of 6,7-dehydroserine dimethyl ether (CA-7a). The rate is 94%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6. (1H, d, J = 1.3 Hz), 4.65 (1H, dd, J = 3.2, 0.9), 3.88 (1H, d, J = 3.0 Hz), 3.69 (3H) , s), 3.22 (1H, m), 3.07 (1H, s), 2.93 (1H, m), 1.98 (1H, s), 1.00-2.20 (m), 1.13 (3H, d, J = 6.9 Hz) , 1.12 (3H, d, J = 6.9 Hz), 1.01 (3H, s), 0.90 (3H, s); EIMS m/z 358 (M+).

The phenolic methyl etherification product such as CA-12, CA-19 can be obtained by controlling the reaction equivalent of dimethyl sulfate and replacing different reaction substrates.

.

Example 2: Discovery of hypolipidemic activity of rosin-type diterpenoids

The isolated compound LSP-6-1 to LSP-6-6 (final concentration: 5 μM) was used to treat HepG2 cells deficient in serum for 12 hours for 24 hours, and fluorescently labeled low density lipoprotein (DiI-LDL) was added at 20 μg/ml. After incubating at 37 ° C for 4 hours, the cells were gently washed with phosphate buffered saline (PBS) for 5 times, and the lipid was extracted with isopropyl alcohol, and the fluorescence reading (excitation light: 520 nm; emission light 570 nm) was measured on a microplate reader. The cells were then lysed with 0.2 M sodium hydroxide, the protein content was determined, and the fluorescence/protein values were calculated. The experimental results are shown in Table 1 and Figure 1. Six compounds at 5 μM significantly increased the uptake of low-density lipoprotein LDL by hepatocyte HepG2.

Table 1. Effect of Compounds LSP-6-1 to LSP-6-6 on Low Density Lipoprotein Uptake in Hepatocytes

化合物编号Compound number	低密度脂蛋白摄取率Low density lipoprotein uptake rate

DMSODMSO	11
ZBM30(Nagilactone B(7))ZBM30 (Nagilactone B(7))	1.46^& 1.46 ^&
LSP-6-1LSP-6-1	1.111.11
LSP-6-2LSP-6-2	1.26^* 1.26 ^*
LSP-6-3LSP-6-3	1.16^* 1.16 ^*
LSP-6-4LSP-6-4	1.29^* 1.29 ^*
LSP-6-5LSP-6-5	1.26^* 1.26 ^*
LSP-6-6LSP-6-6	1.33^* 1.33 ^*

(*p<0.05, ^& p<0.01vs control)

HepG2 cells deficient in serum for 12 hours were treated with different concentrations of compound LSP-6-6 (5, 10, 20 μM, respectively) for 24 hours. The uptake rate of low density lipoprotein was calculated according to the above method. The relationship between -6 dose and activity. The experimental results are shown in Table 2 and Figure 2.

Table 2. Effect of compound LSP-6-6 on hepatocyte low density lipoprotein uptake at different concentrations

化合物编号Compound number	低密度脂蛋白摄取率Low density lipoprotein uptake rate

DMSODMSO	11
ZBM30ZBM30	1.49^& 1.49 ^&
LSP-6-6(5μM)LSP-6-6 (5μM)	1.28^* 1.28 ^*
LSP-6-6(10μM)LSP-6-6 (10μM)	1.38^* 1.38 ^*
LSP-6-6(20μM)LSP-6-6 (20μM)	1.47^& 1.47 ^&

( ^* p<0.05, ^& p<0.01vs control)

The above results indicated that the compound LSP-6-6 increased the phagocytosis of LDL by HepG2 cells in a dose-dependent manner; the effect of increasing LDL uptake at 20 μM was comparable to that of ZBM30.

Example 3 Compound LSP-6-6 up-regulates the expression level of low density lipoprotein receptor (LDLR) in hepatocytes

Compound LSP-6-6, berberine (BBR) and ZBM30 were treated with hepatocytes at different concentrations for 24 hours. Cells were lysed in the same manner as in Example 2, and total RNA was extracted with TRIzol reagent, and 3 μg of RNA was used. M-MLV (reverse transcriptase) was reverse transcribed into cDNA, and real-time PCR (real-time quantitative PCR) was performed using specific primers of LDLR, and GAPDH was used as an internal reference gene to modulate the LDLR gene. See Figure 3 for the experimental results. The above results indicated that the compound LSP-6-6 significantly increased the expression of LDLR gene and increased the expression level of low density lipoprotein receptor (LDLR) in hepatocytes, and the LDLR protein level increased with the increase of drug concentration. From the increase in the amount of LDLR, the activity of LSP-6-6 was comparable to that of berberine at the same dose, but the dose-effect relationship was more pronounced.

