CN107089993A - Podocarpus nagi Inner ester type compounds with hypolipidemic activity, preparation method and the usage - Google Patents

Podocarpus nagi Inner ester type compounds with hypolipidemic activity, preparation method and the usage Download PDF

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CN107089993A
CN107089993A CN201610089376.3A CN201610089376A CN107089993A CN 107089993 A CN107089993 A CN 107089993A CN 201610089376 A CN201610089376 A CN 201610089376A CN 107089993 A CN107089993 A CN 107089993A
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unsubstituted
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substituted
alkyl
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叶阳
王逸平
姚胜
马艳玲
唐春萍
赵晶
柯昌强
徐文伟
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Shanghai Institute of Materia Medica of CAS
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Priority to PCT/CN2017/073964 priority patent/WO2017140268A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/20—Spiro-condensed systems

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention provides the podocarpus nagi Inner ester type compounds that a class has hypolipidemic activity, preparation method and the usage, specifically, described compound have structure shown in formula I, wherein, the definition of each group is as noted in the discussion.The compound of the present invention has the activity of inner or in vitro increase low-density lipoprotein intake, with the potentiality as new blood lipid-lowering medicine.

Description

Podocarpus nagi Inner ester type compounds with hypolipidemic activity, preparation method and the usage
Technical field
The invention belongs to medicinal chemistry art, more specifically, it is related to the podocarpus nagi Inner with hypolipidemic activity of a class newly Ester type compound, its preparation method and for reducing blood lipid atherosclerosis medicine in purposes.
Background technology
Atherosclerosis is because of chronic formed by the inflammatory reaction between inflammatory cell and arterial wall constantly deterioration Inflammatory disease, is one of lethal dose highest factor in current Western society.Lipid lowering remedy is to be directed to Atherosclerosis Change maximally effective treatment means, wherein Statins occupies very big part as star's medicine in lipid-lowering medicine in lipid-loweringing market Volume, the very effective generation for reducing high fat of blood people's angiocardiopathy and fatal rate.However, Statins is not to all High fat of blood, and the patient of high atherosclerosis hardening risk are effective, and a big chunk patient reacts insensitive to Statins, The development process of its atherosclerosis can not be prevented by Statins, the task of the blood lipid-lowering medicine of Development of Novel is extremely urgent.
In summary, this area is in the urgent need to providing the new compound with hypolipidemic activity.
The content of the invention
It is an object of the invention to provide the compound that a class has hypolipidemic activity.
There is provided a kind of compound as shown in following formula I, or its pharmaceutically acceptable salt for the first aspect of the present invention：
Wherein, Formulas I is selected from one of Formulas I -1, I-2 or I-3：
A is selected from the group：N-R、O；Wherein, R is selected from the group：H、C1-C4Acyl group, C1-C4Alkyl, C1-C4Alkyl halide Base, substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted C1-C10Heteroaryl；
R1It is selected from the group：H, substituted or unsubstituted C1-C4Alkyl, C1-C4Haloalkyl, substituted or unsubstituted C1-C4Alkyl (such as 2- hydroxyethyls, 2- hydroxymethyl ethyls), substituted or unsubstituted vinyl；
R2It is selected from the group：Nothing, H, oxygen atom, substituted or unsubstituted C2-C10Ester group ,-OR, wherein, described R is selected from The following group：H, substituted or unsubstituted C2-C10Acyl group, fluorenes methoxy carbonyl acyl group (Fmoc) or substituted or unsubstituted C1-C10Alkane Base；It is preferred that R ' is H；
R3It is selected from the group：H, halogen, C1-C4Alkyl, C1-C4Haloalkyl ,-OH, substituted or unsubstituted C2-C10's Ester group ,-NH-R；Wherein, R is selected from the group：H、C1-C4Acyl group, substituted or unsubstituted C1-C4Alkyl；
R4It is selected from the group：H, halogen, oxygen atom, cyano group, hydroxyl, carboxyl, C1-C4Alkoxy, C1-C4Alkyl, C1-C4 Haloalkyl, substituted or unsubstituted C2-C10Ester group ,-OC (O)-R ,-NH-R；Wherein, R is selected from the group：H、C1-C4Acyl Base, substituted or unsubstituted C1-C4Alkyl；
R5It is selected from the group：H, halogen, cyano group, hydroxyl ,-OR ,-COOR, substitution or unsubstituted C1-C10Alkyl, substitution or not Substituted C1-C10Haloalkyl, substituted or unsubstituted C2-C30Ester group, the C of substitution or unsubstituted (preferably replace)7-C11 Aryl-acyl group ,-NH-R；Wherein, R is selected from the group：H、C1-C4Acyl group, substituted or unsubstituted C1-C4Alkyl；
Or R4And R5Collectively form-R "-O-R "-, wherein, described R " is nothing, or substituted or unsubstituted C1-C4Asia Alkyl；
R6It is selected from the group：H, halogen, oxygen atom, cyano group, carboxyl, hydroxyl ,-OR ,-COOR, substitution or unsubstituted C1-C10Alkane Base, substituted or unsubstituted C1-C10Haloalkyl, substituted or unsubstituted C2-C10Ester group, substitution or it is unsubstituted (be preferably Substitution) C7-C11Aryl-acyl ,-NH-R；Wherein, R is selected from the group：H、C1-C4Acyl group, substituted or unsubstituted C1-C4's Alkyl；
Or R5And R6Collectively form-R "-O-R "-, wherein, described R " is nothing, or substituted or unsubstituted C1-C4Asia Alkyl；
R7It is selected from the group：H、C1-C4Alkyl, C1-C4Haloalkyl；
R8For nothing, H or R8With R2Collectively form-R "-O-R "-, wherein, described R " is nothing or C1-C4Alkylidene：
R9For nothing, H or R9For-OH；
Described "" it is double bond or singly-bound；
One or more hydrogen atoms that described " substitution " refers on group are selected from the substituent substitution of the following group：Carboxyl, not Substitution or the C of halo1-C6Alkyl, unsubstituted or halo C3-C6Cycloalkyl, unsubstituted or halo C2-C10Ester group, halogen Element, C1-C10Alkyl-epoxide, unsubstituted or halo C2-C10Acyl group, hydroxyl, hydroxyl-C1-C10Alkylidene, unsubstituted or halogen The phenyl in generation；
And when parent nucleus is I-1 structures, R2、R5And R6In at least one be the group being selected from the group：- OR or substitution or Unsubstituted C2-C10Ester group；Or R5And R6It is collectively forming-OC (CH)2- O- structures；
When parent nucleus is I-3 structures, R2、R4And R6In at least one be oxygen atom；
Or described compound of formula I has following structure：
In another preference, in the compound, each asymmetric carbon atom can be optionally R configurations or S configurations.
In another preference, described C2-C10Acyl group refer to C2-C10Acid lose the group of hydroxyl formation, and Described acid is selected from the group：Carboxylic acid, carbonic acid.
In another preference, described carboxylic acid includes saturated carboxylic acid, unsaturated carboxylic acid or aromatic carboxylic acid.
In another preference, described R2For C2-C10Aromatic ester groups, be preferably chosen from the following group：Benzoyl takes The benzoyl in generation；Wherein, described substitution refers to that one or more hydrogen atoms on benzoyl are selected from the substitution of the following group Base replaces：Halogen, nitro, amino, methyl, methoxyl group.
In another preference, described R2For carbonate group.
In another preference, as described R2During for hydroxyl, also optionally with hydroxyl protecting group；It is preferred that described Hydroxyl protecting group be the protection group with acyl chlorides or free acid.
In another preference, described R1、R3And R7It is each independently C1-C4Alkyl.
In another preference, described R4For H or hydroxyl.
In another preference, described R5For H or hydroxyl.
In another preference, described R1For isopropyl.
In another preference, described R3And R7It is each independently methyl.
In another preference, described compound of formula I has with the structure shown in following formula I a：
In formula,
R1It is selected from the group：Substituted or unsubstituted C1-C4Alkyl, C1-C4Haloalkyl；Wherein, described substitution refers to One or more hydrogen atoms on group are by C1-C4Ester group substitution；
R2For-OH ,-OR or substituted or unsubstituted C2-C10Ester group；
R7It is selected from the group：C1-C4Alkyl, C1-C4Haloalkyl；
The definition of remaining each group is as described in first aspect present invention.
In another preference, described compound of formula I has with the structure shown in following formula I b：
In formula,
R1It is selected from the group：Substituted or unsubstituted C1-C4Alkyl, C1-C4Haloalkyl；
R2With R8Collectively form-O-；
R7It is selected from the group：C1-C4Alkyl, C1-C4Haloalkyl；
The definition of remaining each group is as described in first aspect present invention.
In another preference, R5It is selected from the group：Halogen, cyano group, hydroxyl, C1-C4Alkoxy ,-COOR, substitution or not Substituted C2-C10Ester group, substitution or unsubstituted C1-C10Alkyl, substituted or unsubstituted C1-C10Haloalkyl ,-NH-R；Its In, R is selected from the group：H、C1-C4Acyl group, C1-C4Alkyl, C1-C4Haloalkyl, substitution or unsubstituted (preferably replace) C7-C11Aryl-acyl group.
In another preference, R6It is selected from the group：Halogen, cyano group, carboxyl, hydroxyl, C1-C4Alkoxy, substitution or do not take The C in generation2-C10Ester group, substitution or unsubstituted C1-C10Alkyl, substituted or unsubstituted C1-C10Haloalkyl, substitution do not take The C in generation (preferably replacing)7-C11Aryl-acyl group ,-NH-R；Wherein, R is selected from the group：H、C1-C4Acyl group, C1-C4Alkyl, C1-C4Haloalkyl.
In another preference, in another preference, R2It is selected from the group：O-R ', wherein, described R ' is selected from the group： H, substituted or unsubstituted C2-C10Acyl group or substituted or unsubstituted C1-C10Alkyl；
R4It is selected from the group：H, halogen, cyano group, carboxyl, hydroxyl, C1-C4Alkoxy, substituted or unsubstituted C2-C10Ester Base；
R5It is selected from the group：H, halogen, cyano group, hydroxyl, C1-C4Alkoxy ,-COOR, substituted or unsubstituted C2-C10's Ester group, substitution or unsubstituted C1-C10Alkyl, substituted or unsubstituted C1-C10Haloalkyl ,-NH-R；Wherein, R is selected from the group： H、C1-C4Acyl group, C1-C4Alkyl, C1-C4Haloalkyl, the C of substitution or unsubstituted (preferably replace)7-C11Aryl- Acyl group；
R6It is selected from the group：H, halogen, cyano group, carboxyl, hydroxyl, C1-C4Alkoxy, substituted or unsubstituted C2-C10Ester Base, substitution or unsubstituted C1-C10Alkyl, substituted or unsubstituted C1-C10Haloalkyl, substitution or unsubstituted (preferably replacing) C7-C11Aryl-acyl group ,-NH-R；Wherein, R is selected from the group：H、C1-C4Acyl group, C1-C4Alkyl, C1-C4Alkyl halide Base；
One or more hydrogen atoms that described " substitution " refers on group are selected from the substituent substitution of the following group：Carboxyl, benzene Base, C3-C6Cycloalkyl, C1-C10Ester group, halogen, C1-C10Alkyl-epoxide, C2-C10Acyl group, hydroxyl, hydroxyl-C1-C10Asia Alkyl.
In another preference, described R2、R4、R5And R6It is each independently the group being selected from the group：- OR ', and institute The R ' stated is selected from the group：
In another preference, described A, R1、R2、R3、R4、R5、R6、R7、R8And R9For each specific chemical combination in such as embodiment Group corresponding to thing.
In another preference, described compound has the structure being selected from the group：
Or described compound be as shown in formula 3B, 4A or 4B, wherein, Ra, Rb, Rc and Rd definition such as table 1, the and of table 2 Described in table 3：
The second aspect of the present invention is used for what is be selected from the group there is provided a kind of compound as described in the first aspect of the invention One or more purposes：
A) pharmaceutical composition for reducing blood lipid is prepared；
B) prepare for reducing the pharmaceutical composition of low-density lipoprotein (LDL) content；
C) pharmaceutical composition for stablizing LDLR gene stabilities is prepared；
D) pharmaceutical composition for raising LDLR gene expressions is prepared；
E) prepare for increasing the pharmaceutical composition of surface of hepatocytes LDLR acceptor quantities；
F) pharmaceutical composition for reducing LDLR receptor degradations is prepared；
G) prepare for reducing the pharmaceutical composition of TC and/or TG concentration in blood；
H) prepare for increasing the pharmaceutical composition of blood high-density lipoprotein (HDL) concentration；
I) prepare for improving the pharmaceutical composition of liver dysfunction.
In another preference, described liver dysfunction is the liver dysfunction that high fat is induced.
In another preference, described improvement liver dysfunction for reduction ALT AST indexs.
In another preference, described pharmaceutical composition is additionally operable to the purposes being selected from the group：
J) (external non-therapeutic) increase uptake ratio of the liver cell to LDL；
K) (external non-therapeutic) upregulating hepatocyte cell LDLR gene expression doses.
In another preference, in described pharmaceutical composition, the effective dose of the compound of formula I is 0.1-50mg/ Kg body weight, preferably 1-20mg/kg body weight.
In another preference, described pharmaceutical composition is the formulation being selected from the group：Peroral dosage form, injection type.
In another preference, described formulation includes tablet, granule, capsule, pill etc..
The third aspect of the present invention contains there is provided a kind of medicine box, the medicine box：
(i) the first container, and loaded on active component (a) compound of formula I in first container；Or contain active component (a) medicine；
(ii) second container, and loaded on active component (b) statins in the second container, or it pharmaceutically may be used The salt of receiving；Or the medicine containing active component (b)；And
(iii) recorded in specification, the specification and active component (a) and active component (b) is given in combination to drop The explanation of low-density lipoprotein content in low use subject.
