CN108610333A - Induce MDM2 self degradation E3 ubiquitin ligase dimer amide micromoleculars PROTACs - Google Patents
Induce MDM2 self degradation E3 ubiquitin ligase dimer amide micromoleculars PROTACs Download PDFInfo
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Abstract
The present invention provides induction MDM2 self degradation E3 ubiquitin ligase dimer amide micromoleculars PROTACs.PROTACs structures of the present invention are as follows：Wherein, in compound (I), L1For the linear or branched alkyl group of the C1 C30 of with or without substituent group, L1In arbitrary carbon atom is optional is replaced by hetero atom；R1、R2、R3、R4It is independently the alkyl of the linear chain or branched chain of the C1 C30 of with or without substituent group, the aryl of the C1 C30 of with or without substituent group, the aryl alkyl of the linear chain or branched chain of the alkylaryl of the linear chain or branched chain of the C1 C30 of with or without substituent group or the C1 C30 of with or without substituent group；X1、X2、X3、X4It is independently halogen.
Description
Technical field
The present invention relates to treatment and prevention of tumour drug fields, in particular to induction MDM2 self degradation E3 ubiquitin ligases
Dimer amide micromolecular PROTACs.
Background technology
Malignant tumour is to seriously threaten one of great disease occurred frequently of human health, and guiding principle is planned in China's scientific and technological development
The basic and applied research of malignant tumour to be classified as to the key scientific problems of public health and important diseases prevention.Therefore,
The research of new type antineoplastic medicine be not only clinical cancer therapy and improve the health of our people it is horizontal force needs, and it is right
It is of great significance in China's medicinal industry and social development.
In many tumor-related gene networks, p53 genes are and the highest tumor suppression of human malignancies correlation
Gene, it all plays an important role in DNA transcriptions, cell growth and proliferation and many metabolic processes, can effectively inhibit group
It knits hyperplasia, promote Apoptosis, have the function of maintaining stable genome, inhibition or prevent cell transformation, to inhibit pernicious
The occurrence and development of tumour.P53 genes are adjusted by the numerous factors in downstream, wherein MDM2 albumen plays the balance and activity of p53
Most important adjustment effect.
MDM2 be with the highest E3 ligases of p53 correlations, fine balance is remain between p53.MDM2 albumen with
Wild type p53 (p53 gene expressions generation) mutual antagonism, on the one hand, the two forms negative-feedback regu- lation access (Negative
Feedback Loop), it is common to adjust the cell cycle；MDM2 also plays the effect of E3 ubiquitin ligases, and p53 is by protease for induction
Body identification is degraded and is directly removed.On the other hand, the MDM2 albumen of high expression can be such that p53 genes inactivate, intracellular low concentration
P53 genes can reduce mdm2 genetic transcriptions again, close p53-MDM2 feedback loops, so that p53 genes is returned to and maintain cell normal
The level of functional status.In human tumor cells, MDM2 albumen can generate overexpression accumulation due to various reasons, thus with
Adjustment effect disequilibrium between p53.
E3 ubiquitin ligases are the key enzymes in Ubiquitin-proteasome systerm, and the ubiquitination of catalytic proteins targets egg
White enzyme body degradation.E3 ligases become more and more important as the target of small molecule, can be not only used for directly inhibiting, and can be by double
The degradation of the new matrix of functional compounds PROTACs targeted induction non-naturals.
However, existing PROTACs still has many shortcomings in bioavilability and stability etc., this is also limited
The use of PROTACs.
In view of this, special propose the present invention.
Invention content
The first object of the present invention is to provide a kind of induction MDM2 self degradations E3 ubiquitin ligase dimer amides
Small molecule PROTACs, to solve the shortcoming present in existing compound.
The second object of the present invention is to provide a kind of induction MDM2 self degradation E3 ubiquitin ligase dimers
The preparation method of amide micromolecular PROTACs.
The third object of the present invention is to provide a kind of induction MDM2 self degradation E3 ubiquitin ligase dimers
The application of amide micromolecular PROTACs.
The fourth object of the present invention is that it includes the induction MDM2 self degradation E3 ubiquitin ligases two to provide a kind of
Aggressiveness amide micromolecular PROTACs drugs or pharmaceutical composition.
