WO2012103813A1

WO2012103813A1 - Danshensu and chuanxiongqin derivatives, process for preparation, and use thereof

Info

Publication number: WO2012103813A1
Application number: PCT/CN2012/070832
Authority: WO
Inventors: Yuqiang Wang; Pei Yu; Jie Jiang; Luchen SHAN; Gaoxiao Zhang; Zaijun Zhang; Yonghong CHEN
Original assignee: Jinan University
Priority date: 2011-02-01
Filing date: 2012-02-01
Publication date: 2012-08-09

Abstract

The present invention provides Danshensu derivatives containing a moiety of Chuanxiongqin (tetramethylpyrazine), and pharmaceutical compositions containing the Danshensu derivatives or their salts and pharmaceutically acceptable carriers. The invention also provides methods for preparing the Danshensu derivatives or their salts, and uses of the compositions in manufacture of medicaments for prevention and treatment of diseases or disorders including cardiovascular and cerebrovascular diseases and their complications.

Description

DANSHENSU AND CHUANXIONGQIN DERIVATIVES, PROCESS FOR PREPARATION, AND USE THEREOF

FIELD OF THE INVENTION

The present invention relates to Danshensu derivatives or pharmaceutically acceptable salts thereof, processes for preparation thereof, and also uses of the compositions of the Danshensu derivatives or their salts in medicament manufacture and medical treatments.

BACKGROUND OF THE INVENTION

Cardiovascular diseases, including, for example, coronary heart disease, angina, myocardial infarction, cerebral infarction, cerebral dementia and cerebral hemorrhage, are common diseases which could cause serious health threat to human beings especially the elderly. So it becomes very important to find new drugs to prevent and treat

cardiovascular diseases.

Danshensu (DSS) is a water soluble component and one of the major active ingredients of Chinese herbal medicine Salvia Miltiorrhiza (Danshen). Based on records in literature, Danshensu is the major pharmaceutically effective component of Danshen for the treatments of, such as, coronary heart disease and myocardial infarction. The clinical uses of compound injections of Danshen, however, may cause allergic reactions, such as severe diarrhea, hypotension, tachycardia, local pain, swelling, or hemolytic uremic syndrome.

Danshensu, when isolated from an aqueous solution of Danshen, shows anti-platelet aggregation, anti-inflammatory, anti-liver fibrosis, anti-atherosclerotic, anti-tumor, anti-thrombosis and hepato-protective effects. Danshensu, however, is very susceptible to oxidative deterioration, and thus is difficult to store due to its instability. Furthermore, Danshensu contains hydroxyl and carboxyl groups, and can be bonded with glucuronic acids and excreted with urine, which shortens significantly its half-life in vivo, and makes repetitive administration necessary for its use, and thus restricts its clinical applications.

Danshen, as being used in China for a long time for treatment of stroke, has effects on improving blood circulation and removing blood stasis. More than fifty kinds of compounds have been found in Danshen, the active ingredients of which can be categorized into lipid soluble and water soluble ones. The lipid soluble compounds, mainly including Tanshinone (Danshentong), Tanshinone IIA (Danshentong IIA) and Cryptotanshinone, clearly show anti-inflammatory, antibacterial and anti-myocardial ischemia effects. The major water soluble compounds, including Danshensu and salvianolic acid which contains one or two Danshensu moieties, also show strong anti-myocardial ischemia effect. Natural Danshensu (shown in FIG. 1), being dextrorotatory, has been widely used in clinically for treating cardiovascular disease, improving cardiac function, coronary circulation and microcirculation and alleviating coagulation. Danshensu not only shows clear effects on treatment of heart disease, but also has anti- inflammatory, anti-tumor, anti-thrombosis and hepatic effects.

Tetramethylpyrazine (TMP, also called Chuanxiongqin or Ligustrazine, shown in FIG. 1), an alkaloid extracted from Umbelliferous herb Ligusticum wallichii (Chuanxiong) of traditional Chinese medicine, is one of the active ingredients of Chuanxiong and has been widely used to treat cardiovascular and cerebrovascular diseases. TMP shows many pharmacological activities, some of which, as being related to treatment of ischemic stroke, are described as follows:

TMP has significant anticoagulation effect. TMP can significantly inhibit the expression of LPS-induced PAI-1 protein and its mRNA in endothelial cells (Song, et al., Chinese Medical J. 113: 136, 2000). TMP, in a low-dose, can inhibit the decomposition of phosphatidylinositol and the formation of TXA2, while in a high dose, can inhibit platelet aggregation through combination of glycoprotein Ilb/IIIa (Sheu, et al., Thromb Res.

88:259, 1997).

TMP has direct thrombolytic effect. Both artery and venous thrombosis models in rats indicate that TMP has anti-thrombolytic effect (Liu and Sylvester, Thromb Res.

58: 129, 1990), which may be related to TMP's inhibition on platelet activity, including

2__|_

inhibition of intracellular Ca activity, inhibition of phosphate diesterase activity, increase of intracellular cAMP level, and reduction of exposure of glycoprotein Ilb/IIIa on the platelet surface (Liu and Sylvester, Thromb Res. 75:51, 1994). TMP can significantly reduce mortality of mice due to ADP-induced acute pulmonary embolism, and

intravenous TMP can significantly prolong mesenteric artery bleeding time of rats for up to 1.5 times, which indicates that TMP has significant anti-thrombotic activity in vivo (Sheu et al, Thromb Res . 88:259, 1997).

TMP has significant effect on protecting nerve cells. TMP may significantly alleviate the MCAo-induced ischemia in rat brain cells, and may significantly remove free radicals produced by human neutrophils. TMP may also protect nerve cells through regulation on the expression of Bcl-2 and Bax to reduce apoptosis (Hsiao, et al., Planta Med.

72:411-417, 2006; Kao, et al, Neurochem Int. 48: 166, 2006).

TMP is a calcium channel blocker, and at the same time can facilitate the potassium channel opening. TMP has the effects of inhibiting calcium influx, inhibiting the formation of free radicals, enhancing the activity of superoxide dismutase (SOD), inhibiting lipid peroxidation, and inhibiting inflammatory responses (Zhu , et al., Eur. J. Pharmacol. 510: 187, 2005).

Although Danshensu is used clinically for the treatments of many diseases such as cardiovascular and cerebrovascular diseases, it has ortho-dihydroxy diphenol and a-hydroxy carboxylic acid groups, and thus is chemically very unstable and is prone to experience oxidation and decarboxylation reactions. Such property is adversary for drug keeping and storage, may also reduce the half-life in vivo after drug administration, and may even disrupt maintenance of effective blood concentration. In addition, due to its low activity and restricted mechanism, the pharmaceutical applications of Danshensu were found rather limited.

As described here below, the present invention provides useful ways to effectively overcome the problems caused by the defects in the pharmaceutical use of natural Danshensu and to significantly enhance the efficacy as well by incorporating into the Danshensu with TMP and other active moieties. It should be understood, however, that the invention as described herein is not limited to deal with the above-mentioned problems or limited to employ the specific embodiments or examples disclosed below to achieve the objectives of medicament manufacture and medical treatments.

SUMMARY OF THE INVENTION

The present invention is directed to Danshensu derivatives or pharmaceutically acceptable salts, and compositions thereof. The invention is also directed to processes for preparing Danshensu derivatives or pharmaceutically acceptable salts thereof. The invention is further directed to the uses of Danshensu derivatives or pharmaceutically acceptable salts thereof for medicament manufacture and medical treatments.

The Danshensu derivatives or pharmaceutically acceptable salts thereof provided herein, compared to the existing medicines, are advantageous in their increased lipid solubility, improved acceptability, higher stability, enhanced efficacy, and lower toxicity.

The present invention, in one aspect, provides novel Danshensu derivatives of general formula I:

or pharmaceutically acceptable salts thereof, wherein:

Ri is hydrogen, substituted or un-substituted aryl, heterocyclic aryl or alkyl, heterocyclic groups;

X is nitrogen, oxygen, or sulfur;

R₂, R3 and R₄, being the same or different, are each independently hydrogen, substituted or un-substituted alkyl, aryl, heterocyclic aryl, C(0)-alkyl, C(0)-aryl, or C(0)-heterocyclic aryl or biologically active groups such as lipoic acid, TMP, or bornyl group; with the proviso that:

If X is oxygen, then R_ls R₂, R₃ and R₄ cannot be simultaneously hydrogen;

If X is oxygen and Ri is methyl, then there is no simultaneous presence of the following: R₂ is acetyl, and both R₃ and R₄ are methylene, methyl, ethyl, propyl, isopropyl, benzyl, acetyl, propionyl or benzoyl; If X is oxygen and i is hydrogen, then R₂, R₃ and R4 cannot be

simultaneously hydrogen, benzoyl, benzyl, Ci-C₆ alkyl, or C(0)-(C₂-C6 alkyl);

If X is oxygen and both Ri and R₂ are hydrogen, then R₃ and R₄ cannot be simultaneously methylene, methyl, ethyl, propyl, isopropyl, benzyl, propionyl, or benzoyl; and

If X is nitrogen, then Ri cannot be (R)-(3 -phenyl- l-ethyloxyformyl)propyl.

In some preferred embodiments, the present invention provides also the Danshensu derivatives of formula I shown above with X being oxygen, i.e., of formula II below:

or pharmaceutically acceptable salts thereof, wherein:

Ri is substituted or un-substituted aryl, heterocyclic aryl, heterocyclic or monocyclic terpene group;

R₂, R₃ and R₄, being the same or different, are each independently hydrogen, substituted or un-substituted alkyl, aryl, heterocyclic aryl, C(0)-alkyl, C(0)-aryl, or C(0)-heterocyclic aryl, or biologically active group such as lipoic acid, TMP, or bornyl group; with the proviso that:

If Ri is methyl, then simultaneous presence of the following does not occur: R₂ is acetyl, and both R₃ and R₄ are methylene, methyl, ethyl, propyl, isopropyl, benzyl, acetyl, propionyl, or benzoyl;

If R₂ is hydrogen, then R₃ and R₄ cannot both be methylene, methyl, ethyl, propyl, isopropyl, benzyl, propionyl, or benzoyl; and

If R₂ is acetyl, then R₃ and R₄ cannot both be methylene, methyl, ethyl, propyl, isopropyl, benzyl, acetyl, propionyl, or benzoyl.

The present invention, according to its preferred embodiments, also provides Danshensu derivatives of a general formula IV below, containing a moiety of

Chuanxiongqin (Tetramethylpyrazine, TMP):

or pharmaceutically acceptable salts thereof, wherein:

R₂ is hydrogen, alkyl, aryl, heterocyclic aryl, C(0)-alkyl, C(O)-;

C(0)-heterocyclic aryl; ₅ is substituted or un-substituted alkyl;

R₀, R₇ and R₈, being the same or different, are each independently hydrogen, alkyl, C(0)-alkyl, C(0)-aryl, C(0)-heterocyclic aryl, N0₂, NH₂, COOH, CN, F, CI, Br, or I.

The present invention, according to its preferred embodiments, also provides Danshensu derivatives of a general formula V shown below, containing a moiety of TMP:

wherein, R₂ and R₅ are each independently substituted or un-substituted alkyl, or biologically active lipoic acid or bornyl group.

In another aspect, the present invention also provides pharmaceutically acceptable salts of Danshensu derivatives, including but not limited to the salts formed from the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid, citric acid, tartaric acid, phosphoric acid, malic acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methylsulfonic acid, phenylsulfonic acid, or p-toluenesulfonic acid.

In yet another aspect, the present invention further provides methods for preparing Danshensu derivatives and pharmaceutically acceptable salts thereof. In the design of the methods of preparation, the following considerations, inclusive but not exclusive, have been taken into account: First, for the purpose of finding Danshensu derivatives with increased activity and extended half-life, the structurally volatile phenol and a-hydroxy carboxylic acid groups are protected to increase the in vivo metabolic stability of the drug, and once inside the body, the protection of the groups was removed with the help of an esterase to allow the active ingredients starting to have their pharmaceutical effects;

second, the active phenolic hydroxyl, a-hydroxyl and carboxylic groups are, respectively, modified chemically and further incorporated with other active groups to synergically enhance medical efficacy; and third, upon the above-mentioned compounds,

pharmacological activity tests, including cell and animal experiments, are carried out to study the structure-activity relationship, the results of which can be further provided to guide the efforts of chemical synthesis to find pharmaceutically more active and chemically more stable new drugs for clinical applications.

In the present invention, accordingly, experiments on the pharmacological effects of the new Danshensu derivatives and their pharmaceutically acceptable salts were carried out. Danshensu has antioxidant effects and is protective to cells and tissues by eliminating free radicals. Thus, the activities of the new compounds towards free radicals were first evaluated. As a free radical, l,l-Diphenyl-2-picrylhydrazyl (DPPH) has been widely used to assess the anti-free radical property of compounds. The tests herein revealed that the new Danshensu compounds herein have very strong anti-free radical ability. Dihydrouracil dehydrogenase (NAD), as an electron acceptor existing in a wide variety of tissue cells, can inhibit the formation of hydroxyl radicals. It is found from the

experiments of this invention that the new Danshensu compounds showed enhanced activities compared to Danshensu.

For finding new drugs with higher activity compared to Danshensu, experiments were carried out to determine the protective effect of the new compounds upon primary myocardial cells in rats. The test results indicated that many new compounds have activities which are higher than that of natural Danshensu; ADTM, a Danshensu derivative, shows excellent protective effect at least 10 times higher than that of natural Danshensu (DDS) (FIGS. 11-15), and is 2 to 4 times more active than Salvia acid B (Sal B) (shown in FIG. 16). Then, a rat acute myocardial ischemia model was established, and the protective effects of these compounds, including ADTM, on myocardial ischemia were determined. The test results showed that the Danshensu derivative ADTM not only has a strong protective effect on cat acute myocardial ischemia, but also the effect is at least 8 times stronger than that of Danshensu (DSS) (FIG. 17).

The compounds of this invention can be used for manufacturing medicaments for treatment or prophylaxis of cardiovascular and cerebrovascular diseases and related complications, including cardiovascular diseases such as arrhythmias, ventricular fibrosis, myocardial infarction, coronary disease, angina pectoris, cardiac failure, congestive heart failure, myocardial ischemia, cardiac ischemia or reperfusion, cachexia, myocarditis, atherosclerosis, peripheral ischemia of tissues or limbs, shock, ischemia or

reperfusion-induced acute or chronic damage to tissues and organs, and disorders or indirect sequelae, also including cerebrovascular diseases such as stroke, trauma, epilepsy, Parkinson's disease, Huntington's disease, muscular atrophy (spinal cord) lateral sclerosis, Alzheimer's disease, hypoxic-ischemic brain injury, AIDS, dementia, multiple sclerosis, ischemic symptoms of peripheral or central nervous system, ischemic stroke symptoms, and brain disease with chronic pain. The compounds of this invention can be also used for manufacturing medicaments for treatment or prophylaxis of infectious inflammatory diseases, including inflammatory bowel disease, diabetes, rheumatoid arthritis, asthma, cirrhosis, allograft rejection, encephalomyelitis, meningitis, pancreatitis, peritonitis, vasculitis, lymphocytic choriomeningitis, choriomeningitis, glomerulonephritis, systemic lupus erythematosus, gastrointestinal motility disorders, obesity, hungry disease, hepatitis, renal failure, diabetic retinopathy, uveitis, glaucoma, blepharitis, chalazion, allergic eye disease, corneal ulcers, keratitis, cataract, age-related macular degeneration, and optic neuritis. The compounds of this invention can also be used in preparation of medicaments for treatment or prophylaxis of cancers.

Through chemical modifications of Danshensu, the present invention provided novel Danshensu derivatives and pharmaceutically acceptable salts thereof. The Danshensu derivatives described herein have the following advantageous features: First, the lipid solubility of the drug is increased, consequently the half-life is extended and the efficacy is enhanced, as the drug is delivered into the body in the form of pre-drug, and the metabolism of which, under the in vivo conditions of enzymatic reactions and acidic environment of gastric juice in case of oral administration, leads to pharmaceutically effective ingredients showing pharmaceutical effects; Second, the stability of the drug is increased, as the core structure of the drug is not destructed to maintain the integrity of the active sites of the drug; Third, the synergetic effect of the pharmaceutical components is enhanced to give higher efficacy.

DESCRIPTION OF DRAWINGS

FIG. 1 shows the structures of Danshensu and Chuanxiongqin (Tetramethylpyrazine, TMP)

FIG. 2 illustrates the synthesis of Danshensu derivatives D001-D004 in accordance with one embodiment of the present invention.

FIG. 3 illustrates the synthesis of Danshensu derivatives D005-D010 in accordance with a further embodiment of the present invention.

FIG. 4 illustrates the synthesis of Danshensu derivatives D011-D019 in accordance with a further embodiment of the present invention.

FIG. 5 illustrates the synthesis of Danshensu derivative ADTM in accordance with further embodiments of the present invention.

FIG. 6 illustrates the synthesis of Danshensu derivative ADAM in accordance with a further embodiment of the present invention.

FIG. 7 illustrates the synthesis of Danshensu derivative of ADTZ in accordance with a further embodiment of the present invention.

FIG. 8 illustrates the synthesis of Danshensu derivative ABBM in accordance with a further embodiment of the present invention.

FIG. 9 illustrates the synthesis of Danshensu derivative ADTE in accordance with a further embodiment of the present invention.

FIG. 10 illustrates the synthesis of Danshensu derivative ADBE in accordance with a further embodiment of the present invention.

