CN106946868B - Nitric oxide donator type coumarin derivative, preparation method and medical usage - Google Patents

Nitric oxide donator type coumarin derivative, preparation method and medical usage Download PDF

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CN106946868B
CN106946868B CN201611175141.2A CN201611175141A CN106946868B CN 106946868 B CN106946868 B CN 106946868B CN 201611175141 A CN201611175141 A CN 201611175141A CN 106946868 B CN106946868 B CN 106946868B
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furazan
coumarin
carboxy acid
piperazinyl
acid
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CN106946868A (en
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何黎琴
张灼
王蓉
柏志伟
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Anhui University of Traditional Chinese Medicine AHUTCM
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field, and in particular to nitric oxide donator type coumarin derivative and preparation method thereof and the application in pharmacy.Such compound has antitumor action, can be used for preparing anti-tumor drug.

Description

Nitric oxide donator type coumarin derivative, preparation method and medical usage
Technical field
The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field, and in particular to a kind of nitric oxide (NO) donator type tonka-bean Plain derivative or its pharmaceutically acceptable salt, their preparation method and medical usage, are especially preparing anti-tumor drug In application.
Background technique
Malignant tumour is currently to endanger one of the primary killers of human health.Clinically for treating the drug of malignant tumour There are many, but the deficiencies of toxic side effect as existing for it, drug resistance and low selectivity, so that most tumors patient lacks effectively Treatment.Therefore, the new type antineoplastic medicine that drug effect is high, toxic side effect is small is found to shoulder heavy responsibilities.
Natural products is considered as the important sources of effective therapeutic agent for a long time.From natural products find new drug or The research of lead compound is the important research direction and very active research field of current Development of New Drugs both at home and abroad.In addition to from Natural products directly researches exploitation and treats outside novel drugs at effective, the new guideization that natural products or new drug development are relied on Close the inexhaustible source of object.Using natural products as lead compound, integrated structure and Relation between Biological Activity study further into Row structural modification and analog synthesis have become the important channel of new drug initiative, Er Qieyi to improve drug effect and reduce toxicity Through achieving great successes.Coumarin kind compound is widely present in nature, has antibacterial, anticoagulant, anti-oxidant, anti-inflammatory With a variety of physiological activity such as antitumor；Its molecular structure is unique, has good thermodynamics and photochemical stability, is easy to carry out Structural modification simultaneously can be readily incorporated into various functional groups, be constantly subjected to the extensive concern of domestic and foreign scholars.Research in recent years Show some natural coumarin kind compounds can selectively acting in tumour cell, and it is low to normal cell toxicity, such as seven Leaf lactone, and dephnetin, Scopoletin, ovobiocin etc. (Natl.Cancer Inst.2000,92,242-248；Biochem Pharmacoll, 2004,67 (9): 1778-1779), good prospect is provided to research and develop the anti-tumor drug of high-efficiency low-toxicity. Since that there are anti-tumor activities is not strong enough, water-soluble poor or be in vivo metabolized unstable, biological benefit for natural coumarin kind compound The defects such as expenditure is low, are restricted its clinical application.Therefore, it is tied with some theories and means of medicament research and development Structure modification, transformation and structure activity study become the hot spot of field of medicinal chemistry research.The study found that most of with antitumor The coumarin kind compound of effect has hydroxyl at C7, and C3 substd is some to control with high bioactivity or with clinic The 7- hydroxyl for the treatment of effect and C3 tonka bean camphor structures are modified and modification has been appeared in the newspapers (Eur J Med Chem 2013,68: 103-110；Bioorg Med Chem, 2013,21:7107-7117), this is coumarin kind compound in antitumor field Development and utilization provides certain theoretical foundation.
NO is effector molecule important in vivo, participates in many important physiology courses.The study found that the NO of high concentration can be lured Apoptosis of tumor cells is led, the diffusion and transfer (J Med Chem, 2008,51 (15): 4834-4838) of tumour are prevented.Research Show for the compound with certain anti-tumor activity to be coupled with furoxan-based NO donors, obtained conjugate can play collaboration effect It answers, enhancing antitumous effect (J Med Chem, 2014,57:9343-9356).The present invention passes through connecting bridge at cumarin 3- It is combined with the NO donor with antitumor action, designs, synthesized I class NO donator type coumarin derivative.In view of drug It can be just fully absorbed with suitable lipid, reach preferable bioavilability, and amido is most normal in drug The group seen, amine structure is introduced in drug molecule can be improved its water solubility, and is often conducive to compound and passes through hydrogen bond and life Object target combines, and improves its bioavilability to increase its water solubility in its 7- introducing amino fragment, designs, synthesized II Class NO donator type coumarin derivative.
Summary of the invention
Present invention firstly discloses the cumarins of a kind of furoxan-based NO donors class NO donator type with anti-tumor activity to spread out Biology or its pharmaceutically acceptable salt, their preparation method and medical usage, especially in the preparation of antitumor drugs Using.The Pharmacological experiment result shows that such compound has good anti-tumor activity, therefore, such compound may be applicable in In treatment clinically Several Kinds of Malignancy.
Noval chemical compound disclosed by the invention is general formula I, NO donator type coumarin derivative shown in II and its pharmaceutically may be used The salt of receiving:
In general formula I: X representative-O- or-NH-；R representative-(CH2) n-, wherein n=1~6 ,-CH (CH3)CH2,-CH (CH3)(CH2)2,-(CH2)2O(CH2)2,-Ph (CH2)2,-(CH2)2NH(CH2)2,-CH2CH=CHCH2Or-CH2C≡ CCH2-；
In general formula II: n=1~6, X representative-O- or-NH-；R representative-(CH2) m-, wherein m=1~6 ,-CH (CH3) CH2,-CH (CH3)(CH2)2,-(CH2)2O(CH2)2,-Ph (CH2)2,-(CH2)2NH(CH2)2,-CH2CH=CHCH2Or -CH2C≡CCH2-；R1Represent NR1R2；R1And R2It may be the same or different, and represent hydrogen atom, C independently of one another1-C6Alkyl, Phenyl, benzyl, phenethyl or R1And R2The nitrogen-atoms being connect with it is formed together five to seven yuan of aliphatic heterocycles or heteroaromatic, should Ring group can be arbitrarily monosubstituted to five substitutions by following identical or different substituent groups, and the substituent group includes: C1-C6Alkyl, C1-C6Alkoxy, hydroxyl or hydroxyl-(C1-C6) alkyl.
Currently preferred compound is NO donator type coumarin derivative shown in general formula I:
X representative-O- or-NH-；R representative-(CH2) n-, wherein n=2~6 ,-CH (CH3)CH2,-CH (CH3)(CH2)2, -(CH2)2O(CH2)2,-Ph (CH2)2,-CH2CH=CHCH2Or-CH2C≡CCH2-；
Currently preferred compound is NO donator type coumarin derivative and its pharmaceutically acceptable shown in general formula II Salt:
N=2~6；X representative-O- or-NH-；R representative-(CH2) m-, wherein m=2~6 ,-CH (CH3)CH2,-CH (CH3)(CH2)2,-(CH2)2O(CH2)2,-Ph (CH2)2,-CH2CH=CHCH2Or-CH2C≡CCH2-；R1Represent amino, two Methylamino, diethylin, dipropyl amido, di-n-butylamine base, anilino-, benzamido group, phenyl ethylamine base, pyrrole radicals, piperidyl, morphine Quinoline base, imidazole radicals, piperazinyl, 4- methyl piperidine base, N methyl piperazine base, n-ethylpiperazine base or 4- hydroxyethyl piperazine base.
The further preferred compound of the present invention is nitric oxide donator type coumarin derivative shown in general formula I:
X representative-O- or-NH-；R representative-(CH2) n-, wherein n=2~6 ,-CH (CH3)CH2,-CH (CH3)(CH2)2, -(CH2)2O(CH2)2,-Ph (CH2)2Or-CH2C≡CCH2-；
The further preferred compound of the present invention is NO donator type coumarin derivative and its medicine shown in general formula II Upper acceptable salt:
N=2~4；X representative-O- or-NH-；R representative-(CH2) m-, wherein m=2~6 ,-CH (CH3)CH2,-CH (CH3) (CH2)2,-(CH2)2O(CH2)2,-Ph (CH2)2Or-CH2C≡CCH2-；R1Represent amino, dimethylamino, diethylin, benzene Amido, benzamido group, phenyl ethylamine base, piperidyl, morpholine base, piperazinyl, N methyl piperazine base, n-ethylpiperazine base or 4- hydroxyl second Base piperazinyl.