In order to realize that the above-mentioned purpose of the present invention, spy use following technical scheme：
A kind of induction MDM2 self degradations E3 ubiquitin ligase dimer amide micromolecular PROTACs, structure are as follows：
Wherein, in compound (I), L1For the linear or branched alkyl group of the C1-C30 of with or without substituent group, L1In appoint
The carbon atom of meaning is optional to be replaced by hetero atom；
L2、L3It is independently the linear chain or branched chain alkylidene of the C1-C12 of with or without substituent group, carries or not
The sub- virtue of C3-C12 heterocycloalkylene groups, heterocycle of C3-C12 cycloalkylidenes or with or without substituent group with substituent group
Base, hetero atom substitution alkyl chain or amino acid residue；
R1、R2、R3、R4It is independently the alkyl of the linear chain or branched chain of the C1-C30 of with or without substituent group, band
Have or the aryl of C1-C30 without substituent group, the alkyl virtue of the linear chain or branched chain of the C1-C30 of with or without substituent group
The aryl alkyl of the linear chain or branched chain of the C1-C30 of base or with or without substituent group；
X1、X2、X3、X4It is independently halogen.
Preferably, in the compounds of this invention (I), L1For the linear chain or branched chain alkane of the C1-C30 of with or without substituent group
Base, L1At least one of carbon atom replaced by oxygen atom；
L2、L3It is independently the C3-C12 heterocycloalkylene groups of with or without substituent group；
R1、R2、R3、R4It is independently the alkyl of the linear chain or branched chain of the C1-C12 of with or without substituent group, band
Have or the aryl of C1-C12 without substituent group, the alkyl virtue of the linear chain or branched chain of the C1-C12 of with or without substituent group
The aryl alkyl of the linear chain or branched chain of the C1-C12 of base or with or without substituent group；
X1、X2、X3、X4It is independently chlorine, bromine or iodine.
Preferably, in the compounds of this invention (I), L1For R5-O-R6, R7-O-R8-O-R9Or R10-O-R11-O-R12-O-
R13；
Wherein, R5-R13It is independently the linear or branched alkyl group of the C1-C6 of with or without substituent group；
L2、L3It is independently substituted or non-substituted piperazine；
R1、R2、R3、R4The alkyl of the linear chain or branched chain of the C1-C12 of with or without substituent group independently；X1、
X2、X3、X4It is independently chlorine or bromine.
Preferably, induction MDM2 self degradations E3 ubiquitin ligase dimer amide micromoleculars of the present invention
PROTACs is：
Meanwhile the present invention also provides small point of the induction MDM2 self degradation E3 ubiquitin ligases dimer amides
The preparation method of sub- PROTACs, includes the following steps：
(a) piperazine -2- ketone replaces after radical protection, is then deprotected, and obtains
(b) 2,4- 4-dihydroxy benzaldehydes replace, and obtain
(c) 4- halogenated benzaldehydes are reacted with ammonium acetate, are then obtained with strong sulfuric acid response
(d) compound (ii) is reacted with compound (iv), products therefrom hydrolyzes after being reacted with compound (i), obtains
(e) compound (vii) and H2N-L4-NH2(viii) it reacts, obtains product；
Wherein, R14For the linear or branched alkyl group of the C1-C6 of with or without substituent group；
R15、R16Be independently the alkyl of the linear chain or branched chain of the C1-C30 of with or without substituent group, carry or
Without the aryl of the C1-C30 of substituent group, the alkylaryl of the linear chain or branched chain of the C1-C30 of with or without substituent group,
Or the aryl alkyl of the linear chain or branched chain of the C1-C30 of with or without substituent group；
X5、X6It is independently halogen；
L4For the linear or branched alkyl group of the C1-C30 of with or without substituent group, L4In arbitrary carbon atom can appoint
Choosing is replaced by hetero atom.
