WO2012103813A1 - Dérivées de danshensu et de chuanxiongqin, leur procédé de préparation et leur utilisation - Google Patents

Dérivées de danshensu et de chuanxiongqin, leur procédé de préparation et leur utilisation Download PDF

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WO2012103813A1
WO2012103813A1 PCT/CN2012/070832 CN2012070832W WO2012103813A1 WO 2012103813 A1 WO2012103813 A1 WO 2012103813A1 CN 2012070832 W CN2012070832 W CN 2012070832W WO 2012103813 A1 WO2012103813 A1 WO 2012103813A1
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danshensu
derivative
arom
alkyl
aryl
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PCT/CN2012/070832
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Yuqiang Wang
Pei Yu
Jie Jiang
Luchen SHAN
Gaoxiao Zhang
Zaijun Zhang
Yonghong CHEN
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Jinan University
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Priority claimed from CN201110086382.0A external-priority patent/CN102212008B/zh
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Publication of WO2012103813A1 publication Critical patent/WO2012103813A1/fr

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Definitions

  • 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.
  • 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
  • Danshensu 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 is very susceptible to oxidative deterioration, and thus is difficult to store due to its instability.
  • 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.
  • TMP Tetramethylpyrazine
  • Choanxiongqin or Ligustrazine shown in FIG. 1
  • TMP Tetramethylpyrazine
  • Choanxiongqin or Ligustrazine shown in FIG. 1
  • 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.
  • 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.
  • TMP can significantly reduce mortality of mice due to ADP-induced acute pulmonary embolism
  • 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.
  • 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).
  • Danshensu 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.
  • 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.
  • 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 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:
  • Ri is hydrogen, substituted or un-substituted aryl, heterocyclic aryl or alkyl, heterocyclic groups
  • X is nitrogen, oxygen, or sulfur
  • R 2 , R3 and R 4 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:
  • R ls R 2 , R 3 and R 4 cannot be simultaneously hydrogen
  • R 2 is acetyl, and both R 3 and R 4 are methylene, methyl, ethyl, propyl, isopropyl, benzyl, acetyl, propionyl or benzoyl; If X is oxygen and i is hydrogen, then R 2 , R 3 and R4 cannot be
  • R 3 and R 4 cannot be simultaneously methylene, methyl, ethyl, propyl, isopropyl, benzyl, propionyl, or benzoyl;
  • Ri cannot be (R)-(3 -phenyl- l-ethyloxyformyl)propyl.
  • the present invention provides also the Danshensu derivatives of formula I shown above with X being oxygen, i.e., of formula II below:
  • Ri is substituted or un-substituted aryl, heterocyclic aryl, heterocyclic or monocyclic terpene group
  • R 2 , R 3 and R 4 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:
  • R 2 is acetyl
  • both R 3 and R 4 are methylene, methyl, ethyl, propyl, isopropyl, benzyl, acetyl, propionyl, or benzoyl;
  • R 3 and R 4 cannot both be methylene, methyl, ethyl, propyl, isopropyl, benzyl, propionyl, or benzoyl;
  • R 2 is acetyl
  • R 3 and R 4 cannot both be methylene, methyl, ethyl, propyl, isopropyl, benzyl, acetyl, propionyl, or benzoyl.
  • the present invention also provides danshensu derivatives of a general formula IV below, containing a moiety of
  • R 2 is hydrogen, alkyl, aryl, heterocyclic aryl, C(0)-alkyl, C(O)-;
  • R 0 , R 7 and R 8 being the same or different, are each independently hydrogen, alkyl, C(0)-alkyl, C(0)-aryl, C(0)-heterocyclic aryl, N0 2 , NH 2 , COOH, CN, F, CI, Br, or I.
  • the present invention also provides danshensu derivatives of a general formula V shown below, containing a moiety of TMP:
  • R 2 and R 5 are each independently substituted or un-substituted alkyl, or biologically active lipoic acid or bornyl group.
  • 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.
  • 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.
  • the present invention further provides methods for preparing Danshensu derivatives and pharmaceutically acceptable salts thereof.