Specifically, general formula I, coumarin derivative preferably is selected from following compounds shown in II:
Coumarin-3-carboxy acid's -1,2- ethylene glycol furazan；
Coumarin-3-carboxy acid's -1,2- propylene glycol furazan；
Coumarin-3-carboxy acid's -1,3- propylene glycol furazan；
Coumarin-3-carboxy acid -1,3 butylene glycol furazan；
Coumarin-3-carboxy acid's -1,4- butanediol furazan；
Coumarin-3-carboxy acid's diethylene glycol furazan；
Coumarin-3-carboxy acid's -1,4- butynediols furazan；
Coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan；
Cumarin -3- carboxylic ethylaminoethanol furazan；
Coumarin-3-carboxy acid's aminopropanol furazan；
Coumarin-3-carboxy acid's isopropanolamine furazan；
7- (2- amino) ethoxy coumarin -3- carboxylic acid 1,2- ethylene glycol furazan
7- (2- dimethylamino) ethoxy coumarin -3- carboxylic acid 1,2- ethylene glycol furazan；
7- (2- lignocaine) ethoxy coumarin -3- carboxylic acid 1,2- ethylene glycol furazan；
7- (2- phenylamino) ethoxy coumarin -3- carboxylic acid 1,2- ethylene glycol furazan；
7- (2- benzyl amino) ethoxy coumarin -3- carboxylic acid 1,2- ethylene glycol furazan；
7- (2- benzene ethylamino) ethoxy coumarin -3- carboxylic acid 1,2- ethylene glycol furazan；
7- [2- (1- piperidyl)] ethoxy coumarin -3- carboxylic acid 1,2- ethylene glycol furazan；
7- [2- (1- morpholine base)] ethoxy coumarin -3- carboxylic acid 1,2- ethylene glycol furazan；
7- [2- (1- piperazinyl)] ethoxy coumarin -3- carboxylic acid 1,2- ethylene glycol furazan；
7- [2- (4- methyl-1-piperazinyl)] ethoxy coumarin-3- carboxylic acid 1,2- ethylene glycol furazan；
7- [2- (4- ethyl -1- piperazinyl)] ethoxy coumarin -3- carboxylic acid 1,2- ethylene glycol furazan；
7- [2- (4- ethoxy -1- piperazinyl)] ethoxy coumarin -3- carboxylic acid 1,2- ethylene glycol furazan；
7- (2- amino) ethoxy coumarin -3- carboxylic acid 1,2- propylene glycol furazan；
7- (2- dimethylamino) ethoxy coumarin -3- carboxylic acid 1,2- propylene glycol furazan；
7- (2- lignocaine) ethoxy coumarin -3- carboxylic acid 1,2- propylene glycol furazan；
7- (2- phenylamino) ethoxy coumarin -3- carboxylic acid 1,2- propylene glycol furazan；
7- (2- benzyl amino) ethoxy coumarin -3- carboxylic acid 1,2- propylene glycol furazan；
7- (2- benzene ethylamino) ethoxy coumarin -3- carboxylic acid 1,2- propylene glycol furazan；
7- [2- (1- piperidyl)] ethoxy coumarin -3- carboxylic acid 1,2- propylene glycol furazan；
7- [2- (1- morpholine base)] ethoxy coumarin -3- carboxylic acid 1,2- propylene glycol furazan；
7- [2- (1- piperazinyl)] ethoxy coumarin -3- carboxylic acid 1,2- propylene glycol furazan；
7- [2- (4- methyl-1-piperazinyl)] ethoxy coumarin-3- carboxylic acid 1,2- propylene glycol furazan；
7- [2- (4- ethyl -1- piperazinyl)] ethoxy coumarin -3- carboxylic acid 1,2- propylene glycol furazan；
7- [2- (4- ethoxy -1- piperazinyl)] ethoxy coumarin -3- carboxylic acid 1,2- propylene glycol furazan；
7- (2- amino) ethoxy coumarin -3- carboxylic acid 1,3- propylene glycol furazan；
7- (2- dimethylamino) ethoxy coumarin -3- carboxylic acid 1,3- propylene glycol furazan；
7- (2- lignocaine) ethoxy coumarin -3- carboxylic acid 1,3- propylene glycol furazan；
7- (2- phenylamino) ethoxy coumarin -3- carboxylic acid 1,3- propylene glycol furazan；
7- (2- benzyl amino) ethoxy coumarin -3- carboxylic acid 1,3- propylene glycol furazan；
7- (2- benzene ethylamino) ethoxy coumarin -3- carboxylic acid 1,3- propylene glycol furazan；
7- [2- (1- piperidyl)] ethoxy coumarin -3- carboxylic acid 1,3- propylene glycol furazan；
7- [2- (1- morpholine base)] ethoxy coumarin -3- carboxylic acid 1,3- propylene glycol furazan；
7- [2- (1- piperazinyl)] ethoxy coumarin -3- carboxylic acid 1,3- propylene glycol furazan；
7- [2- (4- methyl-1-piperazinyl)] ethoxy coumarin-3- carboxylic acid 1,3- propylene glycol furazan；
7- [2- (4- ethyl -1- piperazinyl)] ethoxy coumarin -3- carboxylic acid 1,3- propylene glycol furazan；
7- [2- (4- ethoxy -1- piperazinyl)] ethoxy coumarin -3- carboxylic acid 1,3- propylene glycol furazan；
7- (2- amino) ethoxy coumarin -3- carboxylic acid 1,3 butylene glycol furazan；
7- (2- dimethylamino) ethoxy coumarin -3- carboxylic acid 1,3 butylene glycol furazan；
7- (2- lignocaine) ethoxy coumarin -3- carboxylic acid 1,3 butylene glycol furazan；
7- (2- phenylamino) ethoxy coumarin -3- carboxylic acid 1,3 butylene glycol furazan；
7- (2- benzyl amino) ethoxy coumarin -3- carboxylic acid 1,3 butylene glycol furazan；
7- (2- benzene ethylamino) ethoxy coumarin -3- carboxylic acid 1,3 butylene glycol furazan；
7- [2- (1- piperidyl)] ethoxy coumarin -3- carboxylic acid 1,3 butylene glycol furazan；
7- [2- (1- morpholine base)] ethoxy coumarin -3- carboxylic acid 1,3 butylene glycol furazan；
7- [2- (1- piperazinyl)] ethoxy coumarin -3- carboxylic acid 1,3 butylene glycol furazan；
7- [2- (4- methyl-1-piperazinyl)] ethoxy coumarin-3- carboxylic acid 1,3 butylene glycol furazan；
7- [2- (4- ethyl -1- piperazinyl)] ethoxy coumarin -3- carboxylic acid 1,3 butylene glycol furazan；
7- [2- (4- ethoxy -1- piperazinyl)] ethoxy coumarin -3- carboxylic acid 1,3 butylene glycol furazan；
7- (2- amino) ethoxy coumarin -3- carboxylic acid 1,4- butanediol furazan；
7- (2- dimethylamino) ethoxy coumarin -3- carboxylic acid 1,4- butanediol furazan；
7- (2- lignocaine) ethoxy coumarin -3- carboxylic acid 1,4- butanediol furazan；
7- (2- phenylamino) ethoxy coumarin -3- carboxylic acid 1,4- butanediol furazan；
7- (2- benzyl amino) ethoxy coumarin -3- carboxylic acid 1,4- butanediol furazan；
7- (2- benzene ethylamino) ethoxy coumarin -3- carboxylic acid 1,4- butanediol furazan；
7- [2- (1- piperidyl)] ethoxy coumarin -3- carboxylic acid 1,4- butanediol furazan；
7- [2- (1- morpholine base)] ethoxy coumarin -3- carboxylic acid 1,4- butanediol furazan；
7- [2- (1- piperazinyl)] ethoxy coumarin -3- carboxylic acid 1,4- butanediol furazan；
7- [2- (4- methyl-1-piperazinyl)] ethoxy coumarin-3- carboxylic acid 1,4- butanediol furazan；
7- [2- (4- ethyl -1- piperazinyl)] ethoxy coumarin -3- carboxylic acid 1,4- butanediol furazan；
7- [2- (4- ethoxy -1- piperazinyl)] ethoxy coumarin -3- carboxylic acid 1,4- butanediol furazan；
7- (2- amino) ethoxy coumarin -3- carboxylic acid diethylene glycol furazan；
7- (2- dimethylamino) ethoxy coumarin -3- carboxylic acid diethylene glycol furazan；
7- (2- lignocaine) ethoxy coumarin -3- carboxylic acid diethylene glycol furazan；
7- (2- phenylamino) ethoxy coumarin -3- carboxylic acid diethylene glycol furazan；
7- (2- benzyl amino) ethoxy coumarin -3- carboxylic acid diethylene glycol furazan；
7- (2- benzene ethylamino) ethoxy coumarin -3- carboxylic acid diethylene glycol furazan；
7- [2- (1- piperidyl)] ethoxy coumarin -3- carboxylic acid diethylene glycol furazan；
7- [2- (1- morpholine base)] ethoxy coumarin -3- carboxylic acid diethylene glycol furazan；
7- [2- (1- piperazinyl)] ethoxy coumarin -3- carboxylic acid diethylene glycol furazan；
7- [2- ((4- methyl) -1- piperazinyl)] ethoxy coumarin -3- carboxylic acid diethylene glycol furazan；
7- [2- (4- ethyl -1- piperazinyl)] ethoxy coumarin -3- carboxylic acid diethylene glycol furazan；
7- [2- (4- ethoxy -1- piperazinyl)] ethoxy coumarin -3- carboxylic acid diethylene glycol furazan；
7- (2- amino) ethoxy coumarin -3- carboxylic acid 1,4- butynediols furazan；
7- (2- dimethylamino) ethoxy coumarin -3- carboxylic acid 1,4- butynediols furazan；
7- (2- lignocaine) ethoxy coumarin -3- carboxylic acid 1,4- butynediols furazan；
7- (2- phenylamino) ethoxy coumarin -3- carboxylic acid 1,4- butynediols furazan；
7- (2- benzyl amino) ethoxy coumarin -3- carboxylic acid 1,4- butynediols furazan；
7- (2- benzene ethylamino) ethoxy coumarin -3- carboxylic acid 1,4- butynediols furazan；
7- [2- (1- piperidyl)] ethoxy coumarin -3- carboxylic acid 1,4- butynediols furazan；
7- [2- (1- morpholine base)] ethoxy coumarin -3- carboxylic acid 1,4- butynediols furazan；
7- [2- (1- piperazinyl)] ethoxy coumarin -3- carboxylic acid 1,4- butynediols furazan；
7- [2- (4- methyl-1-piperazinyl)] ethoxy coumarin-3- carboxylic acid 1,4- butynediols furazan；
7- [2- (4- ethyl -1- piperazinyl)] ethoxy coumarin -3- carboxylic acid 1,4- butynediols furazan；
7- [2- (4- ethoxy -1- piperazinyl)] ethoxy coumarin -3- carboxylic acid 1,4- butynediols furazan；
7- (2- amino) ethoxy coumarin -3- carboxylic acid p-hydroxyphenylethanol furazan；
7- (2- dimethylamino) ethoxy coumarin -3- carboxylic acid p-hydroxyphenylethanol furazan；
7- (2- lignocaine) ethoxy coumarin -3- carboxylic acid p-hydroxyphenylethanol furazan；
7- (2- phenylamino) ethoxy coumarin -3- carboxylic acid p-hydroxyphenylethanol furazan；
7- (2- benzyl amino) ethoxy coumarin -3- carboxylic acid p-hydroxyphenylethanol furazan；
7- (2- benzene ethylamino) ethoxy coumarin -3- carboxylic acid p-hydroxyphenylethanol furazan；
7- [2- (1- piperidyl)] ethoxy coumarin -3- carboxylic acid p-hydroxyphenylethanol furazan；
7- [2- (1- morpholine base)] ethoxy coumarin -3- carboxylic acid p-hydroxyphenylethanol furazan；
7- [2- (1- piperazinyl)] ethoxy coumarin -3- carboxylic acid p-hydroxyphenylethanol furazan；
7- [2- (4- methyl-1-piperazinyl)] ethoxy coumarin-3- carboxylic acid p-hydroxyphenylethanol furazan；
7- [2- (4- ethyl -1- piperazinyl)] ethoxy coumarin -3- carboxylic acid p-hydroxyphenylethanol furazan；
7- [2- (4- ethoxy -1- piperazinyl)] ethoxy coumarin -3- carboxylic acid p-hydroxyphenylethanol furazan；
7- (2- amino) ethoxy coumarin -3- carboxylic acid amide's ethyl alcohol furazan；
7- (2- dimethylamino) ethoxy coumarin -3- carboxylic acid amide's ethyl alcohol furazan；