In another preference, described compound of formula I is as described in first aspect present invention.
In another preference, described use object is mammal, is preferably people.
In another preference, described statins is selected from the group：Pravastatin, Atorvastatin, or its combination.
The fourth aspect of the present invention is there is provided a kind of compound as shown in following formula I, or its pharmaceutically acceptable salt Purposes：
Wherein, A, R1、R2、R3、R4、R5、R6、R7、R8And R9Deng definition as described in first aspect present invention, and it is described "" it is double bond or singly-bound；
Wherein, described compound is used for the purposes being selected from the group：
A) blood lipid level of subject is reduced；
B) subject low-density lipoprotein (LDL) content is reduced；
C) stable subject LDLR gene stabilities；
D) subject LDLR gene expressions are raised；
E) subject surface of hepatocytes LDLR acceptor quantities are increased；
F) subject LDLR receptor degradations are reduced；
G) TC and/or TG concentration in reduction subject blood；
H) subject blood high-density lipoprotein (HDL) concentration is increased；
I) subject liver dysfunction is improved.
In another preference, described subject is mammal, is preferably people.
In another preference, described liver dysfunction is the liver dysfunction that high fat is induced.
In another preference, described improvement liver dysfunction for reduction ALT AST indexs.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment) It can be combined with each other between each technical characteristic of body description, so as to constitute new or preferred technical scheme.As space is limited, exist This no longer tires out one by one states.
Embodiment
The present inventor's in-depth study by long-term, it has unexpectedly been found that, nagilactone class compound has good drop Blood fat activity, and activity is better than existing general reducing blood lipid compound statins.Described compound can be with Time Dependent Property and dose-dependently reduction T-CHOL, triglycerides, ldl concn in vivo or in vitro, and increase highly dense Spend lipoprotein concentration.Based on above-mentioned discovery, inventor completes the present invention.
Term
As used herein, term " C1-C4Alkyl " or " C1-C10Alkyl " refers to straight with 1~4 or 1-10 carbon atom Chain or branched alkyl, such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, or similar group.
Term " C3-C6Cycloalkyl " refers to the cycloalkyl with 3~6 carbon atoms, such as cyclopropyl, cyclobutyl, methyl ring fourth Base, cyclopenta, or similar group.
As used herein, term " C1-C10Acyl group " or " C1-C4Acyl group " finger-type is as " having 0~9 or 0-3 carbon atom Straight or branched alkyl/cycloalkyl/aryl/hetaryl/alkenyl/alkynyl-carbonyl " structure substituent, such as acetyl group, propionyl Base, bytyry, or similar group.
Term " C2-C30The group of ester group " finger-type structure as shown in-OOC-R', wherein, described R' is with 1~9 The group being selected from the group of carbon atom：Straight or branched alkyl, cycloalkyl, alkenyl, alkynyl, the substitution of aryl or heteroaryl moieties Base, such as acetyl group, propiono, bytyry, or similar group.Wherein, described R' can also be further substituted, for example, be chosen Replaced from one or more substituents of the following group：Halogen ,-OH ,-COOH ,-COO (C1-C6Alkyl), unsubstituted or halo benzene Base, unsubstituted or halo C1-C6 alkyl, unsubstituted or halo C2-C6Acyl group, unsubstituted or halo C1-C6Alkyl-hydroxyl Base.
Term " C1-C4C1~C4 alkyl that alkylidene " refers to as described above loses the group formed after a hydrogen atom, Such as-CH2-、-CH2-CH2-, or similar group.
Term " halogen " refers to F, Cl, Br and I.
Term " C6-C10Aryl " refers to the aryl with 6-10 carbon atom, such as phenyl, naphthyl, and described aryl can To be substituted or unsubstituted.
Term " C1-C10Heteroaryl " refers to 1-10 carbon atom and one or more hetero atoms selected from O, S and/or N Heteroaryl, preferred C2-C8 heteroaryls.Described heteroaryl can be substituted or unsubstituted.
In the present invention, term " containing ", "comprising" or " comprising " represent that various composition can be applied to the mixed of the present invention together In compound or composition.Therefore, term " mainly by ... constitute " and " consist of " are included in term " containing ".
In the present invention, term " pharmaceutically acceptable " composition refers to suitable for people and/or animal without excessive bad pair React (such as toxicity, stimulation and allergy), that is, have rational benefit/risk than material.
In the present invention, term " effective dose " refers to therapeutic agent treatment, alleviates or prevent the amount of target disease or situation, or table Reveal the amount of detectable treatment or prevention effect.Accurate effective dose for a certain object depends on the build of the object and is good for The combination of therapeutic agent and/or therapeutic agent that health situation, the nature and extent of illness and selection are given.Therefore, standard is preassigned True effective dose is useless.However, for certain given situation, the effective dose being determined with normal experiment, is faced Bed doctor can interpolate that out.
Herein, except special instruction part, one or more hydrogen atoms that term " substitution " refers on group are selected from down The substituent substitution of group：Halogen ,-OH ,-COOH ,-COO (C1-C6Alkyl), unsubstituted or halo phenyl, unsubstituted or halo C1-C6 alkyl, unsubstituted or halo C2-C6Acyl group, unsubstituted or halo C1-C6Alkyl-hydroxyl.
Unless stated otherwise, in the present invention, the compound occurred is intended to including all possible optical isomer, Such as the mixture (i.e. racemic modification) of the compound of single chiral, or various different chipal compounds.All chemical combination of the present invention Among thing, each asymmetric carbon atom can be optionally R configurations or S configurations, or R configurations and S configurations mixture.
As used herein, term " the compounds of this invention " refers to the compound shown in Formulas I.The term also includes and Formulas I chemical combination Various crystalline forms, pharmaceutically acceptable salt, hydrate or the solvate of thing.
As used herein, term " pharmaceutically acceptable salt " refers to the suitable use that the compounds of this invention is formed with acid or alkali Make the salt of medicine.Pharmaceutically acceptable salt includes inorganic salts and organic salt.The preferred salt of one class is the compounds of this invention and acid The salt of formation.The acid for suitably forming salt includes but is not limited to：Hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid etc. are inorganic Acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, butanedioic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, Picric acid, methanesulfonic acid, benzene methanesulfonic acid, the organic acid such as benzene sulfonic acid；And the acidic amino acid such as aspartic acid, glutamic acid.
Compound based on nagilactone parent nucleus
Podocarpus nagi (Podocarpus nagi) be Podocarpaceae (Podocarpaceae) podocarp, primary chemical into It is divided into drop diterpenoide dilactone, with effects such as antitumor, antibacterial, desinsection, growth regulating suppression.The present inventor has found first, bamboo Cypress lactone compound can strengthen the ability that liver cell absorbs low-density lipoprotein.Internal pharmacodynamic evaluation finds described change Compound can be with the T-CHOL of the Golden Hamster of the high fat inducing lipids metabolic disorder of reduction of highly significant, and triglycerides is low close The blood lipids index such as lipoprotein are spent, ratio of the HDL in T-CHOL is improved, improves its liver function, while can delay Fatty liver caused by solution high fat diet is formed, therefore is a kind of potential hypolipidemic compounds.
Specifically, the present inventor is with isolated drop diterpene lactone from podocarpus nagi bark, branch, leaf and fruit Compound 2,3,4 and 12 etc. is raw material, has carried out a series of structure of modification, by being such as esterified, is eliminated, and the step such as hydrogenation obtains formula 2-B1,3-1~3-4,3-B1~3-B10,7-A1,12-1 and 4-A and 4-B compounds：
Wherein RcAnd RdAs shown in Table 1 below：
Table 1
Wherein RaAnd RbAs shown in Table 2 below：
Table 2
Compound number Ra substituents Rb substituents ESI-MS m/z[M+H]+
4-A1 Me H 363.2
4-A2 H Me 363.2
4-A3 Me Me 377.2
4-A4 Et H 377.2
4-A5 H Et 377.2
4-A6 Et Et 405.3
4-A7 H -CH2- CH=CH2 389.2
4-A8 -CH2- CH=CH2 -CH2- CH=CH2 429.3
Wherein RcAnd RdAs shown in Table 3 below：
Table 3
Wherein, above-mentioned reaction can combine the state of the art by those skilled in the art, according to real reaction Condition is designed, and some exemplary methods (being described in detail see in embodiment 2-8) are provided in the embodiment of the present invention.
Nagilactone class compound reduces the purposes of LDL concentration
LDL receptor (LDLR) is the major receptors that liver reclaims intake low-density lipoprotein LDL, in 1974 Correlative study in terms of year is found, and beginning starts its 26S Proteasome Structure and Function extensively.LDLR is made up of 839 amino acid residues, Synthesize in rough surfaced endoplasmic reticulum (RER), by montage and it is glycosylation modified after be transported to size about 160KD after birth glycoprotein on cell membrane. LDLR gene mutations are the one of the main reasons of heredity hyperlipemia.
The expression of LDLR genes and blood plasma cholesterol level are closely related, positioned at LDLR gene promoter sub-portions SRE regulatory sites are adjusted by intracellular SREBP1/2, and the latter is closely related with intracellular cholesterol levels.But cell inner bag When sterol levels are high, SREBP is fixed on ER films, it is impossible to enter golgiosome activation；When the reduction of intracellular cholesteryl level When, SREBP is released in the presence of cholesterol, is subsequently transferred in golgiosome by montage into activated protein, into cell In core, cholesterol and the fatty acid metabolisms such as the genetic transcription containing SRE, including LDLR, HMG-CoA R are adjusted as transcription factor Related gene.Except cholesterol levels regulation, LDLR genes are also adjusted by many cell factors and growth factor and hormone, Such as estrogen, TNF, phorbol exters, insulin etc..Statins is HMG-CoA R inhibitor, this class medicine By suppressing the synthesis of cholesterol, the content of intracellular cholesteryl is reduced, so that negative feedback type raises LDLR Intracellular levels, Reach the effect for further enhancing its lipid-reducing function.Regulation LDLR levels and function are one of regulation blood lipids level important Approach.
Another feature of LDLR genes is that its gene has after unstable characteristic, gene chemical synthesis in a short period of time Degrade.This process may be relevant with the 3 ' terminal sequences of LDLR genes in itself.Contain AU enrichment regions, this area in the end of LDLR genes 3 ' A fixed characteristic sequence of mrna instability is seen as, many rna binding proteins can be combined with this sequence, so as to cause MRNA rapid degraded.Jamaicin, which is reported, can increase the stability of LDLR genes, improve its gene and protein level, so that Increase LDLR function, reduce plasma LDL levels, it is one effective by regulation to have proven to jamaicin by clinical test LDLR levels play the compound of lipid-lowering effect.
In the application, described nagilactone class compound can raise the gene expression of LDLR albumen in vivo or in vitro Level, while increase the stability of LDLR albumen in itself so that LDLR protein levels are raised, so promote liver cell for The intake of low-density lipoprotein.In testing in vivo, described nagilactone class compound has up-regulation to make to LDLR protein levels With, and then promote liver cell for the intake of low-density lipoprotein, so as to reduce LDL concentration in blood, reach the mesh for removing LDL 's.
In addition, the inventors discovered that, in vivo test in, in addition to LDL levels obtain decline, animal subject Serum total cholesterol (TC) level, triglycerides (TG) level is similarly lowered.Meanwhile, HDL is solid in total courage Ratio in alcohol is significantly improved.This explanation nagilactone class compound has for the fatty liver formation that high fat is induced slows down work With.
In addition, in testing in vivo, giving nagilactone class compound for liver dysfunction caused by high fat diet Certain improvement is generated, aspartate aminotransferase in blood, ALT index level is embodied in Improvement.
Pharmaceutical composition and application process
Because the compounds of this invention has an activity of LDL contents in excellent reduction blood, thus the compounds of this invention and Its various crystal formation, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and be containing the compounds of this invention The pharmaceutical composition of main active can be used for treating, prevent and alleviating due to disease caused by LDL too high levels in blood Disease, such as fatty liver.
The pharmaceutical composition of the present invention comprising the compounds of this invention in the range of safe and effective amount or its be pharmacologically subjected to Salt and pharmacologically acceptable excipient or carrier.Wherein " safe and effective amount " is referred to：The amount of compound is enough substantially Improve the state of an illness, and be unlikely to produce serious side effect.Generally, pharmaceutical composition contains 1-3000 (active dose scope 3- 30mg/kg) mg the compounds of this invention/agent, more preferably, contains 10-2000mg the compounds of this invention/agent.It is preferred that described " one " is a capsule or tablet.
" pharmaceutically acceptable carrier " is referred to：One or more biocompatible solids or liquid filler or jello Matter, they are suitable for people and used and it is necessary to have enough purity and sufficiently low toxicity." compatibility " is referred to herein as combined In thing each component energy and the compound of the present invention and they between mutually admix, and significantly reduce the drug effect of compound.Medicine Acceptable carrier part example has cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose sodium, fibre on Plain acetic acid esters of dimension etc.), gelatin, talcum, kollag (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soya-bean oil, sesame Sesame oil, peanut oil, olive oil etc.), polyalcohol (such as propane diols, glycerine, mannitol, sorbierite), emulsifying agent Wetting agent (such as lauryl sodium sulfate), colouring agent, flavor enhancement, stabilizer, antioxidant, preservative, apirogen water.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, and representational method of application includes (but being not limited to)：Orally, in knurl, rectum, parenteral (intravenous, intramuscular is subcutaneous) and local administration.
