CN106831437B - Ester type compound and its preparation method and application containing nitroethenyl group - Google Patents

Ester type compound and its preparation method and application containing nitroethenyl group Download PDF

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CN106831437B
CN106831437B CN201710058237.9A CN201710058237A CN106831437B CN 106831437 B CN106831437 B CN 106831437B CN 201710058237 A CN201710058237 A CN 201710058237A CN 106831437 B CN106831437 B CN 106831437B
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formula
ester type
compound
type compound
compound represented
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CN106831437A (en
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万坚
韩新亚
陈海峰
黄运远
池波
任彦亮
冯玲玲
饶立
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Huazhong Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
    • C07C205/32—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups bound to acyclic carbon atoms and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
    • C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/36—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
    • C07C205/37—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/50—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C205/53—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/54—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
    • C07C217/84—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom

Abstract

The present invention relates to ester of Harden Young enzyme inhibitor fields, specifically disclose a kind of ester type compound containing nitroethenyl group, and the ester type compound is formula (1) compound represented.The invention also discloses the preparation methods of above-mentioned formula (1) compound represented.Ester type compound the invention also discloses another kind containing nitroethenyl group, the ester type compound are formula (2) compound represented.The invention also discloses the preparation methods of formula (2) compound represented.The present invention also provides the above-mentioned drugs for inhibiting fructose-1,6-diphosphonic acid enzyme in preparation containing the ester type compound of nitroethenyl group or its pharmaceutically acceptable salt, the application on drug of preparation treatment or prevention gluconeogenesis metabolism class disease or thrombus disease etc..

Description

Ester type compound and its preparation method and application containing nitroethenyl group
Technical field
The present invention relates to ester of Harden Young enzyme inhibitor fields, and in particular to the esters chemical combination containing nitroethenyl group Object and its preparation method and application.
Background technique
Nowadays diabetes are known as a kind of worldwide disease by mechanisms such as the World Health Organization, will be futures Lead to one of important diseases that are dead or losing viability in 30 years.Human liver is important endogenous glucose and mainly produces Raw place, existing research shows that the generation of liver endogenous glucose is to cause diabetes patient blood sugar's raising, particularly empty stomach The main reason for blood glucose rise.There are two types of approach for hepatic glucose production: one is glucose is endogenously synthesized, i.e. gluconeogenesis is made With；Another kind is hepatic glycogenolytic.Inhibit regulation gluconeogenesis approach, reduces the generation of endogenous glucose, become exploitation new work With the important new strategy of mechanism hypoglycemic drug.
Human liver's ester of Harden Young enzyme (FBPase) is a key enzyme of gluconeogenesis, and the catalysis of regulation is anti- It should be one of the ratedeterming step that endogenous glucose generates, inhibit the activity of FBPase that can reduce the life of endogenous glucose At reduction blood glucose level.In addition FBPase catalysis reaction is located at the middle part of gluconeogenesis approach, and FBPase is inhibited not inhibit not only The adverse reaction of phosphoenolpyruvate carboxykinase, and may also suppress glycerol and generate glucose, with inhibition glucose -6- phosphorus Sour enzyme is compared, and FBPase is inhibited not will increase the risk of hypoglycemia.Therefore, it is very potential to can be used as hypoglycemic drug by FBPase Target spot, at present still to using FBPase as the inhibitor of target spot, there are biggish demands.
In addition, it is not its hyperglycemia that diabetes are really fearful, but in vivo one brought by long-time hyperglycemia The destructive complication of series, the cardiovascular and cerebrovascular disease as caused by atherosclerosis, hyperlipidemia caused by lipidosis Disease etc..Diabetic's cardiovascular disease incidence is 2-4 times of ordinary people's disease incidence.And the prior art rarely has and can both use The medicine of thrombus, hyperlipidemia complication caused by the treatment or prevention of diabetes can treat again simultaneously or prevent because of diabetes Object.
Summary of the invention
The purpose of the present invention is to provide it is a kind of using FBPase as target spot, be able to suppress FBPase containing nitroethenyl group Ester type compound and its preparation method and application.
To achieve the goals above, the present invention provides a kind of ester type compound containing nitroethenyl group, the esters chemical combination Object is formula (1) compound represented:
Wherein, R1-R5In at least one beRemaining group be each independently selected from H, halogen, The alkoxy ,-NO of the alkyl of C1-C6, C1-C62、-COOH、-CN、-NR2, the alkyl of C1-C6 that is substituted with a substituent and taken For the alkoxy for the C1-C6 that base replaces, R is selected from the alkyl of C1-C6 be substituted with a substituent or unsubstituted, and the substituent group is each From independently selected from halogen ,-COOH and-NO2One of or it is a variety of；R6Selected from H, halogen, the alkyl of C1-C6 and C2-C8 carboxylic Perester radical.
The present invention also provides the preparation methods of the above-mentioned ester type compound containing nitroethenyl group, this method comprises:
(1) in the presence of alkali metal salt and the first organic solvent, by phenol compound shown in formula (1 ') and 2- it is halogenated- 2 Methylpropionic acid ethyl ester carries out substitution reaction, obtains formula (1 ") compound represented；
Wherein, R1'-R5' at least one be-CHO, remaining group is each independently selected from H, halogen, C1-C6 The alkoxy ,-NO of alkyl, C1-C62、-COOH、-CN、-NR2, the alkyl of C1-C6 that is substituted with a substituent and be substituted with a substituent C1-C6 alkoxy, R is selected from alkyl be substituted with a substituent or unsubstituted C1-C6, and the substituent group is each independently Selected from halogen ,-COOH and-NO2One of or it is a variety of；
(2) in the presence of organic ammonium salt and the second organic solvent, by formula (1 ") compound represented and formula R6CH2-NO2Institute The compound shown carries out condensation reaction, obtains formula (1) compound represented.
The present invention also provides a kind of ester type compound containing nitroethenyl group, the ester type compound is shown in formula (2) Compound:
Wherein, R6Selected from H, halogen, the alkyl of C1-C6 and C2-C8 carboxylate.
The present invention also provides the methods for preparing the above-mentioned ester type compound containing nitroethenyl group, this method comprises:
(a) in the presence of organic amine and catalyst, in organic solvent, by formula (2 ') compound represented and formula R6CH2- NO2Compound represented carries out condensation reaction, obtains formula (2 ") compound represented；
(b) under acid catalysis, formula (2 ") compound represented and acetic anhydride is subjected to ester exchange reaction, obtain formula (2) institute The compound shown；
It is being prepared the present invention also provides above-mentioned containing the ester type compound of nitroethenyl group or its pharmaceutically acceptable salt Inhibit the application on the drug of fructose-1,6-diphosphonic acid enzyme.
It is being prepared the present invention also provides above-mentioned containing the ester type compound of nitroethenyl group or its pharmaceutically acceptable salt Treat or prevent the application on the drug of gluconeogenesis metabolism class disease or thrombus disease.
It is being prepared the present invention also provides above-mentioned containing the ester type compound of nitroethenyl group or its pharmaceutically acceptable salt Inhibit the application on the drug of liver cell release glucose or the drug of preparation inhibition platelet aggregation.
It is provided by the invention containing the ester type compound of nitroethenyl group or its pharmaceutically acceptable salt, to human liver fruit Sugar -1,6- diphosphatase has very high inhibiting effect, has on treating or preventing gluconeogenesis metabolism class disease potential Medical value.The present inventor has been unexpectedly discovered that, it is above-mentioned containing the ester type compound of nitroethenyl group or its pharmaceutically may be used The activity that there is the salt of receiving preparation to treat or prevent thrombus disease, thrombus disease especially related with platelet aggregation Treatment or prevention activity.
Other features and advantages of the present invention will the following detailed description will be given in the detailed implementation section.
Specific embodiment
Detailed description of the preferred embodiments below.It should be understood that described herein specific Embodiment is merely to illustrate and explain the present invention, and is not intended to restrict the invention.