7- (2- lignocaine) ethoxy coumarin -3- carboxylic acid amide's ethyl alcohol furazan；
7- (2- phenylamino) ethoxy coumarin -3- carboxylic acid amide's ethyl alcohol furazan；
7- (2- benzyl amino) ethoxy coumarin -3- carboxylic acid amide's ethyl alcohol furazan；
7- (2- benzene ethylamino) ethoxy coumarin -3- carboxylic acid amide's ethyl alcohol furazan；
7- [2- (1- piperidyl)] ethoxy coumarin -3- carboxylic acid amide's ethyl alcohol furazan；
7- [2- (1- morpholine base)] ethoxy coumarin -3- carboxylic acid amide's ethyl alcohol furazan；
7- [2- (1- piperazinyl)] ethoxy coumarin -3- carboxylic acid amide's ethyl alcohol furazan；
7- [2- (4- methyl-1-piperazinyl)] ethoxy coumarin-3- carboxylic acid amide's ethyl alcohol furazan；
7- [2- (4- ethyl -1- piperazinyl)] ethoxy coumarin -3- carboxylic acid amide's ethyl alcohol furazan；
7- [2- (4- ethoxy -1- piperazinyl)] ethoxy coumarin -3- carboxylic acid amide's ethyl alcohol furazan；
7- (2- amino) ethoxy coumarin -3- carboxylic acid amide's propyl alcohol furazan；
7- (2- dimethylamino) ethoxy coumarin -3- carboxylic acid amide's propyl alcohol furazan；
7- (2- lignocaine) ethoxy coumarin -3- carboxylic acid amide's propyl alcohol furazan；
7- (2- phenylamino) ethoxy coumarin -3- carboxylic acid amide's propyl alcohol furazan；
7- (2- benzyl amino) ethoxy coumarin -3- carboxylic acid amide's propyl alcohol furazan；
7- (2- benzene ethylamino) ethoxy coumarin -3- carboxylic acid amide's propyl alcohol furazan；
7- [2- (1- piperidyl)] ethoxy coumarin -3- carboxylic acid amide's propyl alcohol furazan；
7- [2- (1- morpholine base)] ethoxy coumarin -3- carboxylic acid amide's propyl alcohol furazan；
7- [2- (1- piperazinyl)] ethoxy coumarin -3- carboxylic acid amide's propyl alcohol furazan；
7- [2- (4- methyl-1-piperazinyl)] ethoxy coumarin-3- carboxylic acid amide's propyl alcohol furazan；
7- [2- (4- ethyl -1- piperazinyl)] ethoxy coumarin -3- carboxylic acid amide's propyl alcohol furazan；
7- [2- (4- ethoxy -1- piperazinyl)] ethoxy coumarin -3- carboxylic acid amide's propyl alcohol furazan；
7- (2- amino) ethoxy coumarin -3- carboxylic acid isopropanolamine furazan；
7- (2- dimethylamino) ethoxy coumarin -3- carboxylic acid isopropanolamine furazan；
7- (2- lignocaine) ethoxy coumarin -3- carboxylic acid isopropanolamine furazan；
7- (2- phenylamino) ethoxy coumarin -3- carboxylic acid isopropanolamine furazan；
7- (2- benzyl amino) ethoxy coumarin -3- carboxylic acid isopropanolamine furazan；
7- (2- benzene ethylamino) ethoxy coumarin -3- carboxylic acid isopropanolamine furazan；
7- [2- (1- piperidyl)] ethoxy coumarin -3- carboxylic acid isopropanolamine furazan；
7- [2- (1- morpholine base)] ethoxy coumarin -3- carboxylic acid isopropanolamine furazan；
7- [2- (1- piperazinyl)] ethoxy coumarin -3- carboxylic acid isopropanolamine furazan；
7- [2- (4- methyl-1-piperazinyl)] ethoxy coumarin-3- carboxylic acid isopropanolamine furazan；
7- [2- (4- ethyl -1- piperazinyl)] ethoxy coumarin -3- carboxylic acid isopropanolamine furazan；
7- [2- (4- ethoxy -1- piperazinyl)] ethoxy coumarin -3- carboxylic acid isopropanolamine furazan；
7- (3- amino) propoxyl group coumarin-3-carboxy acid's 1,2- ethylene glycol furazan；
7- (3- dimethylamino) propoxyl group coumarin-3-carboxy acid's 1,2- ethylene glycol furazan；
7- (3- lignocaine) propoxyl group coumarin-3-carboxy acid's 1,2- ethylene glycol furazan；
7- (3- phenylamino) propoxyl group coumarin-3-carboxy acid's 1,2- ethylene glycol furazan；
7- (3- benzyl amino) propoxyl group coumarin-3-carboxy acid's 1,2- ethylene glycol furazan；
7- (3- benzene ethylamino) propoxyl group coumarin-3-carboxy acid's 1,2- ethylene glycol furazan；
7- [3- (1- piperidyl)] propoxyl group coumarin-3-carboxy acid's 1,2- ethylene glycol furazan；
7- [3- (1- morpholine base)] propoxyl group coumarin-3-carboxy acid's 1,2- ethylene glycol furazan；
7- [3- (1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,2- ethylene glycol furazan；
7- [3- (4- methyl-1-piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,2- ethylene glycol furazan；
7- [3- (4- ethyl -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,2- ethylene glycol furazan；
7- [3- (4- ethoxy -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,2- ethylene glycol furazan；
7- (3- amino) propoxyl group coumarin-3-carboxy acid's 1,2- propylene glycol furazan；
7- (3- dimethylamino) propoxyl group coumarin-3-carboxy acid's 1,2- propylene glycol furazan；
7- (3- lignocaine) propoxyl group coumarin-3-carboxy acid's 1,2- propylene glycol furazan；
7- (3- phenylamino) propoxyl group coumarin-3-carboxy acid's 1,2- propylene glycol furazan；
7- (3- benzyl amino) propoxyl group coumarin-3-carboxy acid's 1,2- propylene glycol furazan；
7- (3- benzene ethylamino) propoxyl group coumarin-3-carboxy acid's 1,2- propylene glycol furazan；
7- [3- (1- piperidyl)] propoxyl group coumarin-3-carboxy acid's 1,2- propylene glycol furazan；
7- [3- (1- morpholine base)] propoxyl group coumarin-3-carboxy acid's 1,2- propylene glycol furazan；
7- [3- (1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,2- propylene glycol furazan；
7- [3- (4- methyl-1-piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,2- propylene glycol furazan；
7- [3- (4- ethyl -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,2- propylene glycol furazan；
7- [3- (4- ethoxy -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,2- propylene glycol furazan；
7- (3- amino) propoxyl group coumarin-3-carboxy acid's 1,3- propylene glycol furazan；
7- (3- dimethylamino) propoxyl group coumarin-3-carboxy acid's 1,3- propylene glycol furazan；
7- (3- lignocaine) propoxyl group coumarin-3-carboxy acid's 1,3- propylene glycol furazan；
7- (3- phenylamino) propoxyl group coumarin-3-carboxy acid's 1,3- propylene glycol furazan；
7- (3- benzyl amino) propoxyl group coumarin-3-carboxy acid's 1,3- propylene glycol furazan；
7- (3- benzene ethylamino) propoxyl group coumarin-3-carboxy acid's 1,3- propylene glycol furazan；
7- [3- (1- piperidyl)] propoxyl group coumarin-3-carboxy acid's 1,3- propylene glycol furazan；
7- [3- (1- morpholine base)] propoxyl group coumarin-3-carboxy acid's 1,3- propylene glycol furazan；
7- [3- (1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,3- propylene glycol furazan；
7- [3- (4- methyl-1-piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,3- propylene glycol furazan；
7- [3- (4- ethyl -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,3- propylene glycol furazan；
7- [3- (4- ethoxy -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,3- propylene glycol furazan；
7- (3- amino) propoxyl group coumarin-3-carboxy acid's 1,3 butylene glycol furazan；
7- (3- dimethylamino) propoxyl group coumarin-3-carboxy acid's 1,3 butylene glycol furazan；
7- (3- lignocaine) propoxyl group coumarin-3-carboxy acid's 1,3 butylene glycol furazan；
7- (3- phenylamino) propoxyl group coumarin-3-carboxy acid's 1,3 butylene glycol furazan；
7- (3- benzyl amino) propoxyl group coumarin-3-carboxy acid's 1,3 butylene glycol furazan；
7- (3- benzene ethylamino) propoxyl group coumarin-3-carboxy acid's 1,3 butylene glycol furazan；
7- [3- (1- piperidyl)] propoxyl group coumarin-3-carboxy acid's 1,3 butylene glycol furazan；
7- [3- (1- morpholine base)] propoxyl group coumarin-3-carboxy acid's 1,3 butylene glycol furazan；
7- [3- (1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,3 butylene glycol furazan；
7- [3- (4- methyl-1-piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,3 butylene glycol furazan；
7- [3- (4- ethyl -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,3 butylene glycol furazan；
7- [3- (4- ethoxy -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,3 butylene glycol furazan；
7- (3- amino) propoxyl group coumarin-3-carboxy acid's 1,4- butanediol furazan；
7- (3- dimethylamino) propoxyl group coumarin-3-carboxy acid's 1,4- butanediol furazan；
7- (3- lignocaine) propoxyl group coumarin-3-carboxy acid's 1,4- butanediol furazan；
7- (3- phenylamino) propoxyl group coumarin-3-carboxy acid's 1,4- butanediol furazan；
7- (3- benzyl amino) propoxyl group coumarin-3-carboxy acid's 1,4- butanediol furazan；
7- (3- benzene ethylamino) propoxyl group coumarin-3-carboxy acid's 1,4- butanediol furazan；
7- [3- (1- piperidyl)] propoxyl group coumarin-3-carboxy acid's 1,4- butanediol furazan；
7- [3- (1- morpholine base)] propoxyl group coumarin-3-carboxy acid's 1,4- butanediol furazan；
7- [3- (1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,4- butanediol furazan；
7- [3- (4- methyl-1-piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,4- butanediol furazan；
7- [3- (4- ethyl -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,4- butanediol furazan；
7- [3- (4- ethoxy -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,4- butanediol furazan；
7- (3- amino) propoxyl group coumarin-3-carboxy acid's diethylene glycol furazan；
7- (3- dimethylamino) propoxyl group coumarin-3-carboxy acid's diethylene glycol furazan；
7- (3- lignocaine) propoxyl group coumarin-3-carboxy acid's diethylene glycol furazan；
7- (3- phenylamino) propoxyl group coumarin-3-carboxy acid's diethylene glycol furazan；
7- (3- benzyl amino) propoxyl group coumarin-3-carboxy acid's diethylene glycol furazan；
7- (3- benzene ethylamino) propoxyl group coumarin-3-carboxy acid's diethylene glycol furazan；
7- [3- (1- piperidyl)] propoxyl group coumarin-3-carboxy acid's diethylene glycol furazan；
7- [3- (1- morpholine base)] propoxyl group coumarin-3-carboxy acid's diethylene glycol furazan；