Preferably, in preparation method of the present invention, R14For the straight chain alkane of the C1-C6 of with or without substituent group
Base；
And/or R15、R16It is independently the alkyl of the linear chain or branched chain of the C1-C12 of with or without substituent group,
The aryl of the C1-C12 of with or without substituent group, the alkyl of the linear chain or branched chain of the C1-C12 of with or without substituent group
The aryl alkyl of the linear chain or branched chain of the C1-C12 of aryl or with or without substituent group；
X5、X6It is independently chlorine, bromine or iodine；
And/or L4For the linear or branched alkyl group of the C1-C30 of with or without substituent group, L4At least one of carbon
Atom is replaced by oxygen atom；
Preferably, in preparation method of the present invention, R14For the straight chain alkane of the C1-C3 of with or without substituent group
Base；
And/or R15、R16It is independently the alkyl of the linear chain or branched chain of the C1-C12 of with or without substituent group；
And/or X5、X6It is independently chlorine or bromine；
And/or L4For R17-O-R18, R19-O-R20-O-R21Or R22-O-R23-O-R24-O-R25；
Wherein, R5-R13It is independently the linear or branched alkyl group of the C1-C6 of with or without substituent group.
Preferably, in preparation method of the present invention, step (c) includes the following steps：
4- halogenated benzaldehydes are obtained by the reaction with ammonium acetateProduct with
Strong sulfuric acid response obtains (iv)；
Wherein, X7、X8It is independently halogen.
Further, the present invention also provides the induction MDM2 self degradation E3 ubiquitin ligase dimer amides
Applications of the small molecule PROTACs in preparing tumor therapeutic agent.
Likewise, the present invention also provides induce MDM2 self degradation E3 ubiquitin ligase dimer amides comprising the present invention
The drug or pharmaceutical composition of micromolecular PROTACs.
Compared with prior art, beneficial effects of the present invention are：
(1) HOMO-PROTACs chimeric molecules of the present invention are a kind of novel catalyst mechanisms, can not only block p53-
The combination of MDM2 can also be linked the effect degradation target MDM2 albumen of enzyme using MDM2 itself E3 and play antitumor action；
And traditional p53-MDM2 targeting anti-tumor strategies are to inhibit two-way interaction or are the E3 connection enzymatic activitys for inhibiting MDM2,
A new strategy is provided for the access treating cancer, is expected to make up the defect of traditional p53-MDM2 binding inhibitors, to
Obtain more preferably antitumous effect.
(2) its substoichiometric catalytic activity of divalent degradation molecule makes it that need not completely be accounted for as conventional inhibitor
According to target binding site, i.e., the chimeric molecule that targeting proteins are degraded is reusable and to be less than 1:1 chemical equivalent and target
Protein binding reduces the exposed amount of drug in vivo, thus reduces the generation of potential side effect.
(3) compared with target inhibits, the targeting proteins of induction, which exhaust, can have more lasting cytological effect, restore egg
White level can only be recombined, and MDM2 protein levels such as can be overcome to increase this kind of compensatory cell feedback mechanism,
The possibility that negative feedback path is formed is reduced, to reduce drug resistant risk.
Description of the drawings
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technology description to be briefly described.
Fig. 1 is the binding mode of tradition PROTAC molecules；
Fig. 2 is the binding mode of molecule of the present invention；
Fig. 3 is specific embodiment of the invention compound WesternBolt experimental results.
Specific implementation mode
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the invention.It is not specified in embodiment specific
Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is
The conventional products that can be obtained by commercially available purchase.
In view of existing PROTACs (protein proteolysis-targeting chimeras, proteolysis target
To chimeric molecule) bioavilability caused by molecular weight is larger is poor, and the knot with E3 ubiquitin ligases in vivo
The defects of stability is poor is closed, the present invention provides a new class of PROTACs, to solve lacking present in existing compound
It falls into.
Specifically, provided by the present invention can further target protein and E3 ubiquitin ligases, to induce MDM2 self
The structure of the dimer amide micromolecular PROTACs of degradation is as follows：
Wherein, in general formula structure compound (I) as above,
R1、R2、R3、R4It is independently the alkyl of the linear chain or branched chain of the C1-C30 of with or without substituent group, band
Have or the aryl of C1-C30 without substituent group, the alkyl virtue of the linear chain or branched chain of the C1-C30 of with or without substituent group
The aryl alkyl of the linear chain or branched chain of the C1-C30 of base or with or without substituent group.