The present invention provides a kind of ester type compound containing nitroethenyl group, the ester type compound is shown in formula (1) Compound:
Wherein, R1-R5In at least one beRemaining group be each independently selected from H, halogen, The alkoxy ,-NO of the alkyl of C1-C6, C1-C62、-COOH、-CN、-NR2, the alkyl of C1-C6 that is substituted with a substituent and taken For the alkoxy for the C1-C6 that base replaces, R is selected from the alkyl of C1-C6 be substituted with a substituent or unsubstituted, and the substituent group is each From independently selected from halogen ,-COOH and-NO2One of or it is a variety of；R6Selected from H, halogen, the alkyl of C1-C6 and C2-C8 carboxylic Perester radical.
According to the present invention, wherein the halogen for example can be selected from fluorine, chlorine, bromine, iodine etc..
The alkyl of C1-C6 can for example be selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, sec-butyl, tertiary fourth Base, n-pentyl ,-(CH2)2-CH(CH3)2、-CH(CH3)-(CH2)2-CH3, n-hexyl ,-(CH2)3-CH(CH3)2、-CH(CH3)- (CH2)3-CH3。
The Alkoxy of C1-C6 can such as be selected from methoxyl group, ethyoxyl, propoxyl group, butoxy, isobutoxy, Zhong Ding oxygen Base, tert-butoxy, n-pentyloxy ,-O- (CH2)2-CH(CH3)2、-O-CH(CH3)-(CH2)2-CH3, positive hexyloxy ,-O- (CH2)3-CH(CH3)2、-O-CH(CH3)-(CH2)3-CH3。
-NR2Such as-N (CH can be selected from3)2、-N(CH2CH3)2、-N(CH2CH2CH3)2。
The alkyl for the C1-C6 being substituted with a substituent can for example be selected from-CF3、-CCl3、-CHF2、-CHCl2、-CH2Cl、- CH2-CF3。
The Alkoxy for the C1-C4 being substituted with a substituent can such as be selected from-O-CF3、-O-CCl3、-O-CHF2、-O- CHCl2、-O-CH2Cl、-O-CH2-CF3。
The carboxylate of C2-C6 can for example be selected from-C (O) O-CH3、-C(O)O-CH2CH3、-C(O)O-(CH2)2-CH3。
In the case of, according to the invention it is preferred to, in formula (1), R1-R5In in addition to forRemaining base in addition Group is each independently selected from the alkoxy ,-NO of H, halogen, the alkyl of C1-C4, C1-C42、-COOH、-CN、-NR2, be substituted base The alkoxy of the alkyl of substituted C1-C4 and the C1-C4 being substituted with a substituent, R are selected from being substituted with a substituent or unsubstituted The alkyl of C1-C4, the substituent group are each independently selected from halogen ,-COOH and-NO2One of or it is a variety of；R6Selected from H, halogen The carboxylate of element, the alkyl of C1-C4 and C2-C6.
It is highly preferred that in formula (1), R1-R5In in addition to forRemaining group in addition selects each independently From H, F, Cl, Br ,-NO2,-CN, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl ,-NO2、-COOH、-CN、- CF3、-CCl3、-CHF2、-CHCl2、-O-CF3、-O-CCl3、-O-CHF2With-O-CHCl2；R6Selected from H, halogen, methyl, ethyl With-COOCH3；
Wherein,It is selected from Herein, the dotted line on group indicates The connecting key of the group specifies the connection site of the group.
Wherein, R1-R5In at least one beIt is preferred that R1-R5In have one and be It is preferred that there are two be
In the case of, according to the invention it is preferred to, the ester type compound is selected from compound described in following formula:
In a preferred embodiment of the invention, the ester type compound is selected from above-mentioned formula (1-1) to formula (1-6) And one of compound shown in formula (1-11) to formula (1-13) or a variety of.In this case, the esters chemical combination Object has the inhibition of higher ester of Harden Young enzyme, has more on treating or preventing gluconeogenesis metabolism class disease Value outstanding, most preferably, the ester type compound is selected from above-mentioned formula (1-1) to formula (1-6) compound represented One of or it is a variety of.
Another preferred embodiment according to the present invention, the ester type compound are selected from chemical combination described in following formula Object:
The present invention also provides the methods for preparing above-mentioned ester type compound, this method comprises:
1) in the presence of alkali metal salt and the first organic solvent, by phenol compound shown in formula (1 ') and 2- it is halogenated- 2 Methylpropionic acid ethyl ester carries out substitution reaction, obtains formula (1 ") compound represented；
Wherein, R1'-R5'In at least one be-CHO, remaining group is each independently selected from H, halogen, C1-C6 The alkoxy ,-NO of alkyl, C1-C62、-COOH、-CN、-NR2, the alkyl of C1-C6 that is substituted with a substituent and be substituted with a substituent C1-C6 alkoxy, R is selected from alkyl be substituted with a substituent or unsubstituted C1-C6, and the substituent group is each independently Selected from halogen ,-COOH and-NO2One of or it is a variety of；
(2) in the presence of organic ammonium salt and the second organic solvent, by formula (1 ") compound represented and formula R6CH2-NO2Institute The compound shown carries out condensation reaction, obtains formula (1) compound represented.
According to the present invention, formula (1) compound represented being described above can be made in the above method, for this purpose, taking here For base R1'-R5', the substituent R of the formula according to described in above (1) compound represented1-R5It is properly selected, it is right Can be with reference to described above in the description of specific group, details are not described herein.It should be noted that changing shown in formula (1 ') Close the R of object1'-R5'In have one for-CHO, which is the R for formula (1) compound represented to be made1-R5In have one For group, it is, therefore, understood that in addition to different at this, Dai Ji R1'-R5'And R1-R5Remaining benzene Substituent group on ring can be performed in accordance with selection, but this method is not restricted to this.
Wherein, R1'-R5'In at least one be-CHO, preferably R1'-R5'In have one for-CHO, preferably R1'-R5'In have Two are-CHO.
According to the present invention, the step in this method (1) is by phenol compound shown in formula (1 ') and the halogenated -2- methyl of 2- Ethyl propionate carry out substitution reaction, mainly so that 2- it is halogenated -2 Methylpropionic acid ethyl ester in halogen and formula (1 ') shown in benzene Hydrogen on the phenolic hydroxyl group of phenolic compound is sloughed, and remaining group carries out substitution connection, to be made shown in formula (1 ") Compound.
Wherein, the specific example of formula (1 ") compound represented can be for example following formula compound represented:
Wherein, the 2- it is halogenated -2 Methylpropionic acid ethyl ester for example can be the fluoro- 2 Methylpropionic acid ethyl ester of 2-, the chloro- 2- first of 2- One of base ethyl propionate, 2 bromo 2 methyl propionic acid ethyl ester and the iodo- 2 Methylpropionic acid ethyl ester of 2- are a variety of, and preferably 2- is bromo- 2 Methylpropionic acid ethyl ester.
According to the present invention, in order to improve the yield of formula (1 ") compound represented, under preferable case, shown in formula (1 ') Phenol compound and 2- it is halogenated-the dosage molar ratio of 2 Methylpropionic acid ethyl ester is 1:2-4.
According to the present invention, alkali metal salt used by step (1) is mainly strong base-weak acid salt, weak to provide for reaction system Alkalinity, the alkali metal salt are preferably one or more in potassium sulfite, potassium phosphate, potassium acetate, potassium carbonate and vulcanized sodium.For There is no particular limitation for the dosage of the alkali metal salt, as long as above-mentioned effect can be played, under preferable case, and formula (1 ') Shown in the dosage molar ratio of phenol compound and alkali metal salt be 1:2-3.
According to the present invention, for first organic solvent, there is no particular limitation, as long as reactant and not can be dissolved Can bring more side reaction, under preferable case, first organic solvent be n,N-Dimethylformamide, dimethyl sulfoxide, It is one or more in acetone, tetrahydrofuran and acetonitrile.For the dosage of first organic solvent, there is no particular limitation, as long as It can be suitable for the progress of reaction, such as the dosage of first organic solvent makes phenol chemical combination shown in formula (1 ') The concentration of object is 0.1-0.5mmol/mL.