7- [3- (1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's diethylene glycol furazan；
7- [3- (4- methyl-1-piperazinyl)] propoxyl group coumarin-3-carboxy acid's diethylene glycol furazan；
7- [3- (4- ethyl -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's diethylene glycol furazan；
7- [3- (4- ethoxy -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's diethylene glycol furazan；
7- (3- amino) propoxyl group coumarin-3-carboxy acid's 1,4- butynediols furazan；
7- (3- dimethylamino) propoxyl group coumarin-3-carboxy acid's 1,4- butynediols furazan；
7- (3- lignocaine) propoxyl group coumarin-3-carboxy acid's 1,4- butynediols furazan；
7- (3- phenylamino) propoxyl group coumarin-3-carboxy acid's 1,4- butynediols furazan；
7- (3- benzyl amino) propoxyl group coumarin-3-carboxy acid's 1,4- butynediols furazan；
7- (3- benzene ethylamino) propoxyl group coumarin-3-carboxy acid's 1,4- butynediols furazan；
7- [3- (1- piperidyl)] propoxyl group coumarin-3-carboxy acid's 1,4- butynediols furazan；
7- [3- (1- morpholine base)] propoxyl group coumarin-3-carboxy acid's 1,4- butynediols furazan；
7- [3- (1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,4- butynediols furazan；
7- [3- (4- methyl-1-piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,4- butynediols furazan；
7- [3- (4- ethyl -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,4- butynediols furazan；
7- [3- (4- ethoxy -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,4- butynediols furazan；
7- (3- amino) propoxyl group coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan；
7- (3- dimethylamino) propoxyl group coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan；
7- (3- lignocaine) propoxyl group coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan；
7- (3- phenylamino) propoxyl group coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan；
7- (3- benzyl amino) propoxyl group coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan；
7- (3- benzene ethylamino) propoxyl group coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan；
7- [3- (1- piperidyl)] propoxyl group coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan；
7- [3- (1- morpholine base)] propoxyl group coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan；
7- [3- (1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan；
7- [3- (4- methyl-1-piperazinyl)] propoxyl group coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan；
7- [3- (4- ethyl -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan；
7- [3- (4- ethoxy -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan；
7- (3- amino) propoxyl group coumarin-3-carboxy acid's ethylaminoethanol furazan；
7- (3- dimethylamino) propoxyl group coumarin-3-carboxy acid's ethylaminoethanol furazan；
7- (3- lignocaine) propoxyl group coumarin-3-carboxy acid's ethylaminoethanol furazan；
7- (3- phenylamino) propoxyl group coumarin-3-carboxy acid's ethylaminoethanol furazan；
7- (3- benzyl amino) propoxyl group coumarin-3-carboxy acid's ethylaminoethanol furazan；
7- (3- benzene ethylamino) propoxyl group coumarin-3-carboxy acid's ethylaminoethanol furazan；
7- [3- (1- piperidyl)] propoxyl group coumarin-3-carboxy acid's ethylaminoethanol furazan；
7- [3- (1- morpholine base)] propoxyl group coumarin-3-carboxy acid's ethylaminoethanol furazan；
7- [3- (1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's ethylaminoethanol furazan；
7- [3- (4- methyl-1-piperazinyl)] propoxyl group coumarin-3-carboxy acid's ethylaminoethanol furazan；
7- [3- (4- ethyl -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's ethylaminoethanol furazan；
7- [3- (4- ethoxy -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's ethylaminoethanol furazan；
7- (3- amino) propoxyl group coumarin-3-carboxy acid's aminopropanol furazan；
7- (3- dimethylamino) propoxyl group coumarin-3-carboxy acid's aminopropanol furazan；
7- (3- lignocaine) propoxyl group coumarin-3-carboxy acid's aminopropanol furazan；
7- (3- phenylamino) propoxyl group coumarin-3-carboxy acid's aminopropanol furazan；
7- (3- benzyl amino) propoxyl group coumarin-3-carboxy acid's aminopropanol furazan；
7- (3- benzene ethylamino) propoxyl group coumarin-3-carboxy acid's aminopropanol furazan；
7- [3- (1- piperidyl)] propoxyl group coumarin-3-carboxy acid's aminopropanol furazan；
7- [3- (1- morpholine base)] propoxyl group coumarin-3-carboxy acid's aminopropanol furazan；
7- [3- (1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's aminopropanol furazan；
7- [3- (4- methyl-1-piperazinyl)] propoxyl group coumarin-3-carboxy acid's aminopropanol furazan；
7- [3- (4- ethyl -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's aminopropanol furazan；
7- [3- (4- ethoxy -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's aminopropanol furazan；
7- (3- amino) propoxyl group coumarin-3-carboxy acid's isopropanolamine furazan；
7- (3- dimethylamino) propoxyl group coumarin-3-carboxy acid's isopropanolamine furazan；
7- (3- lignocaine) propoxyl group coumarin-3-carboxy acid's isopropanolamine furazan；
7- (3- phenylamino) propoxyl group coumarin-3-carboxy acid's isopropanolamine furazan；
7- (3- benzyl amino) propoxyl group coumarin-3-carboxy acid's isopropanolamine furazan；
7- (3- benzene ethylamino) propoxyl group coumarin-3-carboxy acid's isopropanolamine furazan；
7- [3- (1- piperidyl)] propoxyl group coumarin-3-carboxy acid's isopropanolamine furazan；
7- [3- (1- morpholine base)] propoxyl group coumarin-3-carboxy acid's isopropanolamine furazan；
7- [3- (1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's isopropanolamine furazan；
7- [3- (4- methyl-1-piperazinyl)] propoxyl group coumarin-3-carboxy acid's isopropanolamine furazan；
7- [3- (4- ethyl -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's isopropanolamine furazan；
7- [3- (4- ethoxy -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's isopropanolamine furazan；
7- (4- amino) butoxy coumarin-3-carboxy acid's 1,2- ethylene glycol furazan；
7- (4- dimethylamino) butoxy coumarin-3-carboxy acid's 1,2- ethylene glycol furazan；
7- (4- lignocaine) butoxy coumarin-3-carboxy acid's 1,2- ethylene glycol furazan；
7- (4- phenylamino)] butoxy coumarin-3-carboxy acid's 1,2- ethylene glycol furazan；
7- (4- benzyl amino)] butoxy coumarin-3-carboxy acid's 1,2- ethylene glycol furazan；
7- (4- benzene ethylamino)] butoxy coumarin-3-carboxy acid's 1,2- ethylene glycol furazan；
7- [4- (1- piperidyl)] butoxy coumarin-3-carboxy acid's 1,2- ethylene glycol furazan；
7- [4- (1- morpholine base)] butoxy coumarin-3-carboxy acid's 1,2- ethylene glycol furazan；
7- [4- (1- piperazinyl)] butoxy coumarin-3-carboxy acid's 1,2- ethylene glycol furazan；
7- [4- (4- methyl-1-piperazinyl)] butoxy coumarin-3-carboxy acid's 1,2- ethylene glycol furazan；
7- [4- (4- ethyl -1- piperazinyl)] butoxy coumarin-3-carboxy acid's 1,2- ethylene glycol furazan；
7- [4- (4- ethoxy -1- piperazinyl)] butoxy coumarin-3-carboxy acid's 1,2- ethylene glycol furazan；
7- (4- amino) butoxy coumarin-3-carboxy acid's 1,2- propylene glycol furazan；
7- (4- dimethylamino) butoxy coumarin-3-carboxy acid's 1,2- propylene glycol furazan；
7- (4- lignocaine) butoxy coumarin-3-carboxy acid's 1,2- propylene glycol furazan；
7- (4- phenylamino)] butoxy coumarin-3-carboxy acid's 1,2- propylene glycol furazan；
7- (4- benzyl amino)] butoxy coumarin-3-carboxy acid's 1,2- propylene glycol furazan；
7- (4- benzene ethylamino)] butoxy coumarin-3-carboxy acid's 1,2- propylene glycol furazan；
7- [4- (1- piperidyl)] butoxy coumarin-3-carboxy acid's 1,2- propylene glycol furazan；
7- [4- (1- morpholine base)] butoxy coumarin-3-carboxy acid's 1,2- propylene glycol furazan；
7- [4- (1- piperazinyl)] butoxy coumarin-3-carboxy acid's 1,2- propylene glycol furazan；
7- [4- (4- methyl-1-piperazinyl)] butoxy coumarin-3-carboxy acid's 1,2- propylene glycol furazan；
7- [4- (4- ethyl -1- piperazinyl)] butoxy coumarin-3-carboxy acid's 1,2- propylene glycol furazan；
7- [4- (4- ethoxy -1- piperazinyl)] butoxy coumarin-3-carboxy acid's 1,2- propylene glycol furazan；
7- (4- amino) butoxy coumarin-3-carboxy acid's 1,3- propylene glycol furazan；
7- (4- dimethylamino) butoxy coumarin-3-carboxy acid's 1,3- propylene glycol furazan；
7- (4- lignocaine) butoxy coumarin-3-carboxy acid's 1,3- propylene glycol furazan；
7- (4- phenylamino)] butoxy coumarin-3-carboxy acid's 1,3- propylene glycol furazan；
7- (4- benzyl amino)] butoxy coumarin-3-carboxy acid's 1,3- propylene glycol furazan；
7- (4- benzene ethylamino)] butoxy coumarin-3-carboxy acid's 1,3- propylene glycol furazan；
7- [4- (1- piperidyl)] butoxy coumarin-3-carboxy acid's 1,3- propylene glycol furazan；
7- [4- (1- morpholine base)] butoxy coumarin-3-carboxy acid's 1,3- propylene glycol furazan；
7- [4- (1- piperazinyl)] butoxy coumarin-3-carboxy acid's 1,3- propylene glycol furazan；
7- [4- (4- methyl-1-piperazinyl)] butoxy coumarin-3-carboxy acid's 1,3- propylene glycol furazan；
7- [4- (4- ethyl -1- piperazinyl)] butoxy coumarin-3-carboxy acid's 1,3- propylene glycol furazan；
7- [4- (4- ethoxy -1- piperazinyl)] butoxy coumarin-3-carboxy acid's 1,3- propylene glycol furazan；
7- (4- amino) butoxy coumarin-3-carboxy acid's 1,3 butylene glycol furazan；
7- (4- dimethylamino) butoxy coumarin-3-carboxy acid's 1,3 butylene glycol furazan；
7- (4- lignocaine) butoxy coumarin-3-carboxy acid's 1,3 butylene glycol furazan；
7- (4- phenylamino)] butoxy coumarin-3-carboxy acid's 1,3 butylene glycol furazan；
7- (4- benzyl amino)] butoxy coumarin-3-carboxy acid's 1,3 butylene glycol furazan；