Preferably, R1、R2、R3、R4It is independently the linear chain or branched chain of the C1-C12 of with or without substituent group
Alkyl, the aryl of the C1-C12 of with or without substituent group, the linear chain or branched chain of the C1-C12 of with or without substituent group
Alkylaryl or with or without substituent group C1-C12 linear chain or branched chain aryl alkyl, and R1、R2、R3、R4
Between it is optional to be identical or different.
It is furthermore preferred that R1、R2、R3、R4It is independently the linear chain or branched chain of the C1-C12 of with or without substituent group
Alkyl, and R1、R2、R3、R4Between it is optional to be identical or different.
It is further preferred that R1、R2、R3、R4Be independently the C1-C6 of with or without substituent group straight chain or
The alkyl of branch, and R1、R2、R3、R4Between it is optional to be identical or different；
For example, R1、R2、R3、R4Independently can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary fourth
Base, amyl, isopentyl, neopentyl, hexyl etc., and R1、R2、R3、R4Between it is optional to be identical or different；
Still more preferably, R1、R2、R3、R4It is independently the linear chain or branched chain without the C1-C6 of substituent group
Alkyl, and R1、R3It is identical, R2、R3Also identical.
L1For the linear or branched alkyl group of the C1-C30 of with or without substituent group, L1In arbitrary carbon atom it is optional
Replaced by hetero atom；
Wherein, the hetero atom is the combination of one or more of N, O or S.
Preferably, L1For the linear or branched alkyl group of the C1-C30 of with or without substituent group, L1At least one of carbon
Atom is replaced by oxygen atom, i.e. L1Preferably ether or polyether-based.
It is furthermore preferred that L1For R5-O-R6, R7-O-R8-O-R9Or R10-O-R11-O-R12-O-R13In one kind；
Wherein, R5-R13It is independently the linear or branched alkyl group of the C1-C6 of with or without substituent group, and R5、
R6；R7, R8, R9；R10、R11, R12, R13In this three groups of substituent groups, optional each substituent group is identical or different；
Preferably, R5-R13Respectively without the linear or branched alkyl group of the C1-C6 of substituent group, and R5、R6；R7, R8, R9；
R10、R11, R12, R13In this three groups of substituent groups, optional each substituent group is identical or different；
For example, R5-R13Independently can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary butyl, penta
Base, isopentyl, neopentyl or hexyl etc., and R5、R6；R7, R8, R9；R10、R11, R12, R13It is each to replace in this three groups of substituent groups
Optional base is identical or different.
Still more preferably, L1For symmetrical structure, i.e. R5, R6It is identical；R7, R8, R9It is identical；R10、R11, R12, R13It is identical.
L2、L3It is independently the linear chain or branched chain alkylidene of the C1-C12 of with or without substituent group, carries or not
The C3-C12 heterocycloalkylene groups of C3-C12 cycloalkylidenes or with or without substituent group with substituent group；
Preferably, L2、L3It is independently the C3-C12 heterocycloalkylene groups of with or without substituent group；Aromatic heterocycle
Base；Hetero atom replaces alkyl chain；Or amino acid residue；
It is furthermore preferred that L2、L3It is independently substituted or non-substituted piperazine；
Still more preferably, L2、L3Be 2- oxo-niperazin bases, i.e., (Nitrogen-atoms on piperazine
For linking group).X1、X2、X3、X4It is independently halogen；
Preferably, X1、X2、X3、X4It is independently Cl, Br or I, and X1、X2、X3、X4Between it is optional be phase
It is same or different.
It is furthermore preferred that X1、X2、X3、X4It is independently Cl or Br, and X1、X2、X3、X4Between it is optional to be identical
Or it is different.
Still more preferably, X1、X2、X3、X4It is Cl.