Example 4 Test for LDL uptake activity of rosin-type diterpenoids

The rosin-type diterpenoids isolated in the above plants or in semi-synthesis (final concentration: 5 μM) were treated with HepG2 cells deficient in serum for 12 hours for 24 hours, and fluorescently labeled low-density lipoprotein (DiI-LDL) 20 μg/ was added. After incubating for 4 hours at 37 ° C, the cells were gently washed with phosphate buffered saline (PBS) for 5 times, and the lipid was extracted with isopropyl alcohol, and the fluorescence reading (excitation light: 520 nm; emission light 570 nm) was measured on a microplate reader. The cells were then lysed with 0.2 M sodium hydroxide, the protein content was determined, and the fluorescence/protein values were calculated. The experimental results of some of the compounds are shown in Table 3.

Table 3: Effect of Partial Alkane Diterpenoids on Low Density Lipoprotein Uptake in Hepatocytes

化合物编号Compound number	低密度脂蛋白摄取率/DMSOLow density lipoprotein uptake rate / DMSO
ZBM30^& ZBM30 ^&	++++++
BBR^& BBR ^&	++++++
LS-42^& LS-42 ^&	++
LS-44^& LS-44 ^&	++++++
LS-53^& LS-53 ^&	++++
LS-67^& LS-67 ^&	++++
LS-75^& LS-75 ^&	++++
LS-81^# LS-81 ^#	++++
LS-82^& LS-82 ^&	++++
CS-6^# CS-6 ^#	++
CS-8^# CS-8 ^#	++++
CS-16^& CS-16 ^&	++++
CS-26_& CS-26 _&	++
CS-27^& CS-27 ^&	++
CS-31^& CS-31 ^&	++
CS-37^& CS-37 ^&	++++
CA-1^& CA-1 ^&	++++++
CA-2^# CA-2 ^#	++++++

^{^{# P <0.01 & p <0.05}} ; +: LDL uptake / DMSO 1.20-1.30; ++ LDL uptake / DMSO 1.31-1.40; +++ LDL uptake / DMSO 1.40- 1.60

(The structure of this compound of CS-37 has not appeared in the list, please review it)----P14 page dimer.

Among them, compounds LS-44 and CA-1\2, at the same concentration (5 uM), promoted hepatocyte uptake of LDL activity comparable to ZBM30.

Study on the effect of oral administration of compound LSP-6-6 in oral administration on lipid-lowering effect in vivo

1.4.1. Experimental animals

The male Syrian golden hamster, weighing 100 ± 10 g, was purchased from the Shanghai Experimental Animal Center of the Chinese Academy of Sciences.

1.4.2. Drug preparation

Compound LSP-6-6 was formulated into a suspension solution of 15 mg/ml with 5% DMSO, 2% Tween 80 and 93% physiological saline, and mixed by ultrasound before use; each animal was given a dose of 200 μl/100 g, given The dose was 30 mg/kg.

1.4.3. Experimental methods

Golden hamsters were randomly grouped according to their initial lipid and body weight levels after one week of adaptive feeding. The high-fat model group and the drug-administered group were given high-fat diet. The drug-administered group was given 30 mg/kg of compound LSP-6-6 by intraperitoneal injection. The high-fat model group was orally administered with the same volume of solvent, and the normal feed control group was given normal. feed. At the beginning of the experiment, 16 hours after fasting per week, blood was collected from the subarachnoid vein once, and the blood lipid index was measured. Three weeks later, the golden hamster was sacrificed by cervical dislocation, and the liver was weighed and stored at -80 °C until use.

Determination of blood lipids: The blood was placed at 4 ° C for two hours to stratify, centrifuged at 3000 rpm for 15 minutes, and the supernatant serum was aspirated, diluted 5 times with physiological saline, and the blood lipid index was measured by an automatic biochemical analyzer.