7- (4- benzene ethylamino)] butoxy coumarin-3-carboxy acid's 1,3 butylene glycol furazan；
7- [4- (1- piperidyl)] butoxy coumarin-3-carboxy acid's 1,3 butylene glycol furazan；
7- [4- (1- morpholine base)] butoxy coumarin-3-carboxy acid's 1,3 butylene glycol furazan；
7- [4- (1- piperazinyl)] butoxy coumarin-3-carboxy acid's 1,3 butylene glycol furazan；
7- [4- (4- methyl-1-piperazinyl)] butoxy coumarin-3-carboxy acid's 1,3 butylene glycol furazan；
7- [4- (4- ethyl -1- piperazinyl)] butoxy coumarin-3-carboxy acid's 1,3 butylene glycol furazan；
7- [4- (4- ethoxy -1- piperazinyl)] butoxy coumarin-3-carboxy acid's 1,3 butylene glycol furazan；
7- (4- amino) butoxy coumarin-3-carboxy acid's 1,4- butanediol furazan；
7- (4- dimethylamino) butoxy coumarin-3-carboxy acid's 1,4- butanediol furazan；
7- (4- lignocaine) butoxy coumarin-3-carboxy acid's 1,4- butanediol furazan；
7- (4- phenylamino)] butoxy coumarin-3-carboxy acid's 1,4- butanediol furazan；
7- (4- benzyl amino)] butoxy coumarin-3-carboxy acid's 1,4- butanediol furazan；
7- (4- benzene ethylamino)] butoxy coumarin-3-carboxy acid's 1,4- butanediol furazan；
7- [4- (1- piperidyl)] butoxy coumarin-3-carboxy acid's 1,4- butanediol furazan；
7- [4- (1- morpholine base)] butoxy coumarin-3-carboxy acid's 1,4- butanediol furazan；
7- [4- (1- piperazinyl)] butoxy coumarin-3-carboxy acid's 1,4- butanediol furazan；
7- [4- (4- methyl-1-piperazinyl)] butoxy coumarin-3-carboxy acid's 1,4- butanediol furazan；
7- [4- (4- ethyl -1- piperazinyl)] butoxy coumarin-3-carboxy acid's 1,4- butanediol furazan；
7- [4- (4- ethoxy -1- piperazinyl)] butoxy coumarin-3-carboxy acid's 1,4- butanediol furazan；
7- (4- amino) butoxy coumarin-3-carboxy acid's diethylene glycol furazan；
7- (4- dimethylamino) butoxy coumarin-3-carboxy acid's diethylene glycol furazan；
7- (4- lignocaine) butoxy coumarin-3-carboxy acid's diethylene glycol furazan；
7- (4- phenylamino)] butoxy coumarin-3-carboxy acid's diethylene glycol furazan；
7- (4- benzyl amino)] butoxy coumarin-3-carboxy acid's diethylene glycol furazan；
7- (4- benzene ethylamino)] butoxy coumarin-3-carboxy acid's diethylene glycol furazan；
7- [4- (1- piperidyl)] butoxy coumarin-3-carboxy acid's diethylene glycol furazan；
7- [4- (1- morpholine base)] butoxy coumarin-3-carboxy acid's diethylene glycol furazan；
7- [4- (1- piperazinyl)] butoxy coumarin-3-carboxy acid's diethylene glycol furazan；
7- [4- (4- methyl-1-piperazinyl)] butoxy coumarin-3-carboxy acid's diethylene glycol furazan；
7- [4- (4- ethyl -1- piperazinyl)] butoxy coumarin-3-carboxy acid's diethylene glycol furazan；
7- [4- (4- ethoxy -1- piperazinyl)] butoxy coumarin-3-carboxy acid's diethylene glycol furazan；
7- (4- amino) butoxy coumarin-3-carboxy acid's 1,4- butynediols furazan；
7- (4- dimethylamino) butoxy coumarin-3-carboxy acid's 1,4- butynediols furazan；
7- (4- lignocaine) butoxy coumarin-3-carboxy acid's 1,4- butynediols furazan；
7- (4- phenylamino)] butoxy coumarin-3-carboxy acid's 1,4- butynediols furazan；
7- (4- benzyl amino)] butoxy coumarin-3-carboxy acid's 1,4- butynediols furazan；
7- (4- benzene ethylamino)] butoxy coumarin-3-carboxy acid's 1,4- butynediols furazan；
7- [4- (1- piperidyl)] butoxy coumarin-3-carboxy acid's 1,4- butynediols furazan；
7- [4- (1- morpholine base)] butoxy coumarin-3-carboxy acid's 1,4- butynediols furazan；
7- [4- (1- piperazinyl)] butoxy coumarin-3-carboxy acid's 1,4- butynediols furazan；
7- [4- (4- methyl-1-piperazinyl)] butoxy coumarin-3-carboxy acid's 1,4- butynediols furazan；
7- [4- (4- ethyl -1- piperazinyl)] butoxy coumarin-3-carboxy acid's 1,4- butynediols furazan；
7- [4- (4- ethoxy -1- piperazinyl)] butoxy coumarin-3-carboxy acid's 1,4- butynediols furazan；
7- (4- amino) butoxy coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan；
7- (4- dimethylamino) butoxy coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan；
7- (4- lignocaine) butoxy coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan；
7- (4- phenylamino)] butoxy coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan；
7- (4- benzyl amino)] butoxy coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan；
7- (4- benzene ethylamino)] butoxy coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan；
7- [4- (1- piperidyl)] butoxy coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan；
7- [4- (1- morpholine base)] butoxy coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan；
7- [4- (1- piperazinyl)] butoxy coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan；
7- [4- (4- methyl-1-piperazinyl)] butoxy coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan；
7- [4- (4- ethyl -1- piperazinyl)] butoxy coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan；
7- [4- (4- ethoxy -1- piperazinyl)] butoxy coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan；
7- (4- amino) butoxy coumarin-3-carboxy acid's ethylaminoethanol furazan；
7- (4- dimethylamino) butoxy coumarin-3-carboxy acid's ethylaminoethanol furazan；
7- (4- lignocaine) butoxy coumarin-3-carboxy acid's ethylaminoethanol furazan；
7- (4- phenylamino)] butoxy coumarin-3-carboxy acid's ethylaminoethanol furazan；
7- (4- benzyl amino)] butoxy coumarin-3-carboxy acid's ethylaminoethanol furazan；
7- (4- benzene ethylamino)] butoxy coumarin-3-carboxy acid's ethylaminoethanol furazan；
7- [4- (1- piperidyl)] butoxy coumarin-3-carboxy acid's ethylaminoethanol furazan；
7- [4- (1- morpholine base)] butoxy coumarin-3-carboxy acid's ethylaminoethanol furazan；
7- [4- (1- piperazinyl)] butoxy coumarin-3-carboxy acid's ethylaminoethanol furazan；
7- [4- (4- methyl-1-piperazinyl)] butoxy coumarin-3-carboxy acid's ethylaminoethanol furazan；
7- [4- (4- ethyl -1- piperazinyl)] butoxy coumarin-3-carboxy acid's ethylaminoethanol furazan；
7- [4- (4- ethoxy -1- piperazinyl)] butoxy coumarin-3-carboxy acid's ethylaminoethanol furazan；
7- (4- amino) butoxy coumarin-3-carboxy acid's aminopropanol furazan；
7- (4- dimethylamino) butoxy coumarin-3-carboxy acid's aminopropanol furazan；
7- (4- lignocaine) butoxy coumarin-3-carboxy acid's aminopropanol furazan；
7- (4- phenylamino)] butoxy coumarin-3-carboxy acid's aminopropanol furazan；
7- (4- benzyl amino)] butoxy coumarin-3-carboxy acid's aminopropanol furazan；
7- (4- benzene ethylamino)] butoxy coumarin-3-carboxy acid's aminopropanol furazan；
7- [4- (1- piperidyl)] butoxy coumarin-3-carboxy acid's aminopropanol furazan；
7- [4- (1- morpholine base)] butoxy coumarin-3-carboxy acid's aminopropanol furazan；
7- [4- (1- piperazinyl)] butoxy coumarin-3-carboxy acid's aminopropanol furazan；
7- [4- (4- methyl-1-piperazinyl)] butoxy coumarin-3-carboxy acid's aminopropanol furazan；
7- [4- (4- ethyl -1- piperazinyl)] butoxy coumarin-3-carboxy acid's aminopropanol furazan；
7- [4- (4- ethoxy -1- piperazinyl)] butoxy coumarin-3-carboxy acid's aminopropanol furazan；
7- (4- amino) butoxy coumarin-3-carboxy acid's isopropanolamine furazan；
7- (4- dimethylamino) butoxy coumarin-3-carboxy acid's isopropanolamine furazan；
7- (4- lignocaine) butoxy coumarin-3-carboxy acid's isopropanolamine furazan；
7- (4- phenylamino)] butoxy coumarin-3-carboxy acid's isopropanolamine furazan；
7- (4- benzyl amino)] butoxy coumarin-3-carboxy acid's aminopropanol furazan；
7- (4- benzene ethylamino)] butoxy coumarin-3-carboxy acid's isopropanolamine furazan；
7- [4- (1- piperidyl)] butoxy coumarin-3-carboxy acid's isopropanolamine furazan；
7- [4- (1- morpholine base)] butoxy coumarin-3-carboxy acid's isopropanolamine furazan；
7- [4- (1- piperazinyl)] butoxy coumarin-3-carboxy acid's isopropanolamine furazan；
7- [4- ((4- methyl) -1- piperazinyl)] butoxy coumarin-3-carboxy acid's isopropanolamine furazan；
7- [4- (4- ethyl -1- piperazinyl)] butoxy coumarin-3-carboxy acid's isopropanolamine furazan；
7- [4- (4- ethoxy -1- piperazinyl)] butoxy coumarin-3-carboxy acid's isopropanolamine furazan；
In particular, general formula I, NO donator type coumarin derivative shown in II are further preferably from following compounds:
Coumarin-3-carboxy acid's -1,3- propylene glycol furazan (I1) (compound number: I1, similarly hereinafter)；
Coumarin-3-carboxy acid's -1,4- butanediol furazan (I2)；
Coumarin-3-carboxy acid's diethylene glycol furazan (I3)；
Coumarin-3-carboxy acid's -1,4- butynediols furazan (I4)；
Coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan (I5)；
Cumarin -3- carboxylic ethylaminoethanol furazan (I6)；
Coumarin-3-carboxy acid's aminopropanol furazan (I7)；
7- (3- lignocaine) propoxyl group coumarin-3-carboxy acid's 1,3- propylene glycol furazan (II1)；
7- (3- benzyl amino) propoxyl group coumarin-3-carboxy acid's 1,3- propylene glycol furazan (II2)；
7- [3- (1- morpholine base)] propoxyl group coumarin-3-carboxy acid's 1,3- propylene glycol furazan (II3)；
7- [3- (4- methyl-1-piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,3- propylene glycol furazan (II4)；
7- [3- (4- ethyl -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,3- propylene glycol furazan (II5)；
7- [3- (4- ethoxy -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,3- propylene glycol furazan (II6)；
7- (3- lignocaine) propoxyl group coumarin-3-carboxy acid's 1,4- butanediol furazan (II7)；
7- (3- benzyl amino) propoxyl group coumarin-3-carboxy acid's 1,4- butanediol furazan (II8)；
7- [3- (1- piperidyl)] propoxyl group coumarin-3-carboxy acid's 1,4- butanediol furazan (II9)；
7- [3- (1- morpholine base)] propoxyl group coumarin-3-carboxy acid's 1,4- butanediol furazan (II10)；
7- [3- (4- ethyl -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,4- butanediol furazan (II11)；