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.In these solid formulations In type, reactive compound is mixed with least one conventional inert excipients (or carrier), such as sodium citrate or Dicalcium Phosphate, or with Following compositions are mixed：(a) filler or bulking agent, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid；(b) bond Agent, for example, hydroxymethyl cellulose, alginates, gelatin, PVP, sucrose and Arabic gum；(c) NMF, example Such as, glycerine；(d) disintegrant, for example, agar, calcium carbonate, farina or tapioca, alginic acid, some composition silicates, And sodium carbonate；(e) retarding solvent, such as paraffin；(f) absorbsion accelerator, for example, quaternary ammonium compound；(g) wetting agent, such as spermaceti Alcohol and glycerin monostearate；(h) adsorbent, for example, kaolin；Lubricant, for example, talcum, calcium stearate, tristearin (i) Sour magnesium, solid polyethylene glycol, lauryl sodium sulfate, or its mixture.In capsule, tablet and pill, formulation can also be included Buffer.
Solid dosage forms such as tablet, sugar-pill, capsule, pill and granule can using be coated and shell material prepare, such as casing and Other materials well known in the art.They can include reactive compound or compound in opacifying agent, also, this composition Release can discharge in certain part in a delayed fashion in alimentary canal.The example of adoptable embedding component is polymeric material And Wax.If necessary, reactive compound also can be with one or more formation microencapsulation forms in above-mentioned excipient.
Liquid formulation for oral administration includes pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture. Except active ingredient beyond the region of objective existence, liquid dosage form can include the inert diluent routinely used in this area, and such as water or other solvents increase Solvent and emulsifying agent, example knows, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propane diols, 1,3-BDO, dimethyl formyl The mixture of amine and oil, particularly cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these materials Deng.
In addition to these inert diluents, composition can also include auxiliary agent, such as wetting agent, emulsifying agent and suspending agent, sweet taste Agent, flavouring and spices.
Except active ingredient beyond the region of objective existence, suspension can include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxyethylene Mixture of sorbierite and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or these materials etc..
For parenteral injection composition can comprising physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, Suspension or emulsion, and for being dissolved into the aseptic powdery of sterile Injectable solution or dispersion liquid again.It is suitable aqueous and Nonaqueous carrier, diluent, solvent or excipient include water, ethanol, polyalcohol and its suitable mixture.
Formulation for the local the compounds of this invention being administered includes ointment, powder, patch, propellant and inhalant. Active component aseptically with physiologically acceptable carrier and any preservative, buffer, or if necessary may need Propellant be mixed together.
The compounds of this invention can be administered alone, or with other pharmaceutically acceptable compound administering drug combinations.
It is the mammal that the compounds of this invention of safe and effective amount is applicable to treatment during using pharmaceutical composition (such as people), wherein dosage is the effective dosage pharmaceutically thought when applying, for the people of 60kg body weight, day is to medicament Amount is usually 1~2000mg, preferably 6~600mg.Certainly, specific dosage be also contemplated that method of administration, patient health situation etc. because Element, within the scope of these are all skilled practitioners technical ability.
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention Rather than limitation the scope of the present invention.The experimental method of unreceipted actual conditions in the following example, generally according to conventional strip Part, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise percentage and number are calculated by weight.
Compared with prior art, main advantages of the present invention include：
1. a pair nagilactone class compound is transformed, make it have compared to for natural nagilactone class compound (external activity is suitable with medicine Pravastatin well known in the prior art and Atorvastatin, or is better than for more preferable hypolipidemic activity Above-claimed cpd)；
2. the hypolipidemic activity of the nagilactone compound of the present invention has obvious time dependence and dose dependent；
3. the nagilactone compound of the present invention can effectively reduce LDL concentration mechanism of action in blood：By stable The stability of LDLR genes raises the expression of LDLR genes, so as to increase surface of hepatocytes LDLR acceptor quantities, reaches removing LDL Purpose；
4. the external of the compounds of this invention, activity in vivo are effective, active dose is low, can be in the low dosage up to 3mg/kg Lipid-lowering effect is just shown down, far below the Pravastatin with having reported and berbine drug effect dosage；
5. in addition to reducing LDL, moreover it is possible to reduce TC, TG concentration in blood, and increase HDL (HDLs, to body A kind of favourable albumen) concentration；
6. in addition to reducing blood lipids index, improve significantly function to the liver dysfunction that high fat is induced, can be notable Reduce ALT AST (measurement liver function index).
Instrument and equipment
This external spectrum UV：SHIMADIU UV-2550 and Beckman DU-7 UV-Visible spectrophotometers；
Infrared spectrum IR：The type infrared spectrophotometers of Perkin-Elmer 577；
Low Resolution Mass Spectra LR-EIMS：Finnigan MAT-95；
High resolution mass spectrum HR-EIMS：Kratos 1H spectrometer；
Nuclear magnetic resoance spectrum：The type NMRs of Varian INOVA 600, Bruker AM-500, AM-400, AM-300 types NMR, δ (ppm), using TMS as internal standard；
LC-MS：The liquid phase coupling Bruker esquire mass spectrographs of Agilent 1100；
Analytic type HPLC：The detectors of Waters 2690Separate Model, Waters PDA 996 are coupled Alltch The detectors of ELSD 2000, the operating systems of Millennium 2000, Waters RP18column (5.0 × 125mm, 5 μm, Waters), flow velocity 1.0ml/min, CH3CN (Merck, Germany), H2O (Robust)；Jasco HPLC(Chiralcel IA column, 5 μm, 150 × 4.6mm), flow velocity 0.6ml/min, hexane/ethanol (7:3).
HPLC-MS：The detectors of Waters 2695Separate Model, Waters PDA 2998 are coupled Alltch The detectors of ELSD 2424,3100Ms detector, SunFireTM C-18column (4.6 × 100mm, 3.5 μm, Waters), flow velocity 1.0ml/min, CH3CN (Merck, Germany), H2O (Robust)；Jasco HPLC(Chiralcel IA column, 5 μm, 150 × 4.6mm), flow velocity 0.6ml/min, hexane/ethanol (7:3).
Preparation HPLC：The Single wavelength detector of Varian SD1instrument, Varians 320, C18column (220 × 25nm, 10 μm, Waters), flow velocity 15ml/min, CH3CN (Merck, Germany), H2O (Robust)；
SpectraMax M2eMulti-function microplate reader (molecule instrument company of the U.S.)；
Electrophoresis apparatus and half-dried electric transfer groove (Bio-Rad Laboratories, Hercules, CA)；
PCR instrument (Bio-Rad Laboratories, Hercules, CA)；
Tabletop refrigerated centrifuge (German Hettich companies)；
752C ultraviolet-uisible spectrophotometers (analytical instrument of Shanghai the 3rd)；
DK-8B electric heating constant temperatures tank (the upper grand experimental facilities Co., Ltd of Nereid)；
REVCO CO2gas incubators (REVCO companies of the U.S.)；
Reagent and material
Column chromatography silica gel：100-200 mesh, 200-300 mesh silica gel and silica gel H are Haiyang Chemical Plant, Qingdao's production；
TLC thin layers prepare plate：HSGF254 produces for Yantai chemical plant.
MCI resins：(75-150 μm) of CHP20P is that Mitsubishi is produced；
Sephadex Sephadex LH-20：Pharmacia Biotech AB, Uppsala, Sweden.
Developer：10% sulfuric acid -4-hydroxyl-3-methoxylbenxaldehyde solution, iodine；
Vegetable material：Podocarpus nagi branches and leaves are adopted in Guangxi Tianlin County, and podocarpus nagi bark is adopted in Hainan Island, is marked by Shanghai institute of materia medica This room associate professor Shen Jingui gathers and identified, Saving specimen is in this institute Specimen Room.
DMEM, hyclone (fetal bovine serum, FBS) are purchased from Gibco-BRL (Grand Island, NY)； DiI is purchased from biotuim (Hayward, CA)；β-actin antibody purchased from Cell Signaling Technology (Beverly, MA)；LDLR, PCSK9 antibody are purchased from Abcam (Cambridge, United Kingdom)；PCR primer is in Shanghai life work synthesis. Proteinase inhibitor C ocktail is purchased from Calbiochem (San Diego, CA)；Immobilon-P transfer transfer membranes (PVDF) Millipore Corporation (Bedford, MA) are purchased from；Enhanced chemiluminescence reagent (Enhanced Chemiluminescence reagents, ECL) it is purchased from Pierce (Rockford, IL)；Medical X-ray film is green purchased from China Skies company；TRIzol reagent are purchased from Invitrogen (Carlsbad, CA)；M-MLV reverse transcriptase is purchased from Promega (Madison,WI)；Real time PCR reaction reagents are purchased from Bio-Rad Laboratories；Golden Hamster high lipid food (0.12% cholesterol, 10% coconut oil) is purchased from this Simon Rex company of Shanghai.Protein determination kit is public purchased from the Chinese green skies Department；Liver organization triglycerides TG, T-CHOL TC assays kit is purchased from Shanghai Rong Sheng biotechnologies company.Blood refers to Mark (T-CHOL TC, triglycerides TG, HDL HDL, low-density lipoprotein LDL, ALT ALT, Aspartate aminotransferase AST) kit is determined purchased from Sichuan mikey biotech firm.Other reagents are purchased unless otherwise specified From Shanghai Chinese medicines group.
Experimental animal is male Syrian holden hamsters, 100 ± 10g of body weight, purchased from Chinese Academy of Sciences Shanghai experimental animal Center.Animal is positioned over Shanghai Pharmaceutical Inst., Chinese Academy of Sciences's SPF Animal Houses (23 ± 1 DEG C of temperature；Humidity 60%), it is natural Day night is circulated, and is raised with the food and water of standard.(experiment approval number：SIMM-AE-2010-10-WYP-01)
Method according to the literature obtains compound 2 (3-deoxynagilactone), 3 from podocarpus nagi branches and leaves (nagilactone A)、4(1-deoxy-2-hydroxy-nagilactone A)、7(nagilactone B)、12 (nagilactone E) and further carry out structural modification as raw material.
The extraction separation method of the compound 2,3,4,7,12 of embodiment 1
Podocarpus nagi bark (16.2kg) beat after powder with 95% ethanol soak, room temperature extract three times, merge extract solution simultaneously be concentrated into Without alcohol taste, it is then transferred in tap bottle, is matched somebody with somebody respectively with petroleum ether, chloroform, ethyl acetate, n-butanol and moisture, obtain oil Ether position (95g), chloroform extract (15g), ethyl acetate extract (255g), chloroform extract and ethyl acetate extract merge, silica gel Post purifies (200-300 mesh, Qingdao Haiyang Chemical Manufacture), uses chloroform：Methanol system 200：1,100：1,50：1,30：1,20：1, 10：1,5：1, acetone elution merges after TLC detections and obtains 12 cuts, cut 2 passes through gel filtration chromatography (chloroform/methanol 1： 1), then silica gel column chromatography (chloroform/acetone 50 is passed through：1-10：1) compound 2 (188mg), 12 (209mg) are obtained.Cut 6 passes through Silica gel and gel filtration chromatography and Pre-HPLC preparative separations respectively obtain compound 3 (1.2g) and 4 (2.1g), and cut 7 and 8 is closed And obtain compound 7 (380mg) through MCI and silica gel column chromatography.
Podocarpus nagi branches and leaves (30kg) are crushed, and are soaked three times with 95% ethanol, and then concentrated extracting solution uses stone successively to without alcohol taste Oily ether, dichloromethane, ethyl acetate and n-butanol are matched somebody with somebody with moisture respectively, obtain dichloromethane position (175g) and ethyl acetate portion Position (105g), chloroform and ethyl acetate extract obtain compound 2 through the column chromatography such as silica gel, gel, MCI, Pre-HPLC respectively (800mg), 3 (1.2g), 4 (2.1g), 7 (1.1g).
The characteristic of compound is as follows：
3-Deoxynagilactone(2)
White powder, MF:C19H22O6,ESIMS m/z 347.1[M+H]+,391.3[M+HCOO]-；1H NMR(300MHz, CDCl3):δ 5.90 (s, 1H, H-11), 5.29 (d, J=8.9Hz, 1H, H-7), 4.98 (dd, J=8.7,6.0Hz, 1H, H-6), 3.50 (m, 1H, H-2), 3.25 (d, J=6.8Hz, 1H, H-15), 3.23 (d, J=2.3Hz, 1H, H-1), 2.44 (d, J= 14.5,2.3Hz, 1H, H-3a), 1.85 (d, J=14.4Hz, 1H, H-3b), 1.71 (d, J=5.7Hz, 1H, H-5), 1.55 (s, 3H, H-20), 1.51 (s, 3H, H-18), 1.32 (d, J=6.6Hz, 3H, H-16), 1.25 (d, J=6.6Hz, 3H, H-17)
Nagilactone A(3)
White powder, MF:C19H24O6.ESIMS m/z:349.2[M+H]+,719.3[2M+Na]+.393.2[M+HCOO]- ,1H NMR(300MHz,Pyr):δ 1.26 (d, J=6.6Hz, 3H), 1.30 (d, J=6.6Hz, 3H), 1.33 (s, 3H, H-18), 1.55 (m, 1H), 1.81 (d, J=5.9Hz, 1H, H-5), 2.01 (s, 3H, H-17), 2.55 (m, 1H), 3.50 (m, 1H, H- 15), 4.18 (m, 1H, H-1), 5.17 (dd, J=5.7,8.6Hz, 1H, H-6), 5.67 (d, J=8.2Hz, 1H, H-7), 7.38 (s,1H,H-11).
1-Deoxy-2-hydroxy-nagilactone A(4)
White powder, MF:C19H24O6.ESIMS m/z:349.2[M+H]+,719.3[2M+Na]+,393.7[M+HCOO]- ,1H NMR(300MHz,Pyr):δ 1.26 (d, J=6.7Hz, 3H, H-17), 1.33 (d, J=6.7Hz, 3H, H-16), 1.45 (s, 3H, H-18), 1.84 (s, 3H, H-20), 1.82 (d, J=5.3Hz, H-5), 2.05 (dd, J=13.3,6.5Hz, 1H), 2.24 (dd, J=13.7,4.9Hz, 1H), 2.53 (m, 1H), 2.69 (t, J=13.1Hz, 1H), 3.48 (m, 1H, H-15), 4.35 (br m, 1H, H-2), 5.11 (dd, J=6.5,8.5Hz, 1H, H-6), 5.63 (d, J=8.4Hz, 1H, H-7), 6.33 (s,1H,H-11),7.80(brs,1H).
