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WO2011160597A1 - Furocoumarines agissant contre l'hypertension et procédés pour les préparer - Google Patents

Furocoumarines agissant contre l'hypertension et procédés pour les préparer Download PDF

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Publication number
WO2011160597A1
WO2011160597A1 PCT/CN2011/076242 CN2011076242W WO2011160597A1 WO 2011160597 A1 WO2011160597 A1 WO 2011160597A1 CN 2011076242 W CN2011076242 W CN 2011076242W WO 2011160597 A1 WO2011160597 A1 WO 2011160597A1
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WO
WIPO (PCT)
Prior art keywords
group
compound
furocoumarin
reaction
hydrazine
Prior art date
Application number
PCT/CN2011/076242
Other languages
English (en)
Chinese (zh)
Inventor
贺浪冲
张�杰
李娜
贺建宇
张彦民
周楠
李西玲
王嗣岑
贺怀贞
卢闻
Original Assignee
西安交通大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 西安交通大学 filed Critical 西安交通大学
Publication of WO2011160597A1 publication Critical patent/WO2011160597A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the invention relates to the field of biomedical technology, and relates to a compound for lowering blood pressure, in particular to a furocoumarin compound having hypotensive activity and a preparation method thereof.
  • Hypertension is one of the major diseases that currently seriously affect human health and threaten human life. It is the most common cardiovascular disease and is closely related to myocardial infarction, stroke, coronary heart disease, heart failure, and renal failure. China suffers from nearly 3 million cardiovascular and cerebrovascular diseases each year, accounting for 51% of the total cause of death in our country each year; 75% of the surviving patients lose their ability to work to varying degrees, and 40% are severely disabled. Cardiovascular disease has become the number one killer of human beings. The key to prevention and treatment of cardiovascular and cerebrovascular diseases is the prevention and treatment of hypertension.
  • Chemotherapy for hypertension is one of the basic means of prevention and treatment of hypertension.
  • the research on chemical drugs used in the treatment of hypertension has achieved great success, and a large number of clinical anti-high with different mechanisms of action have been obtained.
  • Blood pressure drugs due to the different degree of toxic and side effects of chemical drugs, different mechanisms of hypertension drugs have different shortcomings, which often make the chemical treatment of hypertension less than expected; and enhance the long-term effect of antihypertensive drugs. Sex and stability are effective ways to improve the action of antihypertensive drugs. Therefore, the research and development of new antihypertensive drugs is one of the hot and difficult issues in the field of pharmacy.
  • the problem to be solved by the present invention is to provide a furocoumarin compound having antihypertensive activity and a preparation method thereof, wherein the furocoumarin compound exhibits diastolic blood vessels and antihypertensive
  • the invention is achieved by the following technical solutions:
  • n 1 to 4, R dimethyl or disubstituted amino.
  • n 2 to 4 carbon atoms
  • the carbon chain is a straight hydrazine hydrocarbon
  • R is a dimethyl group or a disubstituted group.
  • the R is a disubstituted amino group, and the substituent is a fluorenyl group, a cyclodecyl group or an epoxy fluorenyl group.
  • a method for preparing a furocoumarin compound having reduced hypertension comprises the following steps:
  • n 1 to 4
  • R is a hydrogen atom, a dimethyl group or a disubstituted amino group, and the substituent of the disubstituted amino group is an anthracenyl group, a cyclodecyl group or an epoxy fluorenyl group.
  • the boron tribromide-dichloroformamidine solution is added dropwise to the xanthotoxin-dichloroformamidine solution, wherein the molar ratio of boron tribromide to xanthotoxin is 3:1, and then at room temperature.
  • the reaction was carried out for 4 h under the conditions ;
  • the reaction system is transferred to a saturated sodium hydrogencarbonate solution, the reaction is stirred well, and then the whole is transferred to water to thoroughly stir the reaction; the filtration cake is washed with water several times, and the filtrate is adjusted to neutrality to produce a precipitate again; After the resulting precipitate was suction filtered, the filter cake was combined twice and dried under vacuum overnight to give the.
  • the xanthophylls are dissolved in anhydrous hydrazine, hydrazine-dimethylformamide, and then an excess of anhydrous potassium carbonate is added, stirred at room temperature, and then a sufficient amount of side chain to be etherified with the phenolic hydroxyl group is added.
  • the compound, under nitrogen protection, is heated at 80 ° C in an oil bath for 10 to 30 h.
  • the side chain having at least 2 carbon atoms is isopentenyl, isoamyl, allyl, anthracene, fluorenyl-dimethylethyl, ethionylmorpholine, fluorenyl-benzyl-hydrazine- Methyl ethyl, 3-dimethylaminopropyl or piperidinylethyl.
  • the furocoumarin compound having hypotensive activity is applied to the preparation of an antihypertensive drug.
  • the present invention has the following beneficial technical effects:
  • the furocoumarin compound provided by the invention is a novel compound with antihypertensive activity, which is based on the structural modification and optimization of the natural plant extract imperatorin, and retains its pharmacological activity. , improve its physical and chemical properties and enhance its drug-forming properties.
  • the preparation method of the furocoumarin compound provided by the invention has the advantages that the raw material source is easy to obtain, the reaction condition is mild, the reaction process is simple, and the reagent used is cheap and easy to obtain.
  • the present invention can obtain an imperatorin having high antihypertensive activity as compared with natural plant extract, and can significantly reduce the cost.
  • the furocoumarin antihypertensive compound prepared by the present invention is a derivative of imperatorin and has a similar effect to imperatorin.