7- [3- (4- ethoxy -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,4- butanediol furazan (II12)；
7- (3- lignocaine) propoxyl group coumarin-3-carboxy acid's diethylene glycol furazan (II13)；
7- (3- benzyl amino) propoxyl group coumarin-3-carboxy acid's diethylene glycol furazan (II14)；
7- [3- (1- piperidyl)] propoxyl group coumarin-3-carboxy acid's diethylene glycol furazan (II15)；
7- [3- (1- morpholine base)] propoxyl group coumarin-3-carboxy acid's diethylene glycol furazan (II16)；
7- [3- (4- ethyl -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's diethylene glycol furazan (II17)；
7- [3- (4- ethoxy -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's diethylene glycol furazan (II18)；
7- (3- lignocaine) propoxyl group coumarin-3-carboxy acid's 1,4- butynediols furazan (II19)；
7- (3- benzyl amino) propoxyl group coumarin-3-carboxy acid's 1,4- butynediols furazan (II20)；
7- [3- (1- piperidyl)] propoxyl group coumarin-3-carboxy acid's 1,4- butynediols furazan (II21)；
7- [3- (1- morpholine base)] propoxyl group coumarin-3-carboxy acid's 1,4- butynediols furazan (II22)；
7- [3- (4- ethyl -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,4- butynediols furazan (II23)；
7- [3- (4- ethoxy -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's 1,4- butynediols furazan (II24)；
7- [3- (1- morpholine base)] propoxyl group coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan (II25)；
7- [3- (4- ethyl -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan (II26)；
7- [3- (4- ethoxy -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan (II27)；
7- (3- lignocaine) propoxyl group coumarin-3-carboxy acid's ethylaminoethanol furazan (II28)；
7- (3- benzene ethylamino) propoxyl group coumarin-3-carboxy acid's ethylaminoethanol furazan (II29)；
7- [3- (1- morpholine base)] propoxyl group coumarin-3-carboxy acid's ethylaminoethanol furazan (II30)；
7- [3- (4- ethyl -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's ethylaminoethanol furazan (II31)；
7- [3- (4- ethoxy -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's ethylaminoethanol furazan (II32)；
7- [3- (1- morpholine base)] propoxyl group coumarin-3-carboxy acid's aminopropanol furazan (II33)；
7- [3- (1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's aminopropanol furazan (II34)；
7- [3- (4- ethyl -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's aminopropanol furazan (II35)；
7- [3- (4- ethoxy -1- piperazinyl)] propoxyl group coumarin-3-carboxy acid's aminopropanol furazan (II36)；
7- [4- (1- morpholine base)] butoxy coumarin-3-carboxy acid's 1,3- propylene glycol furazan (II37)；
7- [4- (4- ethyl -1- piperazinyl)] butoxy coumarin-3-carboxy acid's 1,3- propylene glycol furazan (II38)；
7- [4- (1- morpholine base)] butoxy coumarin-3-carboxy acid's 1,4- butanediol furazan (II39)；
7- [4- ((4- ethyl) -1- piperazinyl)] butoxy coumarin-3-carboxy acid's 1,4- butanediol furazan (II40)；
7- [4- (1- morpholine base)] butoxy coumarin-3-carboxy acid's diethylene glycol furazan (II41)；
7- [4- (4- ethyl -1- piperazinyl)] butoxy coumarin-3-carboxy acid's diethylene glycol furazan (II42)；
7- [4- (1- morpholine base)] butoxy coumarin-3-carboxy acid's 1,4- butynediols furazan (II43)；
7- [4- ((4- ethyl) -1- piperazinyl)] butoxy coumarin-3-carboxy acid's 1,4- butynediols furazan (II44)；
7- [4- (1- morpholine base)] butoxy coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan (II45)；
7- [4- (4- ethyl -1- piperazinyl)] butoxy coumarin-3-carboxy acid's p-hydroxyphenylethanol furazan (II46)；
7- [4- (1- morpholine base)] butoxy coumarin-3-carboxy acid's ethylaminoethanol furazan (II47)；
7- [4- (4- ethyl -1- piperazinyl)] butoxy coumarin-3-carboxy acid's ethylaminoethanol furazan (II48)；
Preferred compound of the present invention and its intact part of the invention is constituted with the adduct of pharmaceutically acceptable acid；Pharmaceutically acceptable There are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, maleic acid, lemon in acid Acid, ascorbic acid, methanesulfonic acid etc..
Another object of the present invention is to provide the preparation methods of general formula I of the present invention, II compound.
NO donator type coumarin derivative shown in general formula I is prepared in the following manner:
With salicylide (1) for raw material, react to obtain ethyl coumarin-3-carboxylate (2) through Knoevenagel, then hydrolyzed, It is acidified to obtain coumarin-3-carboxy acid (3), coumarin-3-carboxy acid and SOCl2Corresponding acyl chlorides (4) are made in reaction, are catalyzed in triethylamine Under, it is reacted with as benzenethiol for corresponding hydroxyalkyl made from raw material or aminoalkyl furazan (5), obtains object (I)；Synthesize road Line is as follows:
Wherein, X, R are defined as described above.
NO donator type coumarin derivative shown in general formula II is prepared in the following manner:
With Resorcino (1) for raw material, 2,4- 4-dihydroxy benzaldehyde (2) is reacted to obtain through Vilsmeier-Haack, is passed through Knoevenagel reacts to obtain umbelliferone -3- carboxylic acid, ethyl ester (3), compound (3) and dibromo alkane reaction, obtains Mesosome (4).Compound (4) again with corresponding aminated compounds (HR1) reaction obtain compound (6), compound (6) through hydrolysis, Acidification obtain compound (7), EDCI effect under, with as benzenethiol be raw material made from corresponding hydroxyalkyl or aminoalkyl furazan (5) it reacts, is converted into object (II)；Synthetic route is as follows:
Compound 5 are as follows:Wherein, X, R, R1It is defined as described above with n.
These intermediates or target compound can be purified according to conventional isolation techniques, and as needed by its turn It turns to pharmaceutically acceptable acid into salt.
The further object of the present invention is to provide general formula I of the present invention, II compound answering in preparation tumor With the especially application in treatment liver cancer, breast cancer, cervical carcinoma, lung cancer and colon cancer drug.
Here is the pharmacological testing and result of part of compounds of the present invention:
Anticancer Activity in vitro test
Using tetramethyl nitrogen azoles indigo plant colorimetric method (MTT) evaluation the compound of the present invention to the antiproliferative of 7 kinds of man―machine systems Activity.Mtt assay is widely used in large-scale screening anti-tumor medicine, cell toxicity test and the measurement of tumour radiotherapy sensitivity Deng.
Cell strain: human liver cancer cell HepG-2, human cervical carcinoma cell HeLa, human colon cancer cell HCT116 and SW620, people Breast cancer cell MCF-7 and human lung cancer A549.
Experimental method: compound is dissolved with DMSO, is diluted to required concentration with PBS.It takes in exponential phase of growth, growth One bottle of cell in good condition is added 0.25% trypsin digestion, attached cell is made to fall off, and is made every milliliter containing 2 × 104-4 ×104The suspension of a cell.Take cell suspension inoculation on 96 orifice plates, every 180 μ L of hole sets constant temperature CO2Culture 24 is small in incubator When.Liquid is changed, is added by test solution, every 20 μ L of hole, cultivates 48 hours.Tetramethyl nitrogen azoles indigo plant is added in 96 orifice plates, every 20 μ L of hole, training It supports and is reacted 4 hours in case.It sucks supernatant, is added DMSO, every 150 μ L of hole shakes 5 minutes on plate shaker.Use enzyme linked immunological Detector calculates cell inhibitory rate in the trap that wavelength is the every hole of measurement at 490nm.
Pass through probit using SPSS (Staffstical Package for the Social Science) 17.0 Weighted regression method (Bliss method) calculates IC50.Part of test results is as shown in table 1.
Inhibitory activity (inhibiting rate when 10 μm ol/L, %) of 1 the compound of the present invention of table to tumor cell proliferation
Pharmacology data shows that NO donator type coumarin derivative of the present invention can inhibit tumour to some extent The proliferation of cell, and most compounds have very strong inhibition tumor cell proliferation effect.
Specific embodiment:
The contents of the present invention are illustrated below by embodiment.In the present invention, example described below is in order to more The good elaboration present invention, is not for limiting the scope of the invention.
Embodiment 1
The synthesis of coumarin-3-carboxy acid (3)
In dry 100mL round-bottomed flask, 4.2mL (0.04mol) salicylide, 8.5mL (0.056mol) the third two is added Diethyl phthalate, 25mL dehydrated alcohol, 2 drop glacial acetic acid and 0.5mL hexahydropyridine, are heated to reflux 2h.Reactant is poured into after cooling In water, crystallized in ice water.Crude product Coumarin-3-carboxylic Acid Ethyl Ester is filtered to obtain, white crystal 7.5g, yield are recrystallized to obtain 85.4%, m.p.92.0-93.0 DEG C.
In 100mL round-bottomed flask, (8g solid NaOH is dissolved in 50mL water for ethyl alcohol and NaOH solution that 25mL 95% is added In), 6g (0.028mol) Coumarin-3-carboxylic Acid Ethyl Ester is heated to reflux 15min.Reaction mixture is poured into 70mL under stiring In aqueous hydrochloric acid solution, that is, precipitate crystal.The crude product coumarin-3-carboxylic acid of suction filtration, 50% ethyl alcohol recrystallization obtain white crystal tonka-bean Element -3- carboxylic acid 5.2g, yield 95%, m.p.193.2-194.7 DEG C.