Nagilactone B(7)
White powder, MF:C19H24O7,ESIMS m/z:365.2[M+H]+,751.4[2M+Na]+,363.3[M-H]-, 727.5[2M-H]-,1H NMR(300MHz,Pyr):δ 7.04 (s, 1H, H-11), 5.66 (d, J=8.7Hz, 1H, H-7), 5.18 (m, 1H, H-6), 4.33 (m, 2H), 3.50 (m, 1H, H-15), 2.76 (t, J=12.5Hz, 1H), 2.13 (d, J=17.1Hz, 1H), 2.03 (s, 3H, H-20), 1.92 (d, J=6.8Hz, 1H, H-5), 1.48 (s, 3H, H-18), 1.33 (d, J=6.8Hz, 3H, H-16), 1.27 (d, J=6.7Hz, 3H, H-17)
Nagilactone E(12)
White powder, MF:C19H24O6,ESIMS m/z:349.1[M+H]+,719.3[2M+Na]+,347.0[M-H]-.1H NMR(300MHz,CDCl3):δ 5.97 (s, 1H, H-11), 4.99 (d, J=3.7Hz, 1H, H-6), 4.42 (d, J=3.8Hz, 1H, H-14), 3.97 (s, 1H, H-7), 3.67 (m, 1H, H-3), 3.47 (d, J=10.0Hz, 1H), 2.17 (m, 1H), 1.93- 1.72 (m, 3H), 1.59 (s, 3H), 1.52 (s, 3H), 1.24 (d, J=8.1Hz, 3H), 1.11 (dd, J=6.7,4.5Hz, 6H).
The compound 2-B1 of embodiment 2 synthesis
Take compound 2 (30mg, 0.08mmol) to be dissolved in anhydrous pyridine (5ml), add excessive acetic anhydride (0.02ml, 2N), it is stirred overnight at room temperature, TLC detection reaction confirmations terminate, and 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, adds second Acetoacetic ester is extracted, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is pure with P-TLC Change (chloroform/methanol=50/1 (V/V)) and obtain white solid powder 2-B1 (25mg, 74%).2-B1:MF:C21H24O7.MW: 388.ESIMS m/z:389.2[M+H]+,447.2[M+CH3COO]+.1H NMR(300MHz,CDCl3):δ 6.28 (d, J= 9.6Hz,1H,H-7),5.93(s,1H,H-11),5.06(m,1H),3.21(s,1H),2.93(m,1H),2.45(m,1H), 2.15(s,3H,Ac),1.87(m,1H),1.72(s,1H),1.52(s,3H),1.44(s,3H),1.29–1.18(m,6H,H- 16,17).
The compound 3-1 of embodiment 3~3-4 synthesis
Experiment 1：Compound 3-1 and 3-2 synthesis
Compound 3 (30mg, 0.09mmol) is taken, Pd/C (10%) catalyst 5mg is added, methanol 10ml is added, room temperature is stirred Mix, be passed through H2, reaction stays overnight, and TLC detection reaction confirmations terminate, and the insoluble matter in reaction solution are filtered, filtrate concentration, LC/MS Detection has 2 main peaks, is prepared with P-HPLC, obtains white solid 3-1 (14mg, 46%) and 3-2 (8mg, 28%).
3-1:C19H28O6.ESIMS m/z:353.1[M+H]+,375.1[M+Na]+,705.4[2M+H]+,737.4[2M+ Na]+.411.1[M+CH3COO]-,HRESIMS m/z:375.1763[M+Na]+(calcd for C19H28O6Na, 375.1784),1H NMR(300MHz,CDCl3):δ4.69(s,1H),3.89(1H),3.42(m,1H),3.09(1H),2.71– 2.31(m,3H),2.25(s,1H),2.09(1H),1.78(m,1H),1.60(m,1H),1.30(s,3H),1.25(s,2H), (d, J=6.8Hz, the 2H) of 1.16 (m, 3H), 1.10 (s, 2H), 0.94
3-2:C19H28O5.ESIMS m/z:337.1[M+H]+,335.1[M-H]-,335.1[M-H]-,HRESIMS m/z: 359.1850[M+Na]+(calcd for C19H28O5Na,359.1834),1H NMR(300MHz,CDCl3):δ3.99–3.89 (m,1H),3.07(m,1H),2.86(m,1H),2.70(m,1H),2.47–2.29(m,2H),2.29–2.15(m,1H),2.10 (m, 1H), 1.92 (s, 1H), 1.79-1.57 (m, 3H), 1.52 (d, J=11.6Hz, 1H), 1.26 (s, 3H), 1.20 (m, 1H), (d, J=6.4Hz, the 3H) of 1.07 (s, 3H), 0.91 (d, J=6.4Hz, 3H), 0.80
Experiment 2：Compound 3-3's and synthesis
Compound 3 (16mg, 0.04mmol) is taken, methanol 5ml (drying) is added, excessive sodium borohydride (30mg) is added, It is stirred overnight at room temperature, TLC detection reaction confirmations terminate, reaction solution concentration, chloroform extraction, extract pure water, anhydrous sulphur Sour sodium is dried, and P-TLC purifies to obtain white solid 3-3 (4mg, 30%) after concentration.
3-3:C19H24O5.MW:332.ESIMS m/z:333.3[M+H]+,687.4[2M+Na]+,331.1[M-H]-, HRESIMS m/z:355.1529[M+Na]+(calcd for C19H24O5Na,359.1521),1H NMR(300MHz,CDCl3): δ 7.53 (s, 1H, H-11), 5.11 (t, J=5.4Hz, 2H), 4.02 (d, J=5.3Hz, 1H), 2.57 (m, 5H), 2.28 (d, J =5.8Hz, 1H), 2.17 (s, 1H), 2.12 (m, 1H), 1.93 (d, J=7.9Hz, 1H), 1.60 (s, 3H), 1.49 (s, 3H), (d, J=6.7Hz, the 3H) of 1.25 (s, 3H), 1.08 (d, J=6.7Hz, 3H), 0.99
Experiment 3：Compound 3-4 synthesis
Compound 3 (20mg, 0.06mmol) is taken, dry methylene chloride 5ml and 3A molecular sieve is added, is stirred at room temperature, is added The insoluble matter in solution is filtered after PCC (100mg, 8N), TLC monitoring reaction, 2h, filtrate concentration is purified through silica gel column chromatography White solid 3-4 (10mg, 48%) is obtained afterwards.
3-4:C19H22O7.ESIMS m/z:385.2[M+Na]+,747.3[2M+Na]+,361.4[M-H]-,723.6[2M- H]-,HRESIMS m/z:385.1251[M+Na]+(calcd for C19H22O7Na,385.1263),1H NMR(300MHz, CDCl3):δ 6.29 (s, 1H, H-11), 6.09 (d, J=4.0Hz, 1H), 5.04 (t, J=4.7Hz, 1H), 4.52 (d, J= 9.0Hz, 1H), 4.02 (dd, J=14.7,8.4Hz, 1H), 2.62 (s, 2H), 2.47-2.30 (m, 2H), 2.17 (s, 1H), 2.07-1.96 (m, 3H), 1.85 (m, 2H), 1.80-1.68 (m, 2H), 1.66-1.47 (m, 2H), 1.30 (d, J=6.8Hz, 3H), 1.27 (d, J=6.2Hz, 3H), 1.25 (s, 3H), 1.21 (s, 3H), 1.07 (d, J=6.6Hz, 3H), 0.93 (d, J= 6.7Hz,3H).13C NMR(100MHz,MeOD):δ209.8s,209.6s,183.2s,166.0s,153.4s,125.6d, 104.1s,74.2d,56.9d,50.7d,46.6s,44.2s,38.2d,37.3t,29.5t,26.3q,24.0q,18.5q, 17.7q.
Embodiment 4：Compound 3-B1~3-B10 synthesis
Experiment 1：Compound 3-B1 and 3-B4 synthesis
Take compound 3 (70mg, 0.2mmol) to be dissolved in anhydrous pyridine (5ml), add excessive acetic anhydride (0.04ml, 2N), It is stirred overnight at room temperature, TLC detection reaction confirmations terminate, and 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, adds acetic acid second Ester is extracted, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is purified with Pre-TLC (chloroform/methanol=50/1 (V/V)) obtains white solid powder 3-B1 (20mg, 26%) and 3-B4 (41mg, 47%).
3-B1：MF:C21H26O7.ESIMS m/z:391.2[M+H]+,389.1[M-H]-,449.2[M+CH3COO]-.1H NMR(300MHz,CDCl3):δ 6.80 (s, 1H, H-11), 6.30 (d, J=9.1Hz, 1H, H-7), 5.08 (dd, J=9.1, 5.5Hz, 1H, H-6), 4.01 (s, 1H, H-1), 2.96 (dt, J=13.2,6.8Hz, 1H, H-15), 2.44-2.26 (m, 1H), 2.16 (d, J=8.6Hz, 3H, Ac), 1.99-1.85 (m, 1H), 1.82 (d, J=5.6Hz, 1H), 1.74 (dd, J=14.9, 7.0Hz, 1H), 1.62-1.50 (m, 1H), 1.35 (s, 3H, H-20), 1.30 (s, 3H, H-19), 1.24 (t, J=5.9Hz, 6H, H-16,17).
3-B4:MF:C23H28O8.ESIMS m/z:433.2[M+H]+,455.2[M+Na]+.1H NMR(300MHz, CDCl3):δ 6.32 (d, J=9.2Hz, 1H, H-7), 5.85 (s, 1H, H-11), 5.13-4.99 (m, 2H, H-1,6), 2.96 (m, 1H, H-15), 2.30 (dd, J=14.3,4.9Hz, 1H), 2.17 (s, 3H, Ac), 2.14 (s, 3H, Ac), 2.06 (d, J= 7.0Hz, 1H), 1.88 (d, J=5.9Hz, 1H), 1.80-1.65 (m, 1H), 1.45 (s, 3H, H-18), 1.32 (s, 3H, H- 19), 1.23 (t, J=6.7Hz, 6H, H-16,17)
Experiment 2：Compound 3-B2 and 3-B5 synthesis
Take compound 3 (22mg, 0.06mmol) to be dissolved in anhydrous pyridine (5ml), add excessive propionic andydride (0.02ml, 2N), 40 DEG C of oil bath heating, constant temperature stirring, TLC detection reaction confirmations terminate, and 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyrrole Pyridine, adds ethyl acetate extraction, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue With P-TLC purify (chloroform/methanol=50/1 (V/V)) obtain white solid powder 3-B2 (8mg, 28%) and 3-B5 (16mg, 63%).
3-B2:MF:C22H28O7.ESIMS m/z:405.1[M+H]+,427.1[M+Na]+,831.3[2M+Na]+,463.2 [M+CH3COO]+,HRESIMS m/z:427.1707[M+Na]+(calcd for C22H28O7Na,427.1733),1H NMR (300MHz,CDCl3):δ 6.80 (s, 1H, H-11), 6.32 (d, J=9.1Hz, 1H, H-7), 5.08 (dd, J=9.1,5.5Hz, 1H, H-6), 3.99 (m, 1H, H-1), 2.95 (dt, J=13.7,6.9Hz, 1H, H-15), 2.55-2.28 (m, 3H), 2.10 (d, J=4.3Hz, 1H), 1.91 (td, J=12.7,6.3Hz, 1H), 1.81 (d, J=5.5Hz, 1H), 1.73 (dd, J=17.6, 9.2Hz,1H),1.66(s,1H),1.62–1.48(m,1H),1.34(s,3H),1.25(s,3H),1.22(s,3H),1.18(s, 3H).
3-B5:MF:C25H32O8.ESIMS m/z:461.2[M+H]+,943.4[2M+Na]+,HRESIMS m/z: 483.2004[M+Na]+(calcd for C25H32O8Na,483.1995),1H NMR(300MHz,CDCl3):δ 6.35 (d, J= 9.2Hz,1H,H-7),5.84(s,1H,H-11),5.07(m,2H),2.96(m,1H,H-15),2.53–2.24(m,5H),2.06 (m, 1H), 1.89 (d, J=5.9Hz, 1H), 1.71 (d, J=15.5Hz, 2H), 1.46 (s, 3H), 1.32 (s, 3H), 1.28- 1.13(m,9H).
Experiment 3：Compound 3-B3 synthesis
Take compound 3 (17mg, 0.05mmol) to be dissolved in anhydrous pyridine (5ml), add excessive pivalic acid acid anhydride (0.03ml, 1.6N), 50 DEG C of oil bath heating, permanent gentle agitation, TLC detection reaction confirmations terminate, during addition 2N watery hydrochloric acid is used in reaction solution And pyridine, ethyl acetate extraction is added, organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.It is residual Excess purifies (chloroform/methanol=50/1 (V/V)) with P-TLC and obtains white solid powder 3-B3 (13mg, 62%).
3-B3:MF:C24H32O7.ESIMS m/z:433.2[M+H]+,455.2[M+Na]+,887.4[2M+Na]+,431.1 [M-H]-,491.2[M+CH3COO]-,HRESIMS m/z:455.1930[M+Na]+(calcd for C24H32O7Na, 455.2046),1H NMR(300MHz,CDCl3):δ 6.79 (s, 1H, H-11), 6.28 (d, J=9.2Hz, 1H, H-7), 5.08 (dd, J=9.1,5.5Hz, 1H, H-6), 4.00 (t, J=6.5Hz, 1H, H-1), 2.92 (dt, J=13.6,7.0Hz, 1H, H- 15), 2.43-2.25 (m, 9H), 1.90 (m, 1H), 1.82 (m, 1H), 1.75 (d, J=7.5Hz, 1H), 1.52 (m, 2H), 1.35 (s,3H),1.28(s,3H),1.25(s,9H),1.23(m,9H).