  • the study of exovascular ring tension shows that the furocoumarin compound on the rat mesentery Microvessels have a relaxing effect and can be applied to the preparation of antihypertensive drugs.
  • Fig. 1 is a synthetic route diagram of a furocoumarin compound having antihypertensive activity; wherein, compound 1 is xanthotoxin, compound 2 is xanthophylls, and compound 3 is a furocoumarin compound.
  • the reaction conditions indicated in the figure are specifically as follows: a is BBr 3 , CH 2 Cl 2 ; b is DMF, K 2 C0 3 .
  • Figure 2 is a comparison of the diastolic dose-effect diagrams of the vascular rings, wherein Figure 2-1 to Figure 2-9 show the diastolic dose-effect diagrams of different furocoumarins and imperatorin, Control (blank control).
  • the abscissa is the logarithm of the concentration and the ordinate is the maximum diastolic rate.
  • the present invention provides a furocoumarin compound having antihypertensive activity, the furocoumarin compound having properties similar to imperatorin, exhibiting diastolic blood vessel activity in an isolated vascular ring tension study , can be applied to the preparation of antihypertensive drugs.
  • the invention is described in detail below with reference to the drawings and embodiments, which are to be construed as illustrative and not limiting.
  • the present invention provides a furocoumarin compound having antihypertensive activity, and its chemical structural formula is:
  • n 1 to 4
  • R is a hydrogen atom, a dimethyl group or a disubstituted amino group.
  • the n is 2 to 4 carbon atoms, and a double bond is formed between two carbon atoms at the terminal, and R is a hydrogen atom.
  • the n is 2 to 4 carbon atoms, the carbon chain is a direct alkylene hydrocarbon, and R is a dimethyl group or a double Alkenyl.
  • the R is a disubstituted amino group, and the substituent is a fluorenyl group, a cyclodecyl group or an epoxy fluorenyl group.
  • the prepared boron tribromide-dichloroformamidine solution is placed in a constant pressure dropping funnel, and slowly dripped in an eggplant-shaped bottle stirred in an ice bath, and dripped in 30 minutes. . After the completion of the dropwise addition, the ice bath was removed and reacted at room temperature for 4 hours.
  • the reaction system is poured into 160 ml of a stirred saturated sodium hydrogencarbonate solution and stirred for 1 hour, and then transferred to 160 ml of water and stirred for 1 hour ; filtered, the filter cake is washed several times with water, and the filtrate is diluted with 2 mol/L hydrochloric acid. After the neutralization, the precipitate was again produced. After the resulting precipitate was suction filtered, the filter cake was combined twice and dried in vacuo to give a white solid product 3.64 g ( 18.00 mmol), yield 90.0%.
  • Example 2 wherein n is 2 and R is the step 1) is the same as in the first embodiment, that is, the preparation steps are the same from the compound xanthotoxin (1) to the compound xanthohumol (2); then the phenolic hydroxyl group and the isopentenyl group
  • the bromination reaction of bromine is specifically as follows:
  • Embodiment 3 A compound wherein n is 2 and a double bond and R is a hydrogen atom in the structural formula is prepared by the following steps:
  • Step 1) Same as Example 1, that is, the preparation steps from the compound xanthotoxin (1) to the compound xanthohumol (2) are the same; after that, the phenolic hydroxyl group and the allyl bromide are etherified, specifically: 0.40 g (2.00 mmol)
  • Compound (2) was dissolved in 10 ml of treated anhydrous hydrazine, hydrazine-dimethylformamide (DMF), anhydrous potassium carbonate (0.83 g (6.00 mmol)), stirred at room temperature for 30 min, then ally Base bromine 0.25 ml G. OOmol), temperature control reaction in an oil bath at 80 ° C for 19 h under nitrogen protection.
  • Step 1) The same as in Example 1, that is, the preparation steps from the compound xanthotoxin (1) to the compound xanthohumol (2) are the same; after that the phenolic hydroxyl group is ether with hydrazine, hydrazine-dimethylchloroethylamine hydrochloride
  • the reaction is specifically:
  • furocoumarin compound 9-(2-(benzyl(methyl:)amino:)ethoxy)-7H furan [3,2-g] chromen-7-one corresponds to the one shown in FIG. Compound (IMP-6), its structural formula is as follows:
  • Step 1) The same as in Example 1, that is, the preparation steps from the compound xanthotoxin (1) to the compound xanthohumol (2) are the same; after that, the phenolic hydroxyl group is etherified with 3-dimethylaminopropyl chloride hydrochloride.
  • the reaction is specifically as follows:
  • Embodiment 8 A compound wherein n is 1 and R is a cyclodecyl disubstituted amino group, The next step is to prepare:
  • Step 1) Same as Example 1, that is, the preparation steps from the compound xanthotoxin (1) to the compound xanthohumol (2) are the same; then the phenolic hydroxyl group and 1-(2-chloroethyl:) piperidine hydrochloride
  • the etherification reaction occurs, specifically:
  • the furocoumarin compound provided by the invention has antihypertensive effect and has a relaxing effect on rat mesenteric microvasculature, and can be used for treatment of hypertension; compared with the positive control drug imperatorin, individual compounds show higher anti-high resistance. Blood pressure activity. Antihypertensive verification The vascular ring tension method was used to detect the relaxation of mesenteric microvasculature by the furocoumarin compound to be tested:
  • a buffer salt system of calcium chloride was prepared as shown in Table 1, dissolved in 2/3 of the total amount of ultrapure water, and completely dissolved by stirring with a clean glass rod.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des furocoumarines présentant une activité contre l'hypertension, ainsi que des procédés pour les préparer. Les composés furocoumarine selon l'invention présentent des propriétés semblables à celles de l'impératorine, montrent une action de dilatation des vaisseaux sanguins lors d'études portant sur la tension d'anomalies des arcs aortiques isolées, et peuvent être utilisés pour préparer des médicaments hypotenseurs.
PCT/CN2011/076242 2010-06-25 2011-06-24 Furocoumarines agissant contre l'hypertension et procédés pour les préparer WO2011160597A1 (fr)

