CN105189446B - Phloroglucin analog derivative and its purposes in treating neurodegenerative disease - Google Patents

Phloroglucin analog derivative and its purposes in treating neurodegenerative disease Download PDF

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CN105189446B
CN105189446B CN201480026162.0A CN201480026162A CN105189446B CN 105189446 B CN105189446 B CN 105189446B CN 201480026162 A CN201480026162 A CN 201480026162A CN 105189446 B CN105189446 B CN 105189446B
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methyl
unsubstituted
butanone
substitution
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CN105189446A (en
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庾石山
张丹
王亚丹
鲍秀琦
屈晶
徐嵩
泰文娇
武良玉
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Institute of Materia Medica of CAMS
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Abstract

The present invention provides the pharmaceutical compositions of a kind of phloroglucin analog derivative, preparation method including above compound and these compounds to prepare the application in preventing and/or treating the drug of Alzheimer disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, incoordination hair and blood enlargement of pipe disease, bovine spongiform encephalopathy, gram refined Er Shi diseases, Huntington's disease, cerebral atrophy, primary lateral sclerosis, spinal muscular atrophy.

Description

Phloroglucin analog derivative and its purposes in treating neurodegenerative disease
Technical field
The present invention relates to acceptable salt in a kind of phloroglucin analog derivative and its pharmacodynamics, contain their medicine group Close the application of object and this kind of compound in the drug for preparing neurodegenerative disease.
Background technology
Neurodegenerative disease (such as Parkinson's disease, Alzheimer's disease, multiple sclerosis) is world today's range The interior a kind of disease for seriously endangering human health, morbidity and mortality are in ascendant trend year by year.Such disease be by brain and Caused by the damage of the neuron of spinal cord, deteriorate over time, leads to move or remember etc. dysfunction.With the world The continuous exacerbation of aging of population, there is an urgent need to effective medicines.
Recent study finds that intracerebral neuroinflamation and the generation and development of a variety of neurodegenerative diseases are closely related, The lymphocyte that its lesion mediated is mainly invaded by the activation of spongiocyte and periphery discharges caused by the neurotoxicity factor.It is small Spongiocyte and astroglia are the inherent immunity cells in brain parenchym, are in quiescent condition under normal circumstances, have The effect for maintaining central nervous system normal steady state, under the pathological conditions such as brain infection or damage, these cells are activated, and start Immune response and process of tissue reparation remove foreign matter and lesion in brain, once infection or damage are replied, these cells then return To quiescent condition.In the process of neurodegenerative disease, these cells are frequently activated, release a large amount of immune factor and Cytotoxic factor, including arachidonic acid metabolite, cell factor, inflammatory chemokine, nitric oxide, active oxygen radical With excitatory amino acid etc., cause the damage of neuron, denaturation even dead.And the neuron etc. of degeneration necrosis release it is thin Born of the same parents' fragment and bioactive substance can also activate microglia and astroglia again, to cause to be held in brain Continue continuous Neuroinflammation, and then causes the degeneration of neuron dead.Therefore, it develops and develops to have and inhibit neuritis The active drug of disease reduces the overexpression of the activation and immune factor and inflammatory factor of spongiocyte, and treatment nerve is moved back Row disease is of great significance.
Invention content
The technical problems to be solved of the present invention are to provide general formula I0The compound, including raceme and optics it is different The hydrate or pro-drug of acceptable salt, salt on structure body and its pharmacodynamics.
The invention solves another technical problem be to provide a kind of pharmaceutical composition comprising at least one general formula I0 The compound, including raceme and optical isomer, the hydrate or pro-drug of acceptable salt, salt in pharmacodynamics And pharmaceutical carrier and/or excipient.
The invention solves another technical problem be to provide general formula I0The compound, including raceme and optics Isomers, acceptable salt, the hydrate of salt or pro-drug are in the drug for preparing neurodegenerative disease in pharmacodynamics Application.
In order to solve the above technical problems, the technical solution adopted by the present invention is：
According to the present invention, compound passes through general formula I0It indicates：
Wherein, R1Indicate H ,-CF3, substitution or unsubstituted linear chain or branched chain C1-10Alkyl, benzyl ,-NO2Or-CORa1, In,
Substituent group can be selected from the C of-OH ,-F ,-Cl ,-Br, linear chain or branched chain1-6Alkoxy ,-SH, substituted or unsubstituted furan Our base or-COOH, substituted or unsubstituted amido, wherein
Substituent group on furazanyl can be selected from the C of linear chain or branched chain1-10Alkyl, substituted or unsubstituted phenyl, substitution or Unsubstituted benzenesulfonyl, wherein
Substituent group on phenyl and benzenesulfonyl can be selected from the C of-OH ,-F ,-Cl ,-Br ,-COOH, linear chain or branched chain1-6Alkane Base ,-CHF2、-CF3、-CN、-NO2、-OCF3、-ONO2Or the C of linear chain or branched chain1-6Alkoxy,
Substituent group on amido can be selected from the C of linear chain or branched chain1-6Alkyl, C3-6Naphthenic base or substituent group and N atoms are common Constitute it is five-, six- or seven-membered containing 1-3 heteroatomic saturated heterocyclics, can substituted base on heterocycle, wherein
Substituent group on heterocycle can be selected from the C of-OH ,-F ,-Cl ,-Br ,-COOH, linear chain or branched chain1-6Alkyl, C3-6Cycloalkanes The C of base, linear chain or branched chain1-6Alkoxy, substituted or unsubstituted phenyl, wherein
Substituent group on phenyl can be selected from the C of-OH ,-F ,-Cl ,-Br ,-COOH, linear chain or branched chain1-6Alkyl ,-CHF2、- CF3、-CN、-NO2、-OCF3、-ONO2、-NH2Or the C of linear chain or branched chain1-6Alkoxy；
Ra1It can be selected from the C of substituted or unsubstituted linear chain or branched chain2-10Alkyl, wherein
Substituent group on alkyl can be selected from-OH ,-F ,-Cl ,-Br, substituted or unsubstituted phenyl ,-COOH or-NH2, In,
Substituent group can be selected from the C of-OH ,-F ,-Cl ,-Br ,-COOH, linear chain or branched chain1-6Alkyl ,-CHF2、-CF3、-CN、- NO2、-OCF3、-ONO2Or the C of linear chain or branched chain1-6Alkoxy；
R2And R4The independently C of expression-H ,-OH, linear chain or branched chain1-6Alkoxy, benzyloxy ,-OCF3、-ONO2、-F、- Cl、-Br、-CN、-NO2, substitution or unsubstituted linear chain or branched chain C1-10Alkyl ,-CF3, substituted or unsubstituted carbonyl, wherein
C1-10Substituent group on alkyl can be selected from-OH, linear chain or branched chain C1-6Alkoxy ,-F ,-Cl ,-Br ,-COOH ,- NH2,-SH,
Substituent group on carbonyl can be selected from-OH, linear chain or branched chain C1-10Alkyl, contains alkene at substituted or unsubstituted phenyl The C of key or acetylene bond1-10Unsaturated alkyl or substituted or unsubstituted amido, wherein
Substituent group on phenyl can be selected from the C of-OH ,-F ,-Cl ,-Br ,-COOH, linear chain or branched chain1-10Alkyl ,-CHF2、- CF3、-CN、-NO2、-OCF3、-ONO2Or the C of linear chain or branched chain1-6Alkoxy,
Substituent group on amido can be selected from the C of substituted or unsubstituted linear chain or branched chain1-10Alkyl, C3-6Naphthenic base takes Dai Jiyu N atoms collectively form five-, six- or seven-membered containing 1-3 heteroatomic saturated heterocyclics, wherein
Substituent group can be selected from-OH, linear chain or branched chain C1-6Alkoxy ,-F ,-Cl ,-Br ,-COOH ,-NH2；
R3And R5The independently C of expression-H ,-OH, linear chain or branched chain1-6Alkyl ,-ONO2, substituted or unsubstituted straight chain Or the C of branch1-6Substituted or unsubstituted benzyloxy on alkoxy, phenyl ring, wherein
The substituent group can be selected from-OH, linear chain or branched chain C1-6Alkoxy ,-F ,-Cl ,-Br ,-NH2、-COOH；
N can be 1-5,
X indicates the C of H, straight chain or straight chain1-6Alkyl, substituted or unsubstituted amido, wherein
Substituent group can be selected from the C of linear chain or branched chain1-6Alkyl, C3-6Naphthenic base or substituent group and N atoms collectively form five yuan, It is hexa-atomic or seven yuan can substituted base containing 1-3 heteroatomic saturated heterocyclics (except morpholine ring), on heterocycle, wherein
Substituent group can be selected from the C of-OH ,-F ,-Cl ,-Br ,-COOH, linear chain or branched chain1-6Alkyl, C3-6Naphthenic base, straight chain or The C of branch1-6Alkoxy, substituted or unsubstituted phenyl, wherein
Substituent group on phenyl can be selected from the C of-OH ,-F ,-Cl ,-Br ,-COOH, linear chain or branched chain1-6Alkyl ,-CHF2、- CF3、-CN、-NO2、-OCF3、-ONO2、-NH2Or the C of linear chain or branched chain1-6Alkoxy.
According to the present invention, compound is indicated by general formula I：
Wherein, R1Indicate H ,-CF3, substitution or unsubstituted linear chain or branched chain C1-10Alkyl, benzyl ,-NO2Or-CORa1, In,
Substituent group can be selected from the C of-OH ,-F ,-Cl ,-Br, linear chain or branched chain1-6Alkoxy ,-SH, substituted or unsubstituted furan Our base or-COOH, substituted or unsubstituted amido, wherein
Substituent group on furazanyl can be selected from the C of linear chain or branched chain1-10Alkyl, substituted or unsubstituted phenyl, substitution or Unsubstituted benzenesulfonyl, wherein
Substituent group on phenyl and benzenesulfonyl can be selected from the C of-OH ,-F ,-Cl ,-Br ,-COOH, linear chain or branched chain1-6Alkane Base ,-CHF2、-CF3、-CN、-NO2、-OCF3、-ONO2Or the C of linear chain or branched chain1-6Alkoxy,
Substituent group on amido can be selected from the C of linear chain or branched chain1-6Alkyl, C3-6Naphthenic base or substituent group and N atoms are common Constitute it is five-, six- or seven-membered containing 1-3 heteroatomic saturated heterocyclics, can substituted base on heterocycle, wherein
Substituent group on heterocycle can be selected from the C of-OH ,-F ,-Cl ,-Br ,-COOH, linear chain or branched chain1-6Alkyl, C3-6Cycloalkanes The C of base, linear chain or branched chain1-6Alkoxy, substituted or unsubstituted phenyl, wherein
Substituent group on phenyl can be selected from the C of-OH ,-F ,-Cl ,-Br ,-COOH, linear chain or branched chain1-6Alkyl ,-CHF2、- CF3、-CN、-NO2、-OCF3、-ONO2、-NH2Or the C of linear chain or branched chain1-6Alkoxy；
Ra1It can be selected from the C of substituted or unsubstituted linear chain or branched chain2-10Alkyl, wherein
Substituent group on alkyl can be selected from-OH ,-F ,-Cl ,-Br, substituted or unsubstituted phenyl ,-COOH or-NH2, In,
Substituent group can be selected from the C of-OH ,-F ,-Cl ,-Br ,-COOH, linear chain or branched chain1-6Alkyl ,-CHF2、-CF3、-CN、- NO2、-OCF3、-ONO2Or the C of linear chain or branched chain1-6Alkoxy；
R3And R5The independently C of expression-H ,-OH, linear chain or branched chain1-6Alkyl ,-ONO2, substituted or unsubstituted straight chain Or the C of branch1-6Substituted or unsubstituted benzyloxy on alkoxy, phenyl ring, wherein
The substituent group can be selected from-OH, linear chain or branched chain C1-6Alkoxy ,-F ,-Cl ,-Br ,-NH2、-COOH；
N can be 1-5,
X indicates the C of H, straight chain or straight chain1-6Alkyl, substituted or unsubstituted amido, wherein
Substituent group can be selected from the C of linear chain or branched chain1-6Alkyl, C3-6Naphthenic base or substituent group and N atoms collectively form five yuan, It is hexa-atomic or seven yuan can substituted base containing 1-3 heteroatomic saturated heterocyclics (except morpholine ring), on heterocycle, wherein
Substituent group can be selected from the C of-OH ,-F ,-Cl ,-Br ,-COOH, linear chain or branched chain1-6Alkyl, C3-6Naphthenic base, straight chain or The C of branch1-6Alkoxy, substituted or unsubstituted phenyl, wherein
Substituent group on phenyl can be selected from the C of-OH ,-F ,-Cl ,-Br ,-COOH, linear chain or branched chain1-6Alkyl ,-CHF2、- CF3、-CN、-NO2、-OCF3、-ONO2、-NH2Or the C of linear chain or branched chain1-6Alkoxy.
According to the present invention, compound is indicated by general formula IA：
Wherein, RaIndicate the C of substitution or unsubstituted linear chain or branched chain1-10Alkyl, benzyl ,-NO2、-CORa1, wherein substitution Base can be selected from the C of-OH ,-F ,-Cl ,-Br, linear chain or branched chain1-6Alkoxy ,-SH, substituted or unsubstituted furazanyl or-COOH, Wherein,
Substituent group can be selected from the C of linear chain or branched chain1-10Alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzene Sulfonyl, wherein
Substituent group on phenyl and benzenesulfonyl can be selected from the C of-OH ,-F ,-Cl ,-Br ,-COOH, linear chain or branched chain1-6Alkane Base ,-CHF2、-CF3、-CN、-NO2、-OCF3、-ONO2Or the C of linear chain or branched chain1-6Alkoxy,
Ra1It can be selected from the C of substituted or unsubstituted linear chain or branched chain2-10Alkyl, wherein
Substituent group on alkyl can be selected from-OH ,-F ,-Cl ,-Br, substituted or unsubstituted phenyl ,-COOH or-NH2, In,
Substituent group can be selected from the C of-OH ,-F ,-Cl ,-Br ,-COOH, linear chain or branched chain1-6Alkyl ,-CHF2、-CF3、-CN、- NO2、-OCF3、-ONO2Or the C of linear chain or branched chain1-6Alkoxy.
According to the present invention, work as RaIndicate the C of unsubstituted linear chain or branched chain1-10When alkyl, preferred RaBe methyl, ethyl, Propyl, isopropyl, butyl, isobutyl group, tertiary butyl, amyl, isopentyl, hexyl etc., but it is not limited to the above group.
According to the present invention, work as RaIndicate the C of the linear chain or branched chain of substitution1-10When alkyl, preferred RaBase includes, but unlimited The group shown in the general formula IAa：
Wherein, n can indicate 1-5,
Ra2It can be selected from the C of linear chain or branched chain1-10Alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzene sulfonyl Base, wherein
Substituent group on phenyl and benzenesulfonyl can be selected from the C of-OH ,-F ,-Cl ,-Br ,-COOH, linear chain or branched chain1-6Alkane Base ,-CHF2、-CF3、-CN、-NO2、-OCF3、-ONO2Or the C of linear chain or branched chain1-6Alkoxy.
, according to the invention it is preferred to the compound that indicates of general formula IAa include：
Ra2Selected from H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary butyl, amyl, isopentyl, hexyl, take Generation or unsubstituted phenyl, phenyl ring on substituted or unsubstituted benzenesulfonyl, substituent group can be selected from-H ,-OH ,-F ,-Cl ,- Br、-COOH、C1-6Alkyl ,-CHF2、-CF3、-CN、-NO2、-OCF3、-ONO2, linear chain or branched chain C1-6Alkoxy ,-NH2。
According to the present invention, compound is indicated by general formula IB：
Wherein, R3And R5The independently C of expression-H ,-OH, linear chain or branched chain1-6Alkyl ,-ONO2、-ORcOr-SRc, In,
RcIndicate the C of substitution or unsubstituted linear chain or branched chain1-10Alkyl, benzyl, wherein
The substituent group can be selected from-OH, linear chain or branched chain C1-6Alkoxy ,-F ,-Cl ,-Br ,-NH2、-COOH；
Rb1、Rb2Independently indicate H, linear chain or branched chain C1-6Alkyl, C3-6Naphthenic base or-NRb1Rb2Five yuan of composition, six Member or seven yuan can substituted base containing 1-3 heteroatomic saturated heterocyclics, on heterocycle, wherein
Substituent group can be selected from the C of-OH ,-F ,-Cl ,-Br ,-COOH, linear chain or branched chain1-6Alkyl, C3-6Naphthenic base, straight chain or The C of branch1-6Alkoxy, substituted or unsubstituted phenyl, wherein
Substituent group on phenyl can be selected from the C of-OH ,-F ,-Cl ,-Br ,-COOH, linear chain or branched chain1-6Alkyl ,-CHF2、- CF3、-CN、-NO2、-OCF3、-ONO2、-NH2Or the C of linear chain or branched chain1-6Alkoxy.
, according to the invention it is preferred to the compound that indicates of general formula IB include：
R3And R5Be respectively and independently selected from H ,-OH, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary butyl, amyl, The C of isopentyl, hexyl, linear chain or branched chain1-6Alkoxy, benzyloxy,
Rb1、Rb2It is respectively and independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary butyl, amyl, different Amyl, hexyl, cyclopropyl, cyclopenta, cyclohexyl, substituted or unsubstituted benzyl, phenethyl, substitution or unsubstituted on phenyl ring Phenyl, substituent group can be selected from-H ,-OH ,-F ,-Cl ,-Br ,-COOH, C1-6Alkyl ,-CHF2、-CF3、-CN、-NO2、-OCF3、- ONO2, linear chain or branched chain C1-6Alkoxy ,-NH2,
Or-NRb1Rb2It constitutes five-, six- or seven-membered containing 1-3 heteroatomic saturated heterocyclics, can be selected from following miscellaneous Ring：
Wherein, R ' can indicate-OH ,-F ,-Cl ,-Br ,-COOH, C1-6The C of alkyl, linear chain or branched chain1-6Alkoxy, substitution Or unsubstituted phenyl, substituent group can be selected from-H ,-OH ,-F ,-Cl ,-Br ,-COOH, C1-6Alkyl ,-CHF2、-CF3、-CN、- NO2、-OCF3、-ONO2, linear chain or branched chain C1-6Alkoxy ,-NH2。
According to the present invention, compound is indicated by general formula IC：
Wherein, Rd1、Rd2And Rd3Independently expression-H, linear chain or branched chain C2-6Alkyl, benzyl or-CF3,
N can be 2-5,
Re1, Re2Independently indicate H, linear chain or branched chain C1-6Alkyl, C3-6Naphthenic base or-NRe1Re2Five yuan of composition, six Member or seven yuan can substituted base containing 1-3 heteroatomic saturated heterocyclics (except morpholine ring), on heterocycle, wherein
Substituent group can be selected from the C of-OH ,-F ,-Cl ,-Br ,-COOH, linear chain or branched chain1-6Alkyl, C3-6Naphthenic base, straight chain or The C of branch1-6Alkoxy, substituted or unsubstituted phenyl, wherein
Substituent group on phenyl can be selected from the C of-OH ,-F ,-Cl ,-Br ,-COOH, linear chain or branched chain1-6Alkyl ,-CHF2、- CF3、-CN、-NO2、-OCF3、-ONO2、-NH2Or the C of linear chain or branched chain1-6Alkoxy.