FIG. 11 shows the experimental results of the protective effect on myocardial cells by using Danshensu derivatives of D001-D004 based on some embodiments of the present invention.

FIG. 12 shows the experimental results of the protective effect on myocardial cells by using Danshensu derivatives of D005-D010 based on further embodiments of the present invention.

FIG. 13 shows the experimental results of the protective effect on myocardial cells by using Danshensu derivatives of D011-D015 based on further embodiments of the present invention.

FIG. 14 shows the experimental results of the protective effect on myocardial cells by using Danshensu derivatives of ADTM, PDTM, BDTM and iBDTM based on further embodiments of the present invention. FIG. 15 shows the experimental results of the protective effect on myocardial cells by using Danshensu derivatives of ADTZ, PDTZ, BDTZ, iBDTZ based on further embodiments of the present invention.

FIG. 16 shows the experimental results of the protective effect on myocardial cells by using Danshensu derivatives of ADTM and SAB based on further embodiments of the present invention.

FIG. 17 shows the experimental results of the protective effect on myocardial cells by using Danshensu derivatives of ADTM based on further embodiments of the present invention.

DETAILED DESCRIPTION OF THE EMBODIMENTS

1. Definitions

Unless defined otherwise, all technical and scientific terms and phrases used herein have the meaning commonly understood by one of ordinary skill in the pertinent art, while the following terms and phrases as used herein are intended to have the following meanings.

As used herein, the term "alkyl" refers to unsubstituted or substituted straight, branched or cyclic alkyl chain having up to 15 carbon atoms. The straight alkyl includes, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. The cyclic alkyl ("cycloalkyl") includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Alkyl can be substituted with one or more substituents. The non-limiting examples of the substituents include NH₂, N0₂, N(CH₃)₂, ON0₂, F, CI, Br, I, OH, OCH₃, C0₂H, C0₂CH₃, CN, aryl, and hetroaryl. The term "alkyl" also refers to unsubstituted or substituted straight, branched or cyclic alkyl having up to 15 carbon atoms and at least one heteroatom (e.g., nitrogen, oxygen, or sulfur) in its chain. The straight-chain alkyls include, for example, CH₂CH₂OCH₃, CH₂CH₂N(CH₃)₂, and CH₂CH₂SCH₃. The branched alkyls include, for example, CH₂CH(OCH₃)CH₃, CH₂CH(N(CH₃)₂)CH₃, and

CH₂CH(OCH₃)CH₃. The cyclic alkyls include, for example, CH(CH₂CH₂)₂0,

H(CH₂CH₂)₂NCH₃, and CH(CH₂CH₂)₂S. The alkyl can be also substituted with one or more substituents, the non-limiting examples of which include NH₂, N0₂, N(CH₃)₂, ON0₂, F, CI, Br, I, OH, OCH₃, C0₂H, C0₂CH₃, CN, aryl, and heteroaryl.

The term "aryl" as used hrerein refers to unsubstituted or substituted aromatic compounds and carbocyclic groups. The aryl can be either a monocyclic compound or a fused polycyclic compound. For example, phenyl is a monocyclic aryl, and naphtyl is a fused polycyclic aryl. The aryl can be substituted with one or more substituents, the non-limiting examples of which include NH₂, N0₂, N(CH₃)₂, ON0₂, F, CI, Br, I, OH, OCH₃, C0₂H, C0₂CH₃, CN, aryl, and heteroaryl.

The phrase "pharmaceutically acceptable" means that a compound, such as a salt or excipient, has no unacceptable toxicity. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic anions, such as chlorine ion, bromine ion, iodine ion, sulfuric acid radical, sulfurous acid radical, nitric acid radical, nitrous acid radical and phosphoric acid radical; and organic anions, such as acetic acid radical, pyruvic acid radical, propionic acid radical, cinnamic acid radical, tosylic acid radical, citric acid radical, lactic acid radical and gluconic acid radical. Pharmaceutically acceptable excipients are described below, and also in the reference of: E. W. Martin, in Remington's Pharmaceutical Sciences Mack Publishing Company (1995), Philadelphia, PA, 19^th ed. The phrase "therapeutically effective amount" is intended to include an amount of a drug such as a Danshensu derivative described herein in which the drug shows biological activity as used to treat or prevent a disease.

2. Compounds

The present invention provides a novel series of Danshensu derivatives or their pharmaceutically acceptable salts. In embodiments of the present invention the Danshensu derivatives have general formula I:

wherein:

Ri is hydrogen, substituted or un-substituted aryl, heterocyclic aryl, or alkyl, heterocyclic group;

X is nitrogen, oxygen, or sulfur;

R₂, R₃ and R₄, being the same or different, are each independently hydrogen, substituted or un-substituted alkyl, aryl, heterocyclic aryl, C(0)-alkyl, C(0)-aryl, or C(0)-heterocyclic aryl or biologically active groups such as lipoic acid, TMP, or bornyl group; with the proviso that:

If X is oxygen, then Ri, R₂, R₃ and R₄ cannot be simultaneously hydrogen;

If X is oxygen and Ri is methyl, then there is no simultaneous presence of the following: R₂ is acetyl, and both R₃ and R₄ are methylene, methyl, ethyl, propyl, isopropyl, benzyl, acetyl, propionyl or benzoyl;

If X is oxygen and Ri is hydrogen, then R₂, R₃ and R₄ cannot be

If X is nitrogen, then Ri cannot be (R)-(3-phenyl-l-ethyloxyformyl)propyl.

In preferred embodiments of the present invention, the Danshensu derivatives of general formula I shown above, with X being oxygen, can be further defined by general formula II:

wherein:

Ri is substituted or un-substituted aryl, heterocyclic aryl, heterocyclic, or monocyclic terpene group;

R₂, R3 and R₄, being the same or different, are each independently hydrogen, substituted or un-substituted alkyl, aryl, heterocyclic aryl, C(0)-alkyl, C(0)-aryl, or C(0)-heterocyclic aryl, or biologically active groups such as lipoic acid, TMP, or bornyl group; with the proviso that:

If Ri is methyl, then simultaneous presence of the following does not occur: R₂ is acetyl, and both R₃ and R₄ are methylene, methyl, ethyl, propyl, isopropyl, benzyl, acetyl, propionyl, or benzoyl ;

In further preferred embodiments, the Danshensu derivatives of general formula II may be further defined as follows:

Ri is a substituted or un-substituted aryl or heterocyclic aryl group;

R₂, R₃ and R₄, being the same or different, are each independently hydrogen, substituted or un-substituted alkyl, C(0)-alkyl, C(0)-aryl, C(0)-heterocyclic aryl, or biologically active group such as lipoic acid radical, TMP, or bornyl group, with the proviso that R₂, R₃ and R₄ cannot be hydrogen simultaneously.

In further preferred embodiments, the Danshensu derivatives can be further defined by general formula III:

wherein:

benzyl, substituted or un-substituted pyrazine ring or norbornene group; substitute or unsubstituted alkyl.

In other further preferred embodiments, the Danshensu derivatives may include a moiety of TMP, for example, Ri in general formula II is a pyrazine alkyl group, such that the Danshensu derivatives can be further defined by general formula IV:

wherein:

P2 is hydrogen, alkyl, aryl, heterocyclic aryl, C(0)-alkyl, C(0)-aryl, or

C(0)-heterocyclic aryl;

R₅ is substituted or un-substituted alkyl;

6, R₇ and R₈, being the same or different, are each independently hydrogen, alkyl, C(0)-alkyl, C(0)-aryl, C(0)-heterocyclic aryl, N0₂, NH₂, COOH, CN, F, CI, Br, or I.

In yet further preferred embodiments, the Danshensu derivatives of general formula IV containing a moiety of TMP, may be further defined as R6, R7 and R₈ being CH₃. The Danshensu derivatives of general formula IV may be also further defined that R₂ is C(0)-CH₃, C(0)-CH₂CH₃, C(0)-(CH2) ₂CH₃, C(0)-CH(CH₃) ₂ or C(0)-C(CH₃) ₃, R₅ is CH₃, CH₃CH₂, CH₃(CH₂) ₂, (CH₃)₂CH, or (CH₃)₃C.

In a preferred specific embodiment, the Danshensu derivatives of general formula IV containing a moiety of TMP can be further defined in that R₅ is methyl, R₂ is C(0)-CH₃, and R₆, R7 and R₈ are CH₃; such that the structure of which is of ADTM below:

In another preferred specific embodiment, the Danshensu derivatives of general formula IV containing a moiety of Chuanxiongqin (Tetramethylpyrazine, TMP) can be further defined such that the structure of which is of LDTM below:

In yet further preferred embodiments, the Danshensu derivatives of general formula I can be further defined as of general formula V containing a moiety of TMP:

wherein, R₂ and R₅ are each independently substituted or unsubstituted alkyl, or biologically active lipoic acid or bornyl group.

In further preferred embodiments, the Danshensu derivatives of general formula I can be further defined as of general formula VI containing a moiety of TMP:

wherein:

R₇ is alkyl;

Re, R9 and Rio, being the same or different, are each independently hydrogen , alkyl, C(0)-alkyl, C(0)-aryl, C(0)-heterocyclic aryl, N0₂, NH₂, COOH, CN , F, CI, Br, or I.

In a further preferred specific embodiment, the Danshensu derivative has the structure of ADTE below:

The present invention also provides methods of preparing Danshensu derivatives. In one embodiment, the method includes protecting and modifying the carboxylic group and a-hydroxyl groups in the lactic acid structure to give corresponding esters and amides. Danshensu can be used in mice to significantly extend hypoxia endurance time, which is effective against myocardial ischemia, while phenyl lactic acid is an active site with a strong effect for anti-platelet aggregation and disaggregation. The protection and modification of such active groups is effective to increase in vivo metabolic stability of drugs and enhance pharmaceutical efficacy through synergetic effect.

In another embodiment, the method for preparing Danshensu derivatives includes protecting and modifying the phenolic hydroxyl group to synthesize a new Danshensu derivative. The protection and modification of such phenolic hydroxyl group is effective to increase the stability of the compounds since the catechol moiety in the Danshensu structure is rather unstable as being susceptible to oxidation.

In yet another embodiment, the method for preparing Danshensu derivatives includes attaching other functional groups with a strong antioxidant function at an appropriate site. For example, the Danshensu derivatives prepared through such inventive method are highly active for treating heart diseases whereas the Danshensu shows insufficient effect.

As further described in the examples and depicted in the drawings (FIGS. 2-10), methods of preparing the Danshensu derivatives provided herein are exemplarily illustrated.

3. Treatment Methods and Formulations

The pharmaceutical compositions of the invention can be administrated orally, for example, in the form of coated or uncoated tablets, hard or soft gelatin capsules, solutions, emulsions or suspensions. Compositions for oral administration can be prepared by any method known in the art, and these compositions may contain one or more of sweeteners, flavoring agents, coloring agents and preservatives to provide a pharmaceutically palatable preparation. The tablets for oral administration contain an active compound mixed with an excipient which is non-toxic, pharmaceutically acceptable and suitable for tablet manufacturing. Such excipient can be an inert diluent such as calcium carbonate or alginic acid, or a bonding agent such as starch, gelatin or acacia gum, or a lubricating agent such as magnesium stearate, stearic acid or talcum powder. The tablets can be uncoated or coated with any materials known in the art to delay the decomposition and absorption in the gastrointestinal tract and thus to provide a long lasting effect. For example, glycerol stearate can be used as the material to extend the duration of pharmaceutical effect of the drug.

The pharmaceutical compositions of the invention for oral administration can also be in the form of hard capsule, containing the active ingredient mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or of soft capsule containing the active ingredient mixed with water or oil medium such as peanut oil, liquid paraffin or olive oil.

An aqueous suspension contains an active compound mixed with an excipient which is suitable for preparation of the suspension. Such excipient can be a suspending agent such as sodium carboxymethyl cellulose, sodium alginate, polyvinylpyrrolidone, milkvetch root gum and acacia gum; a dispersing or moisturizing agent such as naturally existing phospholipid (e.g., lecithin), or a condensation product of fatty acid alkenyl oxide such as heptadecy ethyleneoxy cetyl alcohol, or a condensation product of ethylene oxide partially from fatty acid and hexose alcohol such as polyoxyethylene sorbierite-oleate. The aqueous suspension can also contain one or more preservatives such as ethylene or n-propyl parabens, one or more coloring agents, one or more flavoring agents, and/or one or more sweeteners such as sugarcane or saccharin.

An oil suspension can be prepared by suspending an active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. The oil suspension may contain a thickening agent such as beeswax, hard paraffin or acetyl alcohol. The sweeteners and flavoring agents, as mentioned above, can be added to provide a dosage form suitable for oral administration. Furthermore, anti-oxidation agents, such as ascorbic acid, can be added for storage.

Dispersible powders or granules, suitable for preparing an aqueous suspension by adding water, contain active ingredients mixed with a dispersing or moisturizing agent, suspensing agent and one or more preservatives, while some appropriate dispersing or moisturizing agents and suspensing agents are exemplarily described above. Additional excipients such as sweetening, flavoring and coloring agents can also be included.

The pharmaceutical compositions of the present invention can be also in the form of oil-in- water emulsion. The oil phase can be of vegetable oil such as olive oil and peanut oil, or of mineral oil such as liquid paraffin, or of a mixture thereof. A proper emulsion agent can be naturally existing gums such as acacia gum and astragalus henryi gum, naturally existing phospholipids such as soybeans and lecithin, or esters or partial esters derived from fatty acids and hexitol, or condensation products made from an anhydride such as dehydrated sorbitol and the above-mentioned partial ester and ethylene oxide. Other agents, such as sweetening, flavoring and coloring agents may also be included.

Syrup can be prepared by using a sweetening agent such as glycerol, glycerin sorbitol or sucrose. Such formulation can also contain a demulcent, preservative, flavoring agent, and coloring agent. The pharmaceutical compositions described herein can be in the form of injectable sterile aqueous or oil suspension. Such suspension can be prepared by using a proper dispersing or moisturizing agent known in the art and an above-mentioned suspending agent. The injectable sterile preparation can also be an injectable sterile solution or suspension in a non-toxic physiologically acceptable diluent or solvent, such as 1,3-butanediol. In these acceptable excipients, a solution such as aqueous Ringer's solution and isotonic chloride solution can be used. In addition, a sterile oil mixture is usually used as solvent or suspension media. For this purpose, any moderate oil mixture containing synthetic monomer or diglyceride can be used, and a fatty acid such as oleic acid can be used in the injectable preparation.

The pharmaceutical compositions containing active compounds can be also rectally administrated in suppository form. These compositions can be prepared by mixing the active compounds with appropriate non-irritating excipients, and the compositions are solid at room temperature but will be melted into a liquid in the rectum to release the active compounds. Such excipients include cocoa butter and polyethylene glycol.

The compositions containing active compounds of the present invention can be also parentarally administrated in a sterile medium. Depending on the types of the excipents and the concentrations of the active compounds, the pharmaceutical compositions can be formulated either as a suspension or being dissolved in an excipent. In the excipient, certain suitable auxiliary agents (e.g., local anesthetics), preservatives and buffering agents can be dissolved.

The compositions of the present invention can be given in a continuous or

intermittent mode via any routes of administrations suitable for particular drug molecules to be delivered. The routes of administration can be of oral or parenteral, including subcutaneous, intravenous, inhalation, nasal, and intraperitoneal. In addition, the compositions can be given in an intermittent mode by injecting a bolus of compositions in a period as desired, for example, once a day, once every other day, once every three days, once a week, twice a week, every two weeks, twice a month, or once a month.

The therapeutic agents of this invention can be given to a particular patient in any suitable mode for direct (e.g., through injection, local implantation, or local tissue position) or systemic (e.g., oral or parenteral) delivery. The parenteral or non-intestinal

administration can be achieved through, for example, intravenous, subcutaneous, ocular, abdominal, intramuscular, oral, rectal, vaginal, subcutaneous, percutaneous, endotracheal, Intracerebral, intracranial, intraspinal, intraventricular, intrathecal, intracisternal, intracapsular, intranasal, or aerosol delivery. The compositions may preferably include water, or physiologically acceptable suspension or solution. Thus, the carriers or excipients, as being physiologically acceptable for delivering a needed composition for a patient, will not interfere the electrolyte and volume balance in the body of the patient. The liquid medium used for pharmaceutical agents may include a conventional saline solution or a buffer solution of pH 3-7.4. In addition, in the methods of this invention, the pharmaceutical compositions described herein can be delivered in a continuous or intermittent mode by using a micro-pump.

The suitable solutions for parenteral administration can be prepared by any known methods in the art, which is described, for example, in emigton's Pharmaceutical

Sciences (Gennaro, A., ed.), Mack Pub., 1990. The therapeutic preparations of this invention may contain, for example, polyalkylidene glycol such as polyethylene glycol, oil of plant origin, or hydrogenated naphthalene. The therapeutic preparation, especially for direct administration, may contain glycerol and other highly viscous compositions for being maintained at desirable sites. Bio-compatible, preferably bio-absorbable polymers, including the polymers of hyaluronic acid, collagen, tricalcium phosphate, poly-butyrate, cyclic diesters and glycolide polymers, and the copolymer of cyclic diester/glycolide, are excipients suitable to control in vivo release of pharmaceutical preparations. Other potentially useful parenteral delivery systems for these preparations include particles of ethylene-vinyl cerotate copolymer, osmotic pump, removable implant, and liposomes. Preparations for inhale administration include an excipient such as of lactose, an aqueous solution such as of polyethylene oxide-9-lauryl ether, glycocholate ester or deoxycholate ester, an oil solution as nasal drops, or a gel for intranasal administration. The

preparations for parenteral administration can also include glycocholates for oral administration, methoxy salicylate for rectal administration, or cutric acid for vaginal administration. Suppositories for rectal administration can also be prepared by mixing the therapeutic agents of this invention (alone or in combination with chemotherapy agents) with a non-irritating excipient, and such excipient can be, for example, cocoa butter or other composition as a solid at the room temperature and as a liquid at the body temperature.