  • 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;
  • 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.
  • 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.
  • 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.
  • infectious inflammatory diseases including inflammatory bowel disease, diabetes, rheumatoid arthritis, asthma, cirrhosis, allograf
  • 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.
  • 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.
  • 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 NH 2 , N0 2 , N(CH 3 ) 2 , ON0 2 , F, CI, Br, I, OH, OCH 3 , C0 2 H, C0 2 CH 3 , CN, aryl, and hetroaryl.
  • 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, CH 2 CH 2 OCH 3 , CH 2 CH 2 N(CH 3 ) 2 , and CH 2 CH 2 SCH 3 .
  • the branched alkyls include, for example, CH 2 CH(OCH 3 )CH 3 , CH 2 CH(N(CH 3 ) 2 )CH 3 , and
  • the cyclic alkyls include, for example, CH(CH 2 CH 2 ) 2 0,
  • the alkyl can be also substituted with one or more substituents, the non-limiting examples of which include NH 2 , N0 2 , N(CH 3 ) 2 , ON0 2 , F, CI, Br, I, OH, OCH 3 , C0 2 H, C0 2 CH 3 , CN, aryl, and heteroaryl.
  • aryl refers to unsubstituted or substituted aromatic compounds and carbocyclic groups.
  • the aryl can be either a monocyclic compound or a fused polycyclic compound.
  • phenyl is a monocyclic aryl
  • naphtyl is a fused polycyclic aryl.
  • the aryl can be substituted with one or more substituents, the non-limiting examples of which include NH 2 , N0 2 , N(CH 3 ) 2 , ON0 2 , F, CI, Br, I, OH, OCH 3 , C0 2 H, C0 2 CH 3 , CN, aryl, and heteroaryl.
  • phrases "pharmaceutically acceptable” means that a compound, such as a salt or excipient, has no unacceptable toxicity.
  • 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.
  • 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
  • organic anions such as acetic acid radical, pyruvic acid radical, propionic acid radical, cinnamic acid radical, to
  • terapéuticaally 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.
  • the present invention provides a novel series of Danshensu derivatives or their pharmaceutically acceptable salts.
  • the Danshensu derivatives have general formula I:
  • Ri is hydrogen, substituted or un-substituted aryl, heterocyclic aryl, or alkyl, heterocyclic group;
  • X is nitrogen, oxygen, or sulfur
  • R 2 , R 3 and R 4 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:
  • R 2 is acetyl
  • both R 3 and R 4 are methylene, methyl, ethyl, propyl, isopropyl, benzyl, acetyl, propionyl or benzoyl;
  • R 3 and R 4 cannot be simultaneously methylene, methyl, ethyl, propyl, isopropyl, benzyl, propionyl, or benzoyl;
  • Ri cannot be (R)-(3-phenyl-l-ethyloxyformyl)propyl.
  • the Danshensu derivatives of general formula I shown above, with X being oxygen can be further defined by general formula II:
  • Ri is substituted or un-substituted aryl, heterocyclic aryl, heterocyclic, or monocyclic terpene group
  • R 2 , R3 and R 4 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:
  • R 2 is acetyl
  • both R 3 and R 4 are methylene, methyl, ethyl, propyl, isopropyl, benzyl, acetyl, propionyl, or benzoyl ;
  • R 3 and R 4 cannot both be methylene, methyl, ethyl, propyl, isopropyl, benzyl, propionyl, or benzoyl;
  • R 2 is acetyl
  • R 3 and R 4 cannot both be methylene, methyl, ethyl, propyl, isopropyl, benzyl, acetyl, propionyl, or benzoyl.
  • 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
  • R 2 , R 3 and R 4 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 R 2 , R 3 and R 4 cannot be hydrogen simultaneously.
  • the danshensu derivatives can be further defined by general formula III:
  • benzyl substituted or un-substituted pyrazine ring or norbornene group; substitute or unsubstituted alkyl.