According to the present invention, to the charging sequence of step (1), there is no particular limitation, such as can be all reactant packets It includes alkali metal salt and the first organic solvent is mixed, preferably first by the alkali metal salt, the first organic solvent and formula (1 ') institute The phenol compound shown is mixed, add the 2- it is halogenated -2 Methylpropionic acid ethyl ester.
In the case of, according to the invention it is preferred to, in step (1), the condition of the substitution reaction includes: that temperature is 80-110 DEG C, time 6-12h.It is preferred that carrying out the reaction by the way of being heated to reflux.
According to the present invention, in order to extracting chemical combination shown in formula (1 ") from reaction product obtained in step (1) Object, this method can also include: that reaction solution obtained by step (1) is separated by solid-liquid separation (such as mode of suction filtration), will be resulting The solvent of liquid phase removes (such as can remove by way of vacuum distillation), and be added water and ethyl acetate extracted (1: 1-2 volume ratio), which can carry out multiple (such as 2-4 times), merge organic phase, and washed with saturated salt solution, will Organic phase after washing is dried using desiccant (such as can use anhydrous sodium sulfate), then pure using silica gel column chromatography The mode of change is made more pure formula (1 ") compound represented.
According to the present invention, the step of above method (2) is in the presence of organic ammonium salt and the second organic solvent, by formula (1 ") institute The compound and formula R shown6CH2-NO2Compound represented carries out condensation reaction, mainly makes in formula (1 ") compound represented - CHO base and R6CH2-NO2The methylene connecting with nitro in compound represented carries out obtaining carbon similar to aldol condensation The condensation reaction of carbon double bond, so that forming group on phenyl ringThus chemical combination shown in formula (1) can be obtained Object.
Wherein, R6CH2-NO2Group R in compound represented6It can be according to shown in formula (1) described above Group in compoundIn R6It is selected, but the present invention has no and is limited to this.For example, working as groupRequired R6When for chlorine, BrCH can also be used2-NO2As R here6CH2-NO2Compound represented, But in the group for obtaining bromoChlorine, those skilled in the art are being substituted by by mode appropriate afterwards This should be well understood by.
According to the present invention, formula R6CH2-NO2Compound represented for example can be nitromethane, BrCH2-NO2、FCH2- NO2、ClCH2-NO2、CH3CH2-NO2、CH3CH2-CH2-NO2、CH3OOC-CH2-NO2Deng one of or it is a variety of.The formula (1 ") Compound represented and formula R6CH2-NO2The dosage molar ratio of compound represented is preferably 1:4-8, uses the molar ratio can be with So that the yield of formula (1 ") compound represented is higher.
According to the present invention, in step (2), used organic ammonium salt has the function of that catalysis reaction carries out, described organic Ammonium salt is preferably one or more in ammonium formate, ammonium citrate, trifluoroacetic acid ammonium, ammonium acetate and ammonium oxalate.For described organic There is no particular limitation for the dosage of ammonium salt, as long as above-mentioned catalytic action can be played, under preferable case, and the formula (1 ") Compound represented and the dosage molar ratio of organic ammonium salt are 1:2-6.
According to the present invention, second solvent is other than having and can dissolve the property of reactant, additionally it is possible to provide acid Environment, under preferable case, second organic solvent is acetic acid.Special limit is had no for the dosage of second organic solvent It is fixed, as long as the progress of reaction can be suitable for, such as the dosage of second organic solvent to change shown in formula (1 ") The concentration for closing object is 0.1-0.5mmol/mL.
In the case of, according to the invention it is preferred to, in step (2), the condition of the condensation reaction includes: that temperature is 100-120 DEG C, time 8-12h.It is preferred that carrying out the reaction by the way of being heated to reflux.
According to the present invention, in order to extracting chemical combination shown in formula (1) from reaction product obtained in step (2) Object, this method can also include: that reaction solution obtained by step (2) is separated by solid-liquid separation (such as mode of suction filtration), will be resulting The solvent of liquid phase removes (such as can remove by way of vacuum distillation), and be added water and ethyl acetate extracted (1: 1-2 volume ratio), which can carry out multiple (such as 2-4 times), merge organic phase, and washed with saturated salt solution, will Organic phase after washing is dried using desiccant (such as can use anhydrous sodium sulfate), then pure using silica gel column chromatography The mode of change is made more pure formula (1) compound represented.
The present invention also provides a kind of ester type compound containing nitroethenyl group, the ester type compound is shown in formula (2) Compound:
Wherein, R6Selected from H, halogen, the alkyl of C1-C6 and C2-C8 carboxylate.
According to the present invention, above-mentioned group R6It is as described above which is not described herein again.
Under preferable case, R6Selected from H, halogen, methyl and ethyl.
It is highly preferred that the ester type compound is selected from compound described in following formula:
The present invention also provides a kind of method for preparing the ester type compound containing nitroethenyl group shown in above-mentioned formula (2), This method comprises:
(a) in the presence of organic amine and catalyst, in organic solvent, by formula (2 ') compound represented and formula R6CH2- NO2Compound represented carries out condensation reaction, obtains formula (2 ") compound represented；
(b) under acid catalysis, formula (2 ") compound represented and acetic anhydride is subjected to ester exchange reaction, obtain formula (2) institute The compound shown；
According to the present invention, the step of above method (a) is in the presence of organic amine and catalyst, by chemical combination shown in formula (2 ') Object and formula R6CH2-NO2Compound represented carries out condensation reaction, mainly make-CHO base in formula (2 ') compound represented with R6CH2-NO2The methylene connecting with nitro in compound represented carries out obtaining the contracting of carbon-carbon double bond similar to aldol condensation Reaction is closed, so that forming group on phenyl ringFormula (2 ") compound represented is made.
Wherein, the specific example of formula (2 ") compound represented can be for example following formula compound represented:
Wherein, R6CH2-NO2Compound represented is as described in above, and details are not described herein.Preferably, step (a) In, formula (2 ') compound represented and formula R6CH2-NO2The dosage molar ratio of compound represented is 1:1.5-6.
It is noted that using Br CH2-NO2As R6CH2-NO2When compound represented is reacted, Ke Yi In the case where using organic amine salt hydrochlorate, it can be madeMiddle R6Chemical combination shown in the formula (2 ") replaced for chlorine Object.
In accordance with the present invention it is preferred that in step (a), the organic amine be selected from dimethylamine hydrochloride, diethylamine hydrochloride and One of triethylamine hydrochloride is a variety of.Preferably, formula (2 ') compound represented and the dosage molar ratio of organic amine are 1: 8-12。
In accordance with the present invention it is preferred that the catalyst is one of potassium fluoride, sodium fluoride and cesium fluoride or a variety of.It is excellent The dosage molar ratio of selection of land, formula (2 ') compound represented and catalyst is 1:0.1-0.2.
According to the present invention, to the organic solvent in step (a), there is no particular limitation, as long as the solvent can dissolve reaction Object and more side reaction will not be brought, it is preferable that the organic solvent be one of toluene, dimethylbenzene and nitrobenzene or It is a variety of.For the dosage of the organic solvent, there is no particular limitation, as long as can be adapted to the progress of the reaction, for example, The dosage of the organic solvent makes the concentration of formula (2 ') compound represented be 0.1-0.3mmol/mL.
In the case of, according to the invention it is preferred to, in step (a), the condition of condensation reaction includes: that temperature is 110-160 DEG C, when Between be 3-12h.It is highly preferred that the condition of condensation reaction includes: that temperature is 120-140 DEG C, time 4-9h in step (a).