The novel compounds of the present invention formulated through dissolution, suspension or emulsion in water or non-aqueous solvent can be administered by injection. Examples of the non-aqueous solvents include methylsulfoxide, Ν,Ν-dimethyl acetyl oxygen, Ν,Ν-dimethylformamide, vegetable oil or similar oil, synthetic fatty acids, glycerides, fatty acid glycol esters, and propylene diols. The compounds are prepared preferably in aqueous solution, such as Hank solution, Ringer's solution, or a buffer solution of physiological saline.

The Danshensu derivatives of the present invention formulated by combining with a pharmaceutically acceptable carrier known in the art can be orally administrated. Carriers are employed to allow such compounds to be formulated into oral tablets, suspensions, liquids or gels suitable for patients. Oral formulations can be prepared in a variety of ways, which include mixing a solid excipient with the compound, optionally grinding the resultant mixture, and adding suitable granule mixture to facilitate the process. The following are some exemplary excipients used for oral administration: Sugars such as lactose, sucrose, mannose or sorbitol; cellulose preparations such as corn starch, wheat starch, potato starch, gelatin, radix astragali gum, methyl cellulose, hydroxypropyl methyl cellulose, sodium hydroxymethyl cellulose and polyvinylpyrrolidone (PVP).

The Danshensu derivatives of the present invention may also be released as aerosols or spraying agents through a pressurized plug, a sprayer or a dry-powder inhaler.

Propellants which may be suitably used in a sprayer include dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane and carbon dioxide. For a pressurized sprayer, the dose of the compound can be controlled by adjusting the valve to release the compound.

The formulations for percutaneous administration can be prepared by spreading the molecules which are able to release the pharmaceutical compositions of this invention to a dermatologically acceptable carrier such as lotion, cream, ointment or soap. It is particularly beneficial that the carriers can form a film or a layer on the skins to avoid the undesirable drug shifting for topical application. For topical administration on tissue skins, the compositions can be dispersed into a tissue-adhesive liquid or other known medium in order to enhance the absorption on the tissue surfaces. To enhance the above beneficial effects, solutions of hydroxypropyl cellulose or fibrinogen/thrombin, for example, can be also used. In other words, tissue coating solutions, such as the preparations containing pectin, can be used.

The compounds of the present invention can be used to treat cardiovascular and cerebrovascular diseases or related complications. These diseases include, but are not limited to, nervous system diseases such as hypoxic-ischemic brain injury, stroke, trauma, Alzheimer's disease, epilepsy, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, AIDS dementia, multiple sclerosis, chronic pain, priapism, cystic fibrosis, schizophrenia, depression, premenstrual syndrome, anxiety, addiction, and migraine; and cardiovascular diseases such as cardiopulmonary bypass, ischemia reperfusion injury, ischemia reperfusion, toxic shock syndrome, adult respiratory distress syndrome, cachexia, myocarditis, atherosclerosis, coronary heart disease, angina, heart disease and heart attack. The compounds of the present invention can be also used to treat inflammatory diseases such as inflammatory bowel disease, diabetes, rheumatoid arthritis, asthma, cirrhosis, allograft rejection, encephalomyelitis, meningitis, pancreatitis, peritonitis, vasculitis, lymphocytic choriomeningitis, glomerulonephritis, systemic lupus erythematosus, gastrointestinal motility disorders, obesity, hyperphagia, hepatitis and renal failure. The compounds of the present invention can be also used to treat ophthalmologic diseases such as diabetic retinopathy, uveitis, glaucoma, blepharitis, chalazion, allergic eye disease, corneal ulcers, keratitis, cataract, age-related macular degeneration, and optic neuritis. These new compounds can also be used for the prevention and treatment of cancers such as neuroblastoma. The compounds of the present invention can also be administered alone or combined with other therapeutic agents.

The pharmaceutical compositions described herein contain a therapeutically effective amount of at least one of the Danshensu derivatives of the present invention. The therapeutically effective amounts of the Danshensu derivatives can be determined by a person of skills in the art.

4. Examples

The following examples are intended for illustration only and are not intended to restrict the scope of the present invention in any way. The efficacy of the compounds of the present invention can be tested in vivo and in experimental animal models by use of the reagents mentioned below.

Example 1. Synthesis of compound BnOH

Danshensu (100 mg, 0.505 mmol) was weighed and placed in a 25 mL single-neck flask, and 2 mL of acetone was added, The content of the flask was stirred at room temperature to reach uniformity, and then anhydrous K₂CO₃ (200 mg, 1.45 mmol) was added and subsequently benzyl bromine (0.2 mL, 1.67 mmol) was added. The reaction was refluxed at 65°C for 24 hours and monitored by TLC. Upon completion, the reaction was cooled to room temperature, acidified with IN of HC1, and diluted with a saturated NaCl solution and ethyl acetate, extracted three times with ethyl acetate (25 mL><3). The organic phase was dried over Na₂S0₄, then spun to dryness, and separated on a silica get column (ethyl acetate : petroleum ether = 1 :2) to give the target compound (130 mg, yield

55.8%) as a solid, mp 92-95°C; 1H NMR (DMSO-t/₆, 500 MHz) δ: 2.88 (dd, J= 6.4, 14.0 Hz, 1 H, CH₂), 3.30 (dd, J= 4.8, 14.0 Hz, 1 H, CH₂), 4.41 (m, 1 H, CH), 5.06 (s, 2 H, CH₂), 5.09 (s, 2 H, CH₂), 5.12 (s, 2 H, CH₂), 6.64 (dd, J= 2.0, 8.0 Hz, 1 H, arom.), 6.80 (d, J= 8.0 Hz, 1 H, arom.), 6.81 (d, J= 2.0 Hz, 1 H, arom.), 7.31 (m, 15 H, arom.); MS (ESI) [M+Na]⁺m/z 491.5. Anal. (C₃oH₂₈0₅) C, H.

Example 2. Synthesis of compound DPNB Danshensu (100 mg, 0.505 mmol) was weighed and placed in a 25 mL single-neck flask, about 2 mL of DMF was added dropwise to dissolve the compound, and then EDCI (125 mg, 0.65 mmol) and HOBt (90 mg, 0.66 mmol) were added. The content of the flask was stirred at room temperature to reach uniformity, and then was cooled to 0°C with an ice bath. Under the N₂ atmosphere, the Boc protected piperazine (112 mg, 0.6 mmol) was added to the reaction system. The reaction was run at room temperature for 17 hours and monitored by TLC. When the starting materials were consumed, the reaction was diluted with iced brine and ethyl acetate, extracted three times with ethyl acetate (25 mL><3). The ethyl acetate layer was washed three times with ice brine to remove DME The organic phase was then dried over anhydrous Na₂S0₄, separated on a silica get column (ethyl acetate : petroleum ether = 2: 1) to give the target compound (120 mg, yield 65%) as a loose white solid. 1H NMR (DMSO-t/₆, 500 MHz ) δ: 2.81 (dd, J= 5.6, 13.6 Hz, 1 H, CH₂), 2.74 (dd, J= 5.6, 13.8 Hz, 1 H, CH₂), 3.32 (m, 4 H, CH₂-CH₂), 3.64 (m, 4 H, CH₂-CH₂), 4.43 (dd, J= 7.2, 14.4 Hz, 1 H, CH), 6.46 (dd, J= 2.0, 8.2 Hz, 1 H, arom.), 6.61 (d, J= 8.2 Hz, 1 H, arom.), 6.63 (d, J= 2.0 Hz, 1 H, arom.), 9.25 (s, 2 H, arom.); MS (ESI) [M+H]⁺ m/z 267.3; FABHRMS: calcd for (Ci₃Hi₉ClN₂0₄) 302.10333, found 302.1043.

Example 3. Synthesis of compound TMPM

Danshensu (100 mg, 0.505 mmol) was weighed and placed in a 25 mL single-neck flask, about 2 mL of dried DMF was added dropwise to dissolve the compound, and then NaHC0₃ (50 mg, 0.595 mmol) was added. The content of the flask was stirred to reach uniformity at room temperature, and the temperature was brought down to 0°C with an ice bath. Under the N₂ atmosphere, 2-bromoethyl-3,5,6-trimethyl-pyrazine (110 mg, 0.514 mmol) was added, and the reaction was allowed to run at room temperature for 17 hours and monitored by TLC. After the starting materials were consumed, the reaction was diluted with iced brine and ethyl acetate, extracted three times with ethyl acetate (25 mLx3). The ethyl acetate layer was washed three times with iced brine to remove DMF from the organic phase. The organic phase was then dried over anhydrous Na₂S0_4j spun to dryness, separated on a silica get column (ethyl acetate : petroleum ether = 1 :2) to give the target compound (108 mg, yield 65.4%) as a white solid. 1H-NMR (DMSO-t/6,400 MHz) δ: 2.39 (s, 3 H, CH₃), 2.42 (s, 3 H, CH₃), 2.44 (s, 3 H, CH₃), 2.66 (dd, J= 8.0, 13.8 Hz, 1 H, CH₂), 2.80 (dd, J= 5.2, 13.8 Hz, 1 H, CH₂), 4.18 (dd, J= 6.0, 13.0 Hz, 1 H, CH), 5.14 (s, 2 H, CH₂), 6.40 (dd, J= 2.4, 8.0 Hz, 1 H, arom.), 6.56 (d, J= 8.0 Hz, 1 H, arom.), 6.59 (d, J= 2.4 Hz, 1 H, arom.); MS (ESI) [M+Na]⁺ 356.1. FABHRMS: calcd for (Ci₇H₂oN₂0₅) 332.13722, found 332.13684. Anal. (Ci₇H₂₀N₂O₅) C, H, N.

Example 4. Synthesis of compound PCDB

The compound (130 mg, 0.28 mmol) of Example 1 was weighed and placed in a 25 mL single-neck flask, about 2 mL of anhydrous THF was added dropwise to dissolve the compound, and then DMAP (14 mg, 10%) was added. The content of the flask was stirred at room temperature to reach uniformity, and propionic anhydride (60 μί, 0.61 mmol) was added, and the reaction was allowed to run at room temperature overnight and monitored by TLC. Upon the completion of the reaction, the resulting reaction materials were directly separated on silica get column (ethyl acetate : petroleum ether = 1 :3) to give the target compound (110 mg, yield 77.5%) as an oily liquid. 1H-NMR (CDC1₃, 500 MHz ) δ: 1.19 (t, J= 12.2 Hz, 3 H, CH₃), 2.29 (m, 2 H, CH₂ ), 2.95 (dd, J= 8.5, 15.7 Hz, 1 H, CH₂), 3.05 (dd, J= 4.5, 12.5 Hz, 1 H, CH₂), 5.06 (s, 2 H, CH₂), 5.09 (s, 2 H, CH₂), 5.12 (s, 2 H, CH₂), 5.17 (dd, J= 5.0, 8.0 Hz, 1 H, CH), 6.67 (dd, J= 2.0, 8.0 Hz, 1 H, arom.), 6.79 (d, J= 8.0 Hz, 1 H, arom.), 6.81 (d, J= 2.0 Hz, 1 H, arom.), 7.35 (m, 15 H, arom.); MS (ESI) [M+Na]⁺ m/z 547.4; Anal. (C₃₃H₃₂0₆) C, H.

Example 5. Synthesis of compound BCDB

The compound (130 mg, 0.28 mmol) of Example 1 was weighed and placed in a 25 mL single-neck flask and dissolved with 2 mL anhydrous THF, and DMAP (14 mg, 10%) was added, stirred uniformly at room temperature. Butyrate anhydride (60 μί, 0.60 mmol) was added, and the reaction was run at room temperature overnight with TLC monitoring. After the completion of the reaction, the resulting materials were separated on a silica get column (ethyl acetate : petroleum ether = 1 : 3) to give the target compound (131 mg, yield 87.9%) as an oily liquid. 1H-NMR (CDC1₃, 500 MHz ), δ: 0.85 (t, J= 7 Hz, 3 H, CH₃), 1.59 (m, 2 H, CH₂), 2.26 (t, J= 14.8 Hz, 2 H, CH₂), 2.95 (dd, J= 8.5, 15.7 Hz, 1 H, CH₂), 3.05 (dd, J= 4.5, 12.5 Hz, 1 H, CH₂), 5.06 (s, 2 H, CH₂), 5.09 (s, 2 H, CH₂), 5.12 (s, 2 H, CH₂), 5.20 (dd, J= 5.0, 8.0 Hz, 1 H, CH), 6.68 (dd, J= 2.0, 8.0 Hz, 1 H, arom.), 6.79 (d, J = 8.0 Hz, 1 H, arom.), 6.81 (d, J= 2.0 Hz, 1 H, arom.), 7.35 (m, 15 H, arom.); MS (ESI) [M+Na]⁺ m/z 561.4; Anal. (C₃₄H₃₄0₆) C, H.

Example 6. Synthesis of compound iBCDB

The compound (130 mg, 0.28 mmol) of Example 1 was weighed and placed in a 25 mL single-neck flask and dissolved with 2 mL anhydrous THF, DMAP (14 mg, 10%) was added, and stirred uniformly at room temperature. Isobutyl anhydride (60 μί, 0.60 mmol) to the reaction system and the reaction was run at room temperature overnight with TLC monitoring. After the reaction was completed, the resulting materials were separated on a silica get column (ethyl acetate : petroleum ether = 1 :3) to give the target compound (129 mg, yield 86.5%) as an oily liquid. ¹H-NMR (CDC1₃, 500 MHz ) δ: 1.12 (dd, J= 7, 14 Hz, 6 H, CH₃), 2.55 (m, 1 H, CH ), 3.05 (dd, J= 8.5, 15.7 Hz, 1 H, CH₂), 3.10 (dd, J= 4.5, 12.5 Hz, 1 H, CH₂), 5.06 (s, 2 H, CH₂), 5.09 (s, 2 H, CH₂), 5.12 (s, 2 H, CH₂), 5.19 (dd, J = 5.0, 8.0 Hz, 1 H, CH), 6.68 (dd, J= 2.0, 8.0 Hz, 1 H, arom.), 6.79 (d, J= 8.0 Hz, 1 H, arom.), 6.81 (d, J= 2.0 Hz, 1 H, arom.), 7.35 (m, 15 H, arom.); MS (ESI) [M+Na]⁺ m/z 561.4; Anal. (C₃₄H₃₄0₆) C, H.

iBCDB

Example 7. Synthesis of compound HDB

The compound (144 mg, 0.5 mmol) of Example 33 was placed in a 25 mL three-neck round-bottom flask, and dried anhydrous THF (2 mL) was added dropwise. The content of the flask was stirred uniformly at room temperature, and then was cooled to 0°C with an ice bath. Under N₂ protection, triethylamine was added as initiator to the reaction, and BTC was added dropwise slowly with an ice bath and magnetic stirring. The reaction was run for 2 hours. The resulting material was washed with a solution of saturated NaHC0₃, and then the organic material was extracted three times with ethyl acetate, and the extract liquid was dried over anhydrous sodium sulfate, spun to dryness, dissolved, and separated on a silica get column (ethyl acetate : petroleum ether = 1 : 1). The fractions containing the target product were collected, rotavapped, and dried in a vacuum oven (50°C) for 1 hour to give a purified solid (113 mg, yield 72%). mp 56-58 °C; 1H-NMR (CDC1₃, 500 MHz) δ: 3.05 (dd, J= 8.5, 15.7 Hz, 1 H, CH₂), 3.10 (dd, J= 4.5, 12.5 Hz, 1 H, CH₂), 4.45 (m, 1 H, CH), 5.19 (s, 2 H, CH₂), 7.13 (d, J = 6.0 Hz, 1 H, CH, arom.), 7.16 (d, J = 6.0 Hz, 1 H, CH, arom.), 7.36 (d, 1 H, CH, arom.), 7.38 (m, 3 H, CH, arom.), 7.42 (m, 2 H, CH, arom.), MS (ESI) [M+Na]⁺m/z 337.1; Anal. (Ci₇Hi₄0₆) C, H.

Example 8. Synthesis of compound DTZB

In a 25 mL three-neck round-bottom flask was added dropwise dry and anhydrous CH₂CI₂ (2 mL) and TMP carboxylic acid oxide (0.25 mmol). The content of the flask was stirred uniformly at room temperature, and then the temperature was brought down to 0°C with an ice bath. Under N₂ protection, a catalyst of DCC was added, and, half an hour later, the compound (110 mg, 0.22 mmol) of Example 1 and the catalyst of DMAP were added. The reaction was stirred magnetically at room temperature for 2 hours and spun to remove CH₂C1₂. Ethyl acetate was added, the resulting mixture was filtered to remove a white precipitate of DCU, and the filtrate was dried over anhydrous sodium sulfate and spun to dryness. The resulting material was dissolved and separated on a silica gel column with EA/PE (1 :2) as eluant, rotavapped, and dried in a vacuum oven (50°C) for 1 hour to give a purified solid (97 mg, yield 71.5%). mp 84-86 °C; 1H-NMR (CDC1₃, 500 MHz) δ: 2.55 (s, 6 H, CH₃), 2.61 (s, 3 H, CH₃), 3.05 (dd, J= 8.5, 14.5 Hz, 1 H, CH₂), 3.15 (dd, J = 4.5, 14.5 Hz, 1 H, CH₂), 5.05 (s, 2 H, CH₂), 5.10 (s, 2 H, CH₂ ), 5.15 (s, 2 H, CH₂), 5.45 (dd, J= 4.5, 8.5, 1 H, CH), 6.68 (dd, J= 2.0, 8.0 Hz, 1 H, arom.), 6.79 (d, J= 8.0 Hz, 1 H, arom.), 6.81 (d, J= 2.0 Hz, 1 H, arom.), 7.35 (m, 15 H, arom.); Anal. (C₃₈H₃₆N₂0₆) C, H, N.