  • 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:
  • P2 is hydrogen, alkyl, aryl, heterocyclic aryl, C(0)-alkyl, C(0)-aryl, or
  • R 5 is substituted or un-substituted alkyl
  • R 7 and R 8 being the same or different, are each independently hydrogen, alkyl, C(0)-alkyl, C(0)-aryl, C(0)-heterocyclic aryl, N0 2 , NH 2 , COOH, CN, F, CI, Br, or I.
  • the Danshensu derivatives of general formula IV containing a moiety of TMP may be further defined as R6, R7 and R 8 being CH 3 .
  • the Danshensu derivatives of general formula IV may be also further defined that R 2 is C(0)-CH 3 , C(0)-CH 2 CH 3 , C(0)-(CH2) 2 CH 3 , C(0)-CH(CH 3 ) 2 or C(0)-C(CH 3 ) 3 , R 5 is CH 3 , CH 3 CH 2 , CH 3 (CH 2 ) 2 , (CH 3 ) 2 CH, or (CH 3 ) 3 C.
  • the Danshensu derivatives of general formula IV containing a moiety of TMP can be further defined in that R 5 is methyl, R 2 is C(0)-CH 3 , and R 6 , R7 and R 8 are CH 3 ; such that the structure of which is of ADTM below:
  • the Danshensu derivatives of general formula IV containing a moiety of Chuanxiongqin can be further defined such that the structure of which is of LDTM below:
  • the Danshensu derivatives of general formula I can be further defined as of general formula V containing a moiety of TMP: wherein, R 2 and R 5 are each independently substituted or unsubstituted alkyl, or biologically active lipoic acid or bornyl group.
  • the Danshensu derivatives of general formula I can be further defined as of general formula VI containing a moiety of TMP:
  • R 7 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, N0 2 , NH 2 , COOH, CN , F, CI, Br, or I.
  • the Danshensu derivative has the structure of ADTE below:
  • the present invention also provides methods of preparing Danshensu derivatives.
  • 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.
  • 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.
  • the method for preparing Danshensu derivatives includes attaching other functional groups with a strong antioxidant function at an appropriate site.
  • the Danshensu derivatives prepared through such inventive method are highly active for treating heart diseases whereas the Danshensu shows insufficient effect.
  • 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.
  • glycerol stearate can be used as the material to extend the duration of pharmaceutical effect of the drug.
  • 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 inert solid diluent such as calcium carbonate, calcium phosphate or kaolin
  • 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.
  • 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.
  • 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
  • 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.
  • preservatives such as ethylene or n-propyl parabens
  • coloring agents such as ethylene or n-propyl parabens
  • flavoring agents such as ethylene or n-propyl parabens
  • 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.
  • 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.
  • a solution such as aqueous Ringer's solution and isotonic chloride solution can be used.
  • a sterile oil mixture is usually used as solvent or suspension media.
  • 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.
  • 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.
  • excipients include cocoa butter and polyethylene glycol.
  • compositions containing active compounds of the present invention can be also parentarally administrated in a sterile medium.
  • the pharmaceutical compositions can be formulated either as a suspension or being dissolved in an excipent.
  • certain suitable auxiliary agents e.g., local anesthetics
  • preservatives and buffering agents can be dissolved.
  • compositions of the present invention can be given in a continuous or
  • the routes of administration can be of oral or parenteral, including subcutaneous, intravenous, inhalation, nasal, and intraperitoneal.
  • 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.
  • direct e.g., through injection, local implantation, or local tissue position
  • systemic e.g., oral or parenteral
  • compositions 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.
  • 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.
  • the pharmaceutical compositions described herein can be delivered in a continuous or intermittent mode by using a micro-pump.
  • suitable solutions for parenteral administration can be prepared by any known methods in the art, which is described, for example, in emigton's Pharmaceutical
  • 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.
  • 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.
  • 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.
  • 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.
  • novel compounds of the present invention formulated through dissolution, suspension or emulsion in water or non-aqueous solvent can be administered by injection.
  • non-aqueous solvents include methylsulfoxide, ⁇ , ⁇ -dimethyl acetyl oxygen, ⁇ , ⁇ -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.
  • 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).