Cumarin -3- formyl chloride (4)
Coumarin-3-carboxy acid (4g, 21.0mmol) is dissolved in 15mL thionyl chloride, 4 drop pyridines are added dropwise, 70 DEG C of reflux are stirred After mixing 6h, decompression boils off excessive thionyl chloride, obtains light yellow solid 1.8g.Crude product obtains white solid after petroleum ether recrystallizes Body 3.25g, yield 82%, m.p.143.6~145.3 DEG C.
The synthesis of 1,4- butynediols furazan (5)
By benzenethiol (12.1g, 0.11mol), sodium hydroxide (4.4g, 0.11mol) is dissolved in 50mL95% ethyl alcohol, is added The 100mL aqueous solution being made by monoxone (11.4g, 0.12mol) and sodium carbonate (6.35g, 0.06mol), is stirred at room temperature 3h, returns Flow 1 h.6mol/L hydrochloric acid tune pH=2 is added after being cooled to room temperature, decompression boils off ethyl alcohol, there is white precipitate generation, filters, obtains 16.4 g white rhabdolith 2- thiophenyl acetic acid, yield 89%, mp:60.1~62.0 DEG C.
2- thiophenyl acetic acid (16.0g, 0.1mol) is dissolved in 65mL glacial acetic acid, be added 30% hydrogen peroxide (20mL, 0.2 mol), 2.5h is stirred at room temperature, obtains colorless cleared solution, the fuming nitric aicd (40mL, 0.9mol) for being added dropwise 95% is warming up to 90 DEG C reaction 30min, is cooled to room temperature, there is a white needle-like crystals 3,4- dibenzenesulfonyl -1,2, the analysis of 5- oxadiazoles -2- oxide Out, filtration drying obtains 14g, two step yields 76%, mp:154.2~156.0 DEG C.
Furazan (1g, 2.7mmol), Isosorbide-5-Nitrae-butynediols (0.86g, 10.0mmol) are dissolved in 10ml tetrahydrofuran, ice It is slowly added dropwise under bath 25% sodium hydrate aqueous solution (0.5mL, 3.0mmol), ice bath stirring, TLC tracking.TLC after about 30mim Substantially completely, 100mL water is added, ethyl acetate extracts (4*30mL), organic to be harmonious in (EA:PE=1:2, V:V) display reaction It is washed 1 time after and with saturated sodium chloride solution, the dry 2h of anhydrous sodium sulfate.Concentration, column chromatography (mobile phase DCM:PE=2:1, V:V), it is concentrated, obtains white solid 0.54g, yield 69%, m.p.116.1~118.0 DEG C.
Coumarin-3-carboxy acid's -1,4- butynediols furazan (I4) synthesis
1,4- butynediols furazan (310mg, 1.0mmol), triethylamine (0.83mL, 6.0mmol) are dissolved in 20mL DCM In, the dichloromethane solution of cumarin -3- formyl chloride (312mg, 1.5mmol) is slowly added dropwise in ice salt bath, drop, which finishes, goes to room Temperature stirring, TLC track reaction process.TLC (EA:PE=1:2, V:V) display reaction substantially completely, adds water 100mL after about 2h, DCM extracts (3*20mL), and organic phase is extracted 1 time after merging with saturated sodium chloride solution, and the dry 2h of anhydrous sodium sulfate is concentrated into It is dry.Column chromatographs (mobile phase EA:PE=1:4, V:V), and decompression boils off mobile phase, obtains white solid 380mg, yield 79%, M.p. 135.1~138.1 DEG C；ES-MS(m/z):505.1[M+Na]+；IR(KBr,cm-1):2914.23,1762.89, 1609.79, 1556.82；1H NMR(400MHz,CDCl3) δ: 8.64 (s, 1H), 8.10 (s, 2H), 7.79 (s, 1H), 7.68 (s,4H), 7.40(s,2H),5.16(s,2H),5.04(s,2H)；
Embodiment 2
Referring to the method for embodiment 1, cumarin -3- formyl chloride and 3,4- dibenzenesulfonyl -1,2,5- oxadiazoles -2- are prepared Oxide.
The preparation of ethylaminoethanol furazan (5)
NaH (142mg, 5.9mmol), ethylaminoethanol (0.2ml, 3.33mmol) are added in 50ml round-bottomed flask, be protected from light, Ice salt bath agitation and dropping has been dissolved in the furazan of THF, i.e. 3,4- dibenzenesulfonyl -1,2,5- oxadiazoles -2- oxide (0.5g, 1.37mmol), ice bath reaction is kept.TLC is detected to fully reacting.Water is added into reaction solution, after EtOAc extraction, organic layer It is washed with saturation NaCl, it is more single that TLC detects organic layer point.Anhydrous Na2SO4It after drying, is concentrated to dryness, weigh 239mg.It receives Rate 62%.
Coumarin-3-carboxy acid-ethanol amine furazan (I6) synthesis
Ethanol amine furazan (285mg, 1.0mmol), triethylamine (0.83ml, 6.0mmol) are dissolved in 20mL DCM, in ice Be slowly added dropwise the DCM solution of cumarin -3- formyl chloride (312mg, 1.2mmol) in salt bath, drop, which finishes to go to, to be stirred at room temperature, TLC with Track reaction process.TLC (MeOH:DCM=1:20, V:V) display reaction substantially completely, adds water 100mL, DCM extraction after about 2h (3*20mL), organic phase are extracted 1 time after merging with saturated sodium chloride solution, and the dry 2h of anhydrous sodium sulfate is concentrated to dryness.Column layer Analysis, mobile phase MeOH:DCM=1:30, decompression boil off mobile phase, obtain light yellow solid 320mg, yield 68%, M.p.142.3~145.7 DEG C.ES-MS(m/z):498.3[M+Na]+；IR(KBr,cm-1)3273.41,3022.18, 2924.72, 1710.34,1650.40,1632.58；1H NMR(400MHz,CDCl3)δ9.05(s,1H),9.00(s,1H), 8.07 (d, J=6.0Hz, 2H), 7.74-7.63 (m, 5H), 7.42 (d, J=7.0Hz, 2H), 4.55 (s, 2H), 3.70 (s, 2H).
Embodiment 3
1,4- butynediols furazan is synthesized referring to embodiment 1.
The synthesis of 2,4- 4-dihydroxy benzaldehyde
DMF (19mL, 210mmol) and acetonitrile (100mL) are added in 500mL three-necked flask, is sufficiently stirred at room temperature.In Phosphorus oxychloride (19mL, 250mmol) is slowly added dropwise under condition of ice bath, 1h is added dropwise, then 1h is stirred at room temperature.By 1,3- Benzenediol (21g, 190mmol) is dissolved in acetonitrile, then is slowly dropped in reaction solution, is had white precipitate generation, is added dropwise Solution stirs 4h under ice bath afterwards, stirs 2h at room temperature.It filters, with ice acetone washing filter cake, obtained solid vacuum in 50 DEG C It dries to weight.Solid is transferred in 500mL round-bottomed flask, 400mL water, 50 DEG C of heating stirring 30min, then room temperature is added and stirs 2h is mixed, has pink needle-like solid to be precipitated.Crude product decolourizes through sodium thiosulfate, and white needle-like crystals are obtained after 50% ethyl alcohol recrystallization 18.5g, yield 70.2%, m.p.134.2~135.8 DEG C.
The synthesis of umbelliferone -3- Ethyl formate
2,4- 4-dihydroxy benzaldehyde (10g, 72.5mmol) and 30mL dehydrated alcohol are added in 250mL round-bottomed flask, stirs It mixes and is allowed to sufficiently dissolve.Be added diethyl malonate (17.2mL, 101.9mmol), hexahydropyridine (0.57mL, 5.76mmol), Glacial acetic acid (0.16mL, 2.88mmol), 90 DEG C of heating stirrings, TLC track reaction process.TLC (EA:PE=1:2) is aobvious after about 15h Show reaction substantially completely.Reaction solution is down to room temperature, 200mL ice water is added, is stood overnight at -20 DEG C.It filters, it is solid to obtain yellow Body 12.4g, yield 73%.95% ethyl alcohol recrystallization of crude product, obtains pale yellow needles solid 10.8g, yield 64%, m.p. 191.7~192.5 DEG C.
The synthesis of 7- (3- bromine propoxyl group) Coumarin-3-carboxylic Acid Ethyl Ester
Umbelliferone -3- Ethyl formate (2g, 8.55mmol), Anhydrous potassium carbonate (1.77g, 12.8mmol) are dissolved in In 20mL DMF, 30min is stirred at 75 DEG C.It is added 1,3- dibromopropane (2.6mL, 25.6mmol), continues at 75 DEG C and stir Reaction, TLC track reaction process.TLC (EA:PE=1:2, V:V) display is reacted substantially completely after about 30min.It is cooled to room temperature, DCM 200mL is added, is washed with water (5*30mL), organic phase is washed 1 time with saturated sodium chloride solution, and anhydrous sodium sulfate is dry 2h.It is concentrated to dryness, column chromatographs (mobile phase EA:PE=1:4, V:V).Decompression boils off solvent, obtains white solid 2.53g, Yield 81%, m.p.152.3~152.9 DEG C
The synthesis of 7- [(- 1 base of 3- morpholine) propoxyl group] coumarin-3-carboxylic acid
By 7- (3- bromine propoxyl group) Coumarin-3-carboxylic Acid Ethyl Ester (354mg, 1.0mmol), Anhydrous potassium carbonate (276mg, 2.0mmol), morpholine (0.26mL, 3.0mmol) is dissolved in 10mL DMF, 85 DEG C of return stirrings, and TLC tracks reaction process.About 1h TLC (MeOH:DCM=1:30, V:V) display reaction substantially completely, reaction mixture is poured into 100mL DCM, is washed with water afterwards It washs (4*30mL), organic phase is washed 1 time after merging with saturated sodium chloride solution, and the dry 2h of anhydrous sodium sulfate is concentrated to dryness. Column chromatographs (mobile phase EA:PE=1:1, V:V).Decompression boils off solvent, obtains light yellow solid 260mg, yield 72%.By product Hydrolyze 30min in the ethanol solution of 30%NaOH, then be acidified through 6mmol/L hydrochloric acid, evaporated under reduced pressure solvent, add acetone solution, Filtering, obtains yellow solid 210mg, crude product direct plunges into subsequent reactions without further purification.