Example 9. Synthesis of compound TMPZ

The compound (123 mg, 0.2 mmol) of Example 7 was placed in a 25 mL single-neck flask, and dissolved with ethanol. Palladium carbon (11 mg, 10%) was added, and H₂ was carefully introduced. The reaction was run at room temperature for 2-4 hours with TLC monitoring. After the reaction was completed, saturated NaCl solution was added. The resulting material was diluted with ethyl acetate, extracted three times with ethyl acetate, dried over Na₂S0₄, spun to dryness, and separated on a silica get column (ethyl acetate : petroleum ether = 1 :2) to give the target compound (57 mg, yield 82.4%>) as a light yellow solid, mp 179-181 °C; 1H-NMR (DMSO-t/₆, 500 MHz ) δ: 2.35 (s, 3 H, CH₃ ), 2.55 (s , 6 H, CH₃), 3.05 (dd, J= 8.5, 14.5 Hz, 1 H, CH₂), 3.15 (dd, J= 4.5, 14.5 Hz, 1 H, CH₂), 5.25 (dd, J= 4.58.5, 1 H, CH), 6.47 (dd, J= 2.0, 8.0 Hz, 1 H, arom.), 6.75 (d, J= 8.0 Hz, 1 H, arom.), 6.64 (d, J= 2.0 Hz, 1 H, arom.), 8.79 (s, 1 H, arom.), 8.85 (s, 1 H, arom.); MS (ESI) [M-H]^" m/z 345.3; Anal. (Ci₇Hi₈N₂0₆) C, H, N.

Example 10. Synthesis of compound ADTZ

The compound (173 mg, 0.5 mmol) of Example 8 was placed in a 25 mL single-neck flask, and dissolved with dried anhydrous THE The content of the flask was stirred at room temperature to reach uniformity, and then the temperature was brought down to 0°C with an ice bath. Under N₂ protection, acetic anhydride as acylating agent and DMAP as catalyst were added, and the reaction was stirred magnetically at room temperature for 2 hours. The resulting material was washed with a solution of saturated NaHCC>3, and the organic material was extracted three times with ethyl acetate, and the extract liquid was dried over anhydrous sodium sulfate, spun to dryness, dissolved, and separated on a silica gel column (ethyl acetate : petroleum ether = 1 : 1). The solution of the fractions containing the target compound was collected and evaporated to dryness on a rotavapor to give a white solid, which was dried in a vacuum oven (50°C) for 1 hour to give a purified compound (204.2 mg, yield 95%). mp 59-61°C; 1H-NMR (CDC1₃, 500 MHz) δ: 2.05 (s, 6 H, CH₃), 2.48 (s, 3 H, CH₃), 2.50 (s, 3 H, CH₃ ), 2.51 (s, 3 H, CH₃ ), 3.35 (m, 2 H, CH₂), 5.65 (m, 1 H, CH), 7.05 (m, 1H, CH, arom.), 7.15 (m, 1 H, CH, arom.), 7.25 (s, 1 H, CH, arom.), MS (ESI) [M+Na]⁺ m/z 453.2. Anal. (C₂iH₂₂N₂0₈) C, H, N.

Example 11. Synthesis of compound TMPMB

The compound (173 mg, 0.5 mmol) of Example 1 was placed in a 25 mL single-neck flask, and dissolved with dried anhydrous THE The content of the flask was stirred at room temperature to reach uniformity, and then the temperature was brought down to 0°C with an ice bath. Under N₂ protection, NaH was added slowly dropwise with magnetic stirring at room temperature for 3 hours with TLC monitoring. Subsequently a TMP brominated compound was added. The reaction was refluxed at 70 °C for 20 hours, and distilled water was added dropwise. The resulting material was extracted three times with ethyl acetate, and the extract liquid was dried over anhydrous sodium sulfate, spun to dryness, dissolved and separated on a silica gel column (ethyl acetate acetate: petroleum ether = 1 : 1). The fractions containing the target product were collected and then evaporated to dryness on a rotavapor to give a white solid, which was dried in a vacuum oven (50 °C) for 1 hour to give a purified compound (55 mg, yield 42%). ^-NMR (CDC1₃, 500 MHz ) δ: 2.55 (s, 6 H, CH₃), 2.6 (s, 3 H, CH₃), 2.85 (dd, J= 7.0, 14.0 Hz, 1 H, CH₂), 3.05 (dd, J= 4.5, 14.5 Hz, 1 H, CH₂), 4.45 (dd, J= 4.5, 7.0 Hz, 1 H, CH), 5.05 (s, 2 H, CH₂), 5.10 (s, 2 H, CH₂), 5.15 (d, 2 H, CH₂), 5.17 (m, 1 H, CH), 6.68 (dd, J= 2.0, 8.0 Hz, 1 H, arom.), 6.79 (d, J= 8.0 Hz, 1 H, arom.), 6.81 (d, J= 2.0 Hz, 1 H, arom.), 7.35 (m, 15 H, arom.); MS (ESI) [M+Na]⁺ m/z 625.4.

TMPMB

Example 12. Synthesis of compound ADTM

The compound (166 mg, 0.5 mmol) of Example 3 was placed in a 25 mL single-neck flask, and dissolved with dried anhydrous THE The content of the flask was stirred at room temperature to reach uniformity, and the temperature was brought down to 0 °C. Under N₂ protection, acetic anhydride as acylating agent and DMAP as catalyst were added, and the reaction was stirred magnetically at room temperature for 2 hours. Then the resulting material was washed with a solution of saturated NaHC0₃, and the organic material was extracted three times with ethyl acetate, and the extract liquid was dried over anhydrous sodium sulfate, spun to dryness, dissolved, and separated on a silica get column (ethyl acetate: petroleum ether = 2: 1). The fractions containing the target product were collected and evaporated to dryness on a rotavapor to give a white solid, which was dried in a vacuum oven (50 °C) for 1 hour to give a purified product (199.7 mg, yield 87.2%). 1H-NMR (CDC1₃, 500 MHz) δ: 2.05 (s, 3 H, CH₃), δ: 2.10 (s, 6 H, CH₃), 2.48 (s, 3 H, CH₃), 2.50 (s, 3 H, CH₃ ), 2.51 (s, 3 H, CH₃ ), 3.05 (dd, J= 9.5, 15.7 Hz, 1 H, CH₂), 3.10 (dd, J= 4.0, 14.0 Hz, 1 H, CH₂), 4.15 (dd, J= 7.0, 14.0 Hz, 1 H, CH), 5.25 (s, 2 H, CH₂), 7.05 (m, 1H, CH, arom.), 7.15 (m, 1 H, CH, arom.), 7.25 (s, 1 H, C H, arom.), MS (ESI) [M+H]⁺ m/z 459.1. Anal. (C₂₃H₂₆N₂0₈) C, H, N.

Example 13. Synthesis of compound ADB

The compound (144 mg, 0.5 mmol) of Example 34 was placed in a 25 mL single-neck flask, and dried anhydrous THF (2 mL) was added dropwise. The content of the flask was stirred at room temperature to reach uniformity, and the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, an appropriate amount of triethylamine was added, and acetic anhydride was added slowly dropwise with an ice bath and magnetic stirring. The reaction was run for 2 hours. The resulting material was washed with a solution of saturated NaHC0₃, and the resulting material was washed three times with ethyl acetate. The extract was dried over anhydrous sodium sulfate, spun to dryness, and separated on a silica get column (ethyl acetate: petroleum ether = 2: 1). A solution of the fractions containing the target compound was collected and evaporated to dryness on a rotavapor to give a solid, which was dried in a vacuum oven (50 °C) for 1 hour to give a purified product (96.7 mg, yield 52.1%). 1H-NMR (CDC1₃, 500 MHz) δ: 2.25 (s, 6 H, CH₃), 3.05 (dd, J= 8.5, 15.7 Hz, 1 H, CH₂), 3.10 (dd, J= 4.5, 12.5 Hz, 1 H, CH₂), 4.45 (m, 1 H, CH), 5.19 (s, 2 H, OCH₂), 7.1 (m, 3 H, CH, arom.), 7.3 (m, 5 H, CH, arom.), MS (ESI) [M+Na]⁺ m/z 395.1. Anal. (Ci₃Hi₄0₇) C, H.

Example 14. Synthesis of compound PDB

The compound (144 mg, 0.5 mmol) of Example 34 was placed in a 25 mL single-neck flask, and dried anhydrous THF (2 mL) was added dropwise. The content of the flask was stirred at room temperature to reach uniformity, and the temperature was brought down to 0°C with an ice bath. Under N₂ protection, an appropriate amount of triethylamine was added, and propinoic anhydride was added slowly dropwise with an ice bath and magnetic stirring. The reaction was run for 2 hours. The resulting material was washed with a solution of saturated NaHC0₃, and the organic material was extracted three times with ethyl acetate, and the extract liquid was dried over anhydrous sodium sulfate, spun to dryness, dissolved, and separated on a silica gel column (ethyl acetate : petroleum ether = 1 :2). A solution of the fractions containing the target compound was collected and evaporated to dryness on a rotavapor to give a solid, which was dried in a vacuum oven (50 °C) for 1 hour to give a purified compound (114 mg, yield 57%). 1H-NMR (CDC1₃, 500 MHz) δ: 1.25 (t, J= 8 Hz, 6 H, CH₃), 2.6 (m, 4 H, CH₂), 3.05 (dd, J = 8.5, 15.7 Hz, 1 H, CH₂), 3.10 (dd, J = 4.5, 12.5 Hz, 1 H, CH₂), 4.45 (m, 1 H, CH), 5.19 (s, 2 H, OCH₂), 6.8 (m, 3 H, CH, arom.), 6.9 (m, 5 H, CH, arom.), MS (ESI) [M+Na]⁺ m/z 423.2. Anal. (C₁₅H₁₈0₇) C, H.

Example 15. Synthesis of compound BDB

The compound (144 mg, 0.5 mmol) of Example34 was placed in a 25 mL

single-neck flask, and dried anhydrous THF (2 mL) was added dropwise. The content of the flask was stirred at room temperature to reach uniformity, and the temperature was brought down to 0°C with an ice bath. Under N₂ protection, an appropriate amount of triethylamine was added, and butyric anhydride was added slowly dropwise with an ice bath and magnetic stirring. The reaction was run for 2 hours. The resulting material was washed with a solution of saturated NaHC0₃ , and the organic material was extracted three times with ethyl acetate, and the extract liquid was dried over anhydrous sodium sulfate, spun to dryness, dissolved and separated on a silica gel column (ethyl acetate : petroleum ether = 1 :2). A solution of the fractions containing the target component was collected and evaporated to dryness on a rotavapor to give a solid, which was dried in a vacuum oven (50 °C) for 1 hour to give a purified compound (100.6 mg, yield 47%). mp

65-66 °C; 1H-NMR (CDC1₃, 500 MHz) δ: 1.0 (t, J= 8 Hz, 6 H, CH₃), 1.15 (m, 4 H, CH₂), 2.6 (t, J= 2.5 Hz, 4 H, CH₂), 3.05 (dd, J= 8.5, 15.7 Hz, 1 H, CH₂), 3.10 (dd, J= 4.5, 12.5 Hz, 1 H, CH₂), 4.45 (m, 1 H, CH), 5.19 (s, 2 H, CH₂), 6.8 (m, 3 H, CH, arom.), 6.9 (m, 5 H, CH, arom.), MS (ESI) [M+Na]⁺ m/z 451.1. Anal. (Ci₇H₂₂0₇) C, H.

Example 16. Synthesis of compound iBDB

The compound (144 mg, 0.5 mmol) of Example 34 was placed in a 25 mL three-neck round-bottom flask, and dried anhydrous THF (2 mL) was added dropwise. The content of the flask was stirred at room temperature to reach uniformity, and then the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, an appropriate amount of triethylamine was added, and isobutyric anhydride was added slowly dropwise with an ice bath and magnetic stirring. The reaction was run for 2 hours. The resulting material was washed with a solution of saturated NaHC0₃. The resulting material was extracted three times with ethyl acetate, the extract was dried over anhydrous sodium sulfate, spun to dryness, dissolved, and separated on a silica gel column (ethyl acetate : petroleum ether = 1:2). The fractions containing the target product were collected and evaporated to dryness on a rotavapor to give a solid, which was dried in a vacuum oven (50 °C) for 1 hour to give a purified compound (89.9 mg, yield 42%). mp 76-78 °C; 1H-NMR (CDC1₃, 500 MHz) δ: 1.25 (d, J= 6.0, 12 H, CH₃), 2.85 (m, 2H, CH), 3.05 (dd, J= 8.5, 15.7 Hz, 1 H, CH₂), 3.10 (dd, J= 4.5, 12.5 Hz, 1 H, CH₂), 4.45 (m, 1 H, CH), 5.19 (s, 2 H, CH₂), 6.8 (m, 3 H, CH, arom.), 6.9 (m, 5 H, CH, arom.), MS (ESI) [M+Na]⁺ m/z 451.3. Anal.

(Ci₇H₂₂0₇) C, H.

Example 17. Synthesis of compound PDTM

The compound (166 mg, 0.5 mmol) of Example 3 was placed in a 25 mL single-neck flask, and dissolved with dried anhydrous THF. The content of the flask was stirred at room temperature to reach uniformity, and then the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, propionic anhydride as acylating agent and DMAP as catalyst were added. The reaction was stirred at room temperature for 2 hours. The resulting material was washed with a solution of saturated NaHC0₃, and the organic material was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, spun to dryness, dissolved, and separated on a silica gel column (ethyl acetate: petroleum ether = 2: 1). The fractions containing the target product were collected and then evaporated to dryness on a rotavapor to give a solid, which was dried in a vacuum oven

(50 °C) for 1 hour to give a purified product (205.7 mg, yield 96.5%). 1H-NMR (CDC1₃, 500 MHz) δ: 1.25 (t, J= 8 Hz, 9 H, CH₃), 2.6 (m, 6 H, CH₂), 2.48 (s, 3 H, CH₃), 2.50 (s, 3 H, CH₃ ), 2.51 (s, 3 H, CH₃ ), 3.10 (dd, J= 8.5, 14.5 Hz, 1 H, CH₂), 3.10 (dd, J= 3.5, 14.5 Hz, 1 H, CH₂), 5.18 (dd, J= 7.5, 14.0 Hz, 1 H, CH), 5.25 (s, 2 H, CH₂), 7.05 (m, 1 H, CH, arom.), 7.15 (m, 1 H, CH, arom.), 7.25 (s, 1 H, CH, arom.), MS (ESI) [M+Na]⁺ m/z 523.5. Anal. (C₂₆H₃₂N₂0₈) C, H, N.

Example 18. Synthesis of compound iBDTM

The compound (166 mg, 0.5 mmol) of Example 3 was placed in a 25 mL single-neck flask, and dissolved with dried anhydrous THF. The content of the flask was stirred at room temperature to reach uniformity, and then the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, isobutyric anhydride as acylating agent and DMAP as catalyst were added. The reaction was magnetically stirred at room temperature for 2 hours. The resulting material was washed with a solution of saturated NaHC0₃, and the organic material was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, spun to dryness, dissolved, and separated on a silica gel column (ethyl acetate: petroleum ether = 2: 1). The fractions containing the target product were collected and then evaporated to dryness on rotavapor to give a solid, which was dried in a vacuum oven (50 °C) for 1 hour to give a purified product (199.8 mg, yield 95.9%). 1H-NMR (CDC1₃, 500 MHz) δ: 1.25 (d, J= 6.0, 18 H, CH₃), 2.85 (m, 3 H, CH), 2.48 (s, 3 H, CH₃), 2.50 (s, 3 H, CH₃ ), 2.51 (s, 3 H, CH₃ ), 3.10 (dd, J= 8.5, 14.5 Hz, 1 H, CH₂), 3.10 (dd, J = 3.5, 14.5 Hz, 1 H, CH₂), 5.18 (dd, J= 7.0, 14.0 Hz, 1 H, CH), 5.25 (s, 2 H, CH₂), 7.05 (m, 1 H, CH, arom.), 7.15 (m, 1 H, CH, arom.), 7.25 (s, 1 H, CH, arom.), MS (ESI) [M+Na]⁺ m/z 565.5. Anal. (C₂₉H₃₈N₂0₈) C, H, N.

iBDTM

Example 19. Synthesis of compound BDTM

The compound (166 mg, 0.5 mmol) of Example 3 was placed in a 25 mL single-neck flask, and dissolved with dried anhydrous THF, and stirred at room temperature to reach uniformity, and then the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, butyric anhydride as acylating agent and DMAP as catalyst were added. The reaction was stirred at room temperature for 2 hours. The resulting material was washed with a solution of saturated NaHC0₃, and the organic material was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, spun to dryness, dissolved, and separated on a silica gel column (ethyl acetate: petroleum ether = 2: 1). The fractions containing the target product were collected and then evaporated to dryness on a rotavapor to give a solid, which was dried in a vacuum oven (50 °C) for 1 hour to give a purified product (198.7 mg, yield 95.7%). 1H-NMR (CDC1₃, 500 MHz) δ: 1.0 (t, J= 8 Hz, 9 H, CH₃), 1.15 (m, 6 H, CH₂), 2.6 (t, J= 2.5 Hz, 6 H, CH₂), 2.48 (s, 3 H, CH₃), 2.50 (s, 3 H, CH₃ ), 2.51 (s, 3 H, CH₃ ), 3.10 (dd, J= 8.5, 14.5 Hz, 1 H, CH₂), 3.10 (dd, J= 3.5, 14.5 Hz, 1 H, CH₂), 4.15 (dd, J= 7.0, 14.0 Hz, 1 H, CH), 5.25 (s, 2 H, CH₂), 7.05 (m, 1 H, CH, arom.), 7.15 (m, 1 H, CH, arom.), 7.25 (s, 1 H, CH, arom.), MS (ESI) [M+Na]⁺ m/z 565.7. Anal. (C₂₉H₃₈N₂0₈) C, H, N.