  • 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).
  • PVP polyvinylpyrrolidone
  • 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.
  • 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.
  • a dermatologically acceptable carrier such as lotion, cream, ointment or soap.
  • the carriers can form a film or a layer on the skins to avoid the undesirable drug shifting for topical application.
  • the compositions can be dispersed into a tissue-adhesive liquid or other known medium in order to enhance the absorption on the tissue surfaces.
  • solutions of hydroxypropyl cellulose or fibrinogen/thrombin for example, can be also used.
  • 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.
  • 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.
  • 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, cyst
  • 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.
  • 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, hyperphag
  • 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.
  • 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.
  • 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 N 2 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.
  • 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 NaHC0 3 (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 N 2 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.
  • 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.
  • DMAP 14 mg, 10%
  • Example 33 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 N 2 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.
  • Example 7 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 H 2 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.
  • Example 8 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 N 2 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 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%).
  • Example 1 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 N 2 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.
  • Example 3 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 N 2 protection, acetic anhydride as acylating agent and DMAP as catalyst were added, and the reaction was stirred magnetically at room temperature for 2 hours.
  • Example 34 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 N 2 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 NaHC0 3 , and the resulting material was washed three times with ethyl acetate.
  • Example 34 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 N 2 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.
  • Example34 The compound (144 mg, 0.5 mmol) of Example34 was placed in a 25 mL
  • Example 34 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 N 2 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 NaHC0 3 .
  • Example 3 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 N 2 protection, propionic anhydride as acylating agent and DMAP as catalyst were added. The reaction was stirred at room temperature for 2 hours.
  • Example 3 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 N 2 protection, isobutyric anhydride as acylating agent and DMAP as catalyst were added. The reaction was magnetically stirred at room temperature for 2 hours.
  • Example 3 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 N 2 protection, butyric anhydride as acylating agent and DMAP as catalyst were added. The reaction was stirred at room temperature for 2 hours.
  • L-lipoic acid (206 mg, 1 mmol) was placed in a 25 mL single-neck flask and dissolved with dried anhydrous CH 2 CI 2 . 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 N 2 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 CH 2 CI 2 was removed from the reaction solution. Ethyl acetate was added, and the white precipitate DCU was filtered.
  • 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%).
  • Example 8 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 N 2 protection, and propionic anhydride as acylating agent and DMAP as catalyst were added, and the reaction was stirred at room temperature for 2 hours.
  • Example 8 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 N 2 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.
  • Example 8 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 N 2 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.
  • Example 3 The compound (157.4 mg, 0.3 mmol) of Example 3 was placed in a 25 mL
  • Example 13 The compound (186 mg, 0.5 mmol) of Example 13 was placed in a 25 mL
  • Example 14 The compound (200 mg, 0.5 mmol) of Example 14 was placed in a 25 mL
  • Example 15 The compound (214 mg, 0.5 mmol) of Example 15 was placed in a 25 mL
  • Example 15 The compound (214 mg, 0.5 mmol) of Example 15 was placed in a 25 mL
  • Example 6 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 H 2 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.
  • 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 NaHC0 3 (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 N 2 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.
  • 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 NaHC0 3 (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 N 2 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.
  • 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 NaHC0 3 (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 N 2 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.
  • Example 2 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.
  • 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
  • HOBt 90 mg, 0.66 mmol
  • 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.
  • n-propylamine 50 ⁇ , 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.
  • 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
  • HOBt 90 mg, 0.66 mmol
  • 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.
  • n-butylamine 55 ⁇ , 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.
  • 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.
  • NaHC0 3 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.
  • 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.
  • 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.
  • NaHC0 3 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.
  • 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.
  • 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.
  • NaHC0 3 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.
  • 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.
  • Example 33 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 N 2 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 NaHC0 3 , and extracted three times with ethyl acetate.
  • Example 34 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 N 2 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 NaHC0 3 , and extracted three times with ethyl acetate.
  • Example 35 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 N 2 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 NaHC0 3 , and extracted three times with ethyl acetate.