, according to the invention it is preferred to the compound that indicates of general formula IC include:
Rd1、Rd2And Rd3It is respectively and independently selected from methyl, ethyl, propyl, isopropyl, benzyl ,-CF3,
N indicates 3-5,
Re1、Re2It is respectively and independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary butyl, amyl, different Amyl, hexyl, cyclopropyl, cyclopenta, cyclohexyl, substituted or unsubstituted benzyl, phenethyl, substitution or unsubstituted on phenyl ring Phenyl, substituent group can be selected from-H ,-OH ,-F ,-Cl ,-Br ,-COOH, C1-6Alkyl ,-CHF2、-CF3、-CN、-NO2、-OCF3、- ONO2, linear chain or branched chain C1-6Alkoxy ,-NH2,
Or-NRe1Re2It constitutes five-, six- or seven-membered containing 1-3 heteroatomic saturated heterocyclics, can be selected from following miscellaneous Ring：
Wherein, R ' can indicate-OH ,-F ,-Cl ,-Br ,-COOH, C1-6The C of alkyl, linear chain or branched chain1-6Alkoxy, substitution Or unsubstituted phenyl, substituent group can be selected from-H ,-OH ,-F ,-Cl ,-Br ,-COOH, C1-6Alkyl ,-CHF2、-CF3、-CN、- NO2、-OCF3、-ONO2, linear chain or branched chain C1-6Alkoxy ,-NH2。
, according to the invention it is preferred to general formula IC compounds represented including but not limited to chemical combination shown in general formula ICa Object：
Wherein, Re1、Re2Independently indicate H, linear chain or branched chain C1-6Alkyl, C3-6Naphthenic base or-NRe1Re2Constitute five It is first, hexa-atomic or seven yuan can substituted base containing 1-3 heteroatomic saturated heterocyclics (except morpholine ring), on heterocycle, wherein
Substituent group can be selected from the C of-OH ,-F ,-Cl ,-Br ,-COOH, linear chain or branched chain1-6Alkyl, C3-6Naphthenic base, straight chain or The C of branch1-6Alkoxy, substituted or unsubstituted phenyl, wherein
Substituent group on phenyl can be selected from the C of-OH ,-F ,-Cl ,-Br ,-COOH, linear chain or branched chain1-6Alkyl ,-CHF2、- CF3、-CN、-NO2、-OCF3、-ONO2、-NH2Or the C of linear chain or branched chain1-6Alkoxy.
, according to the invention it is preferred to the compound that indicates of general formula ICa include：
Re1、Re2It is respectively and independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary butyl, amyl, different Amyl, hexyl, cyclopropyl, cyclopenta, cyclohexyl, substituted or unsubstituted benzyl, phenethyl, substitution or unsubstituted on phenyl ring Phenyl, substituent group can be selected from-H ,-OH ,-F ,-Cl ,-Br ,-COOH, C1-6Alkyl ,-CHF2、-CF3、-CN、-NO2、-OCF3、- ONO2, linear chain or branched chain C1-6Alkoxy ,-NH2。
Or-NRb1Rb2It constitutes five-, six- or seven-membered containing 1-3 heteroatomic saturated heterocyclics, can be selected from following miscellaneous Ring：
Wherein, R ' can indicate-OH ,-F ,-Cl ,-Br ,-COOH, C1-6The C of alkyl, linear chain or branched chain1-6Alkoxy, substitution Or unsubstituted phenyl, substituent group can be selected from-H ,-OH ,-F ,-Cl ,-Br ,-COOH, C1-6Alkyl ,-CHF2、-CF3、-CN、- NO2、-OCF3、-ONO2, linear chain or branched chain C1-6Alkoxy ,-NH2。
According to the present invention, compound is indicated by general formula ID：
Wherein, Rf1、Rf2、Rf3Independently expression-H, linear chain or branched chain C1-6Alkyl, benzyl or-CF3；
R2、R4The independently C of expression-H ,-OH, linear chain or branched chain1-6Alkoxy ,-OCF3、-ONO2、-F、-Cl、-Br、- CN、-NO2, substitution or unsubstituted linear chain or branched chain C1-10Alkyl ,-CF3、-CORg, wherein
Substituent group can be selected from-OH, linear chain or branched chain C1-6Alkoxy ,-F ,-Cl ,-Br ,-COOH ,-NH2,-SH,
RgIt can indicate the C of H ,-OH, linear chain or branched chain1-10Alkyl, substituted or unsubstituted phenyl, containing ethylene linkage or acetylene bond C1-10Unsaturated alkyl or-NRg1Rg2, wherein
Substituent group can be selected from the C of-OH ,-F ,-Cl ,-Br ,-COOH, linear chain or branched chain1-10Alkyl ,-CHF2、-CF3、-CN、- NO2、-OCF3、-ONO2Or the C of linear chain or branched chain1-6Alkoxy,
Rg1、Rg2Independently indicate the C of H, substitution or unsubstituted linear chain or branched chain1-10Alkyl, C3-6Naphthenic base or- NRg1Rg2It constitutes five-, six- or seven-membered containing 1-3 heteroatomic saturated heterocyclics, wherein
Substituent group can be selected from-OH, linear chain or branched chain C1-6Alkoxy ,-F ,-Cl ,-Br ,-COOH ,-NH2；
N can be 1-5,
R6It can indicate the C of H, substitution or unsubstituted linear chain or branched chain1-10Alkyl, C3-6Naphthenic base or and R7、R8And connected C Four-seven yuan of atom and N atomic buildings containing 1-3 heteroatomic saturated heterocyclics, wherein
Substituent group can be selected from-OH, linear chain or branched chain C1-6Alkoxy ,-F ,-Cl ,-Br ,-COOH ,-NH2；
R7With R8Independently indicate the C of H, substitution or unsubstituted linear chain or branched chain1-10Alkyl or and R6And connected C is former Containing 1-3 heteroatomic saturated heterocyclics, condition is R for four-seven yuan of son and N atomic buildings7With R8Cannot be H simultaneously, wherein
Substituent group can be selected from-OH, linear chain or branched chain C1-6Alkoxy ,-F ,-Cl ,-Br ,-COOH ,-NH2、-SH、-SRh、- CONH2, guanidine radicals, substituted or unsubstituted phenyl and heterocyclic base, wherein
Substituent group on phenyl and heterocyclic base can be selected from the C of-OH ,-F ,-Cl ,-Br ,-COOH, linear chain or branched chain1-10Alkane Base ,-CHF2、-CF3、-CN、-NO2、-OCF3、-ONO2Or the C of linear chain or branched chain1-6Alkoxy,
RhIndicate the C of linear chain or branched chain1-10Alkyl.
, according to the invention it is preferred to general formula ID compound be general formula IDa compounds represented：
Wherein, Rf1、Rf2、Rf3Independently expression-H, linear chain or branched chain C1-6Alkyl, benzyl or-CF3
R6It can indicate the C of H, substitution or unsubstituted linear chain or branched chain1-10Alkyl, C3-6Naphthenic base, wherein
Substituent group can be selected from-OH, linear chain or branched chain C1-6Alkoxy ,-F ,-Cl ,-Br ,-COOH ,-NH2,
R7With R8Independently indicate the C of H, substitution or unsubstituted linear chain or branched chain1-10Alkyl, condition are R7With R8It cannot be same When be H, wherein
Substituent group can be selected from-OH, linear chain or branched chain C1-6Alkoxy ,-F ,-Cl ,-Br ,-COOH ,-NH2、-SH、-SRh、- CONH2, guanidine radicals, substituted or unsubstituted phenyl and heterocyclic base, wherein
Substituent group on phenyl and heterocyclic base can be selected from the C of-OH ,-F ,-Cl ,-Br ,-COOH, linear chain or branched chain1-10Alkane Base ,-CHF2、-CF3、-CN、-NO2、-OCF3、-ONO2Or the C of linear chain or branched chain1-6Alkoxy,
RhIndicate the C of linear chain or branched chain1-10Alkyl.
, according to the invention it is preferred to general formula IDa compounds represented include：
Rf1、Rf2、Rf3Selected from methyl, ethyl, propyl, isopropyl, benzyl ,-CF3,
R6Selected from H, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and substituted or unsubstituted methyl, ethyl, propyl, Isopropyl, butyl, isobutyl group, tertiary butyl, amyl, isopentyl, hexyl, substituent group can be selected from-OH, linear chain or branched chain C1-6Alkane Oxygroup ,-F ,-Cl ,-Br ,-COOH ,-NH2,
R7、R8It is respectively and independently selected from H (the two cannot be H simultaneously), substituted or unsubstituted methyl, ethyl, propyl, isopropyl Base, butyl, isobutyl group, tertiary butyl, amyl, isopentyl, hexyl, substituent group can be selected from-OH ,-COOH ,-NH2、-SH、-SCH3、- CONH2, guanidine radicals, substituted or unsubstituted phenyl and heterocyclic base, wherein the substituent group of phenyl can be-OH ,-F ,-Cl ,-Br ,- COOH, methyl, ethyl, isopropyl ,-CHF2、-CF3、-CN、-NO2、-OCF3、-ONO2Or the C of linear chain or branched chain1-6Alkoxy, virtue Miscellaneous base can be selected from furyl, imidazole radicals, pyrazolyl, pyridyl group, thienyl, pyrrole radicals, thiazolyl, pyrimidine radicals, indyl etc..
, according to the invention it is preferred to general formula IDa compounds represented be general formula IDa1 compounds represented：
Wherein, R7Indicate the C of substitution or unsubstituted linear chain or branched chain1-10Alkyl,
Substituent group can be selected from-OH, linear chain or branched chain C1-6Alkoxy ,-F ,-Cl ,-Br ,-COOH ,-NH2、-SH、-SRh、- CONH2, guanidine radicals, substituted or unsubstituted phenyl and heterocyclic base, wherein
Substituent group on phenyl and heterocyclic base can be selected from the C of-OH ,-F ,-Cl ,-Br ,-COOH, linear chain or branched chain1-10Alkane Base ,-CHF2、-CF3、-CN、-NO2、-OCF3、-ONO2Or the C of linear chain or branched chain1-6Alkoxy,
RhIndicate the C of linear chain or branched chain1-10Alkyl.
, according to the invention it is preferred to general formula IDa1 compounds represented include：
Rf1、Rf2、Rf3Selected from methyl, ethyl, propyl, isopropyl, benzyl ,-CF3,
R7Selected from H, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary butyl, amyl, Isopentyl, hexyl, substituent group can be selected from-OH ,-COOH ,-NH2、-SH、-SCH3、-CONH2, guanidine radicals, substituted or unsubstituted benzene Base and heterocyclic base, the wherein substituent group of phenyl can be-OH ,-F ,-Cl ,-Br ,-COOH, methyl, ethyl, isopropyl ,- CHF2、-CF3、-CN、-NO2、-OCF3、-ONO2Or the C of linear chain or branched chain1-6Alkoxy, heterocyclic base can be selected from furyl, imidazoles Base, pyrazolyl, pyridyl group, thienyl, pyrrole radicals, thiazolyl, pyrimidine radicals, indyl etc..
, according to the invention it is preferred to general formula ID compounds represented include general formula IDb compounds represented：
Wherein, Rf1、Rf2、Rf3Independently expression-H, linear chain or branched chain C1-10Alkyl, benzyl or-CF3
N atoms and ortho position C atoms participates in constituting jointly four-seven yuan containing a heteroatomic saturated heterocyclics of 1-3.
, according to the invention it is preferred to general formula IDb compounds represented include：
Rf1、Rf2、Rf3Selected from methyl, ethyl, propyl, isopropyl, benzyl ,-CF3,
M rings are selected from
In the present invention, alkoxy refers to the alkoxy of the C1-6 of linear chain or branched chain, the methoxyl group that can illustrate, ethyoxyl, positive third Oxygroup, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isoamoxy, positive hexyloxy, Dissident's oxygroup etc..
, according to the invention it is preferred to compound include but are not limited to following compound：
1- (2- methoxyl group -4,6- dihydroxy phenyls) -3- methyl-1s-butanone
1- (2- ethyoxyl -4,6- dihydroxy phenyls) -3- methyl-1s-butanone
1- (2- isopropoxy -4,6- dihydroxy phenyls) -3- methyl-1s-butanone
1- (2- propionyloxy -4,6- dihydroxy phenyls) -3- methyl-1s-butanone
3- [3,5- dihydroxy -2- (3- methylbutyryls) phenoxy group] methyl 4-phenyl furazan
(±) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4,6- dihydroxy phenyls] -3- methyl-1s-butanone hydrochloric acid Salt
(R) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4,6- dihydroxy phenyls] -3- methyl-1s-butanone hydrochloric acid Salt
(S) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4,6- dihydroxy phenyls] -3- methyl-1s-butanone hydrochloric acid Salt
(±) -1- [2- (2- hydroxyl -3- tert-butylamine bases propoxyl group) -4,6- dihydroxy phenyls] -3- methyl-1s-butanone hydrochloric acid Salt
(R) -1- [2- (2- hydroxyl -3- tert-butylamine bases propoxyl group) -4,6- dihydroxy phenyls] -3- methyl-1s-butanone hydrochloric acid
(S) -1- [2- (2- hydroxyl -3- tert-butylamine bases propoxyl group) -4,6- dihydroxy phenyls] -3- methyl-1s-butanone hydrochloric acid Salt
(±) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4- methoxyphenyls] -3- methyl-1s-butanone hydrochloric acid Salt,
(R) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4- methoxyphenyls] -3- methyl-1s-butanone hydrochloride
(S) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4- methoxyphenyls] -3- methyl-1s-butanone hydrochloride
(±) -1- [2- (2- hydroxyl -3- tert-butylamine bases propoxyl group) -4- methoxyphenyls] -3- methyl-1s-butanone hydrochloride
(R) -1- [2- (2- hydroxyl -3- tert-butylamine bases propoxyl group) -4- methoxyphenyls] -3- methyl-1s-butanone hydrochloride
(S) -1- [2- (2- hydroxyl -3- tert-butylamine bases propoxyl group) -4- methoxyphenyls] -3- methyl-1s-butanone hydrochloride
(±) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4,6- Dimethoxyphenyls] -3- methyl-1s-butanone salt Hydrochlorate
(R) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4,6- Dimethoxyphenyls] -3- methyl-1s-butanone salt Hydrochlorate
(S) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4,6- Dimethoxyphenyls] -3- methyl-1s-butanone salt Hydrochlorate
(±) -1- [2- (2- hydroxyl -3- tert-butylamine bases propoxyl group) -4,6- Dimethoxyphenyls] -3- methyl-1s-butanone salt Hydrochlorate
(R) -1- [2- (2- hydroxyl -3- tert-butylamine bases propoxyl group) -4,6- Dimethoxyphenyls] -3- methyl-1s-butanone salt Hydrochlorate
(S) -1- [2- (2- hydroxyl -3- tert-butylamine bases propoxyl group) -4,6- Dimethoxyphenyls] -3- methyl-1s-butanone salt Hydrochlorate
4- (piperidin-1-yl) -1- (2,4,6- trihydroxies phenyl) -1- butanone hydrochlorides
4- (methylcyclohexyl amine) -1- (2,4,6- trihydroxies phenyl) -1- butanone hydrochlorides
4- [4- (3- chlorphenyls) piperazine -1- bases] -1- (2,4,6- trihydroxies phenyl) 1- butanone hydrochlorides
(S) -2- (2,4,6- trihydroxy benzenes methylamino) propionic acid
(S) -2- (2,4,6- trihydroxy benzenes methylamino) -3 Methylbutanoic acid
(S) -2- (2,4,6- trihydroxy benzenes methylamino) -4- methylvaleric acids
(S) -2- (2,4,6- trihydroxy benzenes methylamino) -3 methylvaleric acid
(S) -2- (2,4,6- trimethoxy-benzenes methylamino) -3- phenylpropionic acids
(S) -2- (2,4,6- trimethoxy-benzenes methylamino) -3- (4- hydroxy phenyls) propionic acid
(S) -2- (2,4,6- trimethoxy-benzenes methylamino) glutaric acid
(S) -2- (2,4,6- trimethoxy-benzenes methylamino) -3- hydracrylic acids
(S) -2- (2,4,6- trimethoxy-benzenes methylamino) succinic acid
(2S) -2- (2,4,6- trimethoxy-benzenes methylamino) -3-hydroxybutyrate
(R) -2- (2,4,6- trimethoxy-benzenes methylamino) -3- mercaptopropionic acids
(S) -2- (2,4,6- trimethoxy-benzenes methylamino) -4- methylmercapto butyric acids
(S) -2- (2,4,6- trimethoxy-benzenes methylamino) -6-aminocaprolc acid
(S) -2- (2,4,6- trimethoxy-benzenes methylamino) -5- guanidinopentanoic acids
(S) -2- (2,4,6- trimethoxy-benzenes methylamino) -4- amino -4- oxy butyrates
(S) -2- (2,4,6- trimethoxy-benzenes methylamino) -5- amino -5- oxy pentanoic acids
(S) -2- (2,4,6- trimethoxy-benzenes methylamino) -3- (1H- imidazoles -5- bases) propionic acid
(S) -2- (2,4,6- trimethoxy-benzenes methylamino) -3- (1H- indol-3-yls) propionic acid
(S) -1- (2,4,6- trimethoxyphenyls) pyrroles -2- acid
The compound as described in each situations of general formula I that the invention further relates to a kind of containing medicine effective dose and pharmaceutically may be used The pharmaceutical composition of the carrier of receiving.
According to the present invention, the compounds of this invention can exist in the form of isomers, and the usually described " chemical combination of the present invention Object " includes the isomers of the compound.
Embodiment according to the present invention, the compounds of this invention further include acceptable salt, salt in its pharmacodynamics Hydrate or pro-drug.