Example 20. Synthesis of compound LDTM

L-lipoic acid (206 mg, 1 mmol) was placed in a 25 mL single-neck flask and dissolved with dried anhydrous CH₂CI₂. The content of the flask was stirred at room temperature to reach uniformity, and then the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, DCC (103 mg, 0.500mmol) was added, and the material was stirred at room temperature for 2 hours with magnetic stirring. The compound (166 mg, 0.5 mmol) of Example 3 and DMAP as catalyst were added, and the reaction was stirred at room temperature overnight. Then CH₂CI₂ was removed from the reaction solution. Ethyl acetate was added, and the white precipitate DCU was filtered. The filtrate was dried over anhydrous sodium sulfate, spun to dryness, dissolved, and separated on a silica gel column with EA/PE = 1 :2 as eluant. The fractions containing the target product were collected and then evaporated to dryness on a rotavapor to give a solid, which was then dried in a vacuum oven (50 °C) for 1 hour to give a purified product (127 mg, yield 36%).

1H-NMR (CDCI₁₃, 300 MHz) δ: 1.50-1.80 (m, 12 H, CH₂), 1.82-2.01 (m, 4 H, CH₂), 2.42-2.60 (m, 13 H, CH₃, CH₂), 2.90-3.02 (m, 2 H, CH₂), 3.10-3.30 (m, 4 H, CH₂), 3.60 (m, 2 H,CH), 4.50 (s, 1 H, CH), 5.3 (s, 2 H, CH₂ ), 7.04-7.14 (m, 3 H, CH, arom.), MS (ESI) [M+Na]⁺ m/z 731.4.

Example 21. Synthesis of compound PDTZ

The compound (173 mg, 0.5 mmol) of Example 8 was placed in a 25 mL single-neck flask, and dissolved with dried anhydrous THE The content of the flask was stirred at room temperature to reach uniformity, and then the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, and propionic anhydride as acylating agent and DMAP as catalyst were added, and the reaction was stirred at room temperature for 2 hours. Then the resulting material was washed with a solution of saturated NaHC0₃, and the organic material was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, spun to dryness, dissolved, and separated on a silica gel column (ethyl acetate : petroleum ether = 1 : 1). The fractions containing the target product were collected and then evaporated to dryness on a rotavapor to give a solid, which was dried in a vacuum oven (50 °C) for 1 hour to give a purified product (206.2 mg, yield 95.6%). mp 65-67°C; 1H-NMR (CDC1₃, 500 MHz) δ: 1.25 (t, J= 8 Hz, 6 H, CH₃), 2.6 (m, 4 H, CH₂), 2.48 (s, 3 H, CH₃), 2.50 (s, 3 H, CH₃ ), 2.51 (s, 3 H, CH₃ ), 3.25 (m, 2 H, CH₂), 5.65 (m, 1 H, CH), 7.05 (m, 1 H, CH, arom.), 7.15 (m, 1 H, CH, arom.), 7.25 (s, 1 H, C H, arom.), MS (ESI) [M+Na]⁺ m/z 481.2. Anal. (C₂₃H₂₆N₂0₈) C, H, N.

Example 22. Synthesis of compound BDTZ

The compound (173 mg, 0.5 mmol) of Example 8 was placed in a 25 mL single-neck flask, and dissolved with dried anhydrous THF. The content of the flask was stirred at room temperature to reach uniformity, and then the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, and butyric anhydride as acylating agent and DMAP as catalyst were added. The reaction was stirred at room temperature for 2 hours with magnetic stirring. Then the resulting material was washed with a solution of saturated NaHC0₃, and the organic material was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, spun to dryness, dissolved, and separated on a silica gel column chromatography (ethyl acetate : petroleum ether = 1 : 1). The fractions containing the target product were collected and then evaporated to dryness on a rotavapor to give a white solid, which was dried in a vacuum oven (50 °C) for 1 hour to give a purified product (207.5 mg, yield 95.8%). mp 77-79°C; 1H-NMR (CDC1₃, 500 MHz) δ: 1.0 (t, J = 8 Hz, 6 H, CH₃), 1.15 (m, 4 H, CH₂), 2.6 (t, J= 2.5 Hz, 4 H, CH₂), 2.48 (s, 3 H, CH₃), 2.50 (s, 3 H, CH₃ ), 2.51 (s, 3 H, CH₃ ), 3.25 (m, 2 H, CH₂), 5.65 (m, 1 H, CH), 7.05 (m, 1 H, CH, arom.), 7.15 (m, 1 H, CH, arom.), 7.25 (s, 1 H, CH, arom.), MS (ESI) [M+Na]⁺ m/z 509.3. Anal. (C₂5H3oN₂0₈) C, H, N.

Example 23. Synthesis of compound iBDTZ

The compound (173 mg, 0.5 mmol) of Example 8 was placed in a 25 mL single-neck flask, and dissolved with dried anhydrous THF. The content of the flask was stirred at room temperature to reach uniformity, and then the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, isobutyric anhydride as acylating agent and DMAP as catalyst were added, and the reaction was stirred at room temperature for 2 hours with magnetic stirring. The resulting material was washed with a solution of saturated NaHC0₃, and the organic material was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, spun to dryness, dissolved, and separated on a silica gel column (ethyl acetate : petroleum ether = 1 : 1). The fractions containing the target product were collected and then evaporated to dryness on a rotavapor to give a white solid, which was dried in a vacuum oven (50 °C) for 1 hour to give a purified product (198.2 mg, yield

95.3%). mp 69-71°C; 1H-NMR (CDC1₃, 500 MHz) δ: 1.25 (d, J= 6.0, 12 H, CH₃), 2.85 (m, 2 H, CH), 2.48 (s, 3 H, CH₃), 2.50 (s, 3 H, CH₃ ), 2.51 (s, 3 H, CH₃ ), 3.25 (m, 2 H, CH₂), 5.65 (m, 1 H, CH), 7.05 (m, 1 H, CH, arom.), 7.15 (m, 1 H, CH, arom.), 7.25 (s, 1 H, CH, arom.), MS (ESI) [M+Na]⁺ m/z 509.2. Anal. (C₂₅H₃₀N₂O₈) C, H, N.

iBDTZ

Example 24. Synthesis of compound D002

The compound (157.4 mg, 0.3 mmol) of Example 3 was placed in a 25 mL

single-neck flask and dissolved with ethanol. Palladium carbon (11 mg, 10%) was added, and H₂ was carefully introduced. The reaction was run at room temperature for 2-4 hours with TLC monitoring. After the reaction was completed, saturated NaCl solution and ethyl acetate were added for dilution. The resulting material was extracted three times with ethyl acetate. The extract was dried over Na₂S0₄, spun to dryness, and separated on a silica get column (ethyl acetate : petroleum ether = 1 :2) to give the target compound (67.2 mg, yield 88.2%) as an oily liquid. 1H-NMR (DMSO-t/₆, 500 MHz ) δ: 1.26 (t, J= 7.2 Hz, 3 H, CH₃), 2.25 (m, 2 H, CH₂), 2.80 (dd, J= 8.5, 14.0 Hz, 1 H, CH₂), 2.90 (dd, J= 4.4, 14.4 Hz, 1 H, CH₂), 4.95 (dd, J= 4.5, 8.5 Hz, 1 H, CH), 6.47 (dd, J= 2.0 Hz, 8.0 Hz, 1 H, arom.), 6.75 (d, J= 8.0 Hz, 1 H, arom.), 6.64 (d, J= 2.0 Hz, 1 H, arom.), 8.79 (s, 1 H, arom.), 8.85 (s, 1 H, arom.); MS (ESI) [M-H]^" m/z 253.1. Anal. (Ci₂Hi₄0₆) C, H.

Example 25. Synthesis of compound D003

The compound (161.4 mg, 0.3 mmol) of Example 4 was placed in a 25 mL single-neck flask, and dissolved with ethanol. Palladium carbon (11 mg, 10%) was added, and H₂ was carefully introduced. The reaction was run at room temperature for 2-4 hours with TLC monitoring. After the reaction was completed, saturated NaCl solution and ethyl acetate were added for dilution. The resulting material was extracted three times with ethyl acetate. The extract was dried over Na₂S0₄, spun to dryness, and separated on a silica get column (ethyl acetate : petroleum ether = 1 :2) to give the target compound (70.2 mg, yield 87.5%) as an oily liquid. 1H-NMR (DMSO-t/₆, 500 MHz ) δ: 0.86 (t, J= 14.2 Hz , 3 H, CH₃), 1.6 (m, 2 H, CH₂ ), 2.38 (m, 2 H, CH₂ ), 2.80 (dd, J= 8.5, 14.0 Hz, 1 H, CH₂), 2.90 (dd, J= 4.4, 14.4 Hz, 1 H, CH₂), 4.95 (dd, J= 4.5, 8.5 Hz,l H, CH), 6.47 (dd, J= 2.0, 8.0 Hz, 1 H, arom.), 6.75 (d, J= 8.0 Hz, 1 H, arom.), 6.64 (d, J= 2.0 Hz, 1 H, arom.), 8.79 (s, 1 H, arom.), 8.85 (s, 1 H, arom.); MS (ESI) [M-H]^" m/z 267.2. Anal.

(Ci₃H₁₅0₆) C, H.

Example 26. Synthesis of compound D004

The compound (161.4 mg, 0.3 mmol) of Example 5 was placed in a 25 mL single-neck flask, and dissolved with ethanol. Palladium carbon (11 mg, 10%) was added, and H₂ was carefully introduced. The reaction was run at room temperature for 2-4 hours with TLC monitoring. After the reaction was completed, saturated NaCl solution and ethyl acetate were added for dilution. The resulting material was extracted three times with ethyl acetate. The extract was dried over Na₂S0₄, spun to dryness, and separated on a silica get column (ethyl acetate : petroleum ether = 1 :2) to give the target compound (67.5 mg, yield 84.2%) as an oily liquid. 1H-NMR ( DMSO-t/₆, 500 MHz ) δ: 1.06 (s , 6 H, CH₃), 2.65 (m, 1 H, CH), 2.85 (dd, J= 8.5, 14.0 Hz, 1 H, CH₂), 2.95 (dd, J= 4.4, 14.4 Hz, 1 H, CH₂), 4.95 (dd, J= 4.5, 8.5 Hz,l H, CH), 6.47 (dd, J= 2.0, 8.0 Hz, 1 H, arom.), 6.75 (d, J= 8.0 Hz, 1 H, arom.), 6.64 (d, J= 2.0 Hz, 1 H, arom.), 8.79 (s, 1 H, arom.), 8.85 (s, 1 H, arom.); MS (ESI) [M-H]^" m/z 267.4. Anal. (Ci₃Hi₅0₆) C, H.

Example 27. Synthesis of compound D005

The compound (186 mg, 0.5 mmol) of Example 13 was placed in a 25 mL

single-neck flask, and dissolved in ethanol. Palladium carbon (11 mg, 10%) was added, and H₂ was carefully introduced. The reaction was run at room temperature for 2-4 hours with TLC monitoring. After the reaction was completed, saturated NaCl solution and ethyl acetate were added for dilution. The resulting material was extracted three times with ethyl acetate. The extract was dried over Na₂S0₄, spun to dryness, and separated on a silica get column (ethyl acetate : petroleum ether = 1 :2) to give the target compound

(125.5 mg, yield 89%) as an oily liquid. 1H-NMR (CDC1₃, 500 MHz) δ: 2.08 (s , 6 H, CH₃), 2.95 (dd, J= 8.5, 15.7 Hz, 1 H, CH₂), 3.05 (dd, J= 4.5, 12.5 Hz, 1 H, CH₂), 4.17 (m, 1 H, CH), 7.05 (m, 1 H, CH, arom.), 7.15 (s, 1 H, CH, arom.), 7.89 (s, 1 H, CH, arom.); MS (ESI) [M-H]^" m/z 281.1. Anal. (Ci₃Hi₄0₇) C, H.

Example 28. Synthesis of compound D006

The compound (200 mg, 0.5 mmol) of Example 14 was placed in a 25 mL

single-neck flask, and dissolved in ethanol. Palladium carbon (11 mg, 10%) was added, and H₂ was carefully introduced. The reaction was run at room temperature for 2-4 hours with TLC monitoring. After the reaction was completed, saturated NaCl solution and ethyl acetate were added for dilution. The resulting material was extracted three times with ethyl acetate. The extract was dried over Na₂S0₄, spun to dryness, and separated on a silica get column (ethyl acetate : petroleum ether = 1 :2) to give the target compound (141 mg, yield 91%) as an oily liquid. 1H-NMR (CDC1₃, 500 MHz) δ: 1.15 (t, J= 7.2 Hz, 6 H, CH₃), 2.55 (m, 4 H, CH₂), 2.95 (dd, J= 8.5, 15.7 Hz, 1 H, CH₂), 3.05 (dd, J= 4.5, 12.5 Hz, 1 H, CH₂), 4.17 (m, 1 H, CH), 7.05 (m, 1 H, CH, arom.), 7.15 (s, 1 H, CH, arom.), 8.01 (s, 1 H, CH, arom.); MS (ESI) [M-H]^" m/z 309.1. Anal. (Ci₄Hi₆0₇) C, H.

Example 29. Synthesis of compound D007

The compound (214 mg, 0.5 mmol) of Example 15 was placed in a 25 mL

single-neck flask, and dissolved with ethanol. Palladium carbon (11 mg, 10%>) was added, and H₂ was carefully introduced. The reaction was run at room temperature for 2-4 hours with TLC monitoring. After the reaction was completed, saturated NaCl solution and ethyl acetate were added for dilution. The resulting material was extracted three times with ethyl acetate. The extract was dried over Na₂S0₄, spun to dryness, and separated on a silica get column (ethyl acetate : petroleum ether = 1 :2) to give the target compound (153.8 mg, yield 91%) as an oily liquid. 1H-NMR (CDC1₃, 500 MHz) δ: 1.01 (t, 6 H, CH₃), 1.15 (m, 4 H, CH₂), 2.55 (m, 4 H, CH₂ ), 2.95 (dd, J= 8.5, 15.7 Hz, 1 H, CH₂), 3.05 (dd, J = 4.5, 12.5 Hz, 1 H, CH₂), 4.17 (m, 1 H, CH), 7.05 (m, 1 H, CH, arom.), 7.15 (s, 1 H, CH, arom.), 8.01 (s, 1 H, CH, arom.); MS (ESI) [M-H]^" m/z 337.3. Anal. (Ci₅Hi₇0₇) C, H.

Example 30. Synthesis of compound D008

The compound (214 mg, 0.5 mmol) of Example 15 was placed in a 25 mL

single-neck flask, and dissolved in ethanol. Palladium carbon (11 mg, 10%) was added, and H₂ was carefully introduced. The reaction was run at room temperature for 2-4 hours with TLC monitoring. After the reaction was completed, saturated NaCl solution and ethyl acetate were added for dilution. The resulting material was extracted three times with ethyl acetate. The extract was dried over Na₂S0₄, spun to dryness, and separated on a silica get column (ethyl acetate : petroleum ether = 1 :2) to give the target compound (147.1 mg, yield 87%) as an oily liquid. 1H-NMR (CDC1₃, 500 MHz ) δ: 1.25 (d, J = 9 Hz, 12 H, CH₃), 2.78 (m, 2 H, CH), 2.95 (dd, J= 8.5, 15.7 Hz, 1 H, CH₂), 3.05 (dd, J= 4.5, 12.5 Hz, 1 H, CH₂), 4.17 (m, 1 H, CH), 7.05 (m, 1 H, CH, arom.), 7.15 (s, 1 H, CH, arom.), 8.01 (s, 1 H, CH, arom.); MS (ESI) [M-H]^" m/z 337.1. Anal. (Ci₅Hi₇0₇) C, H.