Statistical methods: At least 6 animals in each group were statistically analyzed using Prism software. Comparison of differences between groups ANOVA analysis was used; t test was used for comparison between the two groups.

Experimental result

As shown in Figure 4, high-fat-fed golden hamsters were treated with LSP-6-6 (30 mg/kg), compared with the high-fat model group, TC (serum total cholesterol), TG (in serum) of golden hamsters. Triglyceride), LDL levels decreased significantly.

By calculation, it was found that the percentage reduction of LSP-6-6 to golden hamster blood lipids was as follows:

	TC(％)TC (%)	TG(％)TG (%)	LDL-C(％)LDL-C (%)
LSP-6-6给药10dLSP-6-6 administration 10d	58.3758.37	62.9362.93	36.1336.13
LSP-6-6给药20dLSP-6-6 administration for 20d	75.0175.01	72.8072.80	57.8857.88

After 20 days of LSP-6-6 administration, the levels of TC, TG, and LDL in blood lipids of the test animals were close to or exceeded 60%, and LSP-6-6 increased the uptake of LDL by hepatocytes in vitro. Therefore, it is speculated that lowering the dose of LSP-6-6 can also reduce the levels of TC, TG and LDL in the blood of the test animals.

All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the In addition, it should be understood that various modifications and changes may be made by those skilled in the art in the form of the appended claims.

Claims

Use of a compound of formula I, a dimer thereof, or a ring-opening product thereof, or a pharmaceutically acceptable salt thereof,

among them,

Ra, Rb, Rc, and Rd are each independently selected from the group consisting of H, halogen, -OH, -OMe, O, -OC 1 -C 6 alkyl, -CHO, -OC 1 -C 6 acyl;

X is selected from the group consisting of CHRe, OC(O), NRe, O, C=Re, C-Re, N; wherein Re is selected from the group consisting of H, -CHO, -COOH, -OH, - OMe, =O, -OC 1 -C 6 alkyl, -OC 1 -C 6 acyl, -OC 2 -C 30 acyl;

M is selected from the group consisting of CHRf, NRf, O, C=Rf, C-Rf, N; wherein the Rf is selected from the group consisting of H, -CHO, -COOH, -OH, -OMe, =O, -OC 1 -C 6 alkyl, -OC 1 -C 6 acyl, -OC 2 -C 30 acyl;

Or any one or two of Re and Rf are substituents selected from the group consisting of:

Or Re, Rf together constitute a structure selected from the group consisting of: -O-, -C 1 -C 6 alkylene-, -C 1 -C 6 alkylene-O-, -OC 1 -C 6 alkylene -O-, or -C 1 -C 6 alkylene-OC 1 -C 6 alkylene-,

Or one of Re and Rf together with one of Ri or Rg constitutes a substituted or unsubstituted -C 1 -C 6 alkylene-, substituted or unsubstituted -C 1 -C 6 alkylene-O-, -C(O)-O-; wherein said substitution means that one or more hydrogen atoms on the group are substituted by =0;

Or X, M and a chemical bond together constitute a group selected from the group consisting of CH-OR', wherein R' is selected from the group consisting of H, C 1 -C 6 alkyl;

Rg, Rh are each independently selected from the group consisting of H, -COOH, substituted or unsubstituted C 1 -C 6 alkyl, -OH, substituted or unsubstituted C 1 -C 6 alkoxy, -COO-substituted Or unsubstituted C 1 -C 6 alkyl, -COO-substituted or unsubstituted C 6 -C 10 aryl, -COO-substituted or unsubstituted C 1 -C 10 heteroaryl, -COO-substituted or An unsubstituted C 1 -C 6 alkoxy group; or Rg and Rh together form =0; wherein said substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, -OH, -COOH;

Ri is selected from the group consisting of H, -COOH, -OH, -Me; or Ra and Ri together form -C(O)-O-;

Rj is one or more substituents on ring A, and said Rj are each independently selected from the group consisting of H, =O, substituted or unsubstituted C 1 -C 6 alkyl, -OH, -COOH, -COO-substituted or unsubstituted C 1 -C 6 alkyl, -COO-substituted or unsubstituted C 6 -C 10 aryl, -COO-substituted or unsubstituted C 1 -C 10 heteroaryl, wherein Said substitution is substituted by one or more substituents selected from the group consisting of halogen, -OH, -COOH;