The invention further relates to the medicines containing the compounds of this invention and customary pharmaceutical excipients or adjuvant as active ingredient Compositions.Usual pharmaceutical composition of the present invention contains the compounds of this invention of 0.1~95 weight %.This hair in unit dosage form The bright general content of compound is 0.1~100mg, and preferred unit dosage form contains 4~50mg.
The pharmaceutical composition of the compounds of this invention can be prepared according to method well known in the art.When for this purpose, if It needs, the compounds of this invention can be combined with one or more solids or liquid pharmaceutical excipients and/or adjuvant, be made and can be used as The administration form or dosage form appropriate that people's medicine or veterinary drug use.
The compounds of this invention can be administered in a unit containing its pharmaceutical composition, and administration route can be enteron aisle Or non-bowel, such as oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritonaeum or rectum.The compounds of this invention contains The administration route of its pharmaceutical composition can be drug administration by injection.Injection includes intravenous injection, intramuscular injection, hypodermic injection, intradermal Injection and acupoint injection therapy etc..
Form of administration can be liquid dosage form, solid dosage forms.If liquid dosage form can be true solution class, colloidal type, particle Dosage form, emulsion dosage form, mixed suspension form.Other dosage forms such as tablet, dripping pill, aerosol, pill, pulvis, solution, mixes capsule Suspension, emulsion, granule, suppository, freeze drying powder injection etc..
The compounds of this invention can be made ordinary preparation, can also be sustained release preparation, controlled release preparation, targeting preparation and various Particulate delivery system.
Such as in order to which tablet is made in unit dosage forms for administration, various carriers well known in the art can be widely used.About The example of carrier is, such as diluent and absorbent, such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, Portugal Grape sugar, urea, calcium carbonate, white bole, microcrystalline cellulose, alumina silicate etc.；Wetting agent and adhesive, such as water, glycerine, poly- second two Alcohol, ethyl alcohol, propyl alcohol, starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, carboxymethyl cellulose Sodium, lac, methylcellulose, potassium phosphate, polyvinylpyrrolidone etc.；Disintegrant, such as dry starch, alginate, agar Powder, laminaran, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol aliphatic ester, dodecyl sodium sulfate, Methylcellulose, ethyl cellulose etc.；Disintegration inhibitor, such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oil and fat etc.；It inhales Receive accelerating agent, such as quaternary ammonium salt, lauryl sodium sulfate etc.；Lubricant, such as talcum powder, silica, cornstarch, tristearin Hydrochlorate, boric acid, atoleine, polyethylene glycol etc..Tablet can also be further made to coating tablet, such as sugar coated tablet, film Coating tablet, enteric coated tablets or double-layer tablets and multilayer tablet.
Such as in order to which pill is made in administration unit, various carriers well known in the art can be widely used.About carrier Example be such as diluent and absorbent, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidine Ketone, single stearic acid glycerine lipoprotein, kaolin, talcum powder etc.；Adhesive, such as Arabic gum, bassora gum, gelatin, ethyl alcohol, honey, liquid Sugar, rice paste or batter etc.；Disintegrant, such as agar powder, dry starch, alginate, dodecyl sodium sulfate, methylcellulose, Ethyl cellulose etc..
Such as in order to which capsule is made in administration unit, active ingredient the compounds of this invention and above-mentioned various carriers are mixed It closes, and thus obtained mixture is placed in hard gelatine capsule or soft capsule.It also can be by active ingredient the compounds of this invention Microcapsules is made, is suspended in aqueous medium and forms suspension, also can be fitted into hard capsule or be made injection application.
For example, injection preparation is made in the compounds of this invention, such as solution, suspension solution, emulsion, freeze-dried powder Agent, this preparation can be aqueous or non-aqueous, can contain acceptable carrier in a kind of and/or a variety of pharmacodynamics, diluent, glue Mixture, lubricant, preservative, surfactant or dispersant.As diluent can be selected from water, ethyl alcohol, polyethylene glycol, 1,3- the third two Alcohol, the isooctadecanol of ethoxylation, polyoxygenated isooctadecanol, polyoxyethylene sorbitol fat, fat acid esters etc..In addition, in order to make Standby isotonic injection, can add suitable sodium chloride, glucose or glycerine, further, it is also possible to add into injection preparation Conventional cosolvent, buffer, pH adjusting agent etc..These auxiliary materials are commonly used in the art.
In addition, if desired, can also be added into pharmaceutical preparation colorant, preservative, fragrance, corrigent, sweetener or Other materials.
To reach medication purpose, enhance therapeutic effect, drug of the invention or pharmaceutical composition well known can be given with any Prescription method is administered.
The dosage of the compounds of this invention pharmaceutical composition depends on many factors, such as to be prevented or be treated disease Property and severity, gender, age, weight, personality and the individual reaction of patient or animal, administration route, administration number of times, Therapeutic purposes, therefore the therapeutic dose of the present invention can have large-scale variation.In general, Chinese pharmacology ingredient of the present invention makes It is well known to those skilled in the art with dosage.It can be according to contained in preparation last in the compounds of this invention composition Actual drug quantity is subject to adjustment appropriate, to reach the requirement of its therapeutically effective amount, completes prevention or the treatment mesh of the present invention 's.The daily Suitable dosage ranges of the compounds of this invention：The dosage of the compound of the present invention is 0.001~100mg/Kg bodies Weight, preferably 0.1~60mg/Kg weight, more preferably 1~30mg/Kg weight, most preferably 2~15mg/Kg weight.Adult The compounds of this invention that patient takes is daily 10~500mg, preferably 20~100mg, can once take or divide 2~3 clothes With；The dosage of children taking is according to 5~30mg of every kg weight, preferably 10~20mg/kg weight.Above-mentioned dosage can be single dose Amount form is divided into several, such as two, three or four dosage forms for administration, this is limited to the clinical experience of administration doctor and controls The dosage regimen for the treatment of means.The compound of the present invention or composition can individually be taken, or with other treatment drug or symptomatic drugs Merge and uses.
The invention further relates to the compound of the present invention to prepare the application in preventing neurodegenerative disease drug.The disease Disease includes Alzheimer disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, the expansion of incoordination hair and blood pipe Open disease, bovine spongiform encephalopathy, gram refined Er Shi diseases, Huntington's disease, cerebral atrophy, primary lateral sclerosis, myeloid flesh Atrophy.
Description of the drawings
Fig. 1 Examples 1 and 28 turn the ethological influence of rod, * * P to mouse<0.01vs.Control mouse, #P< 0.05,##P<0.01vs.MPTP model mices
Fig. 2 Examples 1 and 28 are on the ethological influence of mouse pole-climbing, * * P<0.01vs.Control mouse, #P< 0.05,##P<0.01vs.MPTP model mices
Shadow of Fig. 3 Examples 1 and 28 to dopamine neuron in subacute PD model mices black substance caused by MPTP It rings, * * P<0.01vs.Control mouse, #P<0.05, ##P<0.01vs.MPTP model mices, n=4~5
Influence of Fig. 4 Examples 1 and 28 to dopamine neuron in chronic PD model mices black substance caused by MPTP/p, * P<0.01vs.Control mouse, #P<0.05, ##P<0.01vs.MPTP/p model mices, n=4~5
Specific implementation mode
The following examples are used for further illustrating the present invention, but this does not imply that any limitation of the invention.
The preparation of 1. 1- of embodiment (2- methoxyl group -4,6- dihydroxy phenyls) -3- methyl-1s-butanone
Step 1：The preparation of 1- (2,4,6- trihydroxies phenyl) -3- methyl-1s-butanone
5.00g (40mmol) phloroglucin is dissolved in the mixed solution of 50mL carbon disulfide and 15mL nitrobenzenes, is added 15.6g (120mmol) aluminum trichloride (anhydrous), is stirred at room temperature 10 minutes；20mL is slowly added dropwise into reaction solution and contains 4.82g The carbon disulfide solution of (40mmoll) isoveryl chloride, is heated to reflux at 50 DEG C 30 minutes later；After two sulphur of evaporated under reduced pressure Change carbon, 10mL hydrochloric acid and 20mL mixture of ice and water instilled into residue, extracted with 3 × 50mL ethyl acetate, merges organic layer, It is washed with 3 × 25mL saturated nacl aqueous solutions, anhydrous sodium sulfate drying；After evaporated under reduced pressure solvent, silica gel column chromatography (chlorine is carried out It is imitative:Methanol 20:1) it detaches, obtains 1- (2,4,6- trihydroxy phenyl) -3- methyl-1s-butanone 6.5g, yield 78%.
Step 2：The preparation of 1- [2- hydroxyls -4,6- two (methoxymethoxy) phenyl] -3 methyl-1s-butanone
It will be dissolved in 50mL according to step 1 gained 2.1g (10mmol) 1- (2,4,6- trihydroxies phenyl) -3- methyl-1s-butanone It is cooling at 0 DEG C in dichloromethane, 3.65mL (21mmol) dipropyl ethamine is added, stirs 15 minutes, by 1.6mL (25mmol) chloromethyl methyl ether is dissolved in 20mL dichloromethane, is slowly added dropwise to reaction solution, after at 0 DEG C react 15 points Clock, then at reaction 45 minutes at room temperature.Reaction solution is poured into 100mL water, is extracted with 3 × 50mL chloroforms, organic layer is merged, is used 3 × 15mL saturated nacl aqueous solutions wash, anhydrous sodium sulfate drying.Solvent evaporated carries out silica gel column chromatography (petroleum ether:Acetic acid Ethyl ester 15:1) isolated 1- [2- hydroxyls -4,6- bis- (methoxymethoxy) phenyl] -3- methyl-1s-butanone 1.40g, yield 47%.
Step 3：The preparation of 1- [2- methoxyl groups -4,6- two (methoxymethoxy) phenyl] -3 methyl-1s-butanone
By 300mg (1mmol) 1- [2- hydroxyls -4,6- two (methoxymethoxy) phenyl] -3- first of gained in step 2 Base -1- butanone is dissolved in 20mL acetone, and 276mg (2mmol) Anhydrous potassium carbonate is added, is heated to reflux 20 minutes, into reaction solution 100 μ l (2mmol) dimethyl suflfates are added, continue reflux 5 hours.20mL water is added in residue for evaporated under reduced pressure reaction solution, uses 3 × 25mL ethyl acetate extracts, and merges organic layer, is washed with 3 × 10mL saturated nacl aqueous solutions, anhydrous sodium sulfate drying.It steams Dry solvent carries out silica gel column chromatography (petroleum ether:Ethyl acetate 30:1) isolated 1- [two (methoxy methyls of 2- methoxyl groups -4,6- Oxygroup) phenyl] -3- methyl-1s-butanone 250mg, yield 80%.
Step 4：The preparation of 1- (4- methoxyl group -2,6- dihydroxy phenyls) -3- methyl-1s-butanone
By 250mg (0.80mmol) 1- [2- methoxyl groups -4,6- two (methoxymethoxy) phenyl]-of gained in step 3 3- methyl-1s-butanone is dissolved in 10mL methanol, and 2mL 2N hydrochloric acid is added, is heated to reflux 1 hour, having in evaporated under reduced pressure reaction solution 20mL water is added in residue for solvent, is extracted with 3 × 25mL ethyl acetate, merges organic layer, and chlorination is saturated with 3 × 10mL Sodium solution washs, anhydrous sodium sulfate drying.Solvent evaporated carries out silica gel column chromatography (petroleum ether:Ethyl acetate 20:1) it detaches To 1- (4- methoxyl groups -2,6- dihydroxy phenyl) -3- methyl-1s-butanone 185mg, yield 83%.
1H NMR(500MHz,d6-DMSO)δ13.59(br.s,OH-4′,OH-6′),5.94(1H,s,H-5′),5.85 (1H,s,H-3′),3.80(3H,s,OCH3), 2.77 (2H, d, J=6.5Hz, H-2), 2.07 (1H, m, H-3), 0.89 (6H, d, J=6.5Hz, CH3-4,CH3-5)。13C NMR(125MHz,d6-DMSO)δ204.0,165.7,164.4,162.4,104.2, 95.3,90.9,55.3,51.9,24.5,22.2,22.2。
The preparation of 2. 3- of embodiment [3,5- dihydroxy -2- (3- methylbutyryls) phenoxy group] methyl 4-phenyl furazan
Step 1：The preparation of 3- methylol -4- phenyl furazans
2.00g (15mmol) cinnamyl alcohol is added in 3mL glacial acetic acid, is stirred at room temperature to its dissolving, to anti-under ice bath cooling It answers to be added dropwise in liquid and contains 3.00g (72mmol) NaNO2Saturated aqueous solution, be stirred at room temperature after being added dropwise 5 hours.Into reaction solution 20mL water is added, is extracted with 3 × 50mL ethyl acetate, merges organic layer, successively with 3 × 15mL 5%NaOH solution and 3 × 20mL saturated nacl aqueous solutions wash, and anhydrous sodium sulfate drying, evaporated under reduced pressure obtains grease 2.50g.
Step 2：The preparation of 3- chloromethyl -4- phenyl furazans
The grease 330mg of gained in step 1 is dissolved in 15mL anhydrous methylene chlorides, 0.32mL (4mmol) pyrrole is added 0.35mL SOCl are added dropwise into reaction solution under ice bath cooling for pyridine2, it is stirred at room temperature 3 hours.By reaction solution successively with 3 × 15mL ice Water, 3 × 15mL are saturated Na2CO3Solution and the washing of 3 × 15mL saturated nacl aqueous solutions, anhydrous sodium sulfate drying.Solvent evaporated, into Row silica gel column chromatography (petroleum ether:Ethyl acetate 7:1) isolated 3- chloromethyls -4- phenyl furazan 280mg, yield 78%.
Step 3：The preparation of 3- [3,5- dihydroxy -2- (3- methylbutyryls) phenoxy group] methyl 4-phenyl furazan
3- chloromethyl -4- phenyl furazan the 210mg (1mmol) of gained in step 2 are dissolved in 20mL acetonitriles, 210mg is added (1mmol) is according to 1- (2,4,6- trihydroxy phenyl) -3- methyl-1s-butanone obtained by 1 step 1 of embodiment, 207mg (1.5mmol) anhydrous K2CO3It with a small amount of KI, is heated to reflux 10 hours, pressurization is evaporated reaction solution, and 20mL water is added in residue, uses 3 × 25mL ethyl acetate extracts, and merges organic layer, is washed with 3 × 10mL saturated nacl aqueous solutions, anhydrous sodium sulfate drying.It steams Dry solvent carries out silica gel column chromatography (petroleum ether：Ethyl acetate 5:1) isolated 3- [3,5- dihydroxy -2- (3- methylbutyryls Base) phenoxy group] methyl 4-phenyl furazan 200mg, yield 53%.
1H NMR(500MHz,d6-DMSO)δ13.43(1H,s,OH-6′),10.73(1H,s,OH-4′),7.79(2H,d,J =7.5Hz, H-2 " ', H-6 " '), 7.63 (2H, t, J=7.5Hz, H-3 " ', H-5 " '), 7.59 (1H, t, J=7.5Hz, H- 4 " '), 6.08 (1H, d, J=1.5Hz, H-3 '), 5.96 (1H, d, J=1.5Hz, H-5 '), 5.24 (2H, s, H-1 "), 2.44 (2H, d, J=7.0Hz, H-2), 1.91 (1H, m, H-3), 0.66 (6H, d, J=6.5Hz, CH3-4,CH3-5)。13C NMR (125MHz,d6-DMSO)δ204.1,165.7,164.5,160.2,156.9,131.8,129.7,129.7,127.6,127.6, 125.6,112.3,105.2,96.9,92.6,59.1,52.2,24.5,22.3,22.3。
Embodiment 3. (±) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4,6- dihydroxy phenyls] -3- methyl-1s - The preparation of butanone hydrochloride
Step 1：The preparation of p-methyl benzenesulfonic acid benzyl ester
10.49g (97mmol) benzyl alcohol is dissolved in 200mL anhydrous ethers, 2.4g (10mmol) sodium hydride, heating is added Reflux 12 hours, reaction solution sub-cooled are slowly dropped into the anhydrous second containing 19.5g (102mmol) paratoluensulfonyl chloride to -30 DEG C Ethereal solution 100mL, after reacted 2 hours at -20 DEG C, then react 1 hour at room temperature, filtering, filtrate is evaporated, and carries out silica gel Column chromatography (petroleum ether:Ethyl acetate 40:1) it detaches, obtains p-methyl benzenesulfonic acid benzyl ester 9.8g, yield 37%.
Step 2：The preparation of 1- (2- hydroxyl -4,6- hexichol methoxyphenyl) -3- methyl-1s-butanone
It will be according to embodiment 1 step 1 gained 3g (14.3mmol) 1- (2,4,6- trihydroxies phenyl) -3- methyl-1s-butanone It is dissolved in 200mL acetone, it is anhydrous that gained 7.86g (30mmol) p-methyl benzenesulfonic acid benzyl esters and 25g (181mmol) in step 1 is added Potassium carbonate is heated to reflux 3 hours, and reaction solution is evaporated after cooling, and residue 150mL water dissolutions are extracted with 3 × 50mL ethyl acetate It takes, merges organic layer, washed with 2 × 15mL saturated nacl aqueous solutions, anhydrous sodium sulfate drying.Solvent evaporated carries out silicagel column Chromatography (petroleum ether:Ethyl acetate 30:1) isolated 1- (2- hydroxyl -4,6- hexichol methoxyphenyl) -3- methyl-1s-butanone 2.98g, yield 53%.
Step 3：(±) -1- [2- (epoxy second -2- bases) methoxyl group -4,6- hexichol methoxyphenyl] -3- methyl-1s-butanone Preparation
By 1.00g (2.5mmol) 1- (2- hydroxyl -4,6- hexichol methoxyphenyl) -3- methyl-1s-fourth obtained by step 2 Ketone is dissolved in 100mL n,N-Dimethylformamide, is passed through nitrogen, stirs 5 minutes；0.09g (3.75mmol) sodium hydride is added, in It is reacted 20 minutes at 40 DEG C, is continually fed into nitrogen；1.16g (12.5mmol) (±) -2- chloromethyloxiranes are added, in 90 DEG C Lower reaction 2 hours；It after reaction solution is cooled to room temperature, is poured into 100mL water, is extracted with 3 × 50mL ethyl acetate, merged organic Layer, is washed with 3 × 15mL saturated nacl aqueous solutions, anhydrous sodium sulfate drying；Evaporated under reduced pressure solvent, through silica gel column chromatography (oil Ether：Ethyl acetate 20:1) isolated (±) -1- [2- (epoxy second -2- bases) methoxyl group -4,6- hexichol methoxyphenyl] -3- Methyl-1-butanone 0.90g, yield 81%.