7- [(3- morpholine -1- base) propoxyl group] coumarin-3-carboxy acid's 1,4- butynediols furazan (II22)
By 7- [(3- morpholine -1- base) propoxyl group] coumarin-3-carboxylic acid (330mg, 0.10mmol), 1,4- butynediols furan Our (460mg, 0.15mmol), DMAP (60mg, 0.05mmol), TBAB (320mg, 0.10mmol) are dissolved in 10mL DCM, in The DCM solution of EDCI (190mg, 0.10mmol) is slowly added dropwise under ice bath, drop, which finishes to go to, to be stirred at room temperature, and TLC tracks reaction process. TLC (EA:PE=1:1, V:V) display is reacted substantially completely after 24 hours.Stop stirring, reaction solution be poured into 100ml water, DCM extracts (3*20mL), and organic phase is washed 1 time after merging with saturated sodium chloride solution, is concentrated under reduced pressure.(mobile phase is column chromatography EA:PE=1:1, V:V), decompression boils off solvent, obtains yellow solid 385mg, yield 62%.ES-MS(m/z): 626.6[M+H]+； IR(KBr,cm-1):3512.33,2936.21,1760.60,1629.26,1555.59；1H NMR(400MHz, CDCl3)δ 8.61 (d, J=21.3Hz, 1H), 8.09 (d, J=2.5Hz, 2H), 7.78 (d, J=2.7Hz, 1H), 7.66 (s, 2H), 7.55 (s, 1H), 6.91 (d, J=4.4Hz, 1H), 6.81 (s, 1H), 5.14 (s, 2H), 5.00 (s, 2H), 4.08 (s, 2H), 3.74 (s, 4H),2.48(s,4H),2.40(s,2H),1.87(s,2H),1.59(s,2H),1.53(s,2H).
Embodiment 4
Isosorbide-5-Nitrae-butynediols furazan is synthesized referring to embodiment 1, synthesizes umbelliferone -3- formic acid second referring to embodiment 3 Ester.
The synthesis of 7- (4- bromine butoxy) Coumarin-3-carboxylic Acid Ethyl Ester
Umbelliferone -3- Ethyl formate (2g, 8.55mmol), Anhydrous potassium carbonate (1.77g, 12.8mmol) are dissolved in In 20mL DMF, 30min is stirred at 75 DEG C.It is added Isosorbide-5-Nitrae-dibromobutane (3.06mL, 25.6mmol), continues at 75 DEG C and stir Reaction, TLC track reaction process.TLC (EA:PE=1:2, V:V) display is reacted substantially completely after about 30min.It is cooled to room temperature, DCM 200mL is added, is washed with water (5*30mL), organic phase is washed 1 time with saturated sodium chloride solution, and anhydrous sodium sulfate is dry 2h.It is concentrated to dryness, column chromatographs (mobile phase EA:PE=1:4).Decompression boils off solvent, obtains white solid 2.6g, yield 81%, m.p.140.6~141.0 DEG C.
The synthesis of 7- [4- (4- ethyl -1- piperazinyl)] butoxy coumarin-3-carboxy acid
Cumarin-C4- Bromo-intermediates (369mg, 0.1mmol), Anhydrous potassium carbonate (276mg, 2.0mmol) are dissolved in It in 10mL DMF, is added n-ethylpiperazine (0.52mL, 3.0mmol), 50 DEG C of stirrings, TLC tracks reaction process.TLC after about 1h (MeOH:DCM=1:20) substantially completely, reaction mixture is poured into 100mL water for display reaction, and DCM extracts (3*40mL), Organic phase is washed 1 time after merging with saturated sodium chloride solution, and the dry 2h of anhydrous sodium sulfate is concentrated to dryness.Column chromatography (flowing It is mutually MeOH:DCM=1:20).Decompression boils off solvent, obtains yellow oil 284mg, yield 71%.By product in 30%NaOH Ethanol solution in hydrolyze 30min, then be acidified through 6mmol/L hydrochloric acid, evaporated under reduced pressure solvent, add acetone solution, filtering, obtain yellow Solid 210mg, crude product direct plunge into subsequent reactions without further purification.
7- [4- (4- ethyl -1- piperazinyl)] butoxy coumarin-3-carboxy acid's 1,4- butynediols furazan (II44) synthesis
By 7- [4- (4- ethyl -1- piperazinyl)] butoxy coumarin-3-carboxy acid (370mg, 0.10mmol), 1,4- butine Glycol furazan (460mg, 0.15mmol), DMAP (60mg, 0.05mmol), TBAB (320mg, 0.10mmol) are dissolved in 10mL In DCM, the DCM solution of EDCI (190mg, 0.10mmol) is slowly added dropwise under ice bath, drop, which finishes to go to, to be stirred at room temperature, TLC tracking Reaction process.TLC (MeOH:DCM=1:10, V:V) display is reacted substantially completely after 24 hours.Stop stirring, reaction solution is inclined Enter in 100ml water, DCM extracts (3*20mL), and organic phase is washed 1 time after merging with saturated sodium chloride solution, is concentrated under reduced pressure.Column layer It analyses (mobile phase MeOH:DCM=1:20, V:V), decompression boils off solvent, obtains yellow solid 430mg, yield 65%.
ES-MS(m/z):667.7[M+H]+；IR(KBr,cm-1)3523.18,3064.77,1750.15,1694.57, 1620.86, 1563.35；1H NMR(400MHz,DMSO-d6)δ8.84(s,1H),7.92(s,2H),7.60(s,1H),7.48 (s,1H), 7.32(s,1H),7.06(s,2H),5.08(s,1H),4.14(s,2H),3.50(s,4H),3.18(s,3H), 3.06(s,1H),2.84(s, 2H),2.71(s,2H),1.76(s,2H),1.58(s,3H),1.31(s,2H),1.19(s, 2H),0.94(s,3H).

Claims (10)

1. NO donator type coumarin derivative shown in general formula I:
Wherein:
X representative-O- or-NH-；
R representative-(CH2) n-, wherein n=1~6 ,-CH (CH3)CH2-、-CH(CH3)(CH2)2-、-(CH2)2O(CH2)2-、-Ph (CH2)2-、-(CH2)2NH(CH2)2-、-CH2CH=CHCH2Or-CH2C≡CCH2-。
2. NO donator type coumarin derivative or its pharmaceutically acceptable salt shown in general formula II:
Wherein:
N=1~6；
X is-O- or-NH-；
R representative-(CH2) m-, wherein m=1~6 ,-CH (CH3)CH2-、-CH(CH3)(CH2)2-、-(CH2)2O(CH2)2-、-Ph (CH2)2-、-(CH2)2NH(CH2)2-、-CH2CH=CHCH2Or-CH2C≡CCH2-；
R1Represent NR1R2；
R1And R2It may be the same or different, and represent hydrogen atom, C independently of one another1-C6Alkyl, phenyl, benzyl, phenethyl or R1 And R2The nitrogen-atoms being connect with it is formed together five to seven yuan of aliphatic heterocycles or heteroaromatic, which can be arbitrarily by following phases Same or different substituent group is monosubstituted to five substitutions, and the substituent group includes: C1-C6Alkyl, C1-C6Alkoxy, hydroxyl or hydroxyl Base-(C1-C6) alkyl.
3. compound of Formula I according to claim 1, it is characterised in that:
X is-O- or-NH-；R representative-(CH2) n-, wherein n=2~6 ,-CH (CH3)CH2-、-CH(CH3)(CH2)2-、-(CH2)2O (CH2)2-、-Ph(CH2)2-、-CH2CH=CHCH2Or-CH2C≡CCH2-。
4. II compound of general formula according to claim 2 or its pharmaceutically acceptable salt, it is characterised in that:
N=2~6；X is-O- or-NH-；R representative-(CH2) m-, wherein m=2~6 ,-CH (CH3)CH2-、-CH(CH3) (CH2)2-、-(CH2)2O(CH2)2-、-Ph(CH2)2-、-CH2CH=CHCH2Or-CH2C≡CCH2-；R1Represent amino, dimethylamine Base, diethylin, dipropyl amido, di-n-butylamine base, anilino-, benzamido group, phenyl ethylamine base, pyrrole radicals, piperidyl, morpholine Base, imidazole radicals, piperazinyl, 4- methyl piperidine base, N methyl piperazine base, n-ethylpiperazine base or 4- hydroxyethyl piperazine base.
5. compound of Formula I according to claim 1, it is characterised in that:
X representative-O- or-NH-；R representative-(CH2) n-, wherein n=2~6 ,-CH (CH3)CH2-、-CH(CH3)(CH2)2-、- (CH2)2O(CH2)2-、-Ph(CH2)2Or-CH2C≡CCH2-。
6. II compound of general formula according to claim 2 or its pharmaceutically acceptable salt, it is characterised in that:
N=2~4；X representative-O- or-NH-；R representative-(CH2) m-, wherein m=2~6 ,-CH (CH3)CH2-、-CH(CH3) (CH2)2-、-(CH2)2O(CH2)2-、-Ph(CH2)2Or-CH2C≡CCH2-；R1Represent amino, dimethylamino, diethylin, benzene Amido, benzamido group, phenyl ethylamine base, piperidyl, morpholine base, piperazinyl, N methyl piperazine base, n-ethylpiperazine base or 4- hydroxyl second Base piperazinyl.
7. the preparation method of compound of Formula I described in claim 1, it is characterised in that:
With salicylide (1) for raw material, react to obtain ethyl coumarin-3-carboxylate (2) through Knoevenagel, then hydrolyzed, be acidified Obtain coumarin-3-carboxy acid (3), coumarin-3-carboxy acid and SOCl2Corresponding acyl chlorides (4) are made in reaction, under triethylamine catalysis, It is reacted with as benzenethiol for corresponding hydroxyalkyl made from raw material or aminoalkyl furazan (5), obtains object (I)；Synthetic route It is as follows:
Wherein, the definition of X, R are as described in claim 1.
8. the preparation method of II compound of general formula as claimed in claim 2, it is characterised in that:
With Resorcino (1) for raw material, 2,4- 4-dihydroxy benzaldehyde (2) is reacted to obtain through Vilsmeier-Haack, is passed through Knoevenagel reacts to obtain umbelliferone -3- carboxylic acid, ethyl ester (3), compound (3) and dibromo alkane reaction, obtains Mesosome (4)；Compound (4) again with corresponding aminated compounds HR1Reaction obtains compound (6), and compound (6) is through hydrolysis, acid Change obtain compound (7), EDCI effect under, with as benzenethiol be raw material made from corresponding hydroxyalkyl or aminoalkyl furazan (5) it reacts, is converted into object (II)；Synthetic route is as follows:
Compound 5 are as follows:Wherein, n, R1, the definition of X and R it is as claimed in claim 2.
9. a kind of pharmaceutical composition, wherein compound of Formula I or claim described in claim 1 containing therapeutically effective amount II compound of general formula or its pharmaceutically acceptable salt described in 2.
10. compound of Formula I described in claim 1 or II compound of general formula as claimed in claim 2 or its can pharmaceutically connect Purposes of the salt received in the drug of preparation treatment tumour, wherein tumor disease is liver cancer, breast cancer, cervical carcinoma, lung cancer, colon Cancer.
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