Example 31. Synthesis of compound D009

The the compound (157 mg, 0.5 mmol) of Example 6 was placed in a 25 mL single-neck flask, and dissolved with ethyl acetate. Palladium carbon (11 mg, 10%) was added, and H₂ was carefully introduced. The reaction was run at room temperature for 2-4 hours with TLC monitoring. After the reaction was completed, saturated NaCl solution and ethyl acetate were added for dilution. The resulting material was extracted three times with ethyl acetate. The extract was dried over Na₂S0₄, spun to dryness, and separated on a silica get column (ethyl acetate : petroleum ether = 1 :2) to give the target compound (99.7 mg, yield 89%) as a white solid, mp 110-112 °C; 1H-NMR (CDC1₃, 500 MHz) δ: 3.05 (dd, J= 8.5, 15.7 Hz, 1 H, CH₂), 3.10 (dd, J= 4.5, 12.5 Hz, 1 H, CH₂), 4.45 (m, 1 H, CH), 7.13 (d, J = 6.0 Hz, 1 H, CH, arom.), 7.16 (d, J = 6.0 Hz, 1 H, CH, arom.), 7.36 (d, 1 H, CH, arom.), MS (ESI) [M-H]^" m/z 223.1; Anal. (Ci₀H₈O₆) C, H.

Example 32. Synthesis of compound DOlO

The compound (120 mg) of Example 1 was placed in a 25 mL single-neck flask, and dissolved with aqueous methanol (methanol : water = 9: 1). The content of the flask was stirred at room temperature for 8 hours, and then 3 mL of 10% HC1 was added. A solution of saturated NaCl was added. The resulting material was extracted three times with ethyl acetate, and the organic layer was collected. The extract was dried over sodium sulfate, and purified to give the target compound (40.5 mg, yield 41.8%) as a white solid.

1H-NMR (DMSO-t e, 400 MHz) δ: 2.69 (dd, J= 8.0, 13.6 Hz, 1 H, CH₂), 2.88 (dd, J= 4.4, 13.8 Hz, 1 H, CH₂), 4.16 (dd, J= 4.5, 7.0 Hz, 1 H, CH), 5.07 (s, 4 H, CH₂, CH₂), 6.75 (d, J= 8.0 Hz, 1 H, arom.), 6.93 (d, J= 8.0 Hz, 1 H, arom.), 6.99 (s, 1 H, arom.), 7.37 (m, 10 H, arom.); MS (ESI) [M+Na]⁺ m/z 401.4; FABHRMS: calcd for (C₂₃H₂₂0₅) 378.14672, found 378.14764; Anal. (C₂₃H₂₂0₅) C, H.

Example 33. Synthesis of compound D011

Danshensu (100 mg, 0.505 mmol) was placed in a 25 mL single-neck flask, about 2 mL of dried DMF was added dropwise to dissolve the compound, and NaHC0₃ (50 mg, 0.595 mmol) was added. The content of the flask was stirred at room temperature to reach uniformity, and then the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, allyl bromide (0.1 mL, 0.59 mmol) was added to the reaction, and the reaction was run at room temperature for 17 hours with TLC monitoring. After the reaction was completed, ice brine and ethyl acetate were added for dilution, and the resulting material was extracted three times with ethyl acetate (25 mL><3). The ethyl acetate layer was washed three times with ice brine to remove DMF. The organic phase was then dried over anhydrous Na₂S0₄, spun to dryness, and separated on a silica get column (ethyl acetate : petroleum ether = 1 :2) to give the target compound (80 mg, yield 57.0%>) as an oily liquid. 1H-NMR (DMSO-t e, 400 MHz) δ: 2.66 (dd, J= 7.6, 13.6 Hz, 1 H, CH₂), 2.77 (dd, J= 5.6, 13.6 Hz, 1 H, CH₂), 4.15 (dd, J= 7.0, 12.5 Hz, 1 H, CH), 4.53 (d, J= 5.2 Hz, 2 H, CH₂), 5.25 (m, 1 H, CH₂), 5.35 (m, 1 H, CH₂), 5.87 (m, 1 H, CH), 6.60 (d, J= 8.0 Hz, 1 H, arom.), 6.61 (d, J= 2.0 Hz, 1 H, arom.), 6.43 (dd, J= 2.0, 8.0 Hz, 1 H, arom.); MS (ESI) [M+H]⁺ m/z 239.2; FABHRMS: calcd for (Ci₂Hi₄0₅) 238.08412, found 238.08546. Anal. (Ci₂H₁₄0₅) C, H.

Example 34. Synthesis of compound D012

Danshensu (100 mg, 0.505 mmol) was placed in a 25 mL single-neck flask, about 2 mL of dried DMF was added dropwise to dissolve the compound, and then NaHC0₃ (50 mg, 0.595 mmol) was added. The content of the flask was stirred at room temperature to reach uniformity, and then the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, propargyl bromide (0.1 mL, 0.59 mmol) was added to the reaction, and the reaction was run at room temperature for 17 hours with TLC monitoring. After the reaction was completed, ice brine and ethyl acetate were added for dilution, and the resulting material was extracted three times with ethyl acetate (25 mL><3). The ethyl acetate layer was washed three times with ice brine to remove DMF. The organic phase was then dried over anhydrous Na₂S0₄, spun to dryness, and separated on a silica get column (ethyl acetate : petroleum ether = 1 :2) to give the target compound (80 mg, yield

57.0%) as an oily liquid. 1H-NMR (CDC1₃, 300 MHz) δ: 2.55 (t, J= 1.8 Hz, 1 H, CH), 2.84-2.91 (dd, J= 2.4, 14.1 Hz, 1 H, CH₂), 3.00-3.06 (dd, J= 4.2, 14.1 Hz, 1 H, CH₂), 4.44-4.47 (m, 1H, CH), 4.72-4.80 (m, 2 H, CH₂), 6.60-6.75 (m, 3 H, arom.), MS (ESI) [2M+Na]⁺ m/z 259.4; FABHRMS: calcd for (Ci₂Hi₂0₅) Anal. (Ci₆Hi₆0₅) C, H.

Example 35. Synthesis of compound D013

Danshensu (100 mg, 0.505 mmol) was placed in a 25 mL single-neck flask, about 2 mL of dried DMF was added dropwise to dissolve the compound, and then NaHC0₃ (50 mg, 0.595 mmol) was added. The content of the flask was stirred at room temperature to reach uniformity, and then the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, benzyl bromide (0.125 mL, 0.505 mmol) was added to the reaction, and the reaction was run at room temperature for 17 hours with TLC monitoring. After the reaction was completed, ice brine and ethyl acetate were added for dilution, and the resulting material was extracted three times with ethyl acetate (25 mL><3). The ethyl acetate layer was washed three times with ice brine to remove DMF. The organic phase was then dried over anhydrous Na₂S0₄, spun to dryness, and separated on a silica get column (ethyl acetate : petroleum ether = 1 :2) to give the target compound (80 mg, yield

56%) as an oily liquid.. 1H-NMR (DMSO-t/₆, 400 MHz) δ: 2.69 (dd, J = 7.6, 13.6 Hz, 1 H, CH₂), 2.79 (dd, J= 5.6, 13.8 Hz, 1 H, CH₂), 4.20 (dd, J= 6.0, 13.0 Hz, 1 H, CH), 5.08 (s, 2 H, CH₂), 6.42 (dd, J= 2.0, 8.0 Hz, 1 H, arom.), 6.60 (d, J= 8.0 Hz, 1 H, arom.), 6.62 (d, J= 2.0 Hz, 1 H, arom.), 7.28 (m, 1 H, arom.), 7.32 (m, 2 H, arom.), 7.36 (m, 2 H, arom.); MS (ESI) [2M+Na]⁺ m/z 599.4; FABHRMS: calcd for (Ci₆Hi₆0₅) 288.09977, found 288.10042. Anal. (Ci₆Hi₆0₅) C, H.

Example 36. Synthesis of compound D014

To the compound (120 mg, 0.32 mmol) of Example 2 was added dropwise ethyl acetate saturated with HC1 gas. The reaction was run at room temperature for 1-2 hours with TLC monitoring. After the reaction was completed, the resulting material was spun to dryness. Ethyl acetate was added, stirred, and spun to dryness; such process was repeated 3 times to give the target compound (90 mg, yield 58%) as a hygroscopic, white powder-like solid. 1H NMR (DMSO-t/₆, 400 MHz ) δ: 1.40 (s, 9 H, CH3), 2.51 (dd, J = 7.2, 13.6 Hz, 1 H, CH₂), 2.72 (dd, J= 5.6, 13.6 Hz, 1 H, CH₂), 3.24 (m, 4 H, CH₂), 3.39 (m, 4 H, CH₂), 4.42 (dd, J= 7.6, 13.2 Hz, 1 H, CH), 6.46 (dd, J= 2.0, 8.0 Hz, 1 H, arom.), 6.59 (d, J= 8.0 Hz, 1 H, arom.), 6.61 (d, J= 2.0 Hz, 1 H, arom.), 8.46 (s, 1 H, arom.), 8.53 (s, 1 H, arom.); MS (EI) m/z 366.0.

Example 37. Synthesis of compound D015

Danshensu (100 mg, 0.505 mmol) was placed in a 25 mL single-neck flask, and about 2 mL of DMF was added dropwise to dissolve the compound. EDCI (125 mg, 0.65 mmol) and HOBt (90 mg, 0.66 mmol) were added, the content of the flask was stirred at room temperature to reach uniformity, and the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, n-propylamine (50 μί, 0.603 mmol) was added dropwise to the reaction, and the reaction was run at room temperature for 17 hours with TLC monitoring. After the reaction was completed, ice brine and ethyl acetate were added for dilution. The resulting material was extracted three times with ethyl acetate (25 mL><3). The ethyl acetate layer was washed three times with ice brine to remove DMF. The organic phase was then dried over anhydrous Na₂S0₄, spun to dryness, and separated on a silica get column (ethyl acetate : petroleum ether = 2: 1) to give the target compound (64 mg, yield 56%) as an oily liquid. 1H NMR (DMSO-t/₆, 400 MHz ) δ: 0.79 (t, J= 7.2 Hz, 3 H, CH₃), 1.40 (m, 2 H, CH₂), 2.52 (dd, J= 2.0, 14.0 Hz, 1 H, CH₂), 2.78 (dd, J= 4.0, 14.0 Hz, 1 H, CH₂), 3.02 (dd, J= 1.6, 7.2 Hz, 1 H, CH₂), 3.04 (dd, J= 1.6, 6.8 Hz, 1 H, CH₂), 4.05 (dd, J= 6.0, 13.0 Hz, 1 H, CH), 6.44 (dd, J= 2.0, 8.0 Hz, 1 H, arom.), 6.59 (d, J = 8.0 Hz, 1 H, arom.), 6.61 (d, J= 2.0 Hz, 1 H, arom.), 7.58 (t, J= 6.0 Hz, 1 H, sec.amide), 8.42 (s, 1 H, arom.), 8.48 (s, 1 H, arom.); MS (ESI) [M+Na]⁺ m/z 262.6, MS (ESI) [M-H]^~ m/z 238.7; FABHRMS: calcd for (Ci₂H_nN0₄) 239.11576, found 239.11576. Anal.

(C₁₂H₁₇N0₄) C, H, N.

Example 38. Synthesis of compound D016

Danshensu (100 mg, 0.505 mmol) was placed in a 25 mL single-neck flask, and about 2 mL of DMF was added dropewise to dissolve the compound. EDCI (125 mg, 0.65 mmol) and HOBt (90 mg, 0.66 mmol) were added, the content of the flask was stirred at room temperature to reach uniformity, and the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, n-butylamine (55 μί, 0.60 mmol) was added dropwise to the reaction, and the reaction was run at room temperature for 17 hours with TLC monitoring. After the reaction was completed, ice brine and ethyl acetate were added for dilution. The resulting material was extracted three times with ethyl acetate (25 mL><3). The ethyl acetate layer was washed three times with ice brine to remove DMF. The organic phase was then dried over anhydrous Na₂S0₄, spun to dryness, and separated on a silica get column (ethyl acetate : petroleum ether = 2: 1) to give the target compound (75 mg, yield 58%) as a pale yellow solid, mp 88-92 °C; 1H NMR (DMSO-ifc, 400 MHz ) δ: 0.85 (t, J= 7.2 Hz, 3 H, CH₃), 1.23 (m, 2 H, CH₂), 1.34 (m, 2 H, CH₂), 2.51 (dd, J= 8.0, 13.6 Hz, 1 H, CH₂), 2.77 (dd, J= 2.0, 13.6 Hz, 1 H, CH₂), 3.05 (m, 2 H, CH₂), 4.05 (dd, J = 6.0, 13.0 Hz, 1 H, CH), 6.44 (dd, J= 2.0, 8.0 Hz, 1 H, arom.), 6.58 (d, J= 8.0 Hz, 1 H, arom.), 6.60 (d, J= 2.0 Hz, 1 H, arom.), 7.46 (t, J= 5.6 Hz, 1 H, sec.amide), 8.40 (s, 1 H, arom.), 8.48 (s, 1 H, arom.); MS (ESI) [M+Na]⁺m/z 276.6; MS (ESI) [M-H]^" m/z 252.4; FABHRMS: calcd for (Ci₃Hi₉N0₄) 253.13141, found 253.13168. Anal. (Ci₃Hi₉N0₄) C, H, N.

Example 39. Synthesis of compound D017

Danshensu (100 mg, 0.505 mmol) was placed in a 25 mL single-neck flask, and about 2 mL of DMF was added dropwise to dissolve the compound. NaHC0₃ (50 mg, 0.595 mmol) was added, the content of the flask was stirred at room temperature to reach uniformity, and the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, l-bromoethyl-2,4,5-trimethylbenzene (106 mg, 0.500 mmol) was added to the reaction, and the reaction was run at room temperature for 17 hours with TLC monitoring. After the reaction was completed, ice brine and ethyl acetate was added for dilution. The resulting material was extracted three times with ethyl acetate (25 mL><3). The ethyl acetate layer was washed three times with ice brine to remove DMF. The organic phase was then dried over anhydrous Na₂S0₄, spun to dryness, and separated on a silica get column (ethyl acetate : petroleum ether = 2: 1) to give the target compound (91.4 mg, yield 55.4%) as a white solid. 1H-NMR (CDQ₃, 300 MHz) δ: 2.16 (s, 9 H, CH₃), 2.65(dd, J = 3.8, 3.8 Hz, 1 H, CH₂), 2.75 (dd, J= 2.7, 2.8 Hz, 1 H, CH₂), 4.15 (dd, J= 3.0, 3.0 Hz, 1 H, CH), 5.02 (s, 2 H, CH₂), 6.41 (m, 1 H, CH, arom.), 6.58 (s, 1 H, CH, arom.), 6.61 (s, 1 H, CH, arom.), 6.96 (s, 1H, CH, arom.), 7.01 (s, 1 H, CH, arom.), MS (ESI) [M+Na]⁺ m/z 353.4. Anal.(Ci₉H₂₂0₅) C, H, N.

Example 40. Synthesis of compound D018

Danshensu (100 mg, 0.505 mmol) was placed in a 25 mL single-neck flask, and about 2 mL of DMF was added dropwise to dissolve the compound. NaHC0₃ (50 mg, 0.595 mmol) was added, the content of the flask was stirred at room temperature to reach uniformity, and the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, 2-bromoethyl quinoxaline (0.110 mg, 0.500 mmol) was added dropwise to the reaction, and the reaction was run at room temperature for 17 hours with TLC monitoring. After the reaction was completed, ice brine and ethyl acetate was added for dilution. The resulting material was extracted three times with ethyl acetate (25 mL><3). The ethyl acetate layer was washed three times with ice brine to remove DMF. The organic phase was then dried over anhydrous Na₂S0₄, spun to dryness, and separated on a silica get column (ethyl acetate : petroleum ether = 2: 1) to give the target compound (97 mg, yield 57%) as an oily liquid. 1H-NMR (DMSO-d6, 300 MHz) δ: 2.72(dd, J= 3.9, 3.8 Hz, 1 H, CH₂), 2.87(dd, J= 2.9, 2.8 Hz, 1 H, CH₂), 4.30 (m, 1 H, CH), 5.44 (s, 2 H, CH₂), 6.44 (m, 1 H, CH, arom.), 6.55 (s, 1 H, CH, arom.), 6.65 (m, 1 H, CH, arom.), 7.86(m, 1 H, CH, arom.), 7.89(m, 1 H, CH, arom.), 8.08(m, 1 H, CH, arom.), 8.12(m, 1 H, CH, arom.), 894(s, 1 H, CH, arom.), MS (ESI) [M+Na]⁺ m/z 363.3 Anal.(Ci₈Hi₆N₂0₅) C, H, N.

Example 41. Synthesis of compound D019

Danshensu (100 mg, 0.505 mmol) was placed in a 25 mL single-neck flask, and about 2 mL of dried DMF was added dropwise to dissolve the compound. NaHC0₃ (50 mg, 0.595 mmol) was added, the content of the flask was stirred at room temperature to reach uniformity, and the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, 2-bromoethyl-5,6-dimethyl pyrazine (100 mg, 0.505 mmol) was added dropwise to the reaction, and the reaction was run at room temperature for 17 hours with TLC monitoring. After the reaction was completed, ice brine and ethyl acetate were added for dilution. The resulting material was extracted three times with ethyl acetate (25 mL><3). The ethyl acetate layer was washed three times with ice brine to remove DMF. The organic phase was then dried over anhydrous Na₂S0₄, spun to dryness, and separated on a silica get column (ethyl acetate : petroleum ether = 2: 1) to give the target compound (89 mg, yield 56%) as a white solid. ¹H-NMR (DMSO-t/₆,300 MHz) δ: 2.39 (s, 6 H, CH₃), 2.66 (dd, J= 8.0, 13.8 Hz, 1 H, CH₂), 2.80 (dd, J= 5.2, 13.8 Hz, 1 H, CH₂), 4.18 (dd, J = 6.0, 13.0 Hz, 1 H, CH), 5.14 (s, 2 H, CH₂), 5.48 (s, 1 H, alcohol), 6.40 (dd, J= 2.4, 8.0 Hz, 1 H, arom.), 6.56 (d, J= 8.0 Hz, 1 H, arom.), 6.59 (d, J= 2.4 Hz, 1 H, arom.); 8.22 (s, 1 H arom.). MS (ESI) [M+H]⁺ 319.1. Anal. (Ci₆Hi₈N₂0₅) C, H, N.