Step 4：(±) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4,6- hexichol methoxyphenyl] -3- methyl - The preparation of 1- butanone hydrochlorides
By 450mg (1mmol) (±) -1- [2- (epoxy second -2- bases) methoxyl group -4,6- hexichol methoxies of gained in step 3 Base phenyl] -3- methyl-1s-butanone is placed in heavy wall pressure pipe, and 3mL (35mmol) isopropylamine is added, stirs evenly, at 70 DEG C Reaction 2 hours；Evaporated under reduced pressure reaction solution after cooling, residue 20mL anhydrous ethers dissolve, and stir lower be added dropwise and are saturated hydrogen chloride Diethyl ether solution, filtering, obtains solid (±) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4,6- hexichol methoxyphenyl] - 3- methyl-1s-butanone hydrochloride 400mg, yield 74%.
Step 5：(±) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4,6- dihydroxy phenyls] -3- methyl-1s-fourth The preparation of keto hydrochloride
By in step 4 gained 170mg (0.31mmol) (±) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4, 6- hexichol methoxyphenyl] -3- methyl-1s-butanone hydrochloride is dissolved in 30mL methanol, 100mg palladium carbons and 2mL hydrochloric acid is added, Catalytic hydrogenation 12 hours, filtering are carried out under the pressure of 3atm, filtrate is evaporated, by gained grease carry out preparation HPLC (YMC columns, 22% acetonitrile) separation, obtain (±) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4,6- dihydroxy phenyls] -3- methyl - 1- butanone hydrochloride 50mg, yield 49%.
1H NMR(500MHz,d6- DMSO) δ 5.90 (1H, s, H-3 '), 5.89 (1H, s, H-5 '), 3.99 (1H, dd, J= 3.5,8.0Hz, H-1 " a), 3.92 (b), 1H, overlap, H-1 " 3.88 (1H, m, H-2 "), 2.93 (1H, dd, J=7.0, A), a), 2.84 16.0Hz, H-3 " (1H, dd, J=6.5,16.0Hz, H-3 " 2.77 (1H, m, H-5 "), 2.72 (1H, dd, J= 6.5,13.5Hz, H-2a), 2.60 (1H, dd, J=7.0,13.5Hz, H-2b), 2.13 (1H, m, H-3), 1.00 (3H, d, J= 6.0Hz,CH3), -6 " 0.99 (3H, d, J=6.0Hz, CH3), -7 " 0.90 (3H, d, J=6.5Hz, CH3-4),0.88(3H,d,J =6.5Hz, CH3-5)。13C NMR(125MHz,d6-DMSO)δ204.7,166.2,165.5,162.3,104.7,95.9, 92.2,71.6,68.2,52.3,49.9,48.5,24.5,22.7,22.7,22.6,22.6。
Embodiment 4. (R) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4,6- dihydroxy phenyls] -3- methyl-1s - The preparation of butanone hydrochloride
Step 1：(S) -1- [2- (2,2- dimethyl -1,3- dioxolanes -4- bases) methoxyl group -4,6- hexichol methoxybenzenes Base] -3- methyl-1s-butanone preparation
By 3.00g (7.5mmol) 1- (2- hydroxyl -4,6- hexichol methoxyphenyl) -3- obtained by step 2 in embodiment 3 Methyl-1-butanone is dissolved in 20mL n,N-Dimethylformamide, is passed through nitrogen, stirs 5 minutes；0.27g (11.3mmol) hydrogen is added Change sodium, is reacted 20 minutes at 40 DEG C, be continually fed into nitrogen；3.39g (22.5mmol) (R) -4- chloromethyl -2,2- diformazans are added Base -1,3-dioxolane reacts 24 hours at 90 DEG C；After reaction solution is cooled to room temperature, it is poured into 50mL water, with 3 × 50mL ethyl acetate extracts, and merges organic layer, is washed with 3 × 15mL saturated nacl aqueous solutions, anhydrous sodium sulfate drying；Decompression is steamed Dry solvent, through silica gel column chromatography (petroleum ether：Ethyl acetate 30:1) isolated (S) -1- [2- (2,2- dimethyl -1,3- dioxies Penta ring -4- bases) methoxyl group -4,6- hexichol methoxyphenyl] -3- methyl-1s-butanone 0.90g, yield 23%.
Step 2：(R) -1- [2- (2,3- dihydroxy propoxyl group) -4,6- hexichol methoxyphenyl] -3- methyl-1s-butanone It prepares
By the 900mg obtained in step 1 (1.86mmol) (S) -1- [2- (2,2- dimethyl -1,3- dioxolanes -4- bases) Methoxyl group -4,6- hexichol methoxyphenyl] -3- methyl-1s-butanone is dissolved in 20mL tetrahydrofurans, 4% sulfuric acid is slowly added dropwise 10mL reacts 8 hours at room temperature, and decompression evaporates organic solvent, and surplus solution is extracted with 3 × 30mL ethyl acetate, is merged organic Layer, is washed till neutrality, then washed with 3 × 15mL saturated nacl aqueous solutions with saturated sodium bicarbonate solution, and anhydrous sodium sulfate drying subtracts Pressure is evaporated organic layer, obtains (R) -1- [2- (2,3- dihydroxy propoxyl group) -4,6- hexichol methoxyphenyl] -3- methyl-1s-butanone 840mg, yield 98%.
Step 3：(S) -1- [2- (2- hydroxyl -3- tolysulfonyl oxygroups propoxyl group) -4,6- hexichol methoxyphenyl] -3- The preparation of methyl-1-butanone
By the 800mg obtained in step 2 (1.76mmol) (R) -1- [2- (2,3- dihydroxy propoxyl group) -4,6- hexichol first Phenyl] -3- methyl-1s-butanone is dissolved in 20mL dry methylene chlorides, a small amount of pyridine is added, is slowly added dropwise into reaction solution Dichloromethane solution 10mL containing 336mg (1.76mmol) paratoluensulfonyl chloride reacts 48 hours at room temperature, evaporated under reduced pressure reaction Liquid, through silica gel column chromatography (petroleum ether:Acetoacetic ester 15:1) (S) -1- [2- (2- hydroxyl -3- tolysulfonyl the third oxygen of oxygroup is detached Base) -4,6- hexichol methoxyphenyl] -3- methyl-1s-butanone 320mg, yield 29%.
Step 4：(R) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4,6- dihydroxy phenyls] -3- methyl-1s-fourth The preparation of keto hydrochloride
By 160mg (0.26mmol) (S) -1- [2- (2- hydroxyl -3- tolysulfonyl the third oxygen of oxygroup of gained in step 3 Base) -4,6- hexichol methoxyphenyl] -3- methyl-1s-butanone is placed in heavy wall pressure pipe, 3mL (35mmol) isopropylamine is added, It stirs evenly, is reacted 2 hours at 70 DEG C；Evaporated under reduced pressure reaction solution after cooling obtains grease 100mg.The grease is dissolved in In 30mL methanol, 50mg palladium carbons and 1mL hydrochloric acid is added, catalytic hydrogenation is carried out under the pressure of 3atm 12 hours, filtering, filtrate is steamed It is dry, gained grease is subjected to preparation HPLC (YMC columns, 22% acetonitrile) separation, obtains (R) -1- [2- (2- hydroxyl -3- isopropylamines Base propoxyl group) -4,6- dihydroxy phenyls] -3- methyl-1s-butanone hydrochloride 30mg, yield 32%.
1H NMR(500MHz,d6- DMSO) δ 5.90 (1H, s, H-3 '), 5.89 (1H, s, H-5 '), 3.99 (1H, dd, J= 3.5,8.0Hz, H-1 " a), 3.92 (b), 1H, overlap, H-1 " 3.88 (1H, m, H-2 "), 2.93 (1H, dd, J=7.0, A), a), 2.84 16.0Hz, H-3 " (1H, dd, J=6.5,16.0Hz, H-3 " 2.77 (1H, m, H-5 "), 2.72 (1H, dd, J= 6.5,13.5Hz, H-2a), 2.72 (1H, dd, J=7.0,13.5Hz, H-2b), 2.13 (1H, m, H-3), 1.00 (3H, d, J= 6.0Hz,CH3), -6 " 0.99 (3H, d, J=6.0Hz, CH3), -7 " 0.90 (3H, d, J=6.5Hz, CH3-4),0.88(3H,d,J =6.5Hz, CH3-5)。13C NMR(125MHz,d6-DMSO)δ204.7,166.2,165.5,162.3,104.7,95.9, 92.2,71.6,68.2,52.3,49.9,48.5,24.5,22.7,22.7,22.6,22.6。
Embodiment 5. (S) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4,6- dihydroxy phenyls] -3- methyl-1s - The preparation of butanone hydrochloride
Step 1：(R) -1- [2- (2,2- dimethyl -1,3- dioxolanes -4- bases) methoxyl group -4,6- hexichol methoxybenzenes Base] -3- methyl-1s-butanone preparation
According to the method for step 1 in embodiment 4, using 3.00g (7.5mmol) 1- (2- hydroxyl -4,6- hexichol methoxybenzenes Base) -3- methyl-1s-butanone, 0.27g (11.3mmol) sodium hydrides and 3.39g (22.5mmol) (S) -4- chloromethyl -2,2- diformazans After base -1,3-dioxolane reaction, through silica gel column chromatography (petroleum ether:Ethyl acetate 30:1) isolated (R) -1- [2- (2,2- Dimethyl -1,3-dioxolane -4- bases) methoxyl group -4,6- hexichol methoxyphenyl] -3- methyl-1s-butanone 1.20g, yield 31%.
Step 2：(S) -1- [2- (2,3- dihydroxy propoxyl group) -4,6- hexichol methoxyphenyl] -3- methyl-1s-butanone It prepares
According to the method for step 2 in embodiment 4, using 1.20g (2.38mmol) (R) -1- [2- (2,2- dimethyl -1,3- Dioxolanes -4- bases) methoxyl group -4,6- hexichol methoxyphenyl] -3- methyl-1s-butanone obtains (S) -1- [2- (2,3- dihydroxies Base propoxyl group) -4,6- hexichol methoxyphenyl] -3- methyl-1s-butanone 1.06g, yield 96%.
Step 3：(R) -1- [2- (2- hydroxyl -3- tolysulfonyl oxygroups propoxyl group) -4,6- hexichol methoxyphenyl] -3- The preparation of methyl-1-butanone
According to the method for step 3 in embodiment 4, using obtained in step 2 1.06g (2.28mmol) (S) -1- [2- (2, 3- dihydroxy propoxyl group) -4,6- hexichol methoxyphenyl] -3- methyl-1s-butanone and 434mg (2.28mmol) tolysulfonyl After chlorine reaction, through silica gel column chromatography (petroleum ether:Ethyl acetate 15:1) (R) -1- [2- (2- hydroxyl -3- tolysulfonyl is detached Oxygroup propoxyl group) -4,6- hexichol methoxyphenyl] -3- methyl-1s-butanone 400mg, yield 37%.
Step 4：(S) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4,6- dihydroxy phenyls] -3- methyl-1s-fourth The preparation of keto hydrochloride
According to the method for step 4 in embodiment 4, using 200mg (0.33mmol) (R) -1- [2- (2- of gained in step 3 Hydroxyl -3- tolysulfonyl oxygroups propoxyl group) -4,6- hexichol methoxyphenyl] -3- methyl-1s-butanone and 3mL (35mmol) it is different Propylamine reacts, and obtains grease 120mg.After the grease catalytic hydrogenation, detaches, obtain through preparing HPLC (YMC columns, 22% acetonitrile) (S) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4,6- dihydroxy phenyls] -3- methyl-1s-butanone hydrochloride 45mg are received Rate 38%.
1H NMR(500MHz,d6- DMSO) δ 5.90 (1H, s, H-3 '), 5.89 (1H, s, H-5 '), 3.99 (1H, dd, J= 3.5,8.0Hz, H-1 " a), 3.92 (b), 1H, overlap, H-1 " 3.88 (1H, m, H-2 "), 2.93 (1H, dd, J=7.0, A), a), 2.84 16.0Hz, H-3 " (1H, dd, J=6.5,16.0Hz, H-3 " 2.77 (1H, m, H-5 "), 2.72 (1H, dd, J= 6.5,13.5Hz, H-2a), 2.72 (1H, dd, J=7.0,13.5Hz, H-2b), 2.13 (1H, m, H-3), 1.00 (3H, d, J= 6.0Hz,CH3), -6 " 0.99 (3H, d, J=6.0Hz, CH3), -7 " 0.90 (3H, d, J=6.5Hz, CH3-4),0.88(3H,d,J =6.5Hz, CH3-5)。13C NMR(125MHz,d6-DMSO)δ204.7,166.2,165.5,162.3,104.7,95.9, 92.2,71.6,68.2,52.3,49.9,48.5,24.5,22.7,22.7,22.6,22.6。
Embodiment 6. (±) -1- [2- (2- hydroxyl -3- tert-butylamine bases propoxyl group) -4,6- dihydroxy phenyls] -3- methyl-1s - The preparation of butanone hydrochloride
According to step 1-4 in embodiment 3, with 450mg (1mmol) (±) -1- [2- (epoxy second -2- bases) methoxyl groups 4,6- Hexichol methoxyphenyl] solid (±) -1- [2- (2- are obtained by the reaction in -3- methyl-1s-butanone and 3mL (26.8mmol) tert-butylamine Hydroxyl -3- tert-butylamine bases propoxyl group) -4,6- hexichol methoxyphenyl] -3- methyl-1s-butanone hydrochloride 450mg, yield 81%.
According to step 5 in embodiment 3, by 150mg (0.27mmol) (±) -1- [2- (2- hydroxyl -3- tert-butylamines the third oxygen of base Base) -4,6- hexichol methoxyphenyl] after -3- methyl-1s-butanone hydrochloride carry out catalytic hydrogenation, through prepare HPLC (YMC columns, 22% acetonitrile) separation, obtain (±) -1- [2- (2- hydroxyl -3- tert-butylamine bases propoxyl group) -4,6- dihydroxy phenyls] -3- methyl - 1- butanone hydrochloride 59mg, yield 64%.
1H NMR(500MHz,d6-DMSO)δ5.89(1H,br.s,H-3′),5.81(1H,br.s,H-5′),4.01(1H, B), a), 3.89 dd, J=4.0,9.5Hz, H-1 " (1H, overlap, H-1 " 3.84 (1H, m, H-2 "), 2.94 (1H, dd, J= B), a), 7.0,16.0Hz, H-3 " 2.85 (1H, dd, J=6.5,16.0Hz, H-3 " 2.69 (1H, dd, J=5.0,12.0Hz, H- 2a), 2.62 (1H, dd, J=6.0,12.0Hz, H-2b), 2.13 (1H, m, H-3), 1.05 (9H, s, CH3-6″,CH3-7″,CH3- ), 8 " 0.90 (3H, d, J=6.5Hz, CH3- 4), 0.89 (3H, d, J=6.5Hz, CH3-5)。13C NMR(125MHz,d6-DMSO) δ204.4,166.3,166.2,162.3,104.6,95.9,92.3,71.5,68.7,52.3,50.2,45.4,28.6,28.6, 28.6,24.6,22.7,22.6
Embodiment 7. (R) -1- [2- (2- hydroxyl -3- tert-butylamine bases propoxyl group) -4,6- hydroxy phenyls] -3- methyl-1s-fourth The preparation of keto hydrochloride
According to the method for step 4 in embodiment 4, using the 216mg (0.26mmol) (S)-obtained by step 3 in embodiment 3 1- [2- (2- hydroxyl -3- tolysulfonyl oxygroups propoxyl group) -4,6- hexichol methoxyphenyl] -3- methyl-1s-butanone and 3mL (26.8mmol) tert-butylamine reacts, and obtains grease 110mg.After the grease catalytic hydrogenation, through preparing HPLC (YMC columns, 22% second Nitrile) separation, obtain (R) -1- [2- (2- hydroxyl -3- tert-butylamine bases propoxyl group) -4,6- dihydroxy phenyls] -3- methyl-1s-butanone Hydrochloride 42mg, yield 43%.
1H NMR(500MHz,d6-DMSO)δ5.89(1H,br.s,H-3′),5.81(1H,br.s,H-5′),4.01(1H, B), a), 3.89 dd, J=4.0,9.5Hz, H-1 " (1H, overlap, H-1 " 3.84 (1H, m, H-2 "), 2.94 (1H, dd, J= B), a), 7.0,16.0Hz, H-3 " 2.85 (1H, dd, J=6.5,16.0Hz, H-3 " 2.69 (1H, dd, J=5.0,12.0Hz, H- 2a), 2.62 (1H, dd, J=6.0,12.0Hz, H-2b), 2.13 (1H, m, H-3), 1.05 (9H, s, CH3-6″,CH3-7″,CH3- ), 8 " 0.90 (3H, d, J=6.5Hz, CH3- 4), 0.89 (3H, d, J=6.5Hz, CH3-5)。13C NMR(125MHz,d6-DMSO) δ204.4,166.3,166.2,162.3,104.6,95.9,92.3,71.5,68.7,52.3,50.2,45.4,28.6,28.6, 28.6,24.6,22.7,22.6
Embodiment 8. (S) -1- [2- (2- hydroxyl -3- tert-butylamine bases propoxyl group) -4,6- dihydroxy phenyls] -3- methyl-1s - The preparation of butanone hydrochloride
According to the method for step 4 in embodiment 4, using the 200mg (0.26mmol) (R)-obtained by step 3 in embodiment 5 1- [2- (2- hydroxyl -3- tolysulfonyl oxygroups propoxyl group) -4,6- hexichol methoxyphenyl] -3- methyl-1s-butanone and 3mL (26.8mmol) tert-butylamine reacts, and obtains grease 130mg.After the grease catalytic hydrogenation, through preparing HPLC (YMC columns, 22% second Nitrile) separation, obtain (S) -1- [2- (2- hydroxyl -3- tert-butylamine bases propoxyl group) -4,6- dihydroxy phenyls] -3- methyl-1s-butanone Hydrochloride 40mg, yield 41%.