Particularly, PROTACs provided by the present invention is
As shown in Figure 1, tradition PROTAC technologies are generally made of three parts：Wait for protein degradation, one is connected to two eggs
The recruitment molecule of Bai Peiti raises E3 enzymes, such as VHL, MDM2, IAP, CRBN (cereblon), β-TrCP.PROTACs can
It is positioned at and waits for protein degradation, E3 enzymes are raised with its design feature, promote the ubiquitination for waiting for protein degradation, are realized in cellular level
On treat protein degradation selectivity eliminate.It has been reported that MDM2 albumen can form dimer in vivo and cause general
Elementization is degraded, and illustrates that the ability that MDM2 has the degradation of itself ubiquitination, and the introducing of PROTAC technologies can greatly improve this
The efficiency of auto-degradation, to the inactivation for realizing MDM2 albumen or directly degradation.
Molecular action pattern of the present invention and tradition PROTAC technologies simultaneously differ, and pattern is as shown in Fig. 2, specifically, one
The p53 binding sites of MDM2 albumen are captured in aspect utilization " bullet molecule "；On the other hand, make two molecule MDM2 eggs using connection chain
It is white close to each other with dimerization (dimerization), it is general to obtain " Suicide " to obtain higher sporadic ubiquitination
The purpose of elementization degradation.
The preparation method of the PROTACs of arbitrary structures as above includes the following steps：
(a) piperazine -2- ketone replaces after radical protection, is then deprotected, and obtains
In this step, protected firstly for the imino group of starting piperazine -2- ketone 4, may be used Cbz, Boc,
The common protective agent such as Fmoc, Alloc, Teoc or Tos, TMB carries out radical protection；
Then, by the product and BrCH after radical protection2COOR14Reaction, replaces 1 amino；
Then, it is deprotected, sloughs protecting group, obtain compound (i)；
In step (a), R14For the linear or branched alkyl group of the C1-C6 of with or without substituent group, such as methyl, second
Base, propyl, isopropyl, butyl, isobutyl group, tertiary butyl, amyl, isopentyl, neopentyl or hexyl etc..
(b) 2,4- 4-dihydroxy benzaldehydes replace, and obtain
Then it is the secondary substitution by 2,4- 4-dihydroxy benzaldehydes, to obtain target product in this step；
Preferably, it is substituted in 4 progress of 2,4- 4-dihydroxy benzaldehydes for the first time, is substituted in 2,4- dihydroxy benzenes for the second time
2 progress of formaldehyde.
In this step, R15、R16It is independently the alkane of the linear chain or branched chain of the C1-C30 of with or without substituent group
Base, the aryl of the C1-C30 of with or without substituent group, the linear chain or branched chain of the C1-C30 of with or without substituent group
The aryl alkyl of the linear chain or branched chain of the C1-C30 of alkylaryl or with or without substituent group；
Preferably, R15, R16It is independently the alkane of the linear chain or branched chain of the C1-C12 of with or without substituent group
Base, the aryl of the C1-C12 of with or without substituent group, the linear chain or branched chain of the C1-C12 of with or without substituent group
The aryl alkyl of the linear chain or branched chain of the C1-C12 of alkylaryl or with or without substituent group, and R15, R16It can appoint
Choosing is identical or different.
It is furthermore preferred that R15, R16It is independently the alkane of the linear chain or branched chain of the C1-C12 of with or without substituent group
Base, and R15, R16Optional is identical or different.
It is further preferred that R1、R2、R3、R4Be independently the C1-C6 of with or without substituent group straight chain or
The alkyl of branch, and R15, R16Optional is identical or different；
For example, R15, R16Independently can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary butyl,
Amyl, isopentyl, neopentyl, hexyl etc..
(c) 4- halogenated benzaldehydes are reacted with ammonium acetate, are then obtained with strong sulfuric acid response
This step includes then two reactions, and first is：4- halogenated benzaldehydes and ammonium acetate are anti-under reflux condition
It answers, obtains
Then, exist in the concentrated sulfuric acid (preferably 70% concentrated sulfuric acid), and under heated reflux condition, compound (iii)
By compound (iv) is obtained by the reaction.
In this step, X5、X6、X7、X8It is independently halogen；
Preferably, X5、X6、X7、X8It is independently Cl, Br or iodine, and X5、X6、X7、X8Between it is optional be phase
It is same or different；
It is furthermore preferred that X5、X6It is identical.