According to the present invention, step (b) is anti-by formula (2 ") compound represented and acetic anhydride progress transesterification under acid catalysis It answers, the phenolic hydroxyl group in formula (2 ") compound represented can be made to be esterified by acetic anhydride, so that having formula (2) institute on phenyl ring The ester bond shown.Preferably, formula (2 ") compound represented and the dosage molar ratio of acetic anhydride are 1:8-20, more preferably 1:10- 15.Wherein, acetic anhydride serves not only as reactant, and as the solvent of the ester exchange reaction.
According to the present invention, in step (b), acid used by the acid catalysis can be the catalytic transesterification of this field routine Acid used by reaction, it is preferable that in step (b), the acid of the acid catalysis is sulfuric acid and/or phosphoric acid.The acid catalysis institute The acid of use is preferably concentrated acid, such as concentration reaches the acid of 85 weight % or more, such as the concentrated phosphoric acid of 85 weight %, 98 weight % The concentrated sulfuric acid.For the dosage of the acid, there is no particular limitation, such as relative to the organic solvent of 10mL, the dosage of the acid is 100-200mg。
In the case of, according to the invention it is preferred to, in step (b), the condition of the ester exchange reaction includes: that temperature is 10-40 DEG C, time 3-6h.Formula (2) compound represented can be made in ester exchange reaction condition in this way in more high yield.
According to the present invention, in order to extracting chemical combination shown in formula (2) from reaction product obtained in step (b) Object, this method can also include: that reaction solution obtained by step (b) is separated by solid-liquid separation (such as mode of suction filtration), will be resulting The solvent of liquid phase removes (such as can remove by way of vacuum distillation), and be added water and ethyl acetate extracted (1: 1-2 volume ratio), which can carry out multiple (such as 2-4 times), merge organic phase, and washed with saturated salt solution, will Organic phase after washing is dried using desiccant (such as can use anhydrous sodium sulfate), then pure using silica gel column chromatography The mode of change is made more pure formula (2) compound represented.
The ester type compound that the present invention also provides above-mentioned containing nitroethenyl group (including formula (1) compound represented and Formula (2) compound represented) or its pharmaceutically acceptable salt answering on the drug that preparation inhibits fructose-1,6-diphosphonic acid enzyme With.
According to the present invention, present inventors discovered unexpectedly that, formula (1) compound represented provided by the present invention and Formula (2) compound represented or its pharmaceutically acceptable salt have the inhibitory activity of ester of Harden Young enzyme, particularly suitable In the ester of Harden Young enzyme for inhibiting human liver, it is preferable that for inhibiting the IC50 of ester of Harden Young enzyme can be with Reach 10 μM hereinafter, more preferably 8.5 μM hereinafter, still more preferably for 4 μM hereinafter, be still more preferably 2.5 μM hereinafter, Still more preferably for 2 μM hereinafter, being still more preferably 1 μM or less.
The ester type compound that the present invention also provides aforementioned containing nitroethenyl group (including formula (1) compound represented and formula (2) compound represented) or its pharmaceutically acceptable salt in preparation treat or prevent gluconeogenesis metabolism class disease or thrombus Application on the drug of class disease.
According to the present invention, because it is of the present invention containing the ester type compound of nitroethenyl group or its is pharmaceutically acceptable Salt has preferable ester of Harden Young enzyme inhibition activity, therefore may be used as treating or preventing gluconeogenesis metabolism class disease Drug.Wherein, the gluconeogenesis metabolism class disease preferably includes, but is not limited to diabetes, obesity, hyperlipidemia or non-alcoholic Fatty liver.
According to the present invention, the present inventor has been unexpectedly discovered that, above-mentioned ester type compound containing nitroethenyl group or The activity that there is its pharmaceutically acceptable salt preparation to treat or prevent thrombus disease, it is especially related with platelet aggregation The activity of the treatment or prevention of thrombus disease.The thrombus disease preferably includes, but is not limited to ischemic angiocardiopathy and cerebrovascular disease Disease, atherosclerosis, myocardial infarction, cardiac valve replacement, bypass operation of coronary artery or the postoperative rejection of organ transplantation are anti- Arterial thrombus caused by answering.
It is being prepared the present invention also provides above-mentioned containing the ester type compound of nitroethenyl group or its pharmaceutically acceptable salt Inhibit the application on the drug of liver cell release glucose or the drug of preparation inhibition platelet aggregation.
The invention will be further described with reference to embodiments, but the scope of the present invention is not limited in following implementation Example.
In following embodiment,
The yield of formula (1 ") compound represented be with the amount of the total material of formula (1 ") compound represented with it is used The percentage of the amount of the substance of starting phenol.
The yield of ester type compound shown in formula (1) be the total material of ester type compound shown in formula (1) amount with adopted The percentage of the amount of the substance of formula (1 ") compound represented.
The yield of formula (2 ") compound represented be with the amount of the total material of formula (2 ") compound represented with it is used The percentage of the amount of the substance of salicylic acid compounds raw material.
The yield of ester type compound shown in formula (2) be the total material of ester type compound shown in formula (2) amount with adopted The percentage of the amount of the substance of formula (2 ") compound represented.
Embodiment 1
The present embodiment is used to illustrate the preparation of ester type compound shown in formula of the invention (1-1).
(1) the fluoro- 3- formyl phenol of 0.701g (5mmol) 4-, 10mmol potassium carbonate and 25mL acetonitrile are mixed, then plus Enter 1.5mL (about 10mmol) 2 bromo 2 methyl propionic acid ethyl ester, is then heated to reflux 6h at 80 DEG C；It is then that reaction solution is cooling To room temperature (about 25 DEG C), filters and wash filter cake.Filtrate is collected, and is evaporated under reduced pressure the solvent for removing filtrate.Be added 20mL water and Ethyl acetate (20mL × 3) extraction merges organic phase, and uses 20mL saturated common salt water washing, and organic phase is used anhydrous sulphur Sour sodium is dry.By the organic phase concentration after drying, through silica gel column chromatography, (eluent is the second of volume ratio 1:4 to resulting concentrate Mixed liquor of the acetoacetic ester than petroleum ether) purifying can obtain formula (1 " -1) compound represented (4mmol, yield 80%).
(2) formula (1 " -1) compound represented and 6mmol ammonium acetate of 0.762g (3mmol) are dissolved in the acetic acid of 10mL In, add 0.65mL (about 12mmol) nitromethane.It is heated to reflux 8h at 110 DEG C, gained reaction solution is cooled to room temperature, And solvent is removed by vacuum distillation.Then 15mL water and ethyl acetate (15mL × 3) extraction is added, merges organic phase, and adopt It is with 20mL saturated common salt water washing, the organic phase after washing is dry using anhydrous sodium sulfate.Organic phase after drying is carried out Concentration, gained concentrate is through silica gel column chromatography (mixed liquor of the ethyl acetate than petroleum ether that eluent is volume ratio 1:4) purifying Ester type compound (2.3mmol, yield 77%) shown in formula (1-1) is made.
1H NMR(600MHz,CDCl3) δ 7.96 (d, J=13.8Hz, 1H), 7.67 (d, J=13.8Hz, 1H), 7.06 (t, J=9.5Hz, 1H), 7.03 (dd, J=5.6,2.9Hz, 1H), 6.98 (dt, J=8.4,3.5Hz, 1H), 4.25 (q, J= 7.1Hz, 2H), 1.59 (s, 6H), 1.28 (t, J=7.1Hz, 3H)
13C NMR(151MHz,CDCl3) δ 173.10,157.04 (d, J=242.3Hz), 151.51,138.77, (133.93,122.65,119.07 d, J=23.1Hz), 118.24,116.53 (d, J=23.8Hz), 80.68,61.79, 25.23,13.92.
Embodiment 2
The present embodiment is used to illustrate the preparation of ester type compound shown in formula of the invention (1-2).
According to method described in embodiment 1, the difference is that
In step (1), the fluoro- 3- formyl phenol of 4- is replaced using the chloro- 3- formyl phenol of 4-, to be made shown in formula (1 " -2) Compound (4.1mmol, yield 82%).
In step (2), then formula (1 " -1) compound represented is replaced using formula (1 " -2) compound represented, to be made Ester type compound shown in formula (1-2) (2.3mmol, yield 77%).