1H NMR(500MHz,d6-DMSO)δ5.89(1H,br.s,H-3′),5.81(1H,br.s,H-5′),4.01(1H, B), a), 3.89 dd, J=4.0,9.5Hz, H-1 " (1H, overlap, H-1 " 3.84 (1H, m, H-2 "), 2.94 (1H, dd, J= B), a), 7.0,16.0Hz, H-3 " 2.85 (1H, dd, J=6.5,16.0Hz, H-3 " 2.69 (1H, dd, J=5.0,12.0Hz, H- 2a), 2.62 (1H, dd, J=6.0,12.0Hz, H-2b), 2.13 (1H, m, H-3), 1.05 (9H, s, CH3-6″,CH3-7″,CH3- ), 8 " 0.90 (3H, d, J=6.5Hz, CH3- 4), 0.89 (3H, d, J=6.5Hz, CH3-5)。13C NMR(125MHz,d6-DMSO) δ204.4,166.3,166.2,162.3,104.6,95.9,92.3,71.5,68.7,52.3,50.2,45.4,28.6,28.6, 28.6,24.6,22.7,22.6.
Embodiment 9. (±) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4- methoxyphenyls] -3- methyl-1s-fourth The preparation of keto hydrochloride
Step 1：The preparation of 1- (2- hydroxyl -4- methoxyphenyls) -3- methyl-1s-butanone
1.24g (10mmol) 3- metoxyphenols are dissolved in 30mL boron trifluoride ether solutions, 1.21g is added (10mmol) isoveryl chloride, heating reaction 2 hours at 80 DEG C, are poured into the potassium acetate of 50mL 5% after reaction solution cooling later It in solution, is extracted with 3 × 30mL ethyl acetate, merges organic layer, washed to neutrality with saturated sodium bicarbonate solution, then with 3 × 10mL saturated nacl aqueous solutions wash, anhydrous sodium sulfate drying；After evaporated under reduced pressure solvent, silica gel column chromatography (petroleum ether is carried out:Second Acetoacetic ester 30:1) it detaches, obtains 1- (2- hydroxyl -4- methoxyphenyls) -3- methyl-1s-butanone 1.95g, yield 94%.
Step 2：The preparation of (±) -1- [2- (epoxy second -2- bases) methoxyl group -4- methoxyphenyls] -3- methyl-1s-butanone
1.04g (5mmol) 1- obtained according to step 1 (2- hydroxyl -4- methoxyphenyls) -3- methyl-1s-butanone is molten In 60mL n,N-Dimethylformamide, it is passed through nitrogen, is stirred 5 minutes；0.12g (5mmol) sodium hydride is added, at 40 DEG C Reaction 20 minutes, is continually fed into nitrogen；2.31g (25mmol) (±) 2- chloromethyloxiranes are added, it is small that 2 are reacted at 90 DEG C When；It after reaction solution is cooled to room temperature, is poured into 100mL water, is extracted with 3 × 50mL ethyl acetate, merge organic layer, with 3 × 15mL saturated nacl aqueous solutions wash, anhydrous sodium sulfate drying；Evaporated under reduced pressure solvent, through silica gel column chromatography (petroleum ether：Acetic acid second Ester 10:1) isolated (±) -1- [2- (epoxy second -2- bases) methoxyl group -4- methoxyphenyls] -3- methyl-1s-butanone 0.80g, yield 61%.
Step 3：(±) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4- methoxyphenyls] -3- methyl-1s-butanone It is prepared by hydrochloride
By 264mg (1mmol) (±) -1- [2- (epoxy second -2- bases) methoxyl group -4- methoxybenzenes of gained in step 2 Base] -3- methyl-1s-butanone is placed in heavy wall pressure pipe, and 3mL (35mmol) isopropylamine is added, stirs evenly, is reacted at 70 DEG C 2 hours；Evaporated under reduced pressure reaction solution after cooling, residue 20mL anhydrous ethers dissolve, and stir lower be added dropwise and are saturated hydrogen chloride ether Solution, filtering, obtains solid (±) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4- methoxyphenyls] -3- methyl-1s-fourth Keto hydrochloride 70mg, yield 19%.
1H NMR(500MHz,D2O) δ 7.61 (1H, d, J=8.5Hz, H-6 '), 6.54 (1H, dd, J=8.5,1.5Hz, H- 5 '), 6.47 (1H, d, J=1.5Hz, H-3 '), 4.23 (1H, m, H-2 "), 4.06 (2H, d, J=4.5Hz, H-1 "), 3.74 (3H,s,OCH3), a), 3.39 (1H, m, H-5 "), 3.22 (1H, dd, J=3.5,13.0Hz, H-3 " 3.11 (1H, dd, J= B), 8.0,13.5Hz, H-3 " 2.71 (1H, dd, J=3.5,12.0Hz, H-2a), 2.65 (1H, dd, J=3.5,12.0Hz, H- 2b), 1.93 (1H, m, H-3), 1.24 (3H, d, J=6.0Hz, CH3), -6 " 1.22 (3H, d, J=6.0Hz, CH3-7″),0.77 (6H, d, J=6.5Hz, CH3-4,CH3-5)。13C NMR(125MHz,D2O)δ205.0,165.7,165.3,132.3,114.0, 106.8,100.7,71.8,69.2,55.6,52.7,49.5,45.4,24.5,22.8,22.8,22.6,22.6。
Embodiment 10. (R) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4- methoxyphenyls] -3- methyl-1s-fourth The preparation of ketone
Step 1：(R) preparation of -1- [2- (epoxy second -2- bases) methoxyl group -4- methoxyphenyls] -3- methyl-1s-butanone
By 1.04g (5mmol) 1- obtained according to the method for step 1 in embodiment 9 (2- hydroxyl -4- methoxyphenyls) - 3- methyl-1s-butanone is dissolved in the mixed solution of 1.2mL n,N-Dimethylformamide and 1.8mL water, and 0.93g is added The aqueous solution 5mL containing 0.40g (10mmol) sodium hydroxide is added dropwise to reaction solution in (10mmol) (R) -2- chloromethyloxiranes, in It is stirred to react at room temperature 48 hours.Reaction solution is extracted with 3 × 25mL ethyl acetate, merges organic layer, and chlorination is saturated with 3 × 15mL Sodium solution washs, anhydrous sodium sulfate drying；Evaporated under reduced pressure solvent, through silica gel column chromatography (petroleum ether:Ethyl acetate 10:1) it detaches Obtain (R) -1- [2- (epoxy second -2- bases) methoxyl group -4- methoxyphenyls] -3- methyl-1s-butanone 0.11g, yield 8%.
Step 2：(R) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4- methoxyphenyls] -3- methyl-1s-butanone It is prepared by hydrochloride
According to the method for step 3 in embodiment 9, with 60mg (0.23mmol) (R) -1- [2- (epoxies of gained in step 1 Second -2- bases) methoxyl group -4- methoxyphenyls] -3- methyl-1s-butanone and 3mL (35mmol) isopropylamine reaction, obtain solid (R) - 1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4- methoxyphenyls] -3- methyl-1s-butanone hydrochloride 40mg, yield 48%.
1H NMR(500MHz,D2O) δ 7.61 (1H, d, J=8.5Hz, H-6 '), 6.54 (1H, dd, J=8.5,1.5Hz, H- 5 '), 6.47 (1H, d, J=1.5Hz, H-3 '), 4.23 (1H, m, H-2 "), 4.06 (2H, d, J=4.5Hz, H-1 "), 3.74 (3H,s,OCH3), a), 3.39 (1H, m, H-5 "), 3.22 (1H, dd, J=3.5,13.0Hz, H-3 " 3.11 (1H, dd, J= B), 8.0,13.5Hz, H-3 " 2.71 (1H, dd, J=3.5,12.0Hz, H-2a), 2.65 (1H, dd, J=3.5,12.0Hz, H- 2b), 1.93 (1H, m, H-3), 1.24 (3H, d, J=6.0Hz, CH3), -6 " 1.22 (3H, d, J=6.0Hz, CH3-7″),0.77 (6H, d, J=6.5Hz, CH3-4,CH3-5)。13C NMR(125MHz,D2O)δ205.0,165.7,165.3,132.3,114.0, 106.8,100.7,71.8,69.2,55.6,52.7,49.5,45.4,24.5,22.8,22.8,22.6,22.6。
Embodiment 11. (S) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4- methoxyphenyls] -3- methyl-1s-fourth The preparation of keto hydrochloride
Step 1：(S) preparation of -1- [2- (epoxy second -2- bases) methoxyl group -4- methoxyphenyls] -3- methyl-1s-butanone
According to the method for step 1 in embodiment 10, with 1.04g (5mmol) 1- (2- hydroxyl -4- methoxyphenyls) -3 first Base -1- butanone, 0.93g (10mmol) (S) -2- chloromethyloxiranes and the reaction of 0.40g (10mmol) sodium hydroxide, through silica gel Column chromatography (petroleum ether:Ethyl acetate 10:1) isolated (S) -1- [2- (epoxy second -2- bases) methoxyl group -4- methoxybenzenes Base] -3- methyl-1s-butanone 0.13g, yield 9%.
Step 2：(S) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4- methoxyphenyls] -3- methyl-1s-butanone The preparation of hydrochloride
According to the method for step 3 in embodiment 9, with 60mg (0.23mmol) (S) -1- [2- (epoxies of gained in step 1 Second -2- bases) methoxyl group -4- methoxyphenyls] -3- methyl-1s-butanone and 3mL (35mmol) isopropylamine reaction, obtain solid (S) - 1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4- methoxyphenyls] -3- methyl-1s-butanone hydrochloride 35mg, yield 42%.
1H NMR(500MHz,D2O) δ 7.61 (1H, d, J=8.5Hz, H-6 '), 6.54 (1H, dd, J=8.5,1.5Hz, H- 5 '), 6.47 (1H, d, J=1.5Hz, H-3 '), 4.23 (1H, m, H-2 "), 4.06 (2H, d, J=4.5Hz, H-1 "), 3.74 (3H,s,OCH3), a), 3.39 (1H, m, H-5 "), 3.22 (1H, dd, J=3.5,13.0Hz, H-3 " 3.11 (1H, dd, J= B), 8.0,13.5Hz, H-3 " 2.71 (1H, dd, J=3.5,12.0Hz, H-2a), 2.65 (1H, dd, J=3.5,12.0Hz, H- 2b), 1.93 (1H, m, H-3), 1.24 (3H, d, J=6.0Hz, CH3), -6 " 1.22 (3H, d, J=6.0Hz, CH3-7″),0.77 (6H, d, J=6.5Hz, CH3-4,CH3-5)。13C NMR(125MHz,D2O)δ205.0,165.7,165.3,132.3,114.0, 106.8,100.7,71.8,69.2,55.6,52.7,49.5,45.4,24.5,22.8,22.8,22.6,22.6。
Embodiment 12. (±) -1- [2- (2- hydroxyl -3- tert-butylamine bases propoxyl group) -4- methoxyphenyls] -3- methyl-1s - The preparation of butanone hydrochloride
According to the method for step 2-3 in embodiment 9, with 264mg (1mmol) (±) -1- [2- (epoxy second -2- bases) methoxies Base -4- methoxyphenyls] -3- methyl-1s-butanone and 3mL (28.6mmol) tert-butylamine reaction, obtain solid (±) -1- [2- (2- hydroxyl -3- tert-butylamine bases propoxyl group) -4- methoxyphenyls] -3- methyl-1s-butanone hydrochloride 80mg, yield 21%.
1H NMR(500MHz,D2O) δ 7.62 (1H, d, J=8.5Hz, H-6 '), 6.53 (1H, dd, J=8.5,1.5Hz, H- 5 '), 6.45 (1H, d, J=1.5Hz, H-3 '), 4.27 (1H, m, H-2 "), 4.11 (2H, d, J=4.5Hz, H-1 "), 3.65 (3H,s,OCH3), b), a), 3.30 (3.11 (1H, dd, J=8.0,13.5Hz, H-3 are " by 1H, dd, J=3.5,13.0Hz, H-3 " 2.69 (1H, dd, J=3.5,11.5Hz, H-2a), 2.60 (1H, dd, J=3.5,11.5Hz, H-2b), 1.90 (1H, m, H-3), 1.42(9H,s,CH3-6″,CH3-7″,CH3), -8 ", 0.73 (6H, d, J=6.5Hz, CH3-4,CH3-5)。13C NMR (125MHz,D2O)δ205.0,166.3,164.5,131.7,112.3,105.7,99.9,72.4,69.5,55.6,52.3, 50.4,45.4,28.6,28.6,28.6,24.6,22.6,22.6
Embodiment 13. (R) -1- [2- (2- hydroxyl -3- tert-butylamine bases propoxyl group) -4- methoxyphenyls] -3- methyl-1s-fourth The preparation of keto hydrochloride
According to the method for embodiment 10, with 50mg (0.19mmol) (R) -1- [2- (epoxy second -2- bases) methoxyl group -4- first Phenyl] -3- methyl-1s-butanone and 3mL (26.8mmol) tert-butylamine reaction, obtain solid (R) -1- [2- (2- hydroxyls -3- Tert-butylamine base propoxyl group) -4- methoxyphenyls] -3- methyl-1s-butanone hydrochloride 25mg, yield 35%.
1H NMR(500MHz,D2O) δ 7.62 (1H, d, J=8.5Hz, H-6 '), 6.53 (1H, dd, J=8.5,1.5Hz, H- 5 '), 6.45 (1H, d, J=1.5Hz, H-3 '), 4.27 (1H, m, H-2 "), 4.11 (2H, d, J=4.5Hz, H-1 "), 3.65 (3H,s,OCH3), b), a), 3.30 (3.11 (1H, dd, J=8.0,13.5Hz, H-3 are " by 1H, dd, J=3.5,13.0Hz, H-3 " 2.69 (1H, dd, J=3.5,11.5Hz, H-2a), 2.60 (1H, dd, J=3.5,11.5Hz, H-2b), 1.90 (1H, m, H-3), 1.42(9H,s,CH3-6″,CH3-7″,CH3), -8 ", 0.73 (6H, d, J=6.5Hz, CH3-4,CH3-5)。13C NMR (125MHz,D2O)δ205.0,166.3,164.5,131.7,112.3,105.7,99.9,72.4,69.5,55.6,52.3, 50.4,45.4,28.6,28.6,28.6,24.6,22.6,22.6
Embodiment 14. (S) -1- [2- (2- hydroxyl -3- tert-butylamine bases propoxyl group) -4- methoxyphenyls] -3- methyl-1s-fourth The preparation of keto hydrochloride
According to the method for embodiment 11, with 60mg (0.23mmol) (S) -1- [2- (epoxy second -2- bases) methoxyl group -4- first Phenyl] -3- methyl-1s-butanone and 3mL (26.8mmol) tert-butylamine reaction, obtain solid (S) -1- [2- (2- hydroxyls -3- Tert-butylamine base propoxyl group) -4- methoxyphenyls] -3- methyl-1s-butanone hydrochloride 30mg, yield 34%.
1H NMR(500MHz,D2O) δ 7.62 (1H, d, J=8.5Hz, H-6 '), 6.53 (1H, dd, J=8.5,1.5Hz, H- 5 '), 6.45 (1H, d, J=1.5Hz, H-3 '), 4.27 (1H, m, H-2 "), 4.11 (2H, d, J=4.5Hz, H-1 "), 3.65 (3H,s,OCH3), b), a), 3.30 (3.11 (1H, dd, J=8.0,13.5Hz, H-3 are " by 1H, dd, J=3.5,13.0Hz, H-3 " 2.69 (1H, dd, J=3.5,11.5Hz, H-2a), 2.60 (1H, dd, J=3.5,11.5Hz, H-2b), 1.90 (1H, m, H-3), 1.42(9H,s,CH3-6″,CH3-7″,CH3), -8 ", 0.73 (6H, d, J=6.5Hz, CH3-4,CH3-5)。13C NMR (125MHz,D2O)δ205.0,166.3,164.5,131.7,112.3,105.7,99.9,72.4,69.5,55.6,52.3, 50.4,45.4,28.6,28.6,28.6,24.6,22.6,22.6
Embodiment 15. (±) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4,6- Dimethoxyphenyls] -3- first The preparation of base -1- butanone hydrochlorides
Step 1：The preparation of 1- (2- hydroxyl -4,6- Dimethoxyphenyls) -3- methyl-1s-butanone
1.54g (10mmol) 3,5- syringol is dissolved in 20mL boron trifluoride ether solutions, 1.21g is added (10mmol) isoveryl chloride, heating reaction 2 hours at 80 DEG C, are poured into the potassium acetate of 50mL 5% after reaction solution cooling later It in solution, is extracted with 3 × 30mL ethyl acetate, merges organic layer, washed to neutrality with saturated sodium bicarbonate solution, then with 3 × 10mL saturated nacl aqueous solutions wash, anhydrous sodium sulfate drying；After evaporated under reduced pressure solvent, silica gel column chromatography (petroleum ether is carried out:Second Acetoacetic ester 30:1) it detaches, obtains 1- (2- hydroxyls -4,6- Dimethoxyphenyl) -3- methyl-1s-butanone 1.7g, yield 71%.
Step 2：(±) -1- [2- (epoxy second -2- bases) methoxyl group -4,6- Dimethoxyphenyls] -3- methyl-1s-butanone It prepares
According to the method for step 2 in embodiment 9, with 1.00g (4.2mmol) 1- (the 2- hydroxyls -4,6- obtained in step 1 Dimethoxyphenyl) -3- methyl-1s-butanone, 1.94g (21mmol) (±) 2- chloromethyloxiranes and 0.10g (4.2mmol) Sodium hydride reacts, through silica gel column chromatography (petroleum ether:Ethyl acetate 30:1) (±) -1- [2- (epoxy second -2- bases) methoxies are obtained Base -4,6- Dimethoxyphenyl] -3- methyl-1s-butanone 0.9g, yield 69%.
Step 3：(±) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4,6- Dimethoxyphenyls] -3- methyl-1s - The preparation of butanone hydrochloride
According to the method for step 3 in embodiment 9, with 294mg (1mmol) (±) -1- [2- (epoxies of gained in step 2 Second -2- bases) methoxyl group -4,6- Dimethoxyphenyl] -3- methyl-1s-butanone and 3mL (35mmol) isopropylamine reaction, obtain solid (±) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4,6- Dimethoxyphenyls] -3- methyl-1s-butanone hydrochloride 110mg, yield 28%.