Experiment 4：Compound 3-B6 synthesis
Take compound 3 (18mg, 0.06mmol) to be dissolved in anhydrous methylene chloride (5ml), add DMAP (10mg, 1.6N) and ring Propylformic acid (0.02ml, 4N), is stirred at room temperature, and adds DCC (50mg, 4.7N), and TLC detection reaction confirmations terminate, first will reaction The precipitation filtering of middle generation, white solid powder 3- is obtained after filtrate concentration with silica gel purification (chloroform/methanol=50/1 (V/V)) B6 (12mg, 48%).
3-B6:C27H32O8.ESIMS m/z:485.2[M+H]+,507.1[M+Na]+,HRESIMS m/z:507.1996[M +Na]+(calcd for C27H32O8Na,359.1521),1H NMR(300MHz,CDCl3):δ 6.37 (d, J=9.0Hz, 1H, H- 7),5.87(s,1H,H-11),5.07(m,2H),4.09–3.96(m,1H),3.53–3.37(m,1H),2.97(m,1H,H- 15), 2.32 (m, 1H), 2.13-1.95 (m, 1H), 1.87 (d, J=5.8Hz, 1H), 1.81-1.53 (m, 1H), 1.48 (s, 2H), (d, J=7.9Hz, the 4H) of 1.31 (s, 3H), 1.22 (t, J=5.8Hz, 3H), 1.07 (d, J=11.2Hz, 6H), 0.97
Experiment 5：Compound 3-B7 synthesis
Take compound 3 (32mg, 0.09mmol) to be dissolved in anhydrous pyridine (5ml), add cyclobutylmethyl acyl chlorides (0.03ml, 3N), 50 DEG C of oil bath heating, constant temperature is stirred overnight, and TLC detection reaction confirmations terminate, during addition 2N watery hydrochloric acid is used in reaction solution And pyridine, ethyl acetate extraction is added, organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.It is residual Excess purifies (chloroform/methanol=50/1 (V/V)) with P-TLC and obtains white solid powder 3-B7 (21mg, 45%).
3-B7:C29H36O8.ESIMS m/z:513.4[M+H]+,1047.6[2M+Na]+,557.8[M+HCOO]-, HRESIMS m/z:535.2296[M+Na]+(calcd for C29H36O8Na,535.2308),1H NMR(300MHz,CDCl3): δ 6.32 (d, J=9.1Hz, 1H, H-7), 5.83 (s, 1H, H-11), 5.15-4.99 (m, 2H, H-6, H-1), 3.20 (dd, J= 16.9,8.3Hz, 2H), 3.03-2.85 (m, 1H), 2.32 (dd, J=24.1,15.2Hz, 9H), 2.15-1.77 (m, 8H), (dd, J=11.1,6.8Hz, the 6H) of 1.76-1.51 (m, 3H), 1.45 (s, 3H), 1.32 (s, 3H), 1.22
Experiment 6：Compound 3-B8 synthesis
Take compound 3 (25mg, 0.07mmol) to be dissolved in anhydrous pyridine (5ml), add excessive succinic anhydride (25mg, 3N), 70 DEG C of oil bath heating, constant temperature stirring, TLC detection reaction confirmations terminate, and 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyrrole Pyridine, adds ethyl acetate extraction, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue White solid powder 3-B8 (30mg, 93%) is obtained with silica gel purification (chloroform/methanol=20/1 (V/V)).
3-B8:C23H28O9.ESIMS m/z:449.2[M+H]+,471.2[M+Na]+,919.5[2M+Na]+,895.8[2M- H]-,HRESIMS m/z:471.1617[M+Na]+(calcd for C23H28O9Na,471.1631),1H NMR(300MHz, CDCl3):δ 6.78 (s, 1H, H-11), 6.31 (d, J=9.2Hz, 1H, H-7), 5.08 (dd, J=8.9,5.5Hz, 1H, H-6), 4.00 (t, J=6.4Hz, 1H, H-1), 2.93 (dd, J=13.2,6.6Hz, 1H, H-15), 2.81-2.61 (m, 4H), 2.42- 2.24 (m, 1H), 1.91 (dd, J=14.2,6.7Hz, 1H), 1.81 (d, J=5.4Hz, 1H), 1.76 (d, J=6.8Hz, 1H), 1.62-1.45 (m, 1H), 1.47-1.34 (m, 1H), 1.31 (s, 3H), 1.28 (s, 3H), 1.22 (d, J=2.8Hz, 3H), 1.21(s,3H).
Experiment 7：Compound 3-B9 synthesis
Take compound 3 (21mg, 0.06mmol) to be dissolved in anhydrous pyridine (5ml), add excessive succinic anhydride (25mg, 3N), 70 DEG C of oil bath heating, constant temperature stirring, TLC detection reaction confirmations terminate, and 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyrrole Pyridine, adds ethyl acetate extraction, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue White solid powder 3-B9 (17mg, 61%) is obtained with silica gel purification (chloroform/methanol=20/1 (V/V)).
3-B9:C24H30O9.ESIMS m/z:485.3[M+Na]+,947.5[2M+Na]+.923.8[2M-H]-,HRESIMS m/z:485.1794[M+Na]+(calcd for C24H30O9Na,485.1788),1H NMR(300MHz,CDCl3):δ6.80(s, 1H, H-11), 6.31 (d, J=8.9Hz, 1H, H-7), 5.08 (m, 1H, H-6), 3.99 (s, 1H, H-1), 2.94 (m, 1H), 2.33 (m, 1H), 2.17 (s, 1H), 1.98 (m, 3H), 1.81 (d, J=5.1Hz, 1H), 1.55 (d, J=6.9Hz, 1H), 1.33 (s, 3H), 1.29 (s, 3H), 1.22 (t, J=6.8Hz, 6H)
Experiment 8：Compound 3-B10 synthesis
Take compound 3 (20mg, 0.06mmol) to be dissolved in anhydrous pyridine (5ml), add chlorobenzoyl chloride (0.03ml, 3N), room Temperature stirring, TLC detection reaction confirmations terminate, and 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, adds ethyl acetate extraction, Organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue purifies (chloroform/first with P-TLC Alcohol=50/1 (V/V)) obtain white solid powder 3-B10 (28mg, 88%).
3-B10:C33H32O8,ESIMS m/z:557.2[M+H]+,1135.6[2M+Na]+,601.6[M+HCOO]-, HRESIMS m/z:579.1982[M+Na]+(calcd for C33H32O8Na,579.1995),1H NMR(300MHz,CDCl3): δ 8.04 (t, J=7.4Hz, 4H), 7.69-7.53 (m, 2H), 7.47 (t, J=7.6Hz, 4H), 6.63 (d, J=9.3Hz, 1H, ), H-7 5.99 (s, 1H, H-11), 5.37 (t, J=5.8Hz, 1H, H-1), 5.27 (dd, J=9.0,5.8Hz, 1H, H-6), 3.05 (dt, J=13.5,6.7Hz, 1H, H-15), 2.45-2.30 (m, 1H), 2.29-2.13 (m, 1H), 2.05 (d, J= 5.7Hz, 1H), 1.87 (m, 1H), 1.77 (s, 3H), 1.72-1.54 (m, 2H), 1.38 (s, 3H), 1.25 (d, J=6.6Hz, 3H), 1.12 (d, J=6.7Hz, 3H)
The compound 4-A1 of embodiment 5~4-A8 synthesis
Experiment 1:4-A1 and 4-A2 synthesis
Compound 4 (35mg, 0.1mmol) and dimethyl suflfate (15mg, 0.12mmol) are dissolved in 2ml dry DMF, The NaH (3mg, 0.12mmol) of 1.2 equivalents is added, reaction solution is stirred overnight at room temperature.TLC detections confirm that reaction terminates, instead Answer the NH that 30ml saturations are added in liquid4Cl solution, is extracted three times with 20ml ethyl acetate.Organic phase merges, anhydrous magnesium sulfate Dry, vacuum distillation removes solvent.Residue passes through Pre-TLC (dichloromethane-acetones 20:1) purify, produce compound 4-A1 (15mg, 41%) and 4-A2 (13mg, 36%).
4-A1:White solid, MF:C20H26O6,ESIMS m/z:363.2[M+H]+,1H NMR(600MHz,Pyr-d5):δ 1.26 (d, J=6.8Hz, 3H, H-17), 1.33 (d, J=6.8Hz, 3H, H-16), 1.44 (s, 3H, H-18), 1.76 (s, 3H, H-20), 1.81 (d, J=6.5Hz, 1H, H-5), 1.86 (m, 1H, H-1), 2.17 (m, 1H, H-3), 2.26 (dd, J=13.4, 9.0Hz, 1H, H-1), 2.42 (dd, J=13.7,12.2Hz, 1H, H-3), 3.36 (s, 3H, H-21), 3.48 (m, 1H, H-15), 3.67 (m, 1H, H-2), 5.12 (dd, J=8.3,6.6Hz, 1H, H-6), 5.64 (dd, J=8.4,2.9Hz, 1H, H-7), 6.29 (s, 1H, H-11), 7.86 (d, J=2.8Hz, 1H)
4-A2:White solid, MF:C20H26O6,ESI MS m/z 363.2[M+H]+,1H NMR(500MHz,Pyr-d5): δ 1.24 (d, J=7.0Hz, 3H, H-17), 1.26 (d, J=7.0Hz, 3H, H-16), 1.41 (s, 3H, H-18), 1.62 (s, 3H, H-20), 1.80 (d, J=6.3Hz, 1H, H-5), 2.01 (dd, J=13.4,6.7Hz, 1H, H-1), 2.22 (dd, J=13.6, 5.0Hz, 1H, H-3), 2.48 (dd, J=13.4,6.0Hz, 1H, H-1), 2.63 (t, J=13.0Hz, 1H, H-3), 3.22 (m, 1H, H-15), 3.60 (s, 3H, H-21), 4.33 (m, 1H, H-2), 4.97 (d, J=8.5Hz, 1H, H-7), 5.16 (dd, J= 8.4,6.3Hz, 1H, H-6), 6.29 (s, 1H, H-11), 6.71 (d, J=5.0Hz, 1H)
Experiment 3:4-A3 synthesis
Compound 4 (35mg, 0.1mmol) and dimethyl suflfate (126mg, 1.0mmol) are dissolved in 2ml dry DMF, The NaH (24mg, 1.0mmol) of 10 equivalents is added, reaction solution is stirred overnight at room temperature.TLC detections confirm that reaction terminates, and react The NH of 50ml saturations is added in liquid4Cl solution, is extracted three times with 20ml ethyl acetate.Organic phase merges, and anhydrous magnesium sulfate is done Dry, vacuum distillation removes solvent.Residue passes through Sephadex LH-20 (chloroform-methanols 1:1) purify, produce compound 4-A3 (17mg, 77%).
4-A3:White solid, MF:C21H28O6.ESIMS m/z:377.2[M+H]+,1H NMR(500MHz,Pyr-d5):δ 1.24 (d, J=3.5Hz, 3H, H-17), 1.25 (d, J=3.4Hz, 3H, H-16), 1.40 (s, 3H, H-18), 1.54 (s, 3H, H-20), 1.73 (d, J=6.3Hz, 1H, H-5), 1.83 (dd, J=13.5,6.1Hz, 1H, H-1), 2.12 (dd, J=13.9, 5.5Hz, 1H, H-3), 2.21 (dd, J=13.6,8.8Hz, 1H, H-1), 2.35 (dd, J=13.8,9.2Hz, 1H, H-3), 3.22 (m, 1H, H-15), 3.34 (s, 3H, H-21), 3.59 (s, 3H, H-22), 3.63 (m, 1H, H-2), 4.97 (d, J= 8.5Hz, 1H, H-7), 5.17 (dd, J=8.4,6.3Hz, 1H, H-6), 6.25 (brs, 1H, H-11)
Experiment 4:4-A4 and 4-A5 synthesis
Compound 4 (35mg, 0.1mmol) and dithyl sulfate (18.5mg, 0.12mmol) are dissolved in 2ml dry DMF In, the NaH (3mg, 0.12mmol) of 1.2 equivalents is added, reaction solution is stirred overnight at room temperature.TLC detections confirm that reaction terminates, The NH of 30ml saturations is added in reaction solution4Cl solution, is extracted three times with 20ml ethyl acetate.Organic phase merges, anhydrous slufuric acid Magnesium is dried, vacuum distillation removes solvent.Residue passes through Pre-TLC (dichloromethane-acetones 25:1) purify, produce compound 4- A4 (16mg, 43%) and 4-A5 (17mg, 45%).4-A4:ESI MS m/z 377.2[M+H]+；4-A5:ESI MS m/z 377.2[M+H]+.
Experiment 5:4-A6 synthesis
Compound 4 (35mg, 0.1mmol) and dimethyl suflfate (154mg, 1.0mmol) are dissolved in 2ml dry DMF, The NaH (24mg, 1.0mmol) of 10 equivalents is added, reaction solution is stirred overnight at room temperature.TLC detections confirm that reaction terminates, and react The NH of 50ml saturations is added in liquid4Cl solution, is extracted three times with 20ml ethyl acetate.Organic phase merges, and anhydrous magnesium sulfate is done Dry, vacuum distillation removes solvent.Residue passes through Sephadex LH-20 (chloroform-methanols 1:1) purify, produce compound 4-A6 (32mg, 79%).4-A6:ESI MS m/z 405.3[M+H]+.