1H NMR(600MHz,CDCl3) δ 8.32 (d, J=13.7Hz, 1H), 7.51 (d, J=13.7Hz, 1H), 7.34 (d, J=8.9Hz, 1H), 7.11 (d, J=2.8Hz, 1H), 6.90 (dd, J=8.8,2.8Hz, 1H), 4.25 (q, J=7.1Hz, 2H), 1.62 (s, 6H), 1.26 (t, J=7.1Hz, 3H)
13C NMR(151MHz,CDCl3)δ173.44,154.46,138.85,134.94,131.01,128.96, 128.83,123.19,118.89,79.91,61.75,25.24,14.08.
Embodiment 3
The present embodiment is used to illustrate the preparation of ester type compound shown in formula of the invention (1-3).
According to method described in embodiment 1, the difference is that
In step (1), the fluoro- 3- formyl phenol of 4- is replaced using the bromo- 3- formyl phenol of 4-, to be made shown in formula (1 " -3) Compound (4mmol, yield 80%).
In step (2), then formula (1 " -1) compound represented is replaced using formula (1 " -3) compound represented, to be made Ester type compound shown in formula (1-3) (2.4mmol, yield 80%).
1H NMR(600MHz,CDCl3) δ 8.31 (d, J=13.6Hz, 1H), 7.52 (d, J=8.9Hz, 1H), 7.46 (d, J =13.6Hz, 1H), 7.11 (d, J=3.0Hz, 1H), 6.82 (dd, J=8.8,2.9Hz, 1H), 4.25 (q, J=7.1Hz, 2H), 1.62 (s, 6H), 1.26 (t, J=7.1Hz, 3H)
13C NMR(151MHz,CDCl3)δ173.42,155.11,138.87,137.38,134.20,130.85, 123.22,118.92,118.27,79.86,61.77,25.25,14.08.
Embodiment 4
The present embodiment is used to illustrate the preparation of ester type compound shown in formula of the invention (1-4).
According to method described in embodiment 1, the difference is that
In step (1), the fluoro- 3- formyl phenol of 4- is replaced using the chloro- 3- formyl phenol of 6-, to be made shown in formula (1 " -4) Compound (3.9mmol, yield 78%).
In step (2), then formula (1 " -1) compound represented is replaced using formula (1 " -4) compound represented, to be made Ester type compound shown in formula (1-4) (2.2mmol, yield 73%).
1H NMR(600MHz,CDCl3) δ: 7.89 (d, J=13.7Hz, 1H), 7.49 (d, J=13.6Hz, 1H), 7.45 (d, J=8.2Hz, 1H), 7.17 (dd, J=8.2,1.8Hz, 1H), 7.10 (d, J=1.8Hz, 1H), 4.29 (q, J=7.1Hz, 2H), 1.65 (s, 6H), 1.29 (t, J=7.1Hz, 3H)
13C NMR(151MHz,CDCl3)δ:173.41,152.21,137.86,137.34,131.23,130.85, 129.18,123.58,119.87,81.39,61.76,25.02,14.06.
Embodiment 5
The present embodiment is used to illustrate the preparation of ester type compound shown in formula of the invention (1-5).
According to method described in embodiment 1, the difference is that
In step (1), the fluoro- 3- formyl phenol of 4- is replaced using 6- difluoro-methoxy -3- formyl phenol, thus the formula of being made (1 " -5) compound represented (3.9mmol, yield 78%).
In step (2), then formula (1 " -1) compound represented is replaced using formula (1 " -5) compound represented, to be made Ester type compound shown in formula (1-5) (2.4mmol, yield 80%).
1H NMR(600MHz,CDCl3) δ 7.90 (d, J=13.7Hz, 1H), 7.47 (d, J=13.7Hz, 1H), 7.24 (s, 2H), 7.15 (s, 1H), 6.65 (t, J=74.4Hz, 1H), 4.27 (q, J=7.1Hz, 2H), 1.64 (s, 6H), 1.28 (t, J= 7.1Hz,3H).
13C NMR(151MHz,CDCl3)δ:173.12,147.59,145.82,137.74,137.22,127.97, 124.28,123.05,120.72,115.87(t,JC-F=261.2Hz), 81.46,61.79,24.96,14.00.
Embodiment 6
The present embodiment is used to illustrate the preparation of ester type compound shown in formula of the invention (1-6).
According to method described in embodiment 1, the difference is that
In step (1), the fluoro- 3- formyl phenol of 4- is replaced using 3- formyl phenol, is changed to be made shown in formula (1 " -6) It closes object (4.1mmol, yield 82%).
In step (2), then formula (1 " -1) compound represented is replaced using formula (1 " -6) compound represented, to be made Ester type compound shown in formula (1-6) (2.3mmol, yield 77%).
1H NMR(600MHz,CDCl3) δ 7.93 (d, J=13.7Hz, 1H), 7.54 (d, J=13.6Hz, 1H), 7.32 (t, J=8.0Hz, 1H), 7.19 (d, J=7.6Hz, 1H), 7.05 (s, 1H), 6.96 (d, J=8.2Hz, 1H), 4.25 (q, J= 7.1Hz, 2H), 1.63 (s, 7H), 1.25 (t, J=7.1Hz, 3H)
13C NMR(151MHz,CDCl3)δ173.67,156.05,138.73,137.26,131.11,130.03, 122.78,122.14,119.34,79.45,61.58,25.26,14.02.
Embodiment 7
The present embodiment is used to illustrate the preparation of ester type compound shown in formula of the invention (1-7).
According to method described in embodiment 1, the difference is that
In step (1), the fluoro- 3- formyl phenol of 4- is replaced using 2- formyl phenol, is changed to be made shown in formula (1 " -7) It closes object (4.2mmol, yield 84%).
In step (2), then formula (1 " -1) compound represented is replaced using formula (1 " -7) compound represented, to be made Ester type compound shown in formula (1-7) (2.4mmol, yield 80%).
1H NMR(600MHz,CDCl3) δ 8.22 (d, J=13.7Hz, 1H), 7.84 (d, J=13.7Hz, 1H), 7.49 (d, J=8.8Hz, 1H), 7.35 (t, J=7.9Hz, 1H), 7.03 (t, J=7.5Hz, 1H), 6.75 (d, J=8.4Hz, 1H), 4.25 (q, J=7.1Hz, 2H), 1.72 (s, 7H), 1.23 (t, J=7.1Hz, 3H)
13C NMR(151MHz,CDCl3)δ173.30,155.50,138.10,135.36,132.58,131.75, 121.83,121.00,116.22,80.15,61.76,25.34,13.95.
Embodiment 8
The present embodiment is used to illustrate the preparation of ester type compound shown in formula of the invention (1-8).
According to method described in embodiment 1, the difference is that
In step (1), the fluoro- 3- formyl phenol of 4- is replaced using the fluoro- 2- formyl phenol of 4-, to be made shown in formula (1 " -8) Compound (4mmol, yield 80%).
In step (2), then formula (1 " -1) compound represented is replaced using formula (1 " -8) compound represented, to be made Ester type compound shown in formula (1-8) (2.3mmol, yield 77%).
1H NMR(600MHz,CDCl3) δ 7.96 (d, J=13.8Hz, 1H), 7.67 (d, J=13.8Hz, 1H), 7.06 (t, J=9.5Hz, 1H), 7.03 (dd, J=5.6,2.9Hz, 1H), 6.98 (dt, J=8.4,3.5Hz, 1H), 4.25 (q, J= 7.1Hz, 2H), 1.59 (s, 6H), 1.28 (t, J=7.1Hz, 3H)
13C NMR(151MHz,CDCl3) δ 173.10,157.04 (d, J=242.3Hz), 151.51,138.77, (133.93,122.65,119.07 d, J=23.1Hz), 118.24,116.53 (d, J=23.8Hz), 80.68,61.79, 25.23,13.92.