1H NMR(500MHz,D2O)δ6.15(1H,br.s,H-5′),6.09(1H,br.s,H-3′),4.10(1H,m,H- ), 2 " 3.92 (2H, d, J=4.5Hz, H-1 "), 3.67 (3H, s, OCH3),3.62(3H,s,OCH3),3.33(1H,m,H-5″), 3.08 (1H, dd, J=3.0,13.0Hz, H-3 " a), 2.96 (1H, dd, J=9.0,13.0Hz, H-3 " b), 2.56 (2H, br.d, J=7.0Hz, H-2), 1.86 (1H, m, H-3), 1.18 (3H, d, J=6.5Hz, CH3- 6 "), 1.17 (3H, d, J=6.5Hz, CH3), -7 " 0.72 (6H, d, J=6.5Hz, CH3-4,CH3-5)。13C NMR(125MHz,D2O)δ205.0,165.7,165.3, 162.7,105.8,92.9,90.8,71.8,69.2,56.0,55.9,52.7,49.5,48.7,24.5,22.7,22.7,22.6, 22.6。
Embodiment 16. (R) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4,6- Dimethoxyphenyls] -3- methyl - The preparation of 1- butanone hydrochlorides
Step 1：(R) -1- [2- (epoxy second -2- bases) methoxyl group -4,6- Dimethoxyphenyls] -3- methyl-1s-butanone It prepares
According to the method for step 1 in embodiment 10, with 1.00g (4.2mmol) 1- (2- obtained in 15 step 1 of embodiment Hydroxyl -4,6- Dimethoxyphenyl) -3- methyl-1s-butanone, 1.94g (21mmol) (R) -2- chloromethyloxiranes and 0.10g (4.2mmol) sodium hydroxide reacts, through silica gel column chromatography (petroleum ether:Ethyl acetate 30:1) (R) -1- [2- (epoxy second-is obtained 2- yls) methoxyl group -4,6- Dimethoxyphenyl] -3- methyl-1s-butanone 0.30g, yield 24%.
Step 2：(R) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4,6- Dimethoxyphenyls] -3- methyl-1s - The preparation of butanone hydrochloride
According to the method for step 2 in embodiment 10, with 150mg (0.51mmol) (R) -1- [2- (rings of gained in step 1 Oxygen second -2- bases) methoxyl group -4,6- Dimethoxyphenyl] -3- methyl-1s-butanone and 3mL (35mmol) isopropylamine reaction, must consolidate Body (R) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4,6- Dimethoxyphenyls] -3- methyl-1s-butanone hydrochloride 130mg, yield 65%.
1H NMR(500MHz,D2O)δ6.15(1H,br.s,H-5′),6.09(1H,br.s,H-3′),4.10(1H,m,H- ), 2 " 3.92 (2H, d, J=4.5Hz, H-1 "), 3.67 (3H, s, OCH3),3.62(3H,s,OCH3),3.33(1H,m,H-5″), 3.08 (1H, dd, J=3.0,13.0Hz, H-3 " a), 2.96 (1H, dd, J=9.0,13.0Hz, H-3 " b), 2.56 (2H, br.d, J=7.0Hz, H-2), 1.86 (1H, m, H-3), 1.18 (3H, d, J=6.5Hz, CH3- 6 "), 1.17 (3H, d, J=6.5Hz, CH3), -7 " 0.72 (6H, d, J=6.5Hz, CH3-4,CH3-5)。13C NMR(125MHz,D2O)δ205.0,165.7,165.3, 162.7,105.8,92.9,90.8,71.8,69.2,56.0,55.9,52.7,49.5,48.7,24.5,22.7,22.7,22.6, 22.6。
Embodiment 17. (S) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4,6- Dimethoxyphenyls] -3- methyl - The preparation of 1- butanone hydrochlorides
Step 1：(S) -1- [2- (epoxy second -2- bases) methoxyl group -4,6- Dimethoxyphenyls] -3- methyl-1s-butanone It prepares
According to the method for step 1 in embodiment 11, with 1.00g (4.2mmol) 1- (2- that step 1 obtains in embodiment 15 Hydroxyl -4,6- Dimethoxyphenyl) -3- methyl-1s-butanone, 1.94g (21mmol) (R) -2- chloromethyloxiranes and 0.10g (4.2mmol) sodium hydroxide reacts, through silica gel column chromatography (petroleum ether：Ethyl acetate 30:1) (S) -1- [2- (epoxy second-is obtained 2- yls) methoxyl group -4,6- Dimethoxyphenyl] -3- methyl-1s-butanone 0.27g, yield 22%.
Step 2：(R) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4,6- Dimethoxyphenyls] -3- methyl-1s - The preparation of butanone hydrochloride
According to the method for step 2 in embodiment 11, with 130mg (0.44mmol) (S) -1- [2- (rings of gained in step 1 Oxygen second -2- bases) methoxyl group -4,6- Dimethoxyphenyl] -3- methyl-1s-butanone and 3mL (35mmol) isopropylamine reaction, must consolidate Body (S) -1- [2- (2- hydroxyl -3- isopropylamine bases propoxyl group) -4,6- Dimethoxyphenyls] -3- methyl-1s-butanone hydrochloride 100mg, yield 58%.
1H NMR(500MHz,D2O)δ6.15(1H,br.s,H-5′),6.09(1H,br.s,H-3′),4.10(1H,m,H- ), 2 " 3.92 (2H, d, J=4.5Hz, H-1 "), 3.67 (3H, s, OCH3),3.62(3H,s,OCH3),3.33(1H,m,H-5″), 3.08 (1H, dd, J=3.0,13.0Hz, H-3 " a), 2.96 (1H, dd, J=9.0,13.0Hz, H-3 " b), 2.56 (2H, br.d, J=7.0Hz, H-2), 1.86 (1H, m, H-3), 1.18 (3H, d, J=6.5Hz, CH3- 6 "), 1.17 (3H, d, J=6.5Hz, CH3), -7 " 0.72 (6H, d, J=6.5Hz, CH3-4,CH3-5)。13C NMR(125MHz,D2O)δ205.0,165.7,165.3, 162.7,105.8,92.9,90.8,71.8,69.2,56.0,55.9,52.7,49.5,48.7,24.5,22.7,22.7,22.6, 22.6。
Embodiment 18. (±) -1- [2- (2- hydroxyl -3- tert-butylamine bases propoxyl group) -4,6- Dimethoxyphenyls] -3- first The preparation of base -1- butanone hydrochlorides
According to the method for embodiment 15, with 294mg (1mmol) (±) -1- [2- (epoxy second -2- bases) methoxyl groups -4,6- bis- Methoxyphenyl] -3- methyl-1s-butanone and 3mL (26.8mmol) tert-butylamine reaction, obtain solid (±) -1- [2- (2- hydroxyls - 3- tert-butylamine bases propoxyl group) -4,6- Dimethoxyphenyls] -3- methyl-1s-butanone hydrochloride 200mg, yield 49%.
1H NMR(500MHz,D2O)δ6.23(1H,br.s,H-5′),6.16(1H,br.s,H-3′),4.11(1H,m,H- ), 2 " 3.99 (2H, d, J=4.5Hz, H-1 "), 3.73 (3H, s, OCH3),3.68(3H,s,OCH3),3.33(1H,m,H-5″), 3.13 (1H, dd, J=3.0,13.0Hz, H-3 " a), 2.96 (1H, dd, J=9.0,13.0Hz, H-3 " b), 2.63 (1H, br.d, J=7.0Hz, H-2), 1.91 (1H, m, H-3), 1.41 (9H, s, CH3-6″,CH3-7″,CH3), -8 " 0.76 (6H, d, J= 7.0Hz,CH3-4,CH3-5)。13C NMR(125MHz,D2O)δ205.1,165.5,165.4,162.3,104.9,93.0,90.5, 72.8,68.7,55.8,55.6,52.8,50.8,45.4,28.7,28.7,28.7,24.6,22.6,22.6。
Embodiment 19. (R) -1- [2- (2- hydroxyl -3- tert-butylamine bases propoxyl group) -4,6- Dimethoxyphenyls] -3- methyl - The preparation of 1- butanone hydrochlorides
According to the method for embodiment 16, with 150mg (0.51mmol) (R) -1- [2- (epoxy second -2- bases) methoxyl groups -4,6- Dimethoxyphenyl] -3- methyl-1s-butanone and 3mL (26.8mmol) tert-butylamine reaction, obtain solid (R) -1- [2- (2- hydroxyls Base -3- tert-butylamine bases propoxyl group) -4- methoxyphenyls] -3- methyl-1s-butanone hydrochloride 128mg, yield 62%.
1H NMR(500MHz,D2O)δ6.23(1H,br.s,H-5′),6.16(1H,br.s,H-3′),4.11(1H,m,H- ), 2 " 3.99 (2H, d, J=4.5Hz, H-1 "), 3.73 (3H, s, OCH3),3.68(3H,s,OCH3),3.33(1H,m,H-5″), 3.13 (1H, dd, J=3.0,13.0Hz, H-3 " a), 2.96 (1H, dd, J=9.0,13.0Hz, H-3 " b), 2.63 (1H, br.d, J=7.0Hz, H-2), 1.91 (1H, m, H-3), 1.41 (9H, s, CH3-6″,CH3-7″,CH3), -8 " 0.76 (6H, d, J= 7.0Hz,CH3-4,CH3-5)。13C NMR(125MHz,D2O)δ205.1,165.5,165.4,162.3,104.9,93.0,90.5, 72.8,68.7,55.8,55.6,52.8,50.8,45.4,28.7,28.7,28.7,24.6,22.6,22.6。
Embodiment 20. (S) -1- [2- (2- hydroxyl -3- tert-butylamine bases propoxyl group) -4,6- Dimethoxyphenyls] -3- methyl - The preparation of 1- butanone hydrochlorides
According to the method for embodiment 17, with 130mg (0.44mmol) (S) -1- [2- (epoxy second -2- bases) methoxyl groups -4,6- Dimethoxyphenyl] -3- methyl-1s-butanone and 3mL (26.8mmol) tert-butylamine reaction, obtain solid (S) -1- [2- (2- hydroxyls Base -3- tert-butylamine bases propoxyl group) -4- methoxyphenyls] -3- methyl-1s-butanone hydrochloride 135mg, yield 76%.
1H NMR(500MHz,D2O)δ6.23(1H,br.s,H-5′),6.16(1H,br.s,H-3′),4.11(1H,m,H- ), 2 " 3.99 (2H, d, J=4.5Hz, H-1 "), 3.73 (3H, s, OCH3),3.68(3H,s,OCH3),3.33(1H,m,H-5″), 3.13 (1H, dd, J=3.0,13.0Hz, H-3 " a), 2.96 (1H, dd, J=9.0,13.0Hz, H-3 " b), 2.63 (1H, br.d, J=7.0Hz, H-2), 1.91 (1H, m, H-3), 1.41 (9H, s, CH3-6″,CH3-7″,CH3), -8 " 0.76 (6H, d, J= 7.0Hz,CH3-4,CH3-5)。13C NMR(125MHz,D2O)δ205.1,165.5,165.4,162.3,104.9,93.0,90.5, 72.8,68.7,55.8,55.6,52.8,50.8,45.4,28.7,28.7,28.7,24.6,22.6,22.6。
The preparation of embodiment 21. 4- (piperidin-1-yl) -1- (2,4,6- trihydroxies phenyl) -1- butanone hydrochlorides
Step 1：The preparation of 4- (piperidin-1-yl) butyronitrile
2.58g (25mmol) 4- chlorobutyronitriles are dissolved in 5mL acetonitriles, 3.5g (25mmol) Anhydrous potassium carbonates and a small amount of iodine is added Change sodium, is slowly dropped into 2.13g (25mmol) piperidines, stirs 20h at room temperature.10mL water is added in residue for evaporated under reduced pressure solvent Dissolving is extracted with 3 × 15mL ethyl acetate, is merged organic layer, is washed with 2 × 10mL saturated nacl aqueous solutions, anhydrous sodium sulfate It is dry.Solvent evaporated obtains oily liquids 3.30g.
Step 2：The preparation of 4- (piperidin-1-yl) -1- (2,4,6- trihydroxies phenyl) -1- butanone hydrochlorides
1.33g phloroglucins (10.5mmol) are dissolved in 10mL nitrobenzenes, gained grease 1.60g in step 1 is added, Dry HCl gases are passed through, stir 12h at room temperature.Reaction solution is stood overnight, and solid is dissolved in 10mL water, heats back by filtering Flow 1h.It is cooling, filtering, obtained solid alcohol-water (4:1) it recrystallizes, obtains 4- (piperidin-1-yl) -1- (2,4,6- trihydroxy benzenes Base) -1- butanone hydrochloride 0.67g, yield 20%.
1H NMR(500MHz,d6-DMSO)δ12.23(2H,s,OH-2′,OH-6′),10.45(1H,s,OH-4′),5.81 (2H, s, H-3 ', H-5 '), 3.43 (a), 2H, br.d, J=11.5Hz, H-2 " a, H-6 " 3.08 (2H, t, J=6.5Hz, H-2), B), 3.05 (2H, overlap, H-4), 2.86 (2H, m, H-2 " b, H-6 " 1.94 (2H, m, H-3), 1.79 (2H, br.d, J= 14.0Hz,H-3″a,H-5″a),1.65(2H,overlap,H-3″b,H-5″b),1.60(1H,m,H-4″a,),1.38(1H,m, H-4″b)。13C NMR(125MHz,d6-DMSO)δ202.8,164.5,163.9,163.9,103.4,94.3,94.3,55.2, 51.8,51.8,38.7,22.3,22.3,21.0,17.9。
The preparation of 22. 4- of embodiment (methylcyclohexyl amine) -1- (2,4,6- trihydroxies phenyl) 1- butanone hydrochlorides
Step 1：The preparation of 4- (methylcyclohexyl amine) butyronitrile
According to the method for step 1 in embodiment 21, with 1.98g (19.2mmol) 4- chlorobutyronitriles, 2.56g (19.2mmol) nothing Oily liquids 4.00g is obtained after aqueous carbonate potassium and a small amount of NaI and the reaction of 2.17g (19.2mmol) methylcyclohexyl amine.
Step 2：The preparation of 4- (methylcyclohexyl amine) -1- (2,4,6- trihydroxies phenyl) 1- butanone hydrochlorides
1.05g phloroglucins (8.33mmol) are dissolved in 10mL nitrobenzenes, gained grease 1.5g in step 1 is added, Dry HCl gases are passed through, stir 9h at room temperature.After reaction solution is stood overnight, 15mL water is added, separates water layer, organic layer is with 2 × 15mL water extracts, and combining water layer is heated to reflux 1h.It is cooling, filtering, obtained solid alcohol-water (4:1) it recrystallizes, obtains 4- (methylcyclohexyl amine) -1- (2,4,6- trihydroxy phenyl) 1- butanone hydrochloride 0.30g, yield 11%.
1H NMR(500MHz,d6- DMSO) δ 5.81 (2H, s, H-3 ', H-5 '), 2.98 (2H, t, J=7.0Hz, H-2), 2.44 (2H, t, J=7.0Hz, H-4), 2.35 (1H, m, H-1 "), 2.18 (3H, s, NCH3),1.74(2H,overlap,H-3), B), a), 1.73 (2H, overlap, H-2 " a, H-6 " 1.71 (2H, m, H-2 " b, H-6 " 1.54 (1H, br.d, J=12.5Hz, H- 4″a),1.16(2H,m,H-3″a,H-5″a),1.12(2H,m,H-3″b,H-5″b),1.04(1H,m,H-4″b)。13C NMR (125MHz,d6-DMSO)δ204.9,164.8,164.7,164.7,104.4,94.7,94.7,62.1,52.3,40.3,37.0, 27.8,27.8,25.9,25.4,25.4,22.6。
23. 4- of embodiment [4- (3- chlorphenyls) piperazine -1- bases] -1- (2,4,6- trihydroxies phenyl) 1- butanone hydrochlorides Preparation
Step 1：The preparation of 4- [4- (3- chlorphenyls) piperazine -1- bases] butyronitrile
According to the method for step 1 in embodiment 21, with 1.35g (13mmol) 4- chlorobutyronitriles, 1.80g (15mmol) anhydrous carbon Oily liquids 4.00g is obtained after sour potassium and a small amount of NaI and the reaction of 2.90g (15mmol) 4- (3- chlorphenyls) piperazine.
Step 2：The system of 4- [4- (3- chlorphenyls) piperazine -1- bases] -1- (2,4,6- trihydroxies phenyl) 1- butanone hydrochlorides It is standby
1.05g phloroglucins (8.33mmol) are dissolved in 10mL nitrobenzenes, gained grease 3.00g in step 1 is added, Dry HCl gases are passed through, stir 9h at room temperature.After reaction solution is stood overnight, 15mL water is added, separates water layer, organic layer is with 2 × 15mL water extracts, and combining water layer is heated to reflux 1h.It is cooling, filtering, obtained solid alcohol-water (5:1) it recrystallizes, obtains 4- (methylcyclohexyl amine) -1- (2,4,6- trihydroxy phenyl) 1- butanone hydrochloride 0.45g, yield 13%.
1H NMR(500MHz,d6-DMSO)δ12.21(2H,s,OH-2′,OH-6′),10.43(1H,s,OH-4′),7.26 (1H, t, J=8.0Hz, H-5 " '), 7.05 (1H, br.s, H-H-2 " '), 6.96 (1H, br.d, J=8.0Hz, H-H-4 " '), 6.87 (1H, br.d, J=8.0Hz, H-6 " '), 5.82 (2H, s, H-3 ', H-5 '), 3.90 (2H, br.d, J=12.5Hz, H-2 " B), a), a), 3.59 (3.19 (2H, overlap, H-2 " b, H-6 are " by 2H, br.d, J=11.5Hz, H-3 " a, H-5 " by a, H-6 " B), 3.16 (2H, overlap, H-3 " b, H-5 " 3.10 (2H, t, J=6.5Hz, H-2), 3.01 (2H, t, J=11.5Hz, H- 4),1.99(2H,m,H-3)。13C NMR(125MHz,d6-DMSO)δ203.0,164.8,164.1,164.1,150.7,133.9, 130.6,119.2,115.2,114.1,103.6,94.6,94.6,55.1,50.5,50.5,44.9,44.9,38.9,18.2。
The preparation of embodiment 24. (S) -2- (2,4,6- trimethoxy-benzenes methylamino) propionic acid
Step 1：(S) preparation of -2- (2,4,6- trimethoxy-benzenes methylamino) methyl propionate
2,4,6- trimethoxybenzaldehyde of 196mg (1mmol) is dissolved in 10mL methanol, 76mg (1.2mmol) is added NaBH3CN and 280mg (2mmol) alanine methyl ester hydrochloride, argon gas protection, stir 3h at room temperature.It is added into reaction solution 20mL water is extracted with 3 × 25mL ethyl acetate, is merged organic layer, is washed with 3 × 10mL saturated nacl aqueous solutions, anhydrous slufuric acid Sodium is dried.Solvent evaporated carries out silica gel column chromatography (petroleum ether:Ethyl acetate 4:1) isolated (S) -2- (2,4,6- trimethoxies Base benzene methanamine base) methyl propionate 118mg, yield 42%.