Experiment 6:4-A7 and 4-A8 synthesis
Compound 4 (35mg, 0.1mmol) and 3- bromo -1- propylene (18.2mg, 0.15mmol) are dissolved in the anhydrous of 2ml In DMF, the NaH (4mg, 0.15mmol) of 1.5 equivalents is added, reaction solution is stirred overnight at room temperature.TLC detections confirm reaction knot The NH of 30ml saturations is added in beam, reaction solution4Cl solution, is extracted three times with 20ml ethyl acetate.Organic phase merges, anhydrous sulphur Sour magnesium is dried, vacuum distillation removes solvent.Residue is purified by preparation HPLC, produces compound 4-A7 (12mg, 31%) With 4-A8 (20mg, 47%).
4-A7:White solid, WF：C22H28O6,ESI MS m/z 389.2[M+H]+；1H NMR(600MHz,Pyr-d5): δ 1.25 (d, J=6.7Hz, 3H, H-17), 1.28 (d, J=6.7Hz, 3H, H-16), 1.41 (s, 3H, H-18), 1.65 (s, 3H, H-20), 1.81 (t, J=3.0Hz, 1H, H-5), 2.02 (dd, J=13.4,6.8Hz, 1H, H-1), 2.22 (dd, J=13.6, 5.0Hz, 1H, H-3), 2.49 (dd, J=13.5,9.0Hz, 1H, H-1), 2.63 (t J=13.0Hz, 1H, H-3), 3.25 (m, 1H, H-15), 4.23 (ddt, J=12.5,6.2,1.4Hz, 1H, H-21), 4.33 (m, 1H, H-2), 4.61 (ddt, J=12.5, 5.2,1.5Hz, 1H, H-21), 5.15-5.18 (3H, H-6, H-7, H-23), 5.36 (dq, J=17.2,1.7Hz, 1H, H-23), 6.04(m,1H,H-22),6.31(s,1H,H-11),6.72(brs,1H).
4-A8:White solid, MF:C25H32O6,ESI MS m/z 429.9[M+H]+,1H NMR(600MHz,Pyr-d5): δ 1.24 (d, J=3.5Hz, 3H, H-17), 1.26 (d, J=3.5Hz, 3H, H-16), 1.41 (s, 3H, H-18), 1.59 (s, 3H, H-20), 1.78 (d, J=4.0Hz, 1H, H-5), 1.87 (dd, J=13.5,6.2Hz, 1H, H-1), 2.13 (dd, J=13.8, 5.2Hz, 1H, H-3), 2.26 (dd, J=13.6,8.9Hz, 1H, H-1), 2.40 (dd, J=13.7,8.0Hz, 1H, H-3), 3.25 (m, 1H, H-15), 3.80 (m, 1H, H-2), 4.10 (m, 2H, H-21), 4.23 (ddt, J=12.5,6.0,1.4Hz, 1H, H-24), 4.59 (ddt, J=12.5,6.0,1.5Hz, 1H, H-24), 5.15-5.19 (3H, H-6, H-7, H-26), 5.22 (dq, J=10.6,1.4Hz, 1H, H-23), 5.36 (dq, J=17.3,1.8Hz, 1H, H-26), 5.44 (dq, J=17.2,1.8Hz, 1H,H-23),6.05(m,2H,H-22,H-25),6.28(s,1H,H-11).
The compound 4-B1 of embodiment 6~4-B44 synthesis
Experiment 1:Compound 4-B1 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine (1ml), add chloroacetic chloride (0.004ml, 1.5eq.), it is stirred overnight at room temperature, TLC detections confirm that reaction terminates, 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, plus Enter ethyl acetate extraction, organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is to make Standby HPLC purifying, obtains white solid powder 4-B1 (6mg, 27%).
4-B1:ESIMS m/z:391.2[M+H]+,435.2[M+HCOO]-.MF:C21H26O7.MW:390.ESIMS m/z: 391.2[M+H]+,435.2[M+HCOO]-.1H NMR(500MHz,CDCl3):δ 5.94 (s, 1H, H-11), 5.31 (d, J= 9.1Hz, 1H, H-7), 5.08 (m, 1H, H-2), 4.96 (dd, J=8.3,6.6Hz, 1H, H-6), 3.25 (m, 1H, H-15), 2.40 (dd, J=13.9,9.5Hz, 1H), 2.32 (t, J=11.7Hz, 1H), 2.09 (s, 3H), 2.00 (dd, J=13.9, 5.8Hz, 1H), 1.89 (d, J=6.6Hz, 1H, H-5), 1.77 (dd, J=13.9,6.0Hz, 1H), 1.51 (s, 3H, H-20), (d, J=6.8Hz, 3H, the H-17) of 1.45 (s, 3H, H-19), 1.33 (d, J=6.8Hz, 3H, H-16), 1.25
13C NMR(126MHz,CDCl3):δ180.1,171.6,170.6,164.5,162.1,109.0,106.5,73.8, 66.6,60.3,48.6,42.4,40.1,36.8,32.6,29.6,26.8,24.3,21.3,20.9,20.4.
Experiment 2:Compound 4-B2 synthesis
Compound 4 (20mg, 0.057mmol) is taken to be dissolved in anhydrous pyridine 1ml, plus propionyl chloride (0.008ml, 2.6eq.), room Temperature is stirred overnight, and TLC detections confirm that reaction terminates, and 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, adds ethyl acetate Extraction, organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is purified with preparing HPLC, Obtain white solid powder 4-B2 (5mg, 22%).
4-B2:ESIMS m/z:405.3[M+H]+,449.1[M+HCOO]-.
Experiment 3:Compound 4-B3 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add isobutyryl chloride (0.008ml, 2.2N), It is stirred overnight at room temperature, TLC detections confirm that reaction terminates, 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, adds acetic acid second Ester is extracted, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is pure to prepare HPLC Change, obtain white solid powder 4-B3 (12mg, 50%).
4-B3:ESIMS m/z:419.3[M+H]+,463.3[M+HCOO]-.
Experiment 4:Compound 4-B4 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add positive butyryl (0.008ml, 2.2N), room Temperature is stirred overnight, and TLC detections confirm that reaction terminates, and 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, adds ethyl acetate Extraction, organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is purified with preparing HPLC, Obtain white solid powder 4-B4 (8mg, 34%).
4-B4:ESIMS m/z:419.3[M+H]+,463.3[M+HCOO]-.
Experiment 5:Compound 4-B5 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add positive caproyl chloride (0.012ml, 1.5N), It is stirred overnight at room temperature, TLC detections confirm that reaction terminates, 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, adds acetic acid second Ester is extracted, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is pure to prepare HPLC Change, obtain white solid powder 4-B5 (18mg, 71%).
4-B5:ESIMS m/z:447.4[M+H]+,491.2[M+HCOO]-.
Experiment 6:Compound 4-B6 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add certain herbaceous plants with big flowers acyl chlorides (0.012ml, 1.1N), room Temperature is stirred overnight, and TLC detections confirm that reaction terminates, and 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, adds ethyl acetate Extraction, organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is purified with preparing HPLC, Obtain white solid powder 4-B6 (8mg, 28%).
4-B6:ESIMS m/z:503.4[M+H]+,547.3[M+HCOO]-.
Experiment 7:Compound 4-B7 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add chloroacetic chloride (0.008ml, 3N), room temperature It is stirred overnight, TLC detections confirm that reaction terminates, 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, adds ethyl acetate extraction Take, organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is obtained with preparing HPLC purifying To white solid powder 4-B7 (13mg, 53%).
4-B7:ESIMS m/z:433.2[M+H]+,477.2[M+HCOO]-.
Experiment 8:Compound 4-B8 synthesis
Take compound 4 (10mg, 0.029mmol) to be dissolved in anhydrous pyridine 1ml, add positive caproyl chloride (0.06ml, 1.5N), room Temperature is stirred overnight, and TLC detections confirm that reaction terminates, and 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, adds ethyl acetate Extraction, organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is purified with preparing HPLC, Obtain white solid powder 4-B8 (8mg, 51%).
4-B8:ESIMS m/z:545.4[M+H]+,590.1[M+HCOO]-.
Experiment 9:Compound 4-B9 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add Cyclopropyl carbonyl chloride (0.008ml, 1.5N), it is stirred overnight at room temperature, TLC detections confirm that reaction terminates, 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, is added Ethyl acetate is extracted, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is to prepare HPLC is purified, and obtains white solid powder 4-B9 (12mg, 51%).4-B9:ESIMS m/z:417.2[M+H]+,461.2[M+ HCOO]-.
Experiment 10:Compound 4-B10 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add the formyl chloride of ring penta (0.008ml, 1.2N), it is stirred overnight at room temperature, TLC detections confirm that reaction terminates, 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, is added Ethyl acetate is extracted, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is to prepare HPLC is purified, and obtains white solid powder 4-B10 (10mg, 40%).4-B10:ESIMS m/z:445.3[M+H]+,489.2[M +HCOO]-.
Experiment 11:Compound 4-B11 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add cyclohexanecarbonyl chloride (0.008ml, 1.2N), it is stirred overnight at room temperature, TLC detections confirm that reaction terminates, 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, is added Ethyl acetate is extracted, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is to prepare HPLC is purified, and obtains white solid powder 4-B11 (10mg, 40%).4-B11:ESIMS m/z:459.3[M+H]+,503.3[M +HCOO]-.
Experiment 12:Compound 4-B12 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add 3- cyclohexyl propionyl chloride (0.008ml, 1.2N), it is stirred overnight at room temperature, TLC detections confirm that reaction terminates, 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, is added Ethyl acetate is extracted, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is to prepare HPLC is purified, and obtains white solid powder 4-B12 (8mg, 29%).4-B12:ESIMS m/z:487.4[M+H]+,531.3[M+ CH3COO]-.
Experiment 13:Compound 4-B13 synthesis
Take compound 4 (10mg, 0.029mmol) to be dissolved in anhydrous pyridine 1ml, add Cyclopropyl carbonyl chloride (0.008ml, 3N), it is stirred overnight at room temperature, TLC detections confirm that reaction terminates, 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, adds second Acetoacetic ester is extracted, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is to prepare HPLC is purified, and obtains white solid powder 4-B13 (7mg, 50%).4-B13:ESIMS m/z:485.3[M+H]+,529.3[M+ HCOO]-.
Experiment 14:Compound 4-B14 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add cyclobutyl formate (0.008ml, 1.5N), it is stirred at room temperature, adds DCC (50mg, 4.6N), reaction is stayed overnight, TLC detections confirms that reaction terminates, and 2N is added in reaction solution Watery hydrochloric acid is used to neutralize pyridine, adds ethyl acetate extraction, and organic layer is with saturation NaCl, pure water, anhydrous sodium sulfate drying, Filtering, concentration.Residue obtains white solid powder 4-B14 (17mg, 58%) to prepare HPLC purifying.4-B14:ESIMS m/z:513.3[M+H]+,557.2[M+HCOO]-.
Experiment 15:Compound 4-B15 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add succinic anhydride (20mg, 3.5N), room temperature It is stirred overnight, TLC detections confirm that reaction terminates, 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, adds ethyl acetate extraction Take, organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is obtained with preparing HPLC purifying To white solid powder 4-B15 (10mg, 39%).
4-B15:ESIMS m/z:449.3[M+H]+,447.2[M+HCOO]-.
Experiment 16:Compound 4-B16 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add glutaric anhydride (20mg, 3.1N), room temperature It is stirred overnight, TLC detections confirm that reaction terminates, 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, adds ethyl acetate extraction Take, organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is obtained with preparing HPLC purifying To white solid powder 4-B16 (7mg, 27%).
4-B16:ESIMS m/z:463.3[M+H]+,461.2[M+HCOO]-.
Experiment 17:Compound 4-B17 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add succinic acid monoethyl ester acyl chloride (0.012ml, 1.5N), is stirred overnight at room temperature, and TLC detections confirm that reaction terminates, and 2N watery hydrochloric acid is added in reaction solution to be used to neutralize Pyridine, adds ethyl acetate extraction, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.It is remaining Thing obtains white solid powder 4-B17 (10mg, 37%) to prepare HPLC purifying.4-B17:MF:C25H32O9.MW: 476.ESIMS m/z:477.4[M+H]+,521.3[M+HCOO]-.
Experiment 18:Compound 4-B18 synthesis
Take compound 4 (10mg, 0.029mmol) to be dissolved in anhydrous pyridine 1ml, add succinic acid monoethyl ester acyl chloride (0.012ml, 3N), is stirred overnight at room temperature, and TLC detections confirm that reaction terminates, and 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyrrole Pyridine, adds ethyl acetate extraction, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue To prepare HPLC purifying, white solid powder 4-B18 (17mg, 97%) is obtained.4-B18:ESIMS m/z:605.5[M+H]+, 649.4[M+HCOO]-.
Experiment 19:Compound 4-B19 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add 2 furoyl chloride (0.010ml, 1.8N), it is stirred overnight at room temperature, TLC detections confirm that reaction terminates, 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, is added Ethyl acetate is extracted, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is to prepare HPLC is purified, and obtains white solid powder 4-B19 (12mg, 48%).4-B19:ESIMS m/z:443.3[M+H]+,487.2[M +CH3COO]-.
Experiment 20:Compound 4-B20 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add 2- thiophene chlorides (0.010ml, 1.6N), it is stirred overnight at room temperature, TLC detections confirm that reaction terminates, 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, is added Ethyl acetate is extracted, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is to prepare HPLC is purified, and obtains white solid powder 4-B20 (10mg, 38%).4-B20:ESIMS m/z:459.3[M+H]+,503.2[M +HCOO]-.
Experiment 21:Compound 4-B21 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add 2- chloronicotinoyl chlorides (12mg, 1.2N), room Temperature is stirred overnight, and TLC detections confirm that reaction terminates, and 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, adds ethyl acetate Extraction, organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is purified with preparing HPLC, Obtain white solid powder 4-B21 (14mg, 55%).
4-B21:ESIMS m/z:488.2[M+H]+,532.2[M+HCOO]-.