Embodiment 9
The present embodiment is used to illustrate the preparation of ester type compound shown in formula of the invention (1-9).
According to method described in embodiment 1, the difference is that
In step (1), the fluoro- 3- formyl phenol of 4- is replaced using the chloro- 2- formyl phenol of 4-, to be made shown in formula (1 " -9) Compound (3.9mmol, yield 78%).
In step (2), then formula (1 " -1) compound represented is replaced using formula (1 " -9) compound represented, to be made Ester type compound shown in formula (1-9) (2.4mmol, yield 80%).
1H NMR(600MHz,CDCl3) δ 8.18 (d, J=13.7Hz, 1H), 7.76 (d, J=13.7Hz, 1H), 7.19 (d, J=8.5Hz, 1H), 7.11-7.02 (m, 1H), 6.77 (dd, J=9.1,4.4Hz, 1H), 4.26 (q, J=7.1Hz, 2H), 1.68 (s, 6H), 1.26 (t, J=7.1Hz, 3H)
13C NMR(151MHz,cdcl3) δ 173.10,157.04 (d, J=242.3Hz), 151.51,138.77, (133.93,122.65,119.07 d, J=23.1Hz), 118.24,116.53 (d, J=23.8Hz), 80.68,61.79, 25.23,13.92.
Embodiment 10
The present embodiment is used to illustrate the preparation of ester type compound shown in formula of the invention (1-10).
According to method described in embodiment 1, the difference is that
In step (1), the fluoro- 3- formyl phenol of 4- is replaced using 4- formyl phenol, is changed to be made shown in formula (1 " -10) It closes object (4.1mmol, yield 82%).
In step (2), then formula (1 " -1) compound represented is replaced using formula (1 " -10) compound represented, to make Obtain ester type compound (2.2mmol, yield 73%) shown in formula (1-10).
1H NMR(600MHz,CDCl3) δ 7.96 (d, J=13.6Hz, 1H), 7.52 (d, J=13.6Hz, 1H), 7.50- 7.42 (m, 2H), 6.85 (d, J=8.7Hz, 2H), 4.24 (q, J=7.1Hz, 2H), 1.66 (s, 6H), 1.23 (t, J= 7.1Hz,3H).
13C NMR(151MHz,CDCl3)δ173.50,159.06,138.76,135.31,130.70,123.09, 118.41,79.39,61.70,25.29,14.00.
Embodiment 11
The present embodiment is used to illustrate the preparation of ester type compound shown in formula of the invention (1-11).
According to method described in embodiment 1, the difference is that
In step (1), the fluoro- 3- formyl phenol of 4- is replaced using the chloro- 4- formyl phenol of 2-, so that formula (1 " -11) institute be made The compound (4mmol, yield 80%) shown.
In step (2), then formula (1 " -1) compound represented is replaced using formula (1 " -11) compound represented, to make Obtain ester type compound (2.4mmol, yield 80%) shown in formula (1-11).
1H NMR(600MHz,CDCl3) δ 7.89 (d, J=13.6Hz, 1H), 7.60 (d, J=2.2Hz, 1H), 7.50 (d, J =13.6Hz, 1H), 7.33 (dd, J=8.6,2.3Hz, 1H), 6.83 (d, J=8.6Hz, 1H), 4.26 (q, J=7.1Hz, 2H), 1.69 (s, 6H), 1.25 (t, J=7.1Hz, 3H)
13C NMR(151MHz,CDCl3)δ173.14,154.62,137.39,136.32,130.78,128.56, 126.53,124.20,118.02,81.00,61.81,25.16,14.01.
Embodiment 12
The present embodiment is used to illustrate the preparation of ester type compound shown in formula of the invention (1-12).
According to method described in embodiment 1, the difference is that
In step (1), the fluoro- 3- formyl phenol of 4- is replaced using the chloro- 4- formyl phenol of 3-, so that formula (1 " -12) institute be made The compound (4.1mmol, yield 82%) shown.
In step (2), then formula (1 " -1) compound represented is replaced using formula (1 " -12) compound represented, to make Obtain ester type compound (2.2mmol, yield 73%) shown in formula (1-12).
1H NMR(600MHz,CDCl3) δ 8.35 (d, J=13.7Hz, 1H), 7.56 (d, J=13.6Hz, 1H), 7.50 (d, J=8.8Hz, 1H), 6.93 (d, J=2.6Hz, 1H), 6.75 (dd, J=8.8,2.6Hz, 1H), 4.26 (q, J=7.1Hz, 2H), 1.66 (s, 6H), 1.25 (t, J=7.1Hz, 3H)
13C NMR(151MHz,CDCl3)δ173.02,159.10,137.08,136.97,134.78,129.31, 121.27,119.60,116.92,79.93,61.86,25.26,14.00.
Embodiment 13
The present embodiment is used to illustrate the preparation of ester type compound shown in formula of the invention (1-13).
According to method described in embodiment 1, the difference is that
In step (1), the fluoro- 3- formyl phenol of 4- is replaced using 2- methyl -4- formyl phenol, so that formula (1 " -13) be made Compound represented (3.9mmol, yield 78%).
In step (2), then formula (1 " -1) compound represented is replaced using formula (1 " -13) compound represented, to make Obtain ester type compound (2.4mmol, yield 80%) shown in formula (1-13).
1H NMR(600MHz,CDCl3) δ 7.93 (d, J=13.6Hz, 1H), 7.51 (d, J=13.6Hz, 1H), 7.37 (s, 1H), 7.27 (d, J=8.5Hz, 1H), 6.63 (d, J=8.5Hz, 1H), 4.24 (q, J=7.1Hz, 2H), 2.26 (s, 3H), 1.66 (s, 6H), 1.23 (t, J=7.1Hz, 3H)
13C NMR(151MHz,CDCl3)δ173.64,157.48,139.09,134.98,131.55,130.03, 128.41,122.62,115.19,79.31,61.61,25.39,16.65,13.97.
Embodiment 14
The present embodiment is used to illustrate the preparation of ester type compound shown in formula of the invention (1-27).
According to method described in embodiment 1, the difference is that
In step (1), the fluoro- 3- formyl phenol of 4- is replaced using 3- formyl phenol, is changed to be made shown in formula (1 " -6) It closes object (4.1mmol, yield 82%).
In step (2), then formula (1 " -1) compound represented, nitro-acetic acid are replaced using formula (1 " -6) compound represented Ethyl ester substitutes nitromethane to which ester type compound (2.2mmol, yield 76%) shown in formula (1-27) be made.
1H NMR(600MHz,DMSO-d6) δ 8.15 (d, J=13.3Hz, 1H), 7.91 (d, J=13.3Hz, 1H), 7.61 (d, J=9.0Hz, 1H), 6.43 (d, J=9.0Hz, 1H), 5.84 (s, 1H), 4.19 (q, J=7.1Hz, 2H), 3.36 (s, 4H), 1.65 (s, 4H), 1.59 (s, 2H), 1.18 (q, J=7.2Hz, 3H), 1.10 (t, J=7.3Hz, 6H)
13C NMR(151MHz,DMSO-d6)δ173.20,157.83,152.11,136.43,134.72,134.06, 132.06,107.88,106.43,98.06,88.62,79.84,61.83,44.70,25.30,14.25,12.81,12.55.
Embodiment 15
The present embodiment is used to illustrate the preparation of ester type compound shown in formula of the invention (1-28).
According to method described in embodiment 1, the difference is that
In step (1), the fluoro- 3- formyl phenol of 4- is replaced using 4- (lignocaine) salicylide, so that formula (1 " -18) be made Compound represented (3.1mmol, yield 82%).
In step (2), then formula (1 " -1) compound represented, nitro second are replaced using formula (1 " -18) compound represented Acetoacetic ester substitutes nitromethane to which ester type compound (2.5mmol, yield 81%) shown in formula (1-28) be made.