Rk is selected from the group consisting of H, halogen, C1-C6 alkyl, -CH 2 OH, -CH 2 OCOOR, -COOR; or together with Rc to form a 5-9 membered epoxy ring or lactone ring;

R" is selected from the group consisting of H, -COOH, -OH, -Me;

Unless stated otherwise, "substituted" means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of a carboxy group, a C 1 -C 6 alkyl group, a phenyl group, a C 3 -C 6 ring. An alkyl group, a C 1 -C 10 ester group, a halogen, a C 1 -C 10 alkyl-oxy group, a C 2 -C 10 acyl group, a hydroxyl group, a hydroxy-C 1 -C 10 alkylene group;

The dotted line is a single bond or a double bond;

And
a substituted or unsubstituted aromatic ring (benzene ring or benzoquinone);

Characterized in that the compound is used in one or more uses selected from the group consisting of:

a) preparing a pharmaceutical composition for lowering blood fat;

b) preparing a pharmaceutical composition for lowering the content of low density lipoprotein (LDL);

c) preparing a pharmaceutical composition for stabilizing the stability of the LDLR gene;

d) preparing a pharmaceutical composition for upregulating LDLR gene expression;

e) preparing a pharmaceutical composition for increasing the amount of LDLR receptors on the surface of hepatocytes;

f) preparing a pharmaceutical composition for reducing degradation of the LDLR receptor;

g) preparing a pharmaceutical composition for reducing the concentration of TC and/or TG in the blood;

h) preparing a pharmaceutical composition for increasing the concentration of high density lipoprotein (HDL) in the blood;

i) Preparation of a pharmaceutical composition for improving liver function damage.

In another preferred embodiment, the ring opening product is the product of ring opening of the A ring or the B ring.

In another preferred embodiment, the number of carbon atoms of the ring-opening product remains unchanged before and after ring opening.
The use according to claim 1, characterized in that the dimer of the compound of the formula I has the structure shown in the following formula Ia:

In the formula,

Ra, Rb, Rc, and Rd are each independently selected from the group consisting of H, halogen, -OH, -OMe, -OC 1 -C 6 alkyl, -CHO, -OC 1 -C 6 acyl;

The definitions of the remaining groups are as set forth in claim 1.
The use according to claim 1 wherein:

X is selected from the group consisting of CHRe, O, C=Re, C-Re; wherein Re is selected from the group consisting of H, -CHO, -COOH, -OH, -OMe, =O, -OC 1 - C 6 alkyl, -OC 1 -C 6 acyl;

M is selected from the group consisting of CHRf, O, C=Rf, C-Rf; wherein said Rf is selected from the group consisting of H, -CHO, -COOH, -OH, -OMe, =O, -OC 1 - C 6 alkyl, -OC 1 -C 6 acyl;

Or Re, Rf together constitute a structure selected from the group consisting of: -O-, -C 1 -C 6 alkylene-, -C 1 -C 6 alkylene-O-, -OC 1 -C 6 alkylene -O-, or -C 1 -C 6 alkylene-OC 1 -C 6 alkylene-;

Or one of Re and Rf together with Ri constitutes a substituted or unsubstituted -C 1 -C 6 alkylene-, substituted or unsubstituted -C 1 -C 6 alkylene-O-; wherein Substituting one or more hydrogen atoms on a group for substitution with =0;

Or X, M and a chemical bond together constitute a group selected from the group consisting of CH-OR', wherein R' is selected from the group consisting of H, C 1 -C 6 alkyl;

Rg, Rh are each independently selected from the group consisting of H, -COOH, substituted or unsubstituted C 1 -C 6 alkyl, -OH, substituted or unsubstituted C 1 -C 6 alkoxy, -COO-substituted Or an unsubstituted C 1 -C 6 alkyl group, a -COO-substituted or unsubstituted C 1 -C 6 alkoxy group; or Rg and Rh together form =0; wherein the substituent refers to a group on the group Or a plurality of hydrogen atoms are substituted with a substituent selected from the group consisting of halogen, -OH, -COOH;

Ri is selected from the group consisting of H, -COOH, -Me; or Ra and Ri together form -C(O)-O-;