Experiment 22:Compound 4-B22 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add 1- benzothiophene -3- dicarbonyl chlorides (12mg, 1.1N), is stirred overnight at room temperature, and TLC detections confirm that reaction terminates, and 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyrrole Pyridine, adds ethyl acetate extraction, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue To prepare HPLC purifying, white solid powder 4-B22 (13mg, 45%) is obtained.4-B22:ESIMS m/z:509.3[M+H]+, 553.2[M+HCOO]-.
Experiment 23:Compound 4-B23 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add 1,5- dimethyl -1H- pyrazoles -3- carbonyls Acyl chlorides (10mg, 1.1N), is stirred overnight at room temperature, and TLC detections confirm that reaction terminates, and 2N watery hydrochloric acid is added in reaction solution to be used to neutralize Pyridine, adds ethyl acetate extraction, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.It is remaining Thing obtains white solid powder 4-B23 (9mg, 34%) to prepare HPLC purifying.4-B23:ESIMS m/z:471.3[M+H]+, 515.2[M+HCOO]-.
Experiment 24:Compound 4-B24 synthesis
Take compound B (20mg, 0.057mmol) to be dissolved in anhydrous pyridine (1ml), add 4- methyl -2- phenyl -1,3- thiophenes Azoles -5- phosgenes (15mg, 1.2N), are stirred overnight at room temperature, and TLC detections confirm that reaction terminates, and 2N watery hydrochloric acid is added in reaction solution For neutralizing pyridine, ethyl acetate extraction is added, organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, Concentration.Residue obtains white solid powder 4-B24 (10mg, 35%) to prepare HPLC purifying.4-B24:ESIMS m/z: 550.3[M+H]+,594.2[M+HCOO]-.
Experiment 25:Compound 4-B25 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add chlorobenzoyl chloride (0.010ml, 1.5N), It is stirred overnight at room temperature, TLC detections confirm that reaction terminates, 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, adds acetic acid second Ester is extracted, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is pure to prepare HPLC Change, obtain white solid powder 4-B25 (13mg, 51%).4-B25:ESIMS m/z:453.3[M+H]+,497.2[M+ HCOO]-.
Experiment 26:Compound 4-B26 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add 4- tert-butyl benzoyl chlorides (0.015ml, 1.3N), is stirred overnight at room temperature, and TLC detections confirm that reaction terminates, and 2N watery hydrochloric acid is added in reaction solution to be used to neutralize Pyridine, adds ethyl acetate extraction, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.It is remaining Thing obtains white solid powder 4-B26 (14mg, 48%) to prepare HPLC purifying.4-B26:ESIMS m/z:509.3[M+H ]+,553.2[M+HCOO]-.
Experiment 27:Compound 4-B27 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add 4- tert-butyl benzoyl chlorides (15mg, 1.3N), it is stirred overnight at room temperature, TLC detections confirm that reaction terminates, 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, is added Ethyl acetate is extracted, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is to prepare HPLC is purified, and obtains white solid powder 4-B27 (11mg, 38%).4-B27:ESIMS m/z:513.3[M+H]+,557.2[M +HCOO]-.
Experiment 28:Compound 4-B28 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add trans-cinnamate acyl chlorides (10mg, 1.1N), It is stirred overnight at room temperature, TLC detections confirm that reaction terminates, 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, adds acetic acid second Ester is extracted, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is pure to prepare HPLC Change, obtain white solid powder 4-B28 (10mg, 37%).4-B28:ESIMS m/z:479.3[M+H]+,523.2[M+ HCOO]-.
Experiment 29:Compound 4-B29 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add 3- phenylpropionyl chlorides (0.015ml, 1.3N), it is stirred overnight at room temperature, TLC detections confirm that reaction terminates, 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, is added Ethyl acetate is extracted, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is to prepare HPLC is purified, and obtains white solid powder 4-B29 (12mg, 44%).4-B29:ESIMS m/z:481.3[M+H]+,525.2[M +HCOO]-.
Experiment 30:Compound 4-B30 synthesis
Take compound 4 (10mg, 0.029mmol) to be dissolved in anhydrous pyridine 1ml, add chlorobenzoyl chloride (0.005ml, 1.5N), It is stirred overnight at room temperature, TLC detections confirm that reaction terminates, 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, adds acetic acid second Ester is extracted, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is pure to prepare HPLC Change, obtain white solid powder 4-B30 (7mg, 51%).
4-B30:ESIMS m/z:557.3[M+H]+,601.2[M+HCOO]-.
Experiment 31:Compound 4-B31 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add 2- chlorobenzoyl chlorides (0.010ml, 1.4N), it is stirred overnight at room temperature, TLC detections confirm that reaction terminates, 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, is added Ethyl acetate is extracted, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is to prepare HPLC is purified, and obtains white solid powder 4-B31 (11mg, 40%).4-B31:ESIMS m/z:488.3[M+H]+,532.2[M +HCOO]-.
Experiment 32:Compound 4-B32 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add 2- fluorobenzoyl chlorides (0.010ml, 1.6N), it is stirred overnight at room temperature, TLC detections confirm that reaction terminates, 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, is added Ethyl acetate is extracted, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is to prepare HPLC is purified, and obtains white solid powder 4-B32 (10mg, 40%).4-B32:ESIMS m/z:471.3[M+H]+,515.2[M +HCOO]-.
Experiment 33:Compound 4-B33 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add 3- chlorobenzoyl chlorides (0.010ml, 1.4N), it is stirred overnight at room temperature, TLC detections confirm that reaction terminates, 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, is added Ethyl acetate is extracted, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is to prepare HPLC is purified, and obtains white solid powder B33 (11mg, 40%).4-B33:ESIMS m/z:488.3[M+H]+,532.2[M+ HCOO]-.
Experiment 34:Compound 4-B34 synthesis
Take compound 4 (20mg, 0.057mmo) to be dissolved in anhydrous pyridine 1ml, add 3- bromo-benzoyl chlorides (0.010ml, 1.3N), it is stirred overnight at room temperature, TLC detections confirm that reaction terminates, 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, is added Ethyl acetate is extracted, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is to prepare HPLC is purified, and obtains white solid powder 4-B34 (11mg, 36%).4-B34:ESIMS m/z:532.3[M+H]+,576.2[M +HCOO]-.
Experiment 35:Compound 4-B35 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add 4- bromo-benzoyl chlorides (15mg, 1.2N), It is stirred overnight at room temperature, TLC detections confirm that reaction terminates, 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, adds acetic acid second Ester is extracted, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is pure to prepare HPLC Change, obtain white solid powder 4-B35 (11mg, 36%).4-B35:ESIMS m/z:532.3[M+H]+,576.2[M+ HCOO]-.
Experiment 36:Compound 4-B36 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add 4- chlorobenzoyl chlorides (0.010ml, 1.4N), it is stirred overnight at room temperature, TLC detections confirm that reaction terminates, 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, is added Ethyl acetate is extracted, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is to prepare HPLC is purified, and obtains white solid powder 4-B36 (11mg, 40%).4-B36:ESIMS m/z:488.3[M+H]+,532.2[M +HCOO]-.
Experiment 37:Compound 4-B37 synthesis
Take compound 4 (10mg, 0.029mmol) to be dissolved in anhydrous pyridine 1ml, add 2- chlorobenzoyl chlorides (0.005ml, 1.4N), it is stirred overnight at room temperature, TLC detections confirm that reaction terminates, 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, is added Ethyl acetate is extracted, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is to prepare HPLC is purified, and obtains white solid powder 4-B37 (8mg, 44%).4-B37:ESIMS m/z:666.3[M+H]+,670.2[M+ HCOO]-.
Experiment 38:Compound 4-B38 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add 2- methacrylic chlorides (0.010ml, 1.8N), it is stirred overnight at room temperature, TLC detections confirm that reaction terminates, 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, is added Ethyl acetate is extracted, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is to prepare HPLC is purified, and obtains white solid powder 4-B38 (10mg, 42%).4-B38:ESIMS m/z:417.3[M+H]+,461.2[M +HCOO]-.
Experiment 39:Compound 4-B39 synthesis
Take compound 4 (10mg, 0.029mmol) to be dissolved in anhydrous pyridine 1ml, add crotonyl chloride (10mg, 3.3N), room temperature It is stirred overnight, TLC detections confirm that reaction terminates, 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, adds ethyl acetate extraction Take, organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is obtained with preparing HPLC purifying To white solid powder 4-B39 (12mg, 86%).
4-B39:ESIMS m/z:485.3[M+H]+,529.2[M+HCOO]-.
Experiment 40:Compound 4-B40 synthesis
Take compound 4 (20mg, 0.057mmol) to be dissolved in anhydrous pyridine 1ml, add crotonyl chloride (0.010ml, 1.3N), It is stirred overnight at room temperature, TLC detections confirm that reaction terminates, 2N watery hydrochloric acid is added in reaction solution to be used to neutralize pyridine, adds acetic acid second Ester is extracted, and organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is pure to prepare HPLC Change, obtain white solid powder 4-B40 (8mg, 30%).
4-B40:ESIMS m/z:467.3[M+H]+,511.2[M+HCOO]-.
Experiment 41:Compound 4-B41 synthesis
Take compound 4 (300mg, 0.86mmol) to be dissolved in anhydrous pyridine 2ml, add fluorenes methoxy dicarbonyl chloride (300mg, 1.4N), it is stirred overnight at room temperature, 2N watery hydrochloric acid is added after reaction terminates, in reaction solution to be used to neutralize pyridine, adds ethyl acetate extraction Take, organic layer is filtered with saturation NaCl, pure water, anhydrous sodium sulfate drying, concentration.Residue is with Sephadex LH-20 Purify (chloroform/methanol=1/1 (V/V)), obtain yellow solid powder 4-MOC (205mg, 42%).
Take compound 4-MOC (20mg, 0.035mmol) to be dissolved in anhydrous pyridine 1ml, add chloroacetic chloride (0.008ml, 3.0N), it is stirred overnight at room temperature, after reaction terminates, vacuum distillation removes most of pyridine, and obtained residue is dissolved in dichloromethane Alkane, adds diethylamine (0.1ml), reacts at room temperature 0.5h, and vacuum distillation removes solvent, obtains residue with Sephadex LH-20 Purify (chloroform/methanol=1/1 (V/V)), obtain yellow solid powder 4-B41 (10mg, 73%).4-B41:ESIMS m/z: 391.2[M+H]+,435.2[M+HCOO]-.
Experiment 42:Compound 4-B42 synthesis
Take compound 4-MOC (20mg, 0.035mmol) to be dissolved in anhydrous pyridine 1ml, add isobutyryl chloride (0.008ml, 2.2N), it is stirred overnight at room temperature, after reaction terminates, vacuum distillation removes most of pyridine, and obtained residue is dissolved in dichloromethane Alkane, adds diethylamine (0.1ml), reacts at room temperature 0.5h, and vacuum distillation removes solvent, obtains residue with Sephadex LH-20 Purify (chloroform/methanol=1/1 (V/V)), obtain yellow solid powder 4-B42 (10mg, 68%).4-B42:ESIMS m/z: 419.3[M+H]+,463.3[M+HCOO]-.
Experiment 43:Compound 4-B43 synthesis
Take compound 4-MOC (20mg, 0.035mmol) to be dissolved in anhydrous pyridine 1ml, add n-butyryl chloride (0.008ml, 2.2N), it is stirred overnight at room temperature, after reaction terminates, vacuum distillation removes most of pyridine, and obtained residue is dissolved in dichloromethane Alkane, adds diethylamine 0.1ml, reacts at room temperature 0.5h, and vacuum distillation removes solvent, obtains residue pure with Sephadex LH-20 Change (chloroform/methanol 1:1) yellow solid powder 4-B43 (6mg, 41%), is obtained.4-B43:ESIMS m/z:419.3[M+H]+, 463.3[M+HCOO]-.
Experiment 44:Compound 4-B44 synthesis
Take compound 4-MOC (20mg, 0.035mmol) to be dissolved in anhydrous pyridine 1ml, add parabromobenzoyl chloride (12mg, 1.5N), it is stirred overnight at room temperature, after reaction terminates, vacuum distillation removes most of pyridine, and obtained residue is dissolved in dichloromethane Alkane, adds diethylamine 0.1ml, reacts at room temperature 0.5h, and vacuum distillation removes solvent, obtains residue pure with Sephadex LH-20 Change (chloroform/methanol 1:1) yellow solid powder 4-B44 (18mg, 97%), is obtained.
4-B44:ESIMS m/z:531.3,533.2,[M+H]+,575.2,577.1[M+HCOO]-.
The compound 7-A1 of embodiment 7 synthesis
Compound 7 (20mg, 0.055mmol) is dissolved in 20ml acetone, adds p-methyl benzenesulfonic acid-hydrate (10mg, 0.052mmol), reaction solution is stirred overnight at room temperature.TLC detections confirm that reaction terminates, and 30ml is added in reaction solution The NaHCO of saturation3Solution, is extracted three times with 20ml ethyl acetate.Organic phase merges, and anhydrous magnesium sulfate is dried, vacuum distillation Remove solvent.Residue passes through Sephadex LH-20 (chloroform-methanols 1:1) purify, produce compound 7-A1 (17mg, 77%).
7-A1:White solid, MF:C22H28O7,ESI MS m/z 405.2[M+H]+,13C NMR(125MHz,Pyr-d5): δ182.0(C-19),170.4(C-9),165.6(C-14),162.9(C-12),111.9(C-20),109.8(C-8),108.6 (C-11),79.7(C-6),75.4(C-1),73.1(C-2),60.6(C-7),48.9(C-5),42.4(C-4),41.7(C- 10),34.8(C-3),30.1(C-15),26.8and 25.3(C-21and C-22),24.4(C-18),21.2(C-17), 10.7(C-16),18.8(C-20).