1H NMR(600MHz,DMSO-d6) δ 7.31 (q, J=7.9Hz, 1H), 7.06 (d, J=7.8Hz, 1H), 6.91 (s, 1H), 6.86 (d, J=8.6Hz, 1H), 4.25 (p, J=7.4Hz, 4H), 4.16 (q, J=7.4Hz, 2H), 1.54 (m, 5H), 1.16(s,6H).
13C NMR(151MHz,DMSO-d6)δ173.50,158.91,157.11,156.12,155.75,154.69, 128.87,128.31,124.48,124.20,121.13,119.23,79.20,62.47,61.43,25.34,14.16.
Comparative example 1
The comparative example is used for the preparation of formula (3) compound represented.
Formula (3) compound represented is prepared according to the method for (1) the step of embodiment 1, unlike, using to chlorobenzene Phenol replaces the fluoro- 3- formyl phenol of 4-, so that formula (3) compound represented (4.2mmol, yield 84%) be made.
1H NMR(600MHz,CDCl3) δ 1.34 (t, J=7.1Hz, 3H), 1.59 (s, 6H), 4.23 (q, J=6.6Hz, 2H), 6.79 (d, J=8.9Hz, 2H), 7.19 (d, J=8.9Hz, 2H)
13C NMR(151MHz,CDCl3)δ14.4,24.9,61.5,78.7,115.9,128.3,136.6,155.6, 170.3.
Embodiment 14
The embodiment is used for the preparation of formula (2-1) compound represented.
(a) by 1.66g (10mmol) 5- formylsalicylic acid, 90mmol dimethylamine hydrochloride, 1.5mmol potassium fluoride, 1.8mL (19mmol) bromonitromethane and 40mL toluene are mixed, and are heated to reflux 6h at 120 DEG C；It is then that reaction solution is cooling To room temperature (about 25 DEG C), and it is evaporated under reduced pressure the solvent for removing filtrate.30mL water and ethyl acetate (30mL × 3) extraction is added, closes And organic phase, and 30mL saturated common salt water washing is used, organic phase is dry using anhydrous sodium sulfate.By the organic phase after drying Concentration, resulting concentrate are pure through silica gel column chromatography (eluent is the ethyl acetate of volume ratio 1:4 and the mixed liquor of petroleum ether) Change can obtain formula (2 " -1) compound represented (7.2mmol, yield 72%).
(b) 1.22g (5mmol) formula (2 " -1) compound represented is dissolved in 5mL (50mmol) acetic anhydride, is added dropwise 2 The concentrated phosphoric acid (about 100mg) of 85 weight % is dripped, and the water of 10mL is added, the reaction was continued after reaction 4h under room temperature (about 25 DEG C) 1h.It filters, gained solid phase is washed with water, and formula (2-1) compound represented (4mmol, yield 80%) can be obtained in drying.
1H NMR(600MHz,DMSO-d6) δ 13.48 (s, 1H), 8.72 (s, 1H), 8.56 (d, J=2.4Hz, 1H), 8.22 (dd, J=8.4,2.3Hz, 1H), 7.42 (d, J=8.5Hz, 1H), 2.29 (s, 3H)
Test case 1: the inhibition test of human liver's fructose-1,6-diphosphonic acid enzyme
Reaction system is 50mM Tric-HCl pH 7.4,0.8mM MgCl2, 11.2 μ g/ml, 0.4mM FBP of FBPase (ester of Harden Young) prepares the ester type compound prepared in the above embodiments containing nitroethenyl group and comparative example Compound and aspirin (for purchased from Sinopharm Chemical Reagent Co., Ltd.) are respectively configured as the suppression of suitable concentration gradient Preparation solution terminates enzyme with 1M perchloric acid and urges reaction, using containing for end-point method measurement inorganic phosphate then in 37 DEG C of enzymatic hydrolysis 5min Amount acquires the IC of each inhibitor to measure the activity of liver ester of Harden Young enzyme50, as a result as shown in table 1 below.
Table 1
Compound IC50(μM)
Formula (1-1) 0.87
Formula (1-2) 0.93
Formula (1-3) 0.79
Formula (1-4) 0.83
Formula (1-5) 0.95
Formula (1-6) 0.99
Formula (1-7) 2.68
Formula (1-8) 6.99
Formula (1-9) 8.21
Formula (1-10) 3.68
Formula (1-11) 1.88
Formula (1-12) 1.98
Formula (1-13) 2.18
Formula (1-27) 97.3
Formula (1-28) 65.2
Formula (3) 24.7% (50 μM)
Formula (2-1) 8.1
Aspirin 20.7% (50 μM)
Note: 24.7% (50 μM) expressions in formula (3), the inhibiting rate of 50 μM of formulas (3) is only capable of reaching 24.7%, to Ah Si Woods is done in the same fashion understanding.
It can be seen that the ester type compound provided by the invention containing nitroethenyl group with higher by the data of upper table 1 Ester of Harden Young enzyme inhibition, inhibit ester of Harden Young enzyme IC5010 μM be can achieve hereinafter, more preferably 8.5 μM hereinafter, still more preferably be 4 μM hereinafter, be still more preferably 2.5 μM hereinafter, be still more preferably 2 μM with Under, it is still more preferably 1 μM or less.
Test case 2: the influence to the release of rat hepatocytes glucose
Separation prepares primary hepatocyte from the SD rat of overnight fasting, and liver cell is used and contains 1g/L glucose and 10 The DMEM culture medium (InvitrogenTM) of weight %FBS is resuspended, in 24 orifice plates (every hole about 2 × 105It is a) incubate 4 hours after more Fresh culture is changed to be incubated overnight.Culture medium changes 500 μ L into without containing glucose and phenol later, contains 20mM sodium lactate, 2mM The DMEM culture medium (see the table below shown in 2 using concentration) of Sodium Pyruvate, untested compound takes 50 μ L culture mediums after 4 hours (InvitrogenTM) it is surveyed according to the operation instruction of manufacturer with Glucose Oxidase kit (Fudan-ZhangjiangTM) Determine glucose content.Using DMSO as blank control test, melbine is positive control test, and result is as shown in table 2 below:
Table 2
By upper table 2 as can be seen that the ester type compound provided by the invention containing nitroethenyl group, is 50 μM in concentration When, it will be able to 58% release rate below is obtained, and improves concentration to after 100 μM, release rate is decreased obviously to 50% or less (special It is not formula (1) compound represented, 15% or less can be dropped to), or even than the release of the melbine using higher concentration Rate is all low, this shows that the ester type compound provided by the invention containing nitroethenyl group can preferably inhibit hypoglycemic target enzyme human body Liver ester of Harden Young enzyme, also has a significant impact hepatic glucose burst size.
Test case 3: the test of platelet aggregation is influenced
Blood is taken to healthy volunteer's cubital venous, mixes anticoagulant, room with 3.8 weight % sodium citrates (volume ratio 1:9) The blood plasma (PRP) for being rich in blood platelet is collected within 10 minutes under warm (about 25 DEG C) with 500g centrifugation, remainder is with 18000g centrifugation 10 Minute, prepare the blood plasma (PPP) of Platelet poor.It is returned to zero with PPP, 200 μ L PRP is taken to be added in opacity tube, 5 points are incubated at 37 DEG C Clock is separately added into 1 μ L DMSO or 1 μ L untested compound liquid storage in conjunction with 5min and then adds Thrombin 2nM, small with blood Plate assembles instrument and detects maximum platelet aggregation rate, the results are shown in Table shown in 3.
Table 3
Compound L-Arginine (%, 2 μM)
Formula (1-1) 90.5
Formula (1-3) 87.3
Formula (1-5) 84.2
Formula (1-8) 85.8
Formula (1-12) 88.6
Formula (2-1) 50.9
Formula (3) 5
By upper table 3 as can be seen that the ester type compound provided by the invention containing nitroethenyl group, additionally it is possible to effectively press down Platelet aggregation processed can obtain 50% or more L-Arginine, especially for formula (1) in the case where concentration is 2 μM For compound represented, 80% or more inhibiting rate can be obtained, this shows the ester provided by the invention containing nitroethenyl group Class compound can preferably inhibit platelet aggregation, preparation treat or prevent the drug of thrombus disease using it is upper have it is latent Medical value.