(d) compound (ii) is reacted with compound (iv), products therefrom hydrolyzes after being reacted with compound (i), obtains
In this step, it is that compound (ii) is reacted with compound (iv) first, obtains
Then, compound (v) is reacted with compound (i), obtains compound
Compound (vi) hydrolyzes, and obtains corresponding Carboxylation
Close object (vii)；
(e) compound (vii) and H2N-L4-NH2(viii) it reacts, obtains product；
In this step, L4For the linear or branched alkyl group of the C1-C30 of with or without substituent group, L4In arbitrary carbon it is former
Sub optional is replaced by hetero atom；
Wherein, the hetero atom is the combination of one or more of N, O or S.
Preferably, L4For the linear or branched alkyl group of the C1-C30 of with or without substituent group, L4At least one of carbon
Atom is replaced by oxygen atom, i.e. L1Preferably ether or polyether-based.
It is furthermore preferred that L4For R17-O-R18, R19-O-R20-O-R21Or R22-O-R23-O-R24-O-R25In one kind；
Wherein, R17-R25The respectively linear or branched alkyl group of the C1-C6 of with or without substituent group, and R17、R18；
R19、R20、R21；R22、R23、R24、R25It is identical or different that each substituent group is optional in this three groups of substituent groups, in each group；
Preferably, R17-R25Respectively without the linear or branched alkyl group of the C1-C6 of substituent group, and R17、R18；R19、
R20、R21；R22、R23、R24、R25It is identical or different that each substituent group is optional in this three groups of substituent groups, in each group；
For example, R17-R25Independently can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary butyl,
Amyl, isopentyl, neopentyl or hexyl etc., and R17、R18；R19、R20、R21；R22、R23、R24、R25In this three groups of substituent groups,
It is identical or different that each substituent group is optional in each group.
Still more preferably, L4For symmetrical structure, i.e. R17, R18It is identical；R19, R20, R21It is identical；R22、R23, R24, R25Phase
Together.
It, can be to meet a kind of compound (vii) and H of above-mentioned general formula structure in this step2N-L4-NH2(viii) anti-
It answers, to obtain the product with symmetrical structure；
Alternatively, in this step, it can also be to meet two kinds of compounds (vii) and the H of above-mentioned general formula structure2N-L4-NH2
(viii) it reacts, to obtain the multi-products with symmetry and asymmetry structure, and by separate modes such as column chromatographies, obtains phase
The sterling answered.
And by the PROTACs prepared by the above method, due to the spy with can further target protein and E3 ubiquitin ligases
Property, thus MDM2 self degradations can be induced by the effect of E3 ubiquitin ligases, restore p53-MDM2 balances to play, into
And realize the purpose effect of oncotherapy.
At the same time it can also mix prepared PROTACs with auxiliary material, to prepare the drug of corresponding dosage form, it to be used for cancer
Treatment；
Further, said medicine and other cancer treatment drugs or sensitizer can also be used in conjunction with, to rise
To the effect of multiple therapeutic.
Embodiment 1
By taking product is the preparation of the 15a and 15b of symmetrical structure as an example, PROTACs preparation methods of the present invention are described below：
The synthesis of 3- oxypiperazin -1- t-butyl formates (1)
Piperazine -2- ketone (1.0g, 10mmol) is suspended in 10mL DCM, Boc is slowly added to2O.After the completion of addition, instead
It should be in ambient temperature overnight.After reaction, it is washed three times with 0.1N dilute hydrochloric acid, each 20ml, saturated potassium carbonate washing is used in combination three times,
Each 20ml.It is eventually adding anhydrous sodium sulfate, solution is removed under vacuum, obtains white solid.
Product fusing point：161-162 DEG C,1H NMR(400MHz,CDCl3)δ7.66(s,1H),4.07(s,2H),3.62(t,J
=5.3Hz, 2H), 3.37 (s, 2H), 1.47 (s, 9H).