The compound 12-1 of embodiment 8 synthesis
Compound 12 (75mg, 0.22mmol) is taken, dry methylene chloride 15ml and 3A molecular sieve is added, is stirred at room temperature, plus The insoluble matter in solution is filtered after entering PCC (150mg, 3N), TLC monitoring reactions, 7h, filtrate concentration is pure through silica gel column chromatography White solid 12-1 (61mg, 81%) is obtained after change.
12-1:C19H22O6.ESIMS m/z:347.1[M+H]+,369.1[M+Na]+345.1[M+H]+,HRESIMS m/z: 369.1319[M+Na]+(calcd for C19H22O6Na,369.1314),1H NMR(300MHz,CDCl3):δ6.11(s,1H, ), H-11 4.89 (d, J=4.4Hz, 1H, H-7), 4.48 (d, J=3.4Hz, 1H), 4.03 (s), 2.70 (m, 2H), 2.42 (d, J =4.5Hz, 1H), 2.11 (m, 3H), 2.12 (m, 1H), 1.54 (s, 3H), 1.14 (m, 9H), 0.90 (s, 1H)
The compound activity of embodiment 9 is tested
9.1 nagilactone class compound activities are tested
(final concentration of 5 μM) of each compound processing degreasing serum starvation 12 hours of foregoing separation and chemical synthesis HepG2 cells 24 hours, add the μ g/ml of low-density lipoprotein (DiI-LDL) 20 of fluorescence labeling, 37 DEG C are incubated 4 hours, use phosphorus Phthalate buffer (PBS), which is gently washed, uses isopropyl alcohol extracting lipid after cell 5 times, in determining fluorescence reading (exciting light on ELIASA： 520nm；Launch light 570nm).Then 0.2M sodium hydroxide cell lysis is used, protein content is determined, calculates fluorescence/albumen Numerical value.Experimental result, which is shown in Table in 4, multiple compounds under 5 μM of concentration to play low-density lipoprotein LDL intakes, significantly increases work With.The noval chemical compound obtained to structure of modification, also showing the intake of HepG2 liver cells low-density lipoprotein has humidification (table 4).
The humidification that the part of compounds of table 4. is absorbed to liver cell low-density lipoprotein
Action intensity+101%-120%；++ 121%-140%；+++ 141%-160%；++++161%-180%；+++ ++ 181%-200%；++++++>200%.
9.2 nagilactone class compounds promote liver cell low-density lipoprotein (LDL) picked-up activity Mechanism Study compound Raise LDL receptor (LDLR) gene expression dose
The up-regulation of LDLR protein levels is probably as caused by two aspect reasons：LDLR gene levels rise or LDLR albumen sheets The stability increase of body.Condition based on more than, have detected the expression of LDLR genes.It is dense at 5 μM with the compounds of this invention The lower processing liver cell of degree 24 hours, TRIzol reagents extract cell total rna, take 3 μ g RNA M-MLV (reverse transcriptase) reverse transcriptions Real-time PCR (real-time quantitative PCR) are carried out into cDNA, then with LDLR specific primer, internal reference base is used as using GAPDH Because comparing adjustment effect of the compound to LDLR genes.As a result show, the compounds of this invention conspicuousness improves LDLR genes Expression.
The gene primer sequence and PCR conditions used in experiment are shown in Table 5.
The primer sequence of table 5. and PCR reaction conditions
In summary, unexpected enhancing LDL has been played in the LDL intake experiments of nagilactone class compound in vitro The effect of intake.Which part compound (such as 4-B19,4-B29,4-B31) effect highly significant, it might even be possible to reach>200% Action intensity.Therefore, it is experimentally confirmed that the nagilactone class compound based on new lipid-loweringing target spot has high clinical practice Value and new drug development potentiality.
All documents referred in the present invention are all incorporated as reference in this application, independent just as each document It is incorporated as with reference to such.In addition, it is to be understood that after the above-mentioned instruction content of the present invention has been read, those skilled in the art can To be made various changes or modifications to the present invention, these equivalent form of values equally fall within the model that the application appended claims are limited Enclose.

Claims (10)

1. a kind of compound as shown in following formula I, or its pharmaceutically acceptable salt：
Wherein, Formulas I is selected from one of Formulas I -1, I-2 or I-3：
A is selected from the group：N-R、O；Wherein, R is selected from the group：H、C1-C4Acyl group, C1-C4Alkyl, C1-C4Haloalkyl, take Generation or unsubstituted C6-C10Aryl, substituted or unsubstituted C1-C10Heteroaryl；
R1It is selected from the group：H, substituted or unsubstituted C1-C4Alkyl, C1-C4Haloalkyl, substituted or unsubstituted C1-C4Alkane Base (such as 2- hydroxyethyls, 2- hydroxymethyl ethyls), substituted or unsubstituted vinyl；
R2It is selected from the group：Nothing, H, oxygen atom, substituted or unsubstituted C2-C10Ester group ,-OR, wherein, described R is selected from the group： H, substituted or unsubstituted C2-C10Acyl group, fluorenes methoxy carbonyl acyl group (Fmoc) or substituted or unsubstituted C1-C10Alkyl；Preferably Ground, R ' is H；
R3It is selected from the group：H, halogen, C1-C4Alkyl, C1-C4Haloalkyl ,-OH, substituted or unsubstituted C2-C10Ester Base ,-NH-R；Wherein, R is selected from the group：H、C1-C4Acyl group, substituted or unsubstituted C1-C4Alkyl；
R4It is selected from the group：H, halogen, oxygen atom, cyano group, hydroxyl, carboxyl, C1-C4Alkoxy, C1-C4Alkyl, C1-C4Halogen Substituted alkyl, substituted or unsubstituted C2-C10Ester group ,-OC (O)-R ,-NH-R；Wherein, R is selected from the group：H、C1-C4Acyl group, Substituted or unsubstituted C1-C4Alkyl；
R5It is selected from the group：H, halogen, cyano group, hydroxyl ,-OR ,-COOR, substitution or unsubstituted C1-C10It is alkyl, substituted or unsubstituted C1-C10Haloalkyl, substituted or unsubstituted C2-C30Ester group, the C of substitution or unsubstituted (preferably replace)7-C11Aryl- Acyl group ,-NH-R；Wherein, R is selected from the group：H、C1-C4Acyl group, substituted or unsubstituted C1-C4Alkyl；
Or R4And R5Collectively form-R "-O-R "-, wherein, described R " is nothing, or substituted or unsubstituted C1-C4Alkylidene；
R6It is selected from the group：H, halogen, oxygen atom, cyano group, carboxyl, hydroxyl ,-OR ,-COOR, substitution or unsubstituted C1-C10Alkyl, take Generation or unsubstituted C1-C10Haloalkyl, substituted or unsubstituted C2-C10Ester group, substitution or unsubstituted (preferably replace) C7-C11Aryl-acyl ,-NH-R；Wherein, R is selected from the group：H、C1-C4Acyl group, substituted or unsubstituted C1-C4Alkyl；
Or R5And R6Collectively form-R "-O-R "-, wherein, described R " is nothing, or substituted or unsubstituted C1-C4Alkylidene；
R7It is selected from the group：H、C1-C4Alkyl, C1-C4Haloalkyl；
R8For nothing, H or R8With R2Collectively form-R "-O-R "-, wherein, described R " is nothing or C1-C4Alkylidene：
R9For nothing, H or R9For-OH；
DescribedFor double bond or singly-bound；
One or more hydrogen atoms that described " substitution " refers on group are selected from the substituent substitution of the following group：It is carboxyl, unsubstituted Or the C of halo1-C6Alkyl, unsubstituted or halo C3-C6Cycloalkyl, unsubstituted or halo C2-C10Ester group, halogen, C1-C10Alkyl-epoxide, unsubstituted or halo C2-C10Acyl group, hydroxyl, hydroxyl-C1-C10Alkylidene, unsubstituted or halo Phenyl；
And when parent nucleus is I-1 structures, R2、R5And R6In at least one be the group being selected from the group：- OR or substitution do not take The C in generation2-C10Ester group；Or R5And R6It is collectively forming-OC (CH)2- O- structures；
When parent nucleus is I-3 structures, R2、R4And R6In at least one be oxygen atom；
Or described compound of formula I has following structure：
2. compound as claimed in claim 1, it is characterised in that described compound of formula I has with the knot shown in following formula I a Structure：
In formula,
R1It is selected from the group：Substituted or unsubstituted C1-C4Alkyl, C1-C4Haloalkyl；Wherein, described substitution refers to group On one or more hydrogen atoms by C1-C4Ester group substitution；
R2For-OH ,-OR or substituted or unsubstituted C2-C10Ester group；
R7It is selected from the group：C1-C4Alkyl, C1-C4Haloalkyl；
The definition of remaining each group is as described in the appended claim 1.
3. compound as claimed in claim 1, it is characterised in that described compound of formula I has with the knot shown in following formula I b Structure：
In formula,
R1It is selected from the group：Substituted or unsubstituted C1-C4Alkyl, C1-C4Haloalkyl；
R2With R8Collectively form-O-；
R7It is selected from the group：C1-C4Alkyl, C1-C4Haloalkyl；
The definition of remaining each group is as described in the appended claim 1.
4. the compound as described in claim 1-3 is any, it is characterised in that
R2It is selected from the group：O-R ', wherein, described R ' is selected from the group：H, substituted or unsubstituted C2-C10Acyl group or substitution or Unsubstituted C1-C10Alkyl；
R4It is selected from the group：H, halogen, cyano group, carboxyl, hydroxyl, C1-C4Alkoxy, substituted or unsubstituted C2-C10Ester group；
R5It is selected from the group：H, halogen, cyano group, hydroxyl, C1-C4Alkoxy ,-COOR, substituted or unsubstituted C2-C10Ester group, Substitution or unsubstituted C1-C10Alkyl, substituted or unsubstituted C1-C10Haloalkyl ,-NH-R；Wherein, R is selected from the group：H、C1-C4 Acyl group, C1-C4Alkyl, C1-C4Haloalkyl, the C of substitution or unsubstituted (preferably replace)7-C11Aryl-acyl group；
R6It is selected from the group：H, halogen, cyano group, carboxyl, hydroxyl, C1-C4Alkoxy, substituted or unsubstituted C2-C10Ester group, Substitution or unsubstituted C1-C10Alkyl, substituted or unsubstituted C1-C10Haloalkyl, substitution or unsubstituted (preferably replace) C7-C11Aryl-acyl group ,-NH-R；Wherein, R is selected from the group：H、C1-C4Acyl group, C1-C4Alkyl, C1-C4Haloalkyl；
One or more hydrogen atoms that described " substitution " refers on group are selected from the substituent substitution of the following group：Carboxyl, phenyl, C3- C6Cycloalkyl, C1-C10Ester group, halogen, C1-C10Alkyl-epoxide, C2-C10Acyl group, hydroxyl, hydroxyl-C1-C10Alkylidene.
5. compound as claimed in claim 1, it is characterised in that described R2、R4、R5And R6It is each independently and is selected from the group Group：- OR ', and described R ' is selected from the group：
6. compound as claimed in claim 1, it is characterised in that described compound has the structure being selected from the group：
Or described compound be as shown in formula 3B, 4A or 4B, wherein, in Ra, Rb, Rc and Rd definition such as table 1, table 2 and table 3 It is described：
Table 1
Compound number Rc substituents Rd substituents 3-B1 H A1 3-B2 H A2 3-B3 H A8 3-B4 A1 A1 3-B5 A2 A2 3-B6 C1 C1 3-B7 C2 C2 3-B8 D1 D1 3-B9 D3 D3 3-B10 P1 P2
Table 2
Compound number Ra Rb 4-A1 Me H 4-A2 H Me 4-A3 Me Me 4-A4 Et H 4-A5 H Et 4-A6 Et Et 4-A7 H -CH2- CH=CH2 4-A8 -CH2- CH=CH2 -CH2- CH=CH2
Table 3
7. the purposes of compound as claimed in claim 1, it is characterised in that for the one or more purposes being selected from the group：
A) pharmaceutical composition for reducing blood lipid is prepared；
B) prepare for reducing the pharmaceutical composition of low-density lipoprotein (LDL) content；
C) pharmaceutical composition for stablizing LDLR gene stabilities is prepared；
D) pharmaceutical composition for raising LDLR gene expressions is prepared；
E) prepare for increasing the pharmaceutical composition of surface of hepatocytes LDLR acceptor quantities；
F) pharmaceutical composition for reducing LDLR receptor degradations is prepared；
G) prepare for reducing the pharmaceutical composition of TC and/or TG concentration in blood；
H) prepare for increasing the pharmaceutical composition of blood high-density lipoprotein (HDL) concentration；
I) prepare for improving the pharmaceutical composition of liver dysfunction.
8. purposes as claimed in claim 1, it is characterised in that described pharmaceutical composition is additionally operable to the purposes being selected from the group：
J) (external non-therapeutic) increase uptake ratio of the liver cell to LDL；
K) (external non-therapeutic) upregulating hepatocyte cell LDLR gene expression doses.
9. purposes as claimed in claim 1, it is characterised in that described pharmaceutical composition is the formulation being selected from the group：Orally Formulation, injection type.
10. a kind of medicine box, it is characterised in that the medicine box contains：
(i) the first container, and loaded on active component (a) compound of formula I in first container；Or contain active component (a) Medicine；
(ii) second container, and loaded on active component (b) statins in the second container, or its is pharmaceutically acceptable Salt；Or the medicine containing active component (b)；And
(iii) recorded in specification, the specification and active component (a) and active component (b) is given in combination so that reducing makes With the explanation of low-density lipoprotein content in subject.
CN201610089376.3A 2016-02-17 2016-02-17 Podocarpus nagi Inner ester type compounds with hypolipidemic activity, preparation method and the usage Pending CN107089993A (en)

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