Test case 4: the influence to mouse hepatocyte cell inner lipid deposition
By Primary mouse hepatocyte cultures in 35mm culture dish, after serum starvation overnight, it is changed to containing 30mM grape The DMEM culture medium of sugar and 500nM insulin.Specific grouping are as follows: normal incubation medium control group, high sugar+hyperinsulinism culture medium group Glucose and insulin are added into culture medium with compound+high sugar+hyperinsulinism culture medium group, is allowed to concentration and respectively reaches With hyperglycemia in analogue body and hyperinsulinism environment, inducing hepatocyte lipidosis and IR can occur for 30mM and 500nM.
Lipid within endothelial cells content assaying method specifically: group of cells sucks culture medium after drug-treated, and 100 μ are added The PBS buffer solution of l X-100 containing 10%Triton, places 15min on ice, and then scraping collects sample into centrifuge tube, ultrasound 15min is centrifuged with 4 DEG C, 14000rpm after 30s, then measures the content of TG, TC and protein in supernatant, kit is pressed in operation Specification carries out.Its result is as shown in the following table 4,5.
Table 4
Table 5
Can be seen that the compound of the present invention by the data of table 4 and table 5 has the function of preferable reducing blood lipid, is making The standby drug for treating or preventing hyperlipidemia class disease has potential medical value using upper.
The preferred embodiment of the present invention has been described above in detail, still, during present invention is not limited to the embodiments described above Detail within the scope of the technical concept of the present invention can be with various simple variants of the technical solution of the present invention are made, this A little simple variants all belong to the scope of protection of the present invention.
It is further to note that specific technical features described in the above specific embodiments, in not lance In the case where shield, can be combined in any appropriate way, in order to avoid unnecessary repetition, the present invention to it is various can No further explanation will be given for the combination of energy.
In addition, various embodiments of the present invention can be combined randomly, as long as it is without prejudice to originally The thought of invention, it should also be regarded as the disclosure of the present invention.

Claims (18)

1. a kind of ester type compound containing nitroethenyl group, which is characterized in that the ester type compound is chemical combination shown in formula (1) Object:
Wherein, R1-R5In at least one beRemaining group is each independently selected from H, halogen, C1-C6 Alkyl, C1-C6 alkoxy ,-NO2、-COOH、-CN、-NR2, the alkyl of C1-C6 that is substituted with a substituent and substituted base take The alkoxy of the C1-C6 in generation, R are selected from the alkyl of C1-C6 be substituted with a substituent or unsubstituted, and the substituent group is respectively independent Ground is selected from halogen ,-COOH and-NO2One of or it is a variety of, remaining described group not simultaneously be H；R6Selected from H, halogen, C1- The alkyl of C6 and the carboxylate of C2-C8.
2. ester type compound according to claim 1, wherein in formula (1), R1-R5In in addition to forIn addition Remaining group be each independently selected from the alkoxy ,-NO of H, halogen, the alkyl of C1-C4, C1-C42、-COOH、-CN、- NR2, the alkyl of C1-C4 that is substituted with a substituent and the C1-C4 being substituted with a substituent alkoxy, R is selected from and is substituted with a substituent Or unsubstituted C1-C4 alkyl, the substituent group is each independently selected from halogen ,-COOH and-NO2One of or it is more Kind；R6Selected from H, halogen, the alkyl of C1-C4 and C2-C6 carboxylate.
3. ester type compound according to claim 2, wherein in formula (1), R1-R5In in addition to forIn addition Remaining group be each independently selected from H, F, Cl, Br ,-NO2,-CN, methyl, ethyl, propyl, isopropyl, methoxyl group, second Oxygroup ,-COOH ,-CF3、-CCl3、-CHF2、-CHCl2、-O-CF3、-O-CCl3、-O-CHF2With-O-CHCl2；R6Selected from H, halogen Element, methyl, ethyl and-COOCH3。
4. ester type compound described in any one of -3 according to claim 1, whereinIt is selected from
5. ester type compound described in any one of -3 according to claim 1, wherein the ester type compound is selected from following formula The compound:
6. ester type compound described in any one of -3 according to claim 1, wherein the ester type compound is selected from following formula The compound:
7. a kind of method for preparing ester type compound described in claim 1, this method comprises:
(1) in the presence of alkali metal salt and the first organic solvent, by phenol compound shown in formula (1 ') and the halogenated -2- first of 2- Base ethyl propionate carries out substitution reaction, obtains formula (1 ") compound represented；
Wherein, R1'-R5'In at least one be-CHO, remaining group be each independently selected from H, halogen, C1-C6 alkyl, The alkoxy ,-NO of C1-C62、-COOH、-CN、-NR2, the alkyl of C1-C6 being substituted with a substituent and the C1- being substituted with a substituent The alkoxy of C6, R are selected from the alkyl of C1-C6 be substituted with a substituent or unsubstituted, and the substituent group is each independently selected from Halogen ,-COOH and-NO2One of or it is a variety of, remaining described group not simultaneously be H；
(2) in the presence of organic ammonium salt and the second organic solvent, by formula (1 ") compound represented and formula R6CH2-NO2Shown in Compound carries out condensation reaction, obtains formula (1) compound represented.
8. according to the method described in claim 7, wherein, in step (1), phenol compound shown in formula (1 ') and 2- halogen The dosage molar ratio of generation -2 Methylpropionic acid ethyl ester is 1:2-4.
9. method according to claim 7 or 8, wherein in step (2), formula (1 ") compound represented and formula R6CH2- NO2The dosage molar ratio of the compound shown is 1:4-8.
10. method according to claim 7 or 8, wherein in step (1), the alkali metal salt is potassium sulfite, phosphoric acid It is one or more in potassium, potassium acetate, potassium carbonate and vulcanized sodium；
First organic solvent is a kind of or more in N,N-dimethylformamide, dimethyl sulfoxide, acetone, tetrahydrofuran and acetonitrile Kind.
11. according to the method described in claim 10, wherein, the dosage of phenol compound shown in formula (1 ') and alkali metal salt Molar ratio is 1:2-3.
12. the method according to claim 7 or 9, wherein in step (2), the organic ammonium salt is ammonium formate, citric acid It is one or more in ammonium, trifluoroacetic acid ammonium, ammonium acetate and ammonium oxalate；
Second organic solvent is acetic acid.
13. according to the method for claim 12, wherein the dosage molar ratio of formula (1 ") compound represented and organic ammonium salt For 1:2-6.
14. method according to claim 7 or 8, wherein in step (1), the condition of the substitution reaction includes: temperature It is 80-110 DEG C, time 6-12h；
In step (2), the condition of the condensation reaction includes: that temperature is 100-120 DEG C, time 8-12h.
15. containing the ester type compound of nitroethenyl group or its is pharmaceutically acceptable described in any one of claim 1-6 Application of the salt on the drug that preparation inhibits fructose-1,6-diphosphonic acid enzyme.
16. containing the ester type compound of nitroethenyl group or its is pharmaceutically acceptable described in any one of claim 1-6 Application of the salt on the drug that preparation treats or prevents gluconeogenesis metabolism class disease or thrombus disease.
17. application according to claim 16, wherein the gluconeogenesis metabolism class disease is diabetes, obesity, hyperlipidemia Or nonalcoholic fatty liver；The thrombus disease is related with platelet aggregation, and the thrombus disease is ischemic heart and brain blood Pipe disease, atherosclerosis, myocardial infarction, cardiac valve replacement, bypass operation of coronary artery or the postoperative row of organ transplantation Arterial thrombus caused by different reaction.
18. containing the ester type compound of nitroethenyl group or its is pharmaceutically acceptable described in any one of claim 1-6 Application of the salt on the drug that preparation inhibits the drug of liver cell release glucose or preparation to inhibit platelet aggregation.
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