The definitions of the remaining groups are as set forth in claim 1.
Use according to any of claims 1-3, characterized in that

Ra, Rb, Rc, Rd are each independently selected from the group consisting of H, -OH, -OMe;

X is selected from the group consisting of CHRe, O, C=Re, C-Re; wherein Re is selected from the group consisting of H, -CHO, -COOH, -OH, =O;

M is selected from the group consisting of CHRf, O, C=Rf, C-Rf; wherein the Rf is selected from the group consisting of H, -CHO, -COOH, -OH, =O;

And when X and M are different, it is O;

Rg, Rh are each independently selected from the group consisting of H, -COOH, substituted or unsubstituted C 1 -C 3 alkyl, -OH; wherein the substituent refers to one or more hydrogen atoms on the group a substituent selected from the group consisting of halogen, -OH, -COOH;

Rj is H.
The use according to claim 1 wherein said pharmaceutical composition is further for use in a group selected from the group consisting of:

j) (non-therapeutic in vitro) increase the uptake rate of LDL by hepatocytes;

k) (non-therapeutic in vitro) upregulate the number of LDLR receptors on the surface of hepatocytes.
The use according to claim 1, characterized in that in the pharmaceutical composition, the effective dose of the compound of the formula I is from 0.1 to 50 mg/kg body weight, preferably from 1 to 20 mg/kg body weight.
A kit, characterized in that the kit contains:

(i) a first container, and the active ingredient (a) a compound of formula I contained in the first container; or a drug containing the active ingredient (a);

(ii) a second container, and the active ingredient contained in the second container (b) a statin, or a pharmaceutically acceptable salt thereof; or a drug containing the active ingredient (b);

(iii) A description of the description of the combination of the active ingredient (a) and the active ingredient (b) to reduce the low-density lipoprotein content in the subject.
A compound of the formula I below, or a dimer thereof:

among them,

Ra, Rb, Rc, and Rd are each independently selected from the group consisting of H, halogen, -OH, -OMe, O, -OC 1 -C 6 alkyl, -CHO, -OC 1 -C 6 acyl;

X is selected from the group consisting of CHRe, NRe, O, C=Re, C-Re, N;

M is selected from the group consisting of CHRf, NRf, O, C=Rf, C-Rf, N; wherein, Re and Rf are each independently a substituent selected from the group consisting of:

Or Re, Rf together constitute a structure selected from the group consisting of: -C 1 -C 6 alkylene-O-, -OC 1 -C 6 alkylene-O-, or -C 1 -C 6 alkylene- OC 1 -C 6 alkylene-,

Or one of Re and Rf together with one of Ri or Rg constitutes a substituted or unsubstituted -C 1 -C 6 alkylene-, substituted or unsubstituted -C 1 -C 6 alkylene-O-, -C(O)-O-; wherein said substitution means that one or more hydrogen atoms on the group are substituted by =0;

Or X, M and a chemical bond together constitute a group selected from the group consisting of CH-OR', wherein R' is selected from the group consisting of H, C 1 -C 6 alkyl;

Rg, Rh are each independently selected from the group consisting of H, -COOH, substituted or unsubstituted C 1 -C 6 alkyl, -OH, substituted or unsubstituted C 1 -C 6 alkoxy, -COO-substituted Or unsubstituted C 1 -C 6 alkyl, -COO-substituted or unsubstituted C 6 -C 10 aryl, -COO-substituted or unsubstituted C 1 -C 10 heteroaryl, -COO-substituted or An unsubstituted C 1 -C 6 alkoxy group; or Rg and Rh together form =0; wherein said substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, -OH, -COOH;

Ri is selected from the group consisting of H, -COOH, -OH, -Me; or Ra and Ri together form -C(O)-O-;

Rj is one or more substituents on ring A, and said Rj are each independently selected from the group consisting of H, =O, substituted or unsubstituted C 1 -C 6 alkyl, -OH, -COOH, -COO-substituted or unsubstituted C 1 -C 6 alkyl, -COO-substituted or unsubstituted C 6 -C 10 aryl, -COO-substituted or unsubstituted C 1 -C 10 heteroaryl, wherein Said substitution is substituted by one or more substituents selected from the group consisting of halogen, -OH, -COOH;