Step 2：(S) preparation of -2- (2,4,6- trimethoxy-benzenes methylamino) propionic acid
100mg (0.35mmol) (S) -2- (2,4,6- trimethoxy-benzenes methylamino) methyl propionate that step 1 is obtained is molten Solution is in 20mL 5%KOH ethanol waters (EtOH:H2O=1:1) in solution, 2h is stirred at room temperature, and Amberlite 120H are added+Tree Fat, stirring is to pH value of solution=7, filtering, and filtrate concentration is purified through preparing HPLC (YMC, 20% acetonitrile), obtain (S) -2- (2,4, 6- trimethoxy-benzenes methylamino) propionic acid 85mg, yield 90%.
1H NMR(500MHz,d6-DMSO)δ6.27(2H,s,H-3′,H-5′),4.07(2H,br.s,H-1),3.80(6H, s,OCH3-2′,OCH3-6′),3.79(3H,s,OCH3- 4 '), 3.36 (1H, m, H-3), 1.44 (3H, d, J=6.0Hz, CH3- 5)。13C NMR(125MHz,d6-DMSO)δ170.8,162.5,159.7,159.7,99.3,90.7,90.7,55.9,55.9, 55.6,54.0,37.7,15.2。
The preparation of embodiment 25. (S) -2- (2,4,6- trimethoxy-benzenes methylamino) -3- phenylpropionic acids
Step 1：(S) preparation of -2- (2,4,6- trimethoxy-benzenes methylamino) -3- phenylpropionic acid methyl esters
According to the method for step 1 in embodiment 24, with 2,4,6- trimethoxybenzaldehyde of 196mg (1mmol), 76mg (1.2mmol)NaBH3After CN and 520mg (2mmol) phenylalanine methyl ester hydrochloride react, through silica gel column chromatography (petroleum ether:Second Acetoacetic ester 10:1) isolated (S) -2- (2,4,6- trimethoxy-benzene methylamino) -3- phenylpropionic acid methyl ester 136mg, yield 38%.
Step 2：(S) preparation of -2- (2,4,6- trimethoxy-benzenes methylamino) -3- phenylpropionic acids
According to the method for step 2 in embodiment 24, the 100mg obtained with step 1 (0.28mmol) (S) -2- (2,4,6- tri- Methoxybenzylamine base) -3- phenylpropionic acid methyl esters reaction after, through prepare HPLC (YMC, 30% acetonitrile) purify, obtain (S) -2- (2,4,6- trimethoxy-benzene methylamino) -3- phenylpropionic acid 85mg, yield 88%.
1H NMR(500MHz,d6- DMSO) δ 7.32 (2H, t, J=7.5Hz, H-3 ", H-5 "), 7.26 (1H, t, J= 8.0Hz, H-4 "), 7.22 (2H, d, J=7.5Hz, H-2 ", H-6 "), 6.27 (2H, s, H-3 ', H-5 '), 4.07 (2H, br.s, H-1),3.91(1H,br.s,H-3),3.80(3H,s,OCH3-4′),3.78(6H,s,OCH3-2′,OCH3-6′),3.32(1H, Dd, J=13.5,4.5Hz, H-5a), 3.09 (1H, dd, J=13.5,8.0Hz, H-5b)13C NMR(125MHz,d6-DMSO)δ 169.2,162.4,159.6,159.6,134.8,129.3,129.3,128.4,128.4,127.1,98.8,90.6,90.6, 59.3,55.8,55.8,55.4,38.3,34.9。
The preparation of embodiment 26. (S) -2- (2,4,6- trimethoxy-benzenes methylamino) -5- amino -5- oxy pentanoic acids
Step 1：(S) preparation of -2- (2,4,6- trimethoxy-benzenes methylamino) dimethyl glutarate
According to the method for step 1 in embodiment 24, with 2,4,6- trimethoxybenzaldehyde of 196mg (1mmol), 76mg (1.2mmol)NaBH3After CN and 410mg (2mmol) glutamic acid dimethyl ester hydrochloric acid reactant salt, through silica gel column chromatography (petroleum ether:Second Acetoacetic ester 1:1) isolated (S) -2- (2,4,6- trimethoxy-benzene methylamino) -4- amino -4- oxy butyrate methyl esters 165mg are received Rate 50%.
Step 2：(S) preparation of -2- (2,4,6- trimethoxy-benzenes methylamino) glutaric acid
According to the method for step 2 in embodiment 24, the 100mg obtained with step 1 (0.31mmol) (S) -2- (2,4,6- tri- Methoxybenzylamine base) -5- amino -5- oxy butyrate methyl esters reaction after, through prepare HPLC (YMC, 13% acetonitrile) purify, obtain (S) -2- (2,4,6- trimethoxy-benzene methylamino) glutaric acid 91mg, yield 95%.
1H NMR(500MHz,d6- DMSO) δ 6.26 (2H, s, H-3 ', H-5 '), 4.03 (1H, d, J=13.0Hz, H-1a), 3.97 (1H, d, J=13.0Hz, H-1b), 3.79 (6H, s, OCH3-2′,OCH3-6′),3.78(3H,s,OCH3-4′),3.44 (1H, t, J=6.5Hz, H-3), 2.41 (1H, m, H-5a), 2.32 (1H, m, H-5b), 2.01 (1H, m, H-6a), 1.94 (1H, m,H-6b)。13C NMR(125MHz,d6-DMSO)δ173.7,169.9,162.3,159.6,159.6,99.8,90.7,90.7, 58.8,55.9,55.9,55.5,38.5,30.3,24.9。
The preparation of embodiment 27. (S) -2- (2,4,6- trimethoxy-benzenes methylamino) succinic acid
Step 1：(S) preparation of -2- (2,4,6- trimethoxy-benzenes methylamino) dimethyl succinate
According to the method for step 1 in embodiment 24, with 2,4,6- trimethoxybenzaldehyde of 196mg (1mmol), 76mg (1.2mmol)NaBH3After CN and 420mg (2mmol) aspartic acid diformazan ester hydrochloride react, through silica gel column chromatography (petroleum ether: Ethyl acetate 5:1) isolated (S) -2- (2,4,6- trimethoxy-benzene methylamino) dimethyl succinate 155mg, yield 46%.
Step 2：(S) preparation of -2- (2,4,6- trimethoxy-benzenes methylamino) succinic acid
According to the method for step 2 in embodiment 24, the 100mg obtained with step 1 (0.29mmol) (S) -2- (2,4,6- tri- Methoxybenzylamine base) dimethyl succinate reaction after, through prepare HPLC (YMC, 9% acetonitrile) purify, obtain (S) -2- (2,4, 6- trimethoxy-benzenes methylamino) succinic acid 75mg, yield 85%.
1H NMR(500MHz,d6- DMSO) δ 6.28 (2H, s, H-3 ', H-5 '), 4.17 (1H, d, J=13.0Hz, H-1a), 4.13 (1H, d, J=13.0Hz, H-1b), 3.99 (1H, t, J=6.0Hz, H-3), 3.80 (3H, s, OCH3-4′),3.79(6H, s,OCH3-2′,OCH3-6′),2.84(2H,br.s,H-5)。13C NMR(125MHz,d6-DMSO)δ171.1,169.2,162.5, 159.6,159.6,99.2,90.8,90.8,56.0,56.0,55.5,54.7,39.0,34.0。
The preparation of embodiment 28. (S) -2- (2,4,6- trimethoxy-benzenes methylamino) -3- hydracrylic acids
Step 1：(S) preparation of -2- (2,4,6- trimethoxy-benzenes methylamino) -3- hydroxy methyl propionates
According to the method for step 1 in embodiment 24, with 2,4,6- trimethoxybenzaldehyde of 196mg (1mmol), 76mg (1.2mmol)NaBH3After CN and 310mg (2mmol) serine methyl ester hydrochloride react, through silica gel column chromatography (petroleum ether:Acetic acid Ethyl ester 1:1) isolated (S) -2- (2,4,6- trimethoxy-benzene methylamino) -3- hydroxy methyl propionate 110mg, yield 37%.
Step 2：(S) preparation of -2- (2,4,6- trimethoxy-benzenes methylamino) -3- hydracrylic acids
According to the method for step 2 in embodiment 24, the 100mg obtained with step 1 (0.33mmol) (S) -2- (2,4,6- tri- Methoxybenzylamine base) -3- hydroxy methyl propionates reaction after, through prepare HPLC (YMC, 13% acetonitrile) purify, obtain (S) -2- (2,4,6- trimethoxy-benzene methylamino) -3- hydracrylic acid 86mg, yield 92%.
1H NMR(500MHz,d6-DMSO)δ6.27(2H,s,H-3′,H-5′),4.10(2H,br.s,H-1),3.85(1H, overlap,H-5a),3.85(1H,overlap,H-5b),3.79(6H,s,OCH3-2′,OCH3-6′),3.78(3H,s,OCH3- 4′),3.48(1H,br.s,H-3)。13C NMR(125MHz,d6-DMSO)δ168.4,162.3,159.7,159.7,99.4, 90.8,90.8,60.8,59.3,56.0,56.0,55.5,38.7。
The preparation of embodiment 29. (S) -2- (2,4,6- trihydroxy benzenes methylamino) -3- (1H- imidazoles -5- bases) propionic acid
Step 1：(S) preparation of -2- (2,4,6- trihydroxy benzenes methylamino) -3- (1H- imidazoles -5- bases) methyl propionate
According to the method for step 1 in embodiment 24, with 2,4,6- trimethoxybenzaldehyde of 196mg (1mmol), 76mg (1.2mmol)NaBH3After CN and 411mg (2mmol) histidine methylester hydrochloric acid reactant salt, through silica gel column chromatography (dichloromethane:First Alcohol 10:1) isolated (S) -2- (2,4,6- trihydroxy benzene methylamino) -3- (1H- imidazoles -5- bases) methyl propionate 97mg, yield 28%.
Step 2：(S) preparation of -2- (2,4,6- trihydroxy benzenes methylamino) -3- (1H- imidazoles -5- bases) propionic acid
According to the method for step 2 in embodiment 24, the 97mg obtained with step 1 (0.28mmol) (S) -2- (2,4,6- tri- Hydroxybenzylamine base) -3- (1H- imidazoles -5- bases) methyl propionate reaction after, through prepare HPLC (YMC, 10% acetonitrile) purify, obtain To (S) -2- (2,4,6- trihydroxy benzene methylamino) -3- (1H- imidazoles -5- bases) propionic acid 70mg, yield 74%.
1H NMR(500MHz,d6-DMSO)δ7.95(1H,s,H-3″),7.47(1H,s,H-5″),6.29(2H,s,H-3′, H-5 '), 4.13 (1H, d, J=13.5Hz, H-1a), 4.07 (1H, d, J=13.5Hz, H-1b), 3.91 (1H, br.s, H-3), 3.79(3H,s,OCH3-4′),3.80(6H,s,OCH3-2′,OCH3- 6 '), 3.32 (1H, dd, J=15.5,6.0Hz, H-5a), 3.24 (1H, dd, J=15.5,8.0Hz, H-5b)13C NMR(125MHz,d6-DMSO)δ168.9,162.6,159.8,159.8, 134.5,127.6,117.8,99.1,90.8,90.8,57.4,55.9,55.9,55.6,38.5,24.8。
Pharmacological evaluation
1. experimental example 1 (inhibiting effect that Compound ira vitro discharges NO caused by LPS)
(1) material and method：
Material：BV2 cells (mouse microglia system)
Griess reagents：With distilled water prepare 0.1% naphthodiamide, with 5% phosphoric acid prepare 1% p-aminobenzene sulfonic acid, two Person is before use with 1:1 isometric mixing
Curcumin is prepared with DMSO, and final concentration of 10-5,10-6,10-7mol/L
Lipopolysaccharides is prepared, final concentration of 300ng/mL with sterile PBS
Test-compound is prepared with DMSO, and final concentration of 10-5,10-6,10-7mol/L
Method：
1) BV2 cells are cultivated in the DMEM-F12 culture mediums containing 10% newborn bovine serum, in 37 DEG C, 5%CO2/ 95% Air is grown under 100% relative humidity.
2) the BV2 cells of exponential phase, after digestion counts, with 2 × 104A/hole is inoculated into 96 orifice plates, 24 hours The test-compound and positive control drug curcumin (10 of various concentration are added afterwards-5,10-6,10-7M), LPS is added after 1 hour, eventually A concentration of 300ng/mL continues culture 24 hours, collects medium supernatant.
3) the clear 100 μ L of cell culture fluid upper liquid are taken, isometric Griess reagents are added, are stored at room temperature 20min, distilled water tune Zero, in measuring OD values in microplate reader at 540nm, while using sodium nitrate as standard items, OD values are measured, are calculated in sample to be tested NO2 -Concentration reflection NO concentration.
(2) result
Multiple test-compounds show the good activity (1 × 10 for inhibiting microglia-5Under mol/L concentration, Inhibiting rate>50%) activity (table suitable with positive control medicine curcumin for the compound that, wherein embodiment 1,2,26,28 indicates 1 and Fig. 1).
Table 1：The IC of compound in embodiment50Value
Note：“IC50" indicate concentration when compound reaches 50% to NO inhibiting rates
"-" indicates compound in maximum concentration 1 × 10-550% is less than to NO inhibiting rates under mol/L
2. (Compound ira vitro is to LPS and A β for experimental example 225-35The inhibiting effect of the neuroinflamation of initiation)
(1) material and method：
Material：The SD rat embryos of pregnant 18d
Lipopolysaccharides is prepared, final concentration of 100ng/mL with sterile PBS
Aβ25-35, prepared with sterile PBS, aging 7 days at 37 DEG C, final concentration of 2.5 × 10-5mol/L
Curcumin is prepared with DMSO, and final concentration of 10-5mol/L
Donepezil is prepared with DMSO, and final concentration of 5 × 10-6mol/L
Test-compound (embodiment 1,2,26 and 28), is prepared, final concentration of 10 with DMSO-5,10-6, 10-7mol/L
ELISA kit (R＆D companies)
LDH detection reagents (biological reagent company is built up in Nanjing)
Method：
1) foundation of primary hippocampal neurons/spongiocyte co-culture system：The SD rat embryos of pregnant 18d, are being dissected Hippocampus is detached under mirror, is blown and beaten with pipette, is inoculated in until it can't see tissue block, after filtering in 24 orifice plates.
2) cell administration is handled：After above-mentioned primitive cell culture 7d, respectively with test-compound (10-5,10-6,10-7mol/ ) or positive control drug curcumin (10 L-5Mol/L), donepezil (5 × 10-6Mol/L it) is incubated altogether, stimulant LPS is added after 3h 100ng/mL or A β25-352.5×10-5Culture medium is taken to survey IL-1 β and TNF-α after mol/L, 5h.
3) cell collects culture medium and detects LDH after drug-treated 7d.
(2) result
1) there is inflammatory reaction under LPS stimulations in hippocampal neuron/spongiocyte co-culture system, IL-1 in culture medium The burst size of β, TNF-α and LDH obviously increase, and the latter shows that neuron damages.And what embodiment 1,2,26 and 28 indicated Compound can obviously reduce the level of these three factors, illustrates that it has and inhibits neuroinflamation, protects the effect of neuron, and 10-5Under mol/L concentration, action intensity is suitable with positive control drug curcumin (being shown in Table 2).
Table 2：Inhibiting effect of the compound to neuroinflamation caused by LPS
2) hippocampal neuron/spongiocyte co-culture system is in A β25-35Occurs inflammatory reaction under stimulation, in culture medium The burst size of IL-1 β, TNF-α and LDH obviously increase, and the latter shows that neuron damages.And embodiment 1,2,26 and 28 tables The compound shown can obviously reduce the level of these three factors, illustrates that it has and inhibits neuroinflamation, protects the effect of neuron, And 10-5Under mol/L concentration, action intensity is suitable with positive control drug curcumin.
3 compound of table is to A β25-35The inhibiting effect of caused neuroinflamation
3. (Compound ira vitro is to A β for experimental example 325-35The influence of caused neure damage)
(1) material and method：
Material：Newborn SD rat
Cytarabine (Ara-C) is prepared with deionized water, filtration sterilization, final concentration of 4m mol/L
Aβ25-35, prepared with sterile PBS, aging 7 days at 37 DEG C, final concentration of 2.5 × 10-5mol/L
Donepezil is prepared with DMSO, and final concentration of 5 × 10-6mol/L
Test-compound (embodiment 1,2,26 and 28), is prepared, final concentration of 10 with DMSO-5,10-6, 10-7mol/L
Method：
1) foundation of primary simple cultured hippocampal neuron system：Newborn SD rat detaches hippocampus under anatomical lens, adds pancreas egg White enzymic digestion is blown and beaten after terminating digestion with pipette, and until it can't see tissue block, filtering is inoculated in 96 after centrifugation In orifice plate.Ara-C is added after 48h, inhibits glial growth.
2) cell administration is handled：After above-mentioned primitive cell culture 7d, respectively with test-compound (10-5,10-6,10-7mol/ ) or positive control drug donepezil (5 × 10 L-6Mol/L it) is incubated altogether, stimulant A β is added after 3h25-352.5×10-5mol/L。
3) culture solution is sucked out after drug-treated 7d in cell, and the MTT that the culture medium of serum-free is prepared is added, final concentration of 0.5mg/mL, 37 DEG C are continued after cultivating 4h, add 150 μ L dimethyl sulfoxides to dissolve MTT, absorption value is read at 570nm.With control group Cell survival rate is 100%, calculates the survival rate of different disposal group cell.
(2) result
The neuron of simple hippocampal primary culture is in A β25-35Stimulation under, neuron survival rate is substantially reduced, embodiment 1, 2,26 and 28 compounds indicated can dramatically the survival rate for improving neuron, illustrate that it there is directly protection to make neuron With, and 10-5Under mol/L concentration, effect is better than positive drug donepezil (table 4).
Table 4：Compound is to A β25-35Cause the protective effect of neure damage
4. experimental example 4 (to the influence of the MPTP subacute PD models induced in compound body)
(1) material and method
Material：Animal：Male C57 mouse, 22 ± 1g of weight are purchased from Fukang experimental animal Technology Co., Ltd. of Beijing China. Cleaning grade.Rearing conditions：Barrier grade animal house is raised, credit number：
SYXK (capital) 2009-0004, the interior raising of feeding standard box, per 5, box.
Test medicine：The compound that Examples 1 and 28 indicate
L-DOPA：Madopar (Benserazide piece), Shanghai Co., Ltd of Roche Group, Chinese medicines quasi-word
H10930198, lot number：SH0895.