Example 42. Synthesis of compound ADAM

The compound (119 mg, 0.50 mmol) of Example 33 was placed in a 25 mL single-neck flask, and dissolved with dried anhydrous THF. The content of the flask was stirred at room temperature to reach uniformity, and then the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, acetic anhydride as acylating agent and DMAP as catalyst were added, and the reaction was run at room temperature with magnetic stirring for 2 hours. The resulting material was then washed with a solution of saturated NaHC0₃, and extracted three times with ethyl acetate. The extract was dried over anhydrous sodium sulfate, spun to dryness, dissolved, and separated on a silica gel column (ethyl acetate : petroleum ether = 2: 1). The fractions containing the target product were collected and then evaporated to dryness on a rotavapor to give a white solid, which was dried in a vacuum oven (50 °C)for 1 hour to give a purified product (162 mg, yield

89.3%). 1H-NMR (CDC1₃, 300 MHz) δ: 2.11 (s, 3 H, CH₃), 2.296 (s, 6 H, CH₃), 3.14-3.17

(dd, J= 1.8, 4.5 Hz, 2 H, CH₂ ), 4.61 (s, 1 H,CH₂), 5.19-5.34 (m, 3 H, 1 x CH₂, 1 x CH),

5.80-5.93 (m, 1 H, CH), 7.08 (d, J= 8.0 Hz, 1 H, arom.), 7.13 (s, 2 H, arom.), MS (ESI) [M+H]⁺ m/z 365.2; Anal. (Ci₈H₂₀O₈) C, H.O.

Example 43. Synthesis of compound ADEM

The compound (119 mg, 0.50 mmol) of Example 34 was placed in a 25 mL single-neck flask, and dissolved with dried anhydrous THF. The content of the flask was stirred at room temperature to reach uniformity, and then the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, acetic anhydride as acylating agent and DMAP as catalyst were added, and the reaction was run at room temperature with magnetic stirring for 2 hours. The resulting material was then washed with a solution of saturated NaHC0₃, and extracted three times with ethyl acetate. The extract was dried over anhydrous sodium sulfate, spun to dryness, dissolved, and separated on a silica gel column (ethyl acetate : petroleum ether = 2: 1). The fractions containing the target product were collected and then evaporated to dryness on a rotavapor to give a white solid, which was dried in a vacuum oven (50 °C) for 1 hour to give a purified product (162 mg, yield 89.3%). 1H-NMR (CDC1₃, 300 MHz) δ: 2.21 (s, 3 H, CH₃), 2.27 (s, 6 H, CH₃), 3.11-3.17 (dd, J= 4.5, 10.5 Hz, 2 H, CH₂), 4.71-4.73 (dd, J= 2.4, 4.7 Hz, 2 H, CH₂), 5.19-5.23 (dd, J= 4.5, 8.7 Hz, 1 H, CH), 7.08 (s, 1 H, arom.), 7.12 (s, 1 H, arom.). MS (ESI) [M+Na]⁺ m/z 385, Anal. (Ci₈Hi₈0₈) C, H.

Example 44. Synthesis of compound ADBnM

The compound (144 mg, 0.50 mmol) of Example 35 was placed in a 25 mL single-neck flask, and dissolved with dried anhydrous THF. The content of the flask was stirred at room temperature to reach uniformity, and then the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, acetic anhydride as acylating agent and DMAP as catalyst were added, and the reaction was run at room temperature with magnetic stirring for 2 hours. The resulting material was then washed with a solution of saturated NaHC0₃, and extracted three times with ethyl acetate. The extract was dried over anhydrous sodium sulfate, spun to dryness, dissolved, and separated on a silica gel column (ethyl acetate : petroleum ether = 2: 1). The fractions containing the target product were collected and then evaporated to dryness on a rotavapor to give a white solid, which was dried in a vacuum oven (50 °C)for 1 hour to give a purified product (180 mg, yield 87.2%). 1H-NMR (CDC1₃, 300 MHz) δ: 2.07 (s, 3 H, CH₃), δ: 2.26 (s, 6 H, CH₃),

3.09-3.14 (dd, J=9.3, 4.8 Hz, 2 H, CH₂), 5.14 (s, 2 H, CH₂), 5.20-5.25 (dd, J= 8.4, 4.8 Hz, 1 H, CH), 7.04-7.06 (m, 3H, CH, arom.), 7.27-7.35 (m, 5 H, CH, arom.), MS (ESI)

[M+Na]⁺ m/z 437.2. Anal. (C₂₂H₂₂0₈) C, H, O.

ADBnM

Example 45. Synthesis of compound ADBM

The compound (166 mg, 0.50 mmol) of Example 39 was placed in a 25 mL single-neck flask, and dissolved with dried anhydrous THF. The content of the flask was stirred at room temperature to reach uniformity, and then the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, acetic anhydride as acylating agent and DMAP as catalyst were added, and the reaction was run at room temperature with magnetic stirring for 2 hours. The resulting material was then washed with a solution of saturated NaHC0₃, and extracted three times with ethyl acetate. The extract was dried over anhydrous sodium sulfate, spun to dryness, dissolved, and separated on a silica gel column (ethyl acetate : petroleum ether = 2: 1). The fractions containing the target product were collected and then evaporated to dryness on a rotavapor to give a white solid, which was dried in a vacuum oven (50 °C)for 1 hour to give a purified product (197 mg, yield

86.7%). 1H-NMR (CDC1₃, 300 MHz) δ: 2.07 (s, 3 H, CH₃), δ: 2.22 (s, 9 H, CH₃), δ: 2.27 (s, 6 H, CH₃), 3.06-3.13 (dd, J=12.6, 4.5 Hz, 2 H, CH₂), 5.11-5.12 (d, J= 3 H, CH₂), 5.17-5.21 (dd, J= 9, 4.5 Hz, 1 H, CH), 6.70 (s, 1 H, CH, arom.), 7.04-7.06 (m, 4 H, CH, arom.), MS (ESI) [M+Na]⁺ m/z 479.2. Anal. (C₂₅H₂₈0₈) C, H, O.

Example 46. Synthesis of compound ADQM

The compound (166 mg, 0.50 mmol) of Example 40 was placed in a 25 mL single-neck flask, and dissolved with dried anhydrous THF. The content of the flask was stirred at room temperature to reach uniformity, and then the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, acetic anhydride as acylating agent and DMAP as catalyst were added, and the reaction was run at room temperature with magnetic stirring for 2 hours. The resulting material was then washed with a solution of saturated NaHC0₃, and extracted three times with ethyl acetate. The extract was dried over anhydrous sodium sulfate, spun to dryness, dissolved, and separated on a silica gel column (ethyl acetate : petroleum ether = 2: 1). The fractions containing the target product were collected and then evaporated to dryness on a rotavapor to give a white solid, which was dried in a vacuum oven (50 °C)for 1 hour to give a purified product (210 mg, yield

90.6%). 1H-NMR (CDC1₃, 300 MHz) δ: 2.11 (s, 3 H, CH₃), δ: 2.26 (s, 3 H, CH₃), δ: 2.72 (s, 3 H, CH₃), 3.12-3.30 (m, 2 H, CH₂), 5.28-5.32 (dd, J= 4.5, 8.7 Hz, 2 H, CH₂), 5.49 (s, 2 H, CH₂), 7.08-7.11 (m, 3 H, CH, arom.), 7.76-8.14(m, 4 H, CH, arom), 8.84(s, 1 H, CH, arom). MS (ESI) [M+Na]⁺ m/z 489.2. Anal. (C₂₄H₂₂N₂0₈) C, H, O.

Example 47. Synthesis of compound ADPM

The compound (159 mg, 0.50 mmol) of Example 41 was placed in a 25 mL single-neck flask, and dissolved with dried anhydrous THF. The content of the flask was stirred at room temperature to reach uniformity, and then the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, acetic anhydride as acylating agent and DMAP as catalyst were added, and the reaction was run at room temperature with magnetic stirring for 2 hours. The resulting material was then washed with a solution of saturated NaHC0₃, and extracted three times with ethyl acetate. The extract was dried over anhydrous sodium sulfate, spun to dryness, dissolved, and separated on a silica gel column (ethyl acetate : petroleum ether = 2: 1). The fractions containing the target product were collected and then evaporated to dryness on a rotavapor to give a white solid, which was dried in a vacuum oven (50 °C)for 1 hour to give a purified product (208 mg, yield 93.9%). 1H-NMR (CDCI3, 300 MHz) δ: 2.08 (s, 3 H, CH₃), δ: 2.27 (s, 6 H, CH₃), δ: 2.52 (s, 6 H, CH₃) 3.06-3.28 (m, 2 H, CH₂), 5.23 (s, 1 H, CH), 5.25-5.28 (dd, J= 10.8, 6.6 Hz, 2 H, CH₂), 7.07-7.10 (m, 3 H, CH, arom.), 8.26-8.30 (m, 1 H, CH, arom.), MS (ESI)

[M+Na]⁺ m/z 467.2. Anal. (C₂₂H₂₄N₂0₈) C, H, O.

Example 48. Synthesis of compound BBM

Danshensu (100 mg, 0.505 mmol) was placed in a 25 mL single-neck flask, and about 2 mL of dried DMF was added dropwise to dissolve the compound. NaHC0₃ (50 mg, 0.595 mmol) was added, the content of the flask was stirred at room temperature to reach uniformity, and the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, 2,3-dibromoethyl-5,6-dimethyl pyrazine (150 mg, 0.514 mmol) was added dropwise to the reaction, and the reaction was run at room temperature for 17 hours with TLC monitoring. After the reaction was completed, ice brine and ethyl acetate were added for dilution. The resulting material was extracted three times with ethyl acetate (25 mL><3). The ethyl acetate layer was washed three times with ice brine to remove DMF. The organic phase was then dried over anhydrous Na₂S0₄, spun to dryness, and separated on a silica get column (ethyl acetate : petroleum ether = 2: 1) to give the target compound (95 mg, yield 36%) as a white solid. 1H-NMR (DMSO-t/₆,300 MHz) δ: 2.42 (s, 6 H, CH₃), δ: 2.57-2.84 (m, 4 H, CH₂), δ: 4.18 (s, 2 H, OH), 5.17-5.21 (t, J= 4.5, 4 H, CH₂), 5.50-5.56 (dd, J= 12.3, 5.7 Hz, 2 H, CH), 6.36-6.42 (m, 2 H, CH, arom.), 6.53-6.59 (m, 4 H, CH, arom.), MS (ESI) [M+Na]⁺ m/z 551.2. Anal. (C₂₆H₂₈N₂Oi₀) C, H, O.

Example 49. Synthesis of compound ABBM The compound (264 mg, 0.50 mmol) of Example 48 was placed in a 25 mL single-neck flask, and dissolved with dried anhydrous THF. The content of the flask was stirred at room temperature to reach uniformity, and then the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, acetic anhydride as acylating agent and DMAP as catalyst were added, and the reaction was run at room temperature with magnetic stirring for 2 hours. The resulting material was then washed with a solution of saturated NaHC0₃, and extracted three times with ethyl acetate. The extract was dried over anhydrous sodium sulfate, spun to dryness, dissolved, and separated on a silica gel column (ethyl acetate : petroleum ether = 2: 1). The fractions containing the target product were collected and then evaporated to dryness on a rotavapor to give a white solid, which was dried in a vacuum oven (50 °C) for 1 hour to give a purified product (331 mg, yield

85%). 1H-NMR (CDC1₃, 300 MHz) δ: 2.04-2.08 (m, 6 H, CH₃), δ: 2.27 (s, 12 H, CH₃), δ: 2.50-2.53 (d, J= 9, 6 H, CH₃) 3.04-3.28 (m, 4 H, CH₂), 5.20-5.24 (m, 2 H, CH), 5.27-5.30 (d, J= 5.4 Hz, 4 H, CH₂), 7.07-7.11 (m, 6 H, CH, arom.), MS (ESI) [M+H]⁺ m/z 781.2. Anal. (C₂₂H₂₄N₂0₈) C, H, O.

Example 50. Synthesis of compound PBBM

The compound (264 mg, 0.50 mmol) of Example 48 was placed in a 25 mL single-neck flask, and dissolved with dried anhydrous THF. The content of the flask was stirred at room temperature to reach uniformity, and then the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, propionic anhydride as acylating agent and DMAP as catalyst were added, and the reaction was run at room temperature with magnetic stirring for 2 hours. The resulting material was then washed with a solution of saturated NaHC0₃, and extracted three times with ethyl acetate. The extract was dried over anhydrous sodium sulfate, spun to dryness, dissolved, and separated on a silica gel column (ethyl acetate : petroleum ether = 2: 1). The fractions containing the target product were collected and then evaporated to dryness on a rotavapor to give a white solid, which was dried in a vacuum oven (50 °C) for 1 hour to give a purified product (311 mg, yield 72%). 1H-NMR (CDC1₃, 300 MHz) δ: 1.04-1.11 (m, 6 H, CH₃), δ: 1.21-1.27 (m, 12 H, CH₃), δ: 2.33-2.38 (m, 4 H, CH₂), 2.50-2.58(m, 14 H, 2*CH₃, 4*CH₂) 3.04-3.27 (m, 4 H, CH₂), 5.21-5.24 (m, 6 H, 2*CH, 2*CH₂), 5.27-5.30 (d, J= 5.4 Hz, 4 H, CH₂), 7.07-7.10 (m, 6 H, CH, arom.), MS (ESI) [M+H]⁺ m/z 865.2. Anal. (C₄₄H₅₃N₂Oi₆) C, H, O.

Example 51. Synthesis of compound BBBM

The compound (264 mg, 0.50 mmol) of Example 48 was placed in a 25 mL single-neck flask, and dissolved with dried anhydrous THF. The content of the flask was stirred at room temperature to reach uniformity, and then the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, butyric anhydride as acylating agent and DMAP as catalyst were added, and the reaction was run at room temperature with magnetic stirring for 2 hours. The resulting material was then washed with a solution of saturated NaHC0₃, and extracted three times with ethyl acetate. The extract was dried over anhydrous sodium sulfate, spun to dryness, dissolved, and separated on a silica gel column (ethyl acetate : petroleum ether = 2: 1). The fractions containing the target product were collected and then evaporated to dryness on a rotavapor to give a white solid, which was dried in a vacuum oven (50 °C) for 1 hour to give a purified product (355 mg, yield 76%). 1H-NMR (CDC1₃, 300 MHz) δ: 0.83-0.89(m, 6 H, CH₃), 1.00-1.05 (m, 12 H, CH₃), δ: 1.54-1.82 (m, 12 H, CH₂), 2.27-2.52 (m, 18 H, 2*CH₃, 6*CH₂) 3.04-3.29 (m, 4 H, CH₂), 5.20-5.35 (m, 6 H, 2*CH, 2*CH₂), 5.27-5.30 (d, J= 5.4 Hz, 4 H, CH₂), 7.06-7.10 (m, 6 H, CH, arom.), MS (ESI) [M+H]⁺ m/z 949.2. Anal. (C₄₄H₅₃N₂Oi₆) C, H, O.

Example 52. Synthesis of compound iBBBM

The compound (264 mg, 0.50 mmol) of Example 48 was placed in a 25 mL single-neck flask, and dissolved with dried anhydrous THF. The content of the flask was stirred at room temperature to reach uniformity, and then the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, isobutyric anhydride as acylating agent and DMAP as catalyst were added, and the reaction was run at room temperature with magnetic stirring for 2 hours. The resulting material was then washed with a solution of saturated NaHC0₃, and extracted three times with ethyl acetate. The extract was dried over anhydrous sodium sulfate, spun to dryness, dissolved, and separated on a silica gel column (ethyl acetate : petroleum ether = 2: 1). The fractions containing the target product were collected and then evaporated to dryness on a rotavapor to give a white solid, which was dried in a vacuum oven (50 °C) for 1 hour to give a purified product (317 mg, yield

67%). 1H-NMR (CDC1₃, 300 MHz) δ: 1.06-1.13 (m, 12 H, CH₃), δ: 1.28-1.30 (m, 24 H, CH₃), δ: 2.24-2.32 (m, 2 H, CH), 2.47-2.58(m, 10 H, 2*CH₃, 4*CH) 3.06-3.30 (m, 4 H, CH₂), 5.19-5.37 (m, 6 H, 2*CH, 2*CH₂), 7.05-7.10 (m, 6 H, CH, arom.), MS (ESI)

[M+H]⁺ m/z 949.2. Anal. (C₅₀H₆₄N₂Oi₆) C, H, O.

iBBBM

Example 53. Synthesis of compound ADTEB

The compound (186 mg, 0.5 mmol) of Example 13 was placed in a 25 mL single-neck flask, dissolved with dichloromethane, and then 2-bromoethyl-3,5,6-trimethyl pyrazine (110 mg, 0.514 mmol) and Ag₂0 (174 mg, 0.750 mmol) were added. The reaction was refluxed and monitored by TLC. After the reaction was completed, the reaction material was cooled to room temperature, filtered, dried over Na₂S0₄, spun to dryness, and separated on a silica get column (ethyl acetate : petroleum ether = 1 : 1) to give the target compound (202 mg, yield 80%) as an oily liquid.