Rk is selected from the group consisting of H, halogen, C1-C6 alkyl, -CH 2 OH, -CH 2 OCOOR, -COOR; or together with Rc to form a 5-9 membered epoxy ring or lactone ring;

R" is selected from the group consisting of H, -COOH, -OH, -Me;

Unless stated otherwise, "substituted" means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of a carboxy group, a C 1 -C 6 alkyl group, a phenyl group, a C 3 -C 6 ring. An alkyl group, a C 1 -C 10 ester group, a halogen, a C 1 -C 10 alkyl-oxy group, a C 2 -C 10 acyl group, a hydroxyl group, a hydroxy-C 1 -C 10 alkylene group;

The dotted line is a single bond or a double bond;

And
A substituted or unsubstituted aromatic ring (benzene ring or benzoquinone).
A compound of the formula I below, or a dimer thereof:

among them,

Ra, Rb, Rc, and Rd are each independently selected from the group consisting of H, halogen, -OH, -OMe, O, -OC 1 -C 6 alkyl, -CHO, -OC 1 -C 6 acyl;

X is O;

M is selected from the group consisting of CHRf, NRf, O, C=Rf, C-Rf, N; wherein the Rf is selected from the group consisting of H, -CHO, -COOH, -OH, -OMe, =O, -OC 1 -C 6 alkyl, -OC 1 -C 6 acyl, -OC 2 -C 30 acyl;

Or the Rf is a substituent selected from the group consisting of:

Or Rf together with one of Ri or Rg constitutes a substituted or unsubstituted -C 1 -C 6 alkylene-, substituted or unsubstituted -C 1 -C 6 alkylene-O-; wherein Substituting one or more hydrogen atoms on a group for substitution with =0;

Rg, Rh are each independently selected from the group consisting of H, -COOH, substituted or unsubstituted C 1 -C 6 alkyl, -OH, substituted or unsubstituted C 1 -C 6 alkoxy, -COO-substituted Or unsubstituted C 1 -C 6 alkyl, -COO-substituted or unsubstituted C 6 -C 10 aryl, -COO-substituted or unsubstituted C 1 -C 10 heteroaryl, -COO-substituted or An unsubstituted C 1 -C 6 alkoxy group; or Rg and Rh together form =0; wherein said substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, -OH, -COOH;

Ri is selected from the group consisting of H, -COOH, -OH, -Me; or Ra and Ri together form -C(O)-O-;

Rj is one or more substituents on ring A, and said Rj are each independently selected from the group consisting of H, =O, substituted or unsubstituted C 1 -C 6 alkyl, -OH, -COOH, -COO-substituted or unsubstituted C 1 -C 6 alkyl, -COO-substituted or unsubstituted C 6 -C 10 aryl, -COO-substituted or unsubstituted C 1 -C 10 heteroaryl, wherein Said substitution is substituted by one or more substituents selected from the group consisting of halogen, -OH, -COOH;

Rk is selected from the group consisting of H, halogen, C1-C6 alkyl, -CH 2 OH, -CH 2 OCOOR, -COOR; or together with Rc forms a 5-9 membered oxygen ring (preferably an epoxy ring or a lactone) ring);

R" is selected from the group consisting of H, -COOH, -OH, -Me;

Unless stated otherwise, "substituted" means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of a carboxy group, a C 1 -C 6 alkyl group, a phenyl group, a C 3 -C 6 ring. An alkyl group, a C 1 -C 10 ester group, a halogen, a C 1 -C 10 alkyl-oxy group, a C 2 -C 10 acyl group, a hydroxyl group, a hydroxy-C 1 -C 10 alkylene group;

The dotted line is a single bond or a double bond;

And
A substituted or unsubstituted aromatic ring (benzene ring or benzoquinone).
A compound of the formula I below, or a dimer thereof:

among them,

Ra, Rb, Rc, and Rd are each independently selected from the group consisting of H, halogen, -OH, -OMe, O, -OC 1 -C 6 alkyl, -CHO, -OC 1 -C 6 acyl;

X is selected from the group consisting of CHRe, OC(O), NRe, O, C=Re, C-Re, N; wherein Re is selected from the group consisting of H, -CHO, -COOH, -OH, - OMe, =O, -OC 1 -C 6 alkyl, -OC 1 -C 6 acyl, -OC 2 -C 30 acyl;