The synthesis of 4- (2- methoxyl group -2- oxoethyls) -3- oxypiperazin -1- t-butyl formates (2)
In 500mL three-neck flasks, 12.70g (63.0mmol, 1.0 equivalents) compound 1 is dissolved in 280mL dimethyl
In formamide, and 0 DEG C is cooled in ice bath；1.73g (73.0mmol, 1.15 equivalents) sodium hydride is added, stirs under ice-cooling
It mixes 1 hour, 6.60mL (69.0mmol, 1.10 equivalents) methyl bromoacetate is then added by syringe.Under ice-cooling into one
Reaction solution after twenty minutes, is warming up to room temperature by step stirring.After 18 hours, 10mL methanol is added into reaction solution, 10mL is gone
Ionized water and 180mL saturated nacl aqueous solutions.Water phase is primary with 250mL extractions, three times with the extraction of 140mL ether, it will merge
Organic phase dried with magnesium sulfate, and solvent is evaporated under reduced pressure.Then it is removed under reduced pressure under 55 DEG C of water temperature in 2 hours
Remaining dimethylformamide.13.4g orange liquids are obtained, with petrol ether/ethyl acetate 4:1 → petrol ether/ethyl acetate 2:1
As eluant, eluent by purification by flash chromatography, white solid, yield are obtained：14.16g (82%, 52.0mmol), white solid melt
56-57 DEG C of point.
The synthesis of 2- (2- oxypiperazin -1- bases) methyl acetate (3)
Trifluoroacetic acid (5.0mL) is added to the tertiary fourth of 4- (2- methoxyl group -2- oxoethyls) -3- oxypiperazin -1- formic acid
In ester (0.45g, 1.8mmol), the mixture was stirred overnight and concentrates, and obtains pale solid shape 2- (2- oxypiperazins -1-
Base) methyl acetate trifluoroacetate (0.30g, 91%).
The synthesis of 2- hydroxyls -4-methoxybenzaldehyde (8)
By dimethyl suflfate (2.73mL, 30mmol) be slowly added dropwise (15min) enter 2,4- 4-dihydroxy benzaldehydes (1-1,
4.14g, 30mmol) and acetone (50mL) reaction solution of Anhydrous potassium carbonate (4.14g, 30mmol) in, be stirred at reflux 5h, raw material
The reaction was complete.Reaction solution is cooled to room temperature, solid is filtered off, solvent is recovered under reduced pressure, obtains rufous liquid, ethyl acetate is added
(100mL) makes it dissolve, and is washed respectively with water (3 × 30mL), saturated nacl aqueous solution (3 × 30mL), takes ethyl acetate layer, nothing
Aqueous sodium persulfate is dried, and crude product is recovered under reduced pressure to obtain.Solvent (petrol ether/ethyl acetate=12：1) silica gel column chromatography is carried out, is obtained white
Color solid, yield：55%, fusing point：40.4~42.1 DEG C.
The synthesis of 2- isopropoxies -4-methoxybenzaldehyde (9)
To methoxysalicyl aldehyde (0.76g, 5mmol), isopropyl bromide (0.94g, 10mmol), Anhydrous potassium carbonate (2.07g,
15mmol), DMF (20mL) is put into reaction bulb successively, and lower 40 DEG C of nitrogen protection is reacted 5 hours.Raw material is after the reaction was complete, instead
It answers liquid to be cooled to room temperature, water quenching is added and goes out (50mL), ethyl acetate (3 × 30mL) is used in combination to extract.Ethyl acetate layer is taken, chlorine is saturated
Change sodium solution washing, solvent afforded crude material, solvent (petrol ether/ethyl acetate=3 are recovered under reduced pressure in anhydrous sodium sulfate drying：1) into
Row column chromatography obtains light yellow liquid, yield：92%；GC/MS-ESI:M/z=194 [M]+。
(E) conjunction of the chloro- N- of -4- (bis- (4- chlorphenyls) ethyls of 2- (4- chlorine benzylideneamino) -1,2-) benzamide (10)
At
By 4-chloro-benzaldehyde (0.29g, 2.1mmol), ammonium acetate (0.14g, 7.8mmol) puts into reaction bulb, heats back
Stream 3 hours obtains white solid after cooling, is washed with 95% ethyl alcohol to looking for, then after washed once with absolute ethyl alcohol, vacuum
It is dried to obtain compound 10,254.8~258.3 DEG C of fusing point.