Applications Claiming Priority (2)

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CN201010209383.5 2010-06-25
CN2010102093835A CN101857598B (zh) 2010-06-25 2010-06-25 一种具有降高血压活性的呋喃香豆素类化合物及其制备方法

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2682118A1 (fr) * 2012-07-02 2014-01-08 Max-Delbrück-Centrum für Molekulare Medizin Berlin-Buch Dérivés de psoralène permettant de prévenir ou de traiter l'insuffisance cardiaque ou l'hypertrophie cardiaque
WO2014006045A1 (fr) * 2012-07-02 2014-01-09 Max-Delbrück-Centrum für Molekulare Medizin Dérivés du psoralène en prévention ou en traitement de l'insuffisance cardiaque ou de l'hypertrophie cardiaque
CN110229166A (zh) * 2019-06-18 2019-09-13 延边大学 一种呋喃香豆素类化合物及其制备方法和医用用途

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101857598B (zh) * 2010-06-25 2012-11-28 西安交通大学 一种具有降高血压活性的呋喃香豆素类化合物及其制备方法
CN103254207B (zh) * 2013-05-10 2015-04-29 西安交通大学 一种具有降高血压活性的化合物及其制备方法
CN109503612B (zh) * 2017-09-14 2020-06-16 北京农学院 8-甲氧基补骨脂素的结构修饰物及其制备方法与应用

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US20090155224A1 (en) * 2007-06-28 2009-06-18 Laskin Jeffrey D Dimethyl amino ethyl ether psoralens and methods for their production and use
CN101857598A (zh) * 2010-06-25 2010-10-13 西安交通大学 一种具有降高血压活性的呋喃香豆素类化合物及其制备方法

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2682118A1 (fr) * 2012-07-02 2014-01-08 Max-Delbrück-Centrum für Molekulare Medizin Berlin-Buch Dérivés de psoralène permettant de prévenir ou de traiter l'insuffisance cardiaque ou l'hypertrophie cardiaque
WO2014006045A1 (fr) * 2012-07-02 2014-01-09 Max-Delbrück-Centrum für Molekulare Medizin Dérivés du psoralène en prévention ou en traitement de l'insuffisance cardiaque ou de l'hypertrophie cardiaque
CN110229166A (zh) * 2019-06-18 2019-09-13 延边大学 一种呋喃香豆素类化合物及其制备方法和医用用途
CN110229166B (zh) * 2019-06-18 2021-03-23 延边大学 一种呋喃香豆素类化合物及其制备方法和应用

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