MPTP：Sigma Products, lot number：128k1549..
DA and IP is purchased from Sigma companies.
Method：
1) model foundation：Mouse is 3 days trained in advance using rod method (Rotarod test) is turned, and will move uncoordinated mouse It rejects, it is random to be grouped, every group 15.It is primary that mouse is injected intraperitoneally MPTP (being dissolved in physiological saline) 30mg/kg daily, continuous 5 days.
2) grouping administration：It is divided into the different agent of Normal group, MPTP model groups, 1 various dose group of embodiment, embodiment 28 Amount group and positive drug L-DOPA groups.30min intraperitoneal injection MPTP 30mg/ after 8 various dose of Examples 1 and 2 and positive drug administration Kg, once a day, continuous 5 days.MPTP continues to be administered after stopping injection, once a day, continuous 7 days.Normal group it is oral and The aseptic double-distilled water and physiological saline of same dose, the oral sterile double steamings for giving same dose of MPTP model groups are injected intraperitoneally Water.
3) behaviouristics detects：The sports coordination ability of mouse is evaluated using rod method and pole-climbing method (Pole test) is turned.
1. turning rod method：It is diameter 3cm to turn rod instrument (institute of Materia Medica,Chinese Academy of Medical Sciences development), and long is about 50cm, is used Partition board is divided into 5 sections of horizon bar, ensures that animal is unaffected by each other.Turn rod instrument rotating speed and is set as 14 turns/min of constant speed.By mouse It is placed on bar, turns on the switch, start timing, record from the time for starting to turn rod and being fallen down from bar to mouse, be denoted as incubation period (i.e. The time fallen for the first time), its sports coordination ability is indicated with this.Every mouse is tested 3 times, per minor tick 1h, is averaged. Mouse turned rod test for 9 days and 16 days in the 5th day of experiment.
2. pole-climbing method：Pole-climbing method one diameter 13mm, high 50cm, top have the wooden shot of a diameter 3cm smooth rod (in Develop Academy of Medical Sciences institute of materia medica of state), it is disposed vertically, mouse head is placed on the top ball of bar downwards, allows it along bar Naturally it climbs down, behavior of observation animal during climbing down.Behavior during mouse climbs down is scored by standard, and standards of grading are such as Under：5 points：Operated by arms and legs is coordinated to creep downwards step by step；4 points：It creeps downwards step by step but has hind leg concurrently and slide behavior；3 Point：It is slided under after getting over a half-distance, but bar can be held tightly；2 points：A half-distance is not got over the behavior of sliding occurs；1 point：It climbs Bar cannot be grabbed by crossing after a half-distance falls from bar；0 point：Bar cannot be grabbed by not getting over a half-distance, be fallen from bar.Before experiment Every mouse training is twice.In testing the test of pole-climbing in the 6th, 10,17 day, every mouse is tested 2 times, per minor tick 1h, according to upper The standard of stating scores, and is averaged.
4) striatal dopamine levels detect：HPLC electrochemical detectors detect.High performance liquid chromatograph：Waters, inspection Survey device：2465
Chromatographic condition：Mobile phase：Sodium acetate-citrate buffer solution, 85mM containing citric acid, anhydrous sodium acetate 100mM, EDTA·Na20.2mM is first made into 850ml, and 150ml methanol is added later, and tri-distilled water is settled to 1L, and it is 3.68 to adjust pH, is taken out Appropriate SOS (first plus 90mg, depending on further according to separation situation) is added after filter, positive dibutyl amine (first plus 15 μ L) makes peak be kept completely separate. The preparation of tissue homogenate：A liquid：IP is added in the perchloric acid solution of 0.6mol/L, makes the final concentration of 0.375 μ g/ml of IP, 4 DEG C preserve.B liquid：20mM containing potassium citrate, dipotassium hydrogen phosphate 300mM, EDTANa22mM, 4 DEG C of preservations.
Sample treatment：Tissue sample processing procedure carries out under condition of ice bath, it then follows the quick principle of low temperature.A is added Liquid, homogenate, 4 DEG C, 20000g is centrifuged 20 minutes, draws a certain amount of supernatant, is added the B liquid of half volume, ice bath 30min, and mixing is quiet It sets, 20000g, 4 DEG C centrifuge 20 minutes, draw supernatant, 20000g, 4 DEG C centrifuge 20 minutes, draw supernatant, and 4 DEG C of preservations are to be measured.
5) immunohistochemistry detects nigral dopaminergic neuron：After Behaviors survey, every group takes 5 mouse, perfusion solid at random Brain is taken after fixed, is used for Immunohistochemical detection.The variation of light microscopic observation mouse TH neurons.It takes pictures, counts under 4 times of object lens The brain piece of every mouse is averaged as the last mouse TH positive neurons by number substantia nigra compacta TH positive neuron numbers Number.
6) statistical analysis：It is for statistical analysis with SPSS13.0.Variation variance analysis between different groups, is then used LSD-SNK is examined.P<0.05 is with significant difference.
(2) result
1) improvement result of the compound that Examples 1 and 28 represent to mice behavior
1. after mouse peritoneal injection MPTP, the residence time is substantially reduced on turning rod compared with normal mouse, shows that mouse goes out Existing behaviouristics obstacle.It is oral to give Examples 1 and 28 mouse residence time on turning rod can be improved, and there are apparent dosage effects It should be related to, it is substantially suitable (Fig. 1, table 5) in high dose level and the effect of positive control drug L-DOPA (20mg/kg).
5. compound 1 and 28 of table on mouse turn rod it is ethological influence (N=15)
**P<0.01vs.Control mouse,#P<0.05,##P<0.01vs.MPTP model mices
2. pole-climbing scoring is substantially reduced compared with normal mouse after mouse peritoneal injection MPTP.It is oral to give embodiment 1 He 28 can it is dose-dependent improve mouse pole-climbing scoring, to its behavior disorder have improvement result, and high dose level with The effect of L-DOPA is substantially quite (Fig. 2, table 6).
The influence ethological on mouse pole-climbing of 6. compound 1 and 28 of table (N=15)
**P<0.01vs.Control mouse,#P<0.05,##P<0.01vs.MPTP model mices
2) influence of the compound that Examples 1 and 28 represent to mouse striaturn dopamine
The compound that Examples 1 and 28 represent can dose dependent improve the level of DA in mouse striaturn, and high dose The lower effect of level is suitable with positive control drug L-DOPA (table 7).
Influence of 7. Examples 1 and 28 of table to mouse striaturn DOPAMINE CONTENT IN RABBIT
**P<0.01vs.Control mouse,#P<0.05,##P<0.01vs.MPTP model mices
3) influence of the compound that Examples 1 and 28 represent to mouse DOPA serotonergic neuron
The more normal number of mice amount of MPTP model group mouse substantia nigra compacta TH positive neuron numbers is substantially reduced.Embodiment 1 and 28 can be improved mouse TH positive neuron quantity, and there are apparent dose-effect relationships.Positive drug L-DOPA is small to model Mouse TH neuronal quantities have no significant effect (Fig. 3).
Conclusion：In the subacute PD models of the mouse caused by MPTP, the compound that Examples 1 and 28 represent can be obviously improved Mice behavior obstacle, it is significant improve substantia nigra dopaminergic neuron quantity and striatal dopamine level, prompt this two Kind compound has the potential for being developed into treatment PD drugs.
5. experimental example 5 (influence of the chronic PD models induced MPTP+ probenecid in compound body)
(1) material and method
Material：Animal：Male C57 mouse, 22 ± 1g of weight are purchased from Fukang experimental animal Technology Co., Ltd. of Beijing China. Rearing conditions：Barrier grade animal house is raised, raising in feeding standard box, per 5, box.
Test medicine：The compound that Examples 1 and 28 indicate
L-DOPA：Madopar (Benserazide piece), Shanghai Co., Ltd of Roche Group, Chinese medicines quasi-word
H10930198, lot number：SH0895.
MPTP：Sigma Products, lot number：128k1549..
Probenecid：Beijing lark prestige Science and Technology Ltd., lot number：10139442.
DA, DOPAC, HVA and IP are purchased from Sigma companies.
Method：
1) model foundation：Mouse use turns rod method and trains 3 days in advance, will move uncoordinated mouse and reject.Intraperitoneal injection Probenecid 250mg/kg (is dissolved in DMSO), MPTP 25mg/kg (being dissolved in physiological saline) is subcutaneously injected after 30min, biweekly (3.5 days be spaced), co-injection 10 times (5 weeks), progress Behavior test (turning rod method and pole-climbing method) at 7 weeks, turn rod incubation period or Pole-climbing scoring, which reduces, has the mouse of significant difference to be considered as modeling success, random to be grouped (n=15), and it is real to carry out Subsequent pharmacological treatment It tests.
2) grouping administration：It is divided into Normal group, MPTP+ probenecid model group, 1 various dose group of embodiment, embodiment 28 various dose groups and positive control L-DOPA groups.The compound or L-DOPA mono- that the daily gavage Examples 1 and 28 of mouse represent It is secondary, week for 7 weeks.The aseptic double-distilled water and physiological saline of Normal group gavage and intraperitoneal injection same dose, MPTP+ probenecid Model group gavage gives the aseptic double-distilled water of same dose.
3) behaviouristics detects：The sports coordination ability of mouse is evaluated using rod method and pole-climbing method (Pole test) is turned.
1. turning rod method：Method is the same as embodiment 33.Mouse carries out turning rod test in administration on the 0th, 3,5 and 7 week.
2. pole-climbing method：Method is the same as embodiment 33.Mouse carries out pole-climbing test on the 0th, 3,5 and 7 week in administration.
4) striatal dopamine levels detect：Method is the same as embodiment 33.
5) immunohistochemistry detects nigral dopaminergic neuron：Method is the same as embodiment 33.
7) statistical analysis：It is for statistical analysis with SPSS13.0.Data withIt indicates.Variation between different groups is used Then variance analysis is examined with LSD-SNK.P<0.05 is with significant difference.
(2) result
1) improvement result of the compound that Examples 1 and 28 represent to mice behavior
1. the residence time on turning rod instrument compared with normal mouse of the model mice after screening is substantially reduced (is denoted as 0 at this time Week).It is therapeutic to give the mouse of embodiment 120mg/kg and 40mg/kg group, and give embodiment 2810mg/kg and 20mg/ The mouse of kg groups, at the 5th week and the 7th week, the residence time was considerably longer than model group mouse on turning rod instrument, and there are dosage Effect relation, drug effect are substantially suitable (table 8) with positive control drug L-DOPA.
8. Examples 1 and 28 of table on chronic PD model mices caused by MPTP/p turn rod it is ethological influence (n =15)
**P<0.01vs.Control mouse,#P<0.05,##P<0.01vs.MPTP/p model mices
2. there is apparent pole-climbing behaviouristics obstacle in the mouse of MPTP/p damages.It is therapeutic give embodiment 120mg/kg and The mouse of 40mg/kg groups, and the mouse of embodiment 2810mg/kg and 20mg/kg group is given, the pole-climbing at the 5th week and the 7th week Scoring is obviously higher than model group mouse, and there are dose-effect relationship, drug effect (tables substantially suitable with positive control drug L-DOPA 9)。
The influence ethological on chronic PD model mices pole-climbing caused by MPTP/p of 9. Examples 1 and 28 of table (n =15)
**P<0.01vs.Control mouse,#P<0.05,##P<0.01vs.MPTP/p model mices
2) influence of the compound that Examples 1 and 28 represent to mouse striaturn dopamine
The content of the mouse striaturn DA of MPTP/p damages is decreased obviously, and the compound represented using Examples 1 and 28 is controlled After treating 7 weeks, embodiment 120mg/kg is improved the trend of mouse striaturn DA contents, but no difference of science of statistics, and 40mg/kg can Significantly improve the level of DA.Embodiment 2810mg/kg is improved the trend of DA contents, but no difference of science of statistics, and 20mg/kg can Significantly improve the level (table 10) of DA.
Influence of 10. Examples 1 and 28 of table to the MPTP/p chronic PD model mices Striatal Dopamine Contents induced
**P<0.01vs.Control mouse,#P<0.05,##P<0.01vs.MPTp/p model mices
3) influence of the compound that Examples 1 and 28 represent to mouse DOPA serotonergic neuron
The more normal number of mice amount of MPTP/p model group mouse substantia nigra compacta TH positive neuron numbers is substantially reduced.Implement Mouse TH positive neuron quantity can be improved in example 1 and 28, and there are apparent dose-effect relationships.Positive drug L-DOPA is to model Mouse TH neuronal quantities have no significant effect (Fig. 4).
Conclusion：The compound that Examples 1 and 28 represent has chronic PD mouse models behaviouristics obstacle caused by MPTP/p Preferable improvement result can be improved the quantity of substantia nigra dopaminergic neuron and the level of striatal dopamine, show both Compound is expected to be developed into the new drug for the treatment of PD.
6. experimental example 6 (subacute toxicity test)
(1) material and method
Material：Animal：Male C57 mouse, 22 ± 1g of weight are purchased from Fukang experimental animal Technology Co., Ltd. of Beijing China. Cleaning grade.
Test medicine：The compound that Examples 1 and 28 indicate
Method：
The compound that Examples 1 and 28 represent respectively gives mouse with the dosage gavage of 400mg/Kg, once a day, continuous 13 It.Blood examination blood count biochemical indicator is taken after 13 days.Every group of mouse 8.
Observation index：Mouse weight, food-intake and inflow, blood biochemistry (glutamic-pyruvic transaminase ALT, alkaline phosphatase, Creatinine Cre).
(2) result
1) influence of the compound that Examples 1 and 28 represent to mouse weight
The results show that after intragastric administration on mice gives Examples 1 and 2 8400mg/Kg, weight is without bright compared with the mouse of blank group Aobvious variation (table 11).
11. compound 1 of table and 28 pairs of mouse weights influence (g,)
2) influence that the compound that Examples 1 and 28 represent feeds mouse and intakes
The results show that after intragastric administration on mice gives Examples 1 and 2 8400mg/Kg, compared with the mouse of blank group food-intake and Inflow no significant difference (table 12 and table 13).
The influence (g) of 12. compound 1 of table and the feed of 28 pairs of mouse
The influence (mL) of 13. compound 1 of table and the water inlet of 28 pairs of mouse
3) influence of the compound that Examples 1 and 28 represent to mouse blood biochemistry index
The results show that embodiment 28 has no significant effect ALT, Cre and ALP, it is suitable with blank group.Embodiment 1 causes ALP It is increased compared with blank group, but no difference of science of statistics, ALT and Cre is had no significant effect (table 14).
The influence of table 14. compound 1 and 28 pairs of mouse blood biochemistries
Conclusion：The compound that Examples 1 and 28 represent does not show toxicity under the dosage of 400mg/Kg to mouse.

Claims (7)

1. general formula IDa compounds represented and its pharmaceutically acceptable salt：
Wherein, Rf1、Rf2、Rf3Independently indicate methyl, ethyl, propyl,
R6Indicate H, C1Alkyl,
R7With R8It independently indicates H, substitution or unsubstituted methyl, substitution or unsubstituted ethyl, substitution or unsubstituted propyl, take Generation or unsubstituted butyl, substitution or unsubstituted isobutyl group, substitution or unsubstituted tertiary butyl, substitution or unsubstituted amyl, condition are R7With R8Cannot be H simultaneously, wherein
Substituent group is selected from-OH ,-COOH, phenyl.
2. compound according to claim 1, which is characterized in that the compound is general formula IDa1 compounds represented, and Its pharmaceutically acceptable salt：
Wherein, R7Indicate substitution or unsubstituted methyl, substitution or unsubstituted ethyl, substitution or unsubstituted propyl, substitution or unsubstituted Butyl, substitution or unsubstituted isobutyl group, substitution or unsubstituted tertiary butyl, substitution or unsubstituted amyl,
Substituent group is selected from-OH ,-COOH, phenyl.
3. compound as claimed in one of claims 1-2, which is characterized in that the compound is selected from：1)(S)-2-(2, 4,6- trimethoxy-benzenes methylamino) -3- hydracrylic acids
2) (S) -2- (2,4,6- trimethoxy-benzenes methylamino) succinic acid.
4. a kind of pharmaceutical composition, which is characterized in that as claimed in any one of claims 1-3 any containing effective dose Compound and pharmaceutically acceptable carrier.
5. pharmaceutical composition according to claim 4, which is characterized in that the pharmaceutical composition is selected from tablet, capsule, ball Agent, injection, sustained release preparation, controlled release preparation and various particulate delivery systems.
6. compound as claimed in any one of claims 1-3 is preparing the application in preventing neurodegenerative disease drug.
7. application as claimed in claim 6, it is characterised in that the disease is Alzheimer disease, Parkinson's disease, multiple Property hardening, amyotrophic lateral sclerosis, incoordination hair and blood enlargement of pipe disease, bovine spongiform encephalopathy, gram refined Er Shi diseases, the prosperous court of a feudal ruler Dun Shi diseases, cerebral atrophy, primary lateral sclerosis, spinal muscular atrophy.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2465228A (en) * 2008-11-15 2010-05-19 Athena Health Patents Inc Analogues of phloroglucinols from eucalyptus plant varieties and related compounds and their use in treating neurodegenerative disorders

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4046793A (en) * 1971-10-01 1977-09-06 Ciba-Geigy Corporation Chelates for the regulation of metal-deficiency phenomena in plants
BE789442A (en) * 1971-10-01 1973-03-29 Ciba Geigy CHELATES TO COMBAT METAL DEFICIENCY PHENOMENA IN PLANTS
US4267344A (en) * 1972-09-22 1981-05-12 Proteinkemisk Institut. Tilknyttet Akademiet For De Tekniske Videnskaber N-Substituted N-carboxyanhydrides of α-amino acids and their application in the preparation of peptides
GB2414665A (en) * 2004-06-01 2005-12-07 Pol Lescroart Aminoketone derivatives of phloroglucinol for the treatment of motor neuron disease
EP2112145A1 (en) * 2008-04-24 2009-10-28 AxoGlia Therapeutics S.A. Chromenone derivatives useful for the treatment of neurodegenerative diseases
EP3202398B1 (en) * 2011-06-17 2019-12-25 Ludwig Aigner Chromane-like cyclic prenylflavonoids for the medical intervention in neurological disorders

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2465228A (en) * 2008-11-15 2010-05-19 Athena Health Patents Inc Analogues of phloroglucinols from eucalyptus plant varieties and related compounds and their use in treating neurodegenerative disorders

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