  • Example 39 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 N 2 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 NaHC0 3 , and extracted three times with ethyl acetate.
  • Example 40 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 N 2 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 NaHC0 3 , and extracted three times with ethyl acetate.
  • Example 41 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 N 2 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 NaHC0 3 , and extracted three times with ethyl acetate.
  • 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.
  • NaHC0 3 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.
  • 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.
  • 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 N 2 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 NaHC0 3 , and extracted three times with ethyl acetate.
  • Example 48 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 N 2 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 NaHC0 3 , and extracted three times with ethyl acetate.
  • Example 48 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 N 2 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 NaHC0 3 , and extracted three times with ethyl acetate.
  • Example 48 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 N 2 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 NaHC0 3 , and extracted three times with ethyl acetate.
  • 2-bromoethyl-3,5,6-trimethyl pyrazine 110 mg, 0.514 mmol
  • Ag 2 0 174 mg, 0.750 mmol
  • Example 2 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 Ag 2 0 (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
  • Example 56 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 N 2 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 NaHC0 3 , and the organic material was extracted three times with ethyl acetate.
  • Example 13 The compound (186 mg, 0.5 mmol) of Example 13 was placed in a 25 mL
  • 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 H 2 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.
  • Example 60 Test on free radical scavenging effect of Danshensu derivatives towards
  • scavenging rate In the wells of a 96-well ELISA plate were sequentially added the drug (50 ⁇ ,) for texting in various concentrations, methanol (100 ⁇ ⁇ ), DPPH (50 ⁇ , 0.4 mmol/L). In the well of blank reaction was placed with a solution of the mixture of DPPH (50 ⁇ ) and methanol (150 ⁇ ⁇ ), and in the well of blank control was placed with methanol (200 ⁇ ,); four sets of duplicate were prepared for each sample. Immediately after the addition of DPPH, the absorbance (A 0 ) 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%.
  • a solution of FeS0 4 was added to the sample and mixed uniformly.
  • the absorbance was immediately measured by UV spectrophotometer at 440 nm wavelength, being recorded as A 0 , and thereafter the absorbance was measured once every 10 seconds, until the time point of 100 seconds; the measuring process was repeated three times.
  • 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.
  • 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 ⁇ , 100 ⁇ , 200 ⁇ and 400 ⁇ , respectively, the reaction was run for 1 hour, and then 150 ⁇ of t-BHP was added to intervene for 12 hours.
  • Into each well was added 20 ⁇ ⁇ 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 ⁇ ⁇ 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.
  • 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
  • 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

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Abstract

La présente invention porte sur des dérivés de Danshensu contenant une fraction de Chuanxiongqin (tétraméthylpyrazine) et sur des compositions pharmaceutiques contenant les dérivés de Danshensu ou leurs sels et des véhicules pharmaceutiquement acceptables. L'invention porte également sur des procédés pour la préparation des dérivés de Danshensu ou de leurs sels et sur des utilisations des compositions dans la fabrication de médicaments pour la prévention et le traitement de maladies ou troubles dont les maladies cardiovasculaires et cérébrovasculaires et leurs complications.
PCT/CN2012/070832 2011-02-01 2012-02-01 Dérivées de danshensu et de chuanxiongqin, leur procédé de préparation et leur utilisation WO2012103813A1 (fr)

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KR20150042768A (ko) * 2015-04-01 2015-04-21 경희대학교 산학협력단 생약 추출물을 포함하는 신경안정용 약학적 조성물
JP2018520168A (ja) * 2015-07-07 2018-07-26 グゥアンヂョウ マグパイ ファーマシューティカルズ カンパニー リミテッド 新たなピラジン誘導体及びその調製方法並びに医薬応用
CN115403653A (zh) * 2022-05-19 2022-11-29 首都医科大学 D(+)-β-(3,4-二羟基苯基)-乳酰-Pro-Ala-Lys,其合成及应用
JP7466663B2 (ja) 2020-07-31 2024-04-12 深▲川▼市橄欖生物医薬科技有限公司 複数の機能を有するピラジン化合物とその製造方法及び使用

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