ADTEB

Example 54. Synthesis of compound ADTE

The compound (253 mg, 0.500 mmol) of Example 53 was placed in a 25 mL single-neck flask, and dissolved with ethyl acetate. Palladium carbon (25 mg, 10%) was added, and H₂ was carefully introduced. The reaction was run at room temperature for 2-4 hours with TLC monitoring. After the reaction was completed, saturated NaCl solution and ethyl acetate were added for dilution. The resulting material was extracted three times with ethyl acetate. The organic phase was dried over Na₂S0₄, spun to dryness, and separated on a silica get column (ethyl acetate : petroleum ether = 1 : 1) to give the target compound (187 mg, yield 90%>) as an oily liquid.

Example 55. Synthesis of compound BnDTE

The compound (234mg, 0.500mmol) of Example 1 was placed in a 25 mL single-neck flask and dissolved with dichloromethane, 2-bromoethyl-3,5,6-trimethyl pyrazine (110 mg , 0.514 mmol) and Ag₂0 (174 mg, 0.750 mmol) were added. The reaction was refluxed and monitored by TLC. After the reaction was completed, the resulting material was cooled to room temperature and filtered. The filtrate was dried over

Na₂S0₄, spun to dryness, and separated on a silica get column (ethyl acetate : petroleum ether = 1 : 1) to give the target compound (183 mg, yield 60%) as a white solid. ^-NMR (DMSO-t/₆,300 MHz) δ: 2.22(s, 3 H, CH₃), 2.36(s,6 H, CH3), 2.84(dd, J= 6.9 Hz, 1 H, CH₂), 2.87(dd, J= 6.6 Hz, 1 H, CH₂), 4.30(dd, J= 6.3 Hz, 1 H, CH), 4.45(d, J= 12 Hz, 1 H, CH₂), 4.62(d, J= 12 Hz, 1 H, CH₂), 6.66(d, J= 9 Hz, 1 H, CH), 6.89(d, J= 3 Hz, 1 H, CH), 6.90(d, J = 9 Hz, 1 H, CH), 7.35(m, 15 H, CH, arom).

BnDTE

Example 56. Synthesis of compound DTE

The compound (302 mg, 0.500mmol) of 55 was placed in a 25 mL single-neck flask and dissolved with ethyl acetate. Palladium carbon (30 mg, 10%) was added, and H₂ was carefully introduced. The reaction was run at room temperature for 2-4 hours with TLC monitoring. After the reaction was completed, saturated NaCl solution and ethyl acetate were added for dilution. The resulting material was extracted three times with ethyl acetate, and the extract was dried over Na₂S0₄, Spun to dryness, and separated on a silica gel column (ethyl acetate : petroleum ether = 1 : 1 ) to give the target compound (150 mg, yield 90%) as an oily liquid. 1H-NMR (DMSO-d₆, 300 MHz) δ: 2.26 (s, 3 H, CH₃), 2.39 (s, 3 H, CH₃), 2.40 (s, 3 H, CH₃), 2.70(dd, J= 6, 9 Hz, 1 H, CH₂), 2.78(dd, J= 3, 6 Hz, 1 H, CH₂), 4.03 (dd, J= 3, 3 Hz, 1 H, CH), 4.42 (d, J= 12 Hz, 1 H, CH₂), 4.61 (d, J= 12 Hz, 1 H, CH₂), 6.41 (dd, J= 3, 6 Hz,l H, CH, arom.), 6.54 (d, J= 3 Hz, 1 H, CH, arom.), 6.56 (d, J = 9 Hz, 1 H, CH, arom.), 8.14(s, 1 H, OH), 8.25(s, 1 H, OH). MS (ESI)

[M+Na]⁺ m/z 355.3 Anal.(Ci₇H₂₀N₂O₅) C, H, N.

Example 57. Synthesis of compound ADTE

The compound (166 mg, 0.5 mmol) of Example 56 was placed in a 25 mL single-neck flask and dissolved with dried anhydrous THE The content of the flask was stirred at room temperature to reach uniformity, and then the temperature was brought down to 0 °C with an ice bath. Under N₂ protection, isobutyric anhydride as acylating agent and DMAP as catalyst were added, and the reaction was stirred magnetically at room temperature for 2 hours. The resulting material was washed with a solution of saturated NaHC0₃, and the organic material was extracted three times with ethyl acetate. The extract was dried over anhydrous sodium sulfate, spun to dryness, dissolved, and separated on a silica gel column (ethyl acetate : petroleum ether = 1 : 1). The fractions containing the target product were collected and then evaporated to dryness to give a white solid, which was dried in a vacuum oven (50 °C) for 1 hour to give a purified compound (198.2 mg, yield 95.3%).

Example 58. Synthesis of compound ADBEB

The compound (186 mg, 0.5 mmol) of Example 13 was placed in a 25 mL

single-neck flask and dissolved with dichloromethane. Benzyl bromide (94 mg, 0.550 mmol) and Ag₂0 (174 mg, 0.750 mmol) were added. The reaction was refluxed and monitored by TLC. After the reaction was completed, the resulting material was cooled to room temperature, filtered, dried over Na₂S0₄, spun to dryness, and separated on a silica gel column (ethyl acetate : petroleum ether = 1 : 1) to give the target compound (184 mg, yield 80%) as an oily liquid. 1H-NMR (DMSO-t/₆,300 MHz) δ: 2.28 (s, 6 H, CH₃), 3.04(dd, J= 6 Hz, 1 H, CH₂), 3.05(dd, J=6.6 Hz, 1H, CH₂), 4.32(dd, J= 3.3 Hz, 1 H, CH), 4.44(d, J= 12Hz, 1H, CH₂), 4.59 (d, J= 12Hz, 1 H, CH₂), 5.16(s, 2 H, CH₂), 7.15(m, 5 H, CH, arom), 7.37(m, 8 H, CH, arom).

ADBEB

Example 59. Synthesis of compound ADBE The compound (231 mg, 0.500mmol) of Example 58 was placed in a 25 mL single-neck flask and dissolved in ethyl acetate. Palladium carbon (23 mg, 10%) was added, and H₂ was carefully introduced. The reaction was run at room temperature for 2-4 hours with TLC monitoring. After the reaction was completed, saturated NaCl solution and ethyl acetate were added for dilution. The resulting material was extracted three times with ethyl acetate. The extract was dried over Na₂S0₄, spun to dryness, and separated on a silica get column (ethyl acetate : petroleum ether = 1 : 1 ) to give the target compound (187 mg, yield 90%) as an oily liquid. 1H-NMR (DMSO-t/₆,300 MHz) 5:2.24(s, 3 H, CH₃),

2.27(s, 3 H, CH₃), 2.96-3.05 (m, 2 H, CH₂), 4.16(dd, J= 3 Hz, 1 H,CH), 4.40(d,J

1 H,CH₂), 4.66(d,J=12 Hz, 1 H,CH₂), 7.17(m, 5H, arom), 7.26(m, 3H, arom).

Example 60. Test on free radical scavenging effect of Danshensu derivatives towards

DPPH

Determination of scavenging rate: In the wells of a 96-well ELISA plate were sequentially added the drug (50 μΐ,) for texting in various concentrations, methanol (100 μΐ_^), DPPH (50 μί, 0.4 mmol/L). In the well of blank reaction was placed with a solution of the mixture of DPPH (50 μί) and methanol (150 μΐ_^), and in the well of blank control was placed with methanol (200 μΐ,); four sets of duplicate were prepared for each sample. Immediately after the addition of DPPH, the absorbance (A₀) was measured at 515 nm wavelength with an ELISA reader, and 30 min thereafter the absorbance (Ai) was measured again. The scavenging rate was calculated based on the following formula:

Scavenging rate (%>) = 1- (absorbance difference of drug reaction group - absorbance difference of blank control group) / (absorbance difference of blank reaction group ^_ absorbance difference of blank control group) x 100%.

Example 61. Test on antioxidant activity of Danshensu derivatives by NAD assay

A solution of FeS0₄ was added to the sample and mixed uniformly. The absorbance was immediately measured by UV spectrophotometer at 440 nm wavelength, being recorded as A₀, and thereafter the absorbance was measured once every 10 seconds, until the time point of 100 seconds; the measuring process was repeated three times. Using the group without the drug as the control group, the difference of the absorbance measured at the time point of 100 seconds and the absorbance measured at the time point of 0 second was calculated, the scavenging rate was determined based on the formula below, and a histogram was drawn for scavenging rate vs. concentration of the drug.

Scavenging rate (%) = (1 - (A₀ - Ai_∞) / A₀) 100%

Example 62. Test on cell activity in vitro of Danshensu derivatives (FIGS. 11-16)

MTT assay: Primary cardiac cells were cultured for 48 hours, and then serum-free DMEM was replaced and the cells were further cultured for 12 hours. The Danshensu derivative was supplied in an amount of 50 μΜ, 100 μΜ, 200 μΜ and 400 μΜ, respectively, the reaction was run for 1 hour, and then 150 μΜ of t-BHP was added to intervene for 12 hours. Into each well was added 20 μΐ_^ of MTT, and the samples were continue to be cultured in the incubator for 4 hours. The MTT-containing culture medium was taken, and 150 μΐ_^ of DMSO was added to each well. The sample was gently shaken so that formazan was fully dissolved. OD value was measured at 490 nm. The test was repeated four times for statistical analysis.

Example 63. Evaluation of the size of myocardial infarct (FIG. 17)

After myocardial ischemia occurred for 24 hours, Evans Blue (2 mL, 0.5 g/L) was retrogradely injected into the abdominal aorta. After the non-ischemic area of the heart was fully dyed blue, the heart was taken, cleaned with ice brine (4 °C) with cardiac base tissue, auricle and right ventricle being cut off, and placed in a freezer at -80 °C for 20 min. the left ventricle was cut into slices in a thickness of 1-2 mm from the apex cordis towards the cardiac base parallel to the atrioventricular groove. The heart slices were placed in pH 7.4, 1% TTC phosphate buffer, and incubated at 37 °C for 15 min, then rinsed with cold brine to remove free dye, and fixed with 10% formaldehyde for 48 hours. The dyed blue indicates non-ischemic area, the red (including white) indicates ischemic area, and the white indicates infarct area. Based on the sizes of the colored areas, the extent of myocardial infarct area and myocardial ischemic area were reflected by

(IW/WLV)% and (WR/WLV)%, the percentages of the myocardial infarct area (infarct weight, IW) and the ischemic area (weight of risk, W ) based on the left ventricular area (weight of left ventricule, WLV), respectively. The present invention was described herein with specific embodiments of compounds, methods of preparation and uses thereof, and, for the purpose of illustration, many detailed examples were provided. It should be understood, however, the embodiments and examples provided herein are provided in an exemplary manner, and thus are not intended to limit the scope of the invention in anyway. In fact, for persons of ordinary skills in the art, the present invention can be also practiced through other particular embodiments, and any changes or modifications based on the embodiments described above should be deemed as not being deviated from the spirit and principal of the invention and thus being included in the scope of the invention.

Claims

1. A Danshensu derivative of general formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X is nitrogen, oxygen, or sulfur;

If X is oxygen, then Ri, R₂, R₃ and R₄ cannot be simultaneously hydrogen;

If X is oxygen and Ri is hydrogen, then R₂, R₃ and R₄ cannot be simultaneously hydrogen, benzoyl, benzyl, Ci-C₆ alkyl, or C(0)-(C₂-C6 alkyl);

If X is nitrogen, then Ri cannot be (R)-(3 -phenyl- l-ethyloxyformyl)propyl.

2. The Danshensu derivative or pharmaceutically acceptable salt thereof according to claim 1 , the Danshensu derivative being further defined as of general formula II:

wherein:

R₂, R₃ and R₄, being the same or different, are each independently hydrogen, substituted or un-substituted alkyl, aryl, heterocyclic aryl, C(0)-alkyl, C(0)-aryl, or C(0)-heterocyclic aryl, or biologically active groups such as lipoic acid, TMP, or bornyl group; with the proviso that:

If i is methyl, then simultaneous presence of the following does not occur: R₂ is acetyl, and both R₃ and R₄ are methylene, methyl, ethyl, propyl, isopropyl, benzyl, acetyl, propionyl, or benzoyl ;

3. The Danshensu derivative or pharmaceutically acceptable salt thereof according to claim 2, wherein:

Ri is a substituted or un-substituted aryl or heterocyclic aryl group;

4. The Danshensu derivative or pharmaceutically acceptable salt thereof according to claim 2, the Danshensu derivative being further defined as of general formula III:

wherein:

Ri is benzyl, substituted or un-substituted pyrazine ring or norbornene group;

R₅ is substitute or unsubstituted alkyl.

5. The Danshensu derivative or pharmaceutically acceptable salt thereof according to claim 2, the Danshensu derivative being further defined as of general formula IV containing a moiety of Chuanxiongqin (Tetramethylpyrazine, TMP):

wherein:

R₂ is hydrogen, alkyl, aryl, heterocyclic aryl, C(0)-alkyl, C(0)-aryl, or

C(0)-heterocyclic aryl; R₅ is substituted or un-substituted alkyl;

6, R7 and R₈, being the same or different, are each independently hydrogen, alkyl, C(0)-alkyl, C(0)-aryl, C(0)-heterocyclic aryl, N0₂, NH₂, COOH, CN, F, CI, Br, or I.

6. The Danshensu derivative or pharmaceutically acceptable salt thereof according to claim 5, wherein the Danshensu derivative has a structure of ADTM:

7. The Danshensu derivative or pharmaceutically acceptable salt thereof according to claim 5, wherein the Danshensu derivative has a structure of LDTM:

8. The Danshensu derivative or pharmaceutically acceptable salt thereof according to claim 5, the Danshensu derivative being further defined as of general formula V containing a moiety of TMP:

9. The Danshensu derivative or pharmaceutically acceptable salt thereof according to claim 1 , the Danshensu derivative being further defined as of general formula VI containing a moiety of TMP:

Wherein:

7 is alkyl;

R₈, 9 and Rio, being the same or different, are each independently hydrogen, alkyl, C(0)-alkyl, C(0)-aryl, C(0)-heterocyclic aryl, N0₂, NH₂, COOH, CN , F, CI, Br, or I.

10. The Danshensu derivative or pharmaceutically acceptable salt thereof according to claim 9, wherein the Danshensu derivative has a structure of ADTE:

11. The Danshensu derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein the pharmaceutically acceptable salt is formed from the Danshensu derivative and an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid, citric acid, tartaric acid, phosphoric acid, malic acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methylsulfonic acid, phenylsulfonic acid, and p-toluenesulfonic acid.

12. A method for preparing the Danshensu derivative or pharmaceutically acceptable salt thereof of any one of claims 1 to 10, comprising the step of selective acylation or etherification to form the Danshensu derivative or pharmaceutically acceptable salt thereof.

13. The method according to claim 12, wherein the step of acylation further comprises selectively, simultaneously acylating ortho-dihydroxyl groups to form the Danshensu derivative or pharmaceutically acceptable salt thereof.

14. The method according to claim 12, further comprises selectively acylating a-hydroxyl group to form the Danshensu derivative or pharmaceutically acceptable salt thereof.

15. The method according to claim 12, further comprises selectively acylating carboxyl group to form the Danshensu derivative or pharmaceutically acceptable salt thereof having a substituent of alkyl or heterocyclic ring.

16. A pharmaceutical composition, comprising the Danshensu derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, and a pharmaceutically acceptable carrier.

17. A use for manufacturing medicaments of the Danshensu derivative or the

pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 to prevent or treat cardiovascular diseases, cerebrovascular diseases, inflammatory infection diseases, cancers, and complications thereof.

18. The use for manufacturing medicaments according to claim 17, wherein the cardiovascular diseases and complications thereof comprise: arrhythmias, ventricular fibrosis, myocardial infarction, coronary disease, angina pectoris, cardiac failure, congestive heart failure, myocardial ischemia, cardiac ischemia or reperfusion, cachexia, myocarditis, atherosclerosis, peripheral ischemia of tissues or limbs, shock, ischemia or reperfusion-induced acute or chronic damage to tissues and organs, and disorders or indirect sequelae.

19. The use for manufacturing medicaments according to claim 17, wherein the cerebrovascular diseases and complications thereof comprise: stroke, trauma, epilepsy, Parkinson's disease, Huntington's disease, muscular atrophy (spinal cord) lateral sclerosis, Alzheimer's disease, hypoxic-ischemic brain injury, AIDS, dementia, multiple sclerosis, ischemic symptoms of peripheral or central nervous system, ischemic stroke symptoms, and brain disease with chronic pain.

20. The use for manufacturing medicaments according to claim 17 wherein the inflammatory infection diseases comprise: inflammatory bowel disease, diabetes, rheumatoid arthritis, asthma, cirrhosis, allograft rejection, encephalomyelitis, meningitis, pancreatitis, peritonitis, vasculitis, lymphocytic choriomeningitis, choriomeningitis, glomerulonephritis, systemic lupus erythematosus, gastrointestinal motility disorders, obesity, hungry disease, hepatitis, renal failure, diabetic retinopathy, uveitis, glaucoma, blepharitis, chalazion, allergic eye disease, corneal ulcers, keratitis, cataract, age-related macular degeneration, and optic neuritis.