M is selected from the group consisting of CHRf, NRf, O, C=Rf, C-Rf, N; wherein the Rf is selected from the group consisting of H, -CHO, -COOH, -OH, -OMe, =O, -OC 1 -C 6 alkyl, -OC 1 -C 6 acyl, -OC 2 -C 30 acyl;

Or the Re and Rf are each independently a substituent selected from the group consisting of:

Or Re, Rf together constitute a structure selected from the group consisting of: -C 1 -C 6 alkylene-O-, -OC 1 -C 6 alkylene-O-, or -C 1 -C 6 alkylene- OC 1 -C 6 alkylene-,

Or one of Re, Rf and one of Ri or Rg together constitute a substituted or unsubstituted -C 1 -C 6 alkylene-, substituted or unsubstituted -C 1 -C 6 alkylene-O-; Wherein said substitution means that one or more hydrogen atoms on the group are substituted by =O;

Or X, M and a chemical bond together constitute a group selected from the group consisting of CH-OR', wherein R' is selected from the group consisting of H, C 1 -C 6 alkyl;

Rg is selected from the group consisting of H, -COOH, substituted or unsubstituted C 1 -C 6 alkyl, -OH, substituted or unsubstituted C 1 -C 6 alkoxy, -COO-substituted or unsubstituted C 1- C 6 alkyl, -COO-substituted or unsubstituted C 6 -C 10 aryl, -COO-substituted or unsubstituted C 1 -C 10 heteroaryl, -COO-substituted or unsubstituted C 1 a C 6 alkoxy group; wherein said substituent means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, -OH, -COOH;

Rh is selected from the group consisting of -COOH, -OH, substituted or unsubstituted C 1 -C 6 alkylene-COOH, -COO-substituted or unsubstituted C 1 -C 6 alkyl, -COO-substituted or not Substituted C 6 -C 10 aryl, -COO-substituted or unsubstituted C 1 -C 10 heteroaryl, -COO-substituted or unsubstituted C 1 -C 6 alkoxy; wherein said substitution The one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, -OH, -COOH;

Ri is selected from the group consisting of H, -COOH, -OH, -Me; or Ra and Ri together form -C(O)-O-;

Rj is one or more substituents on ring A, and said Rj are each independently selected from the group consisting of H, =O, substituted or unsubstituted C 1 -C 6 alkyl, -OH, -COOH, -COO-substituted or unsubstituted C 1 -C 6 alkyl, -COO-substituted or unsubstituted C 6 -C 10 aryl, -COO-substituted or unsubstituted C 1 -C 10 heteroaryl, wherein Said substitution is substituted by one or more substituents selected from the group consisting of halogen, -OH, -COOH;

Rk is selected from the group consisting of H, halogen, C1-C6 alkyl, -CH 2 OH, -CH 2 OCOOR, -COOR; or together with Rc forms a 5-9 membered oxygen ring (preferably an epoxy ring or a lactone) ring);

R" is selected from the group consisting of H, -COOH, -OH, -Me;

Unless stated otherwise, "substituted" means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of a carboxy group, a C 1 -C 6 alkyl group, a phenyl group, a C 3 -C 6 ring. An alkyl group, a C 1 -C 10 ester group, a halogen, a C 1 -C 10 alkyl-oxy group, a C 2 -C 10 acyl group, a hydroxyl group, a hydroxy-C 1 -C 10 alkylene group;

The dotted line is a single bond or a double bond;

And
A substituted or unsubstituted aromatic ring (benzene ring or benzoquinone).

In another preferred embodiment, the dimer is a dimer formed from the same or different compounds of formula I, preferably a dimer formed from the same compound of formula I.
The compound or a dimer thereof according to claim 10, wherein Ra, Rb, Rc, and Rd are each independently selected from the group consisting of H, -OH, O, -OC 1 -C 6 alkyl, - OC 1 -C 6 acyl group.
The compound or a dimer thereof according to claim 11, wherein at least one of Ra and Rb is -OH and the other is -OC 1 -C 6 alkyl.
A rosin-type diterpenoid or a ring-opening product thereof, wherein the rosin-type diterpenoid or a ring-opening product thereof is selected from the group consisting of