The synthesis of bis- (4- chlorphenyls) ethane -1, the 2- diamines (11) of (1R, 2S) -1,2-
By compound 10 (0.35g, 1.2mmol), 70% concentrated sulfuric acid (3mL) puts into reaction bulb, is heated to reflux 1 hour,
While hot, it pours into trash ice, collects water layer after ether extraction, be adjusted to neutrality with the sodium hydroxide being almost saturated, be precipitated immediately yellowish
Color precipitates, and is extracted with ether-water, takes organic layer, dry, and solid is finally recrystallized in ether, obtained white solid by recycling design
Body, yield：47%；143.1~146.8 DEG C of fusing point；1H NMR(400MHz,CDCl3):7.30(m,Ar-H,8H),4.00(s,
CH,2H),1.38(s,NH2×2,4H)；MS:M/z=280 [M]+。
Bis- (4- the chlorphenyls) -2- of (4R, 5S) -4,5- (2- isopropoxy -4- methoxyphenyls) -4,5- dihydro -1H- imidazoles
(12) synthesis
By 1,2- along (4- chlorphenyls) ethane -1,2- diamines (300mg, 1.1mmol), 2- isopropoxies -4- methoxyl groups-benzene
Formaldehyde (190mg, 9.8mmol), dichloromethane (5mL) are put into reaction bulb, and after the lower stirring 30min of ice bath cooling, NBS is added
(290mg, 16.3mmol), nitrogen protection are stirred overnight at room temperature, and filter, obtain white solid, are the hydrogen bromide salt of target product.
Institute is basified to pH=8 at salt addition 10%NaOH, and mixture extracts (3 × 20mL) with dichloromethane, takes
Dichloromethane layer, with saturated sodium-chloride brine It (2 × 20mL), solvent is recovered under reduced pressure, with expansion in anhydrous sodium sulfate drying
Agent (petrol ether/ethyl acetate/triethylamine=3：1：1%) column chromatography is carried out, white solid 12, nitrogen protection, low temperature cold are obtained
It hides.
Yield：81%；1H NMR (400MHz, DMSO) δ 7.92 (d, J=8.8Hz, 1H), 7.25 (d, J=8.5Hz,
4H), 7.09 (d, J=8.5Hz, 4H), 6.86 (d, J=2.1Hz, 1H), 6.81 (dd, J=8.8,2.2Hz, 1H), 5.86 (s,
2H), 4.95 (dt, J=12.1,6.0Hz, 1H), 3.91 (s, 3H), 1.39 (d, J=6.0Hz, 6H)
2- (4- ((4R, 5S) -4,5- bis- (4- chlorphenyls) -2- (2- isopropoxy -4- methoxyphenyls) -4,5- dihydros -
- 1 carbonyl of 1H- imidazoles) -2- oxypiperazin -1- bases) methyl acetate (13) synthesis
Compound 12 (60mg, 0.132mmol), triethylamine (0.13mL) is dissolved in anhydrous methylene chloride (10mL), in stirring
Anhydrous methylene chloride (10mL) solution of triphosgene (65.0mg, 0.34mmol) is added dropwise after reacting 30min under ice bath to subtract
Solvent distillation is pressed, intermediate is obtained.The intermediate is redissolved in anhydrous methylene chloride solution (10mL), and instills 2- (2- oxygen
For piperazine -1- bases) dichloromethane solution (5mL) of methyl acetate (245.8mg, 2.56mmol), react at room temperature 15min, recycling
Solvent is extracted with water-ethyl acetate, takes ethyl acetate layer, saturated nacl aqueous solution to wash (2 × 20mL), anhydrous sodium sulfate is dry
It is dry, solvent is recovered under reduced pressure, carries out column chromatography, gradient elution (petrol ether/ethyl acetate/methanol=3:1:0.-1:1:0.1) it obtains in vain
Color solid 13.
Yield：81%；1H NMR(400MHz,CDCl3) δ 7.61 (d, J=8.5Hz, 1H), 7.09 (d, J=8.4Hz,
2H), 7.04 (d, J=8.5Hz, 2H), 6.95 (d, J=8.4Hz, 2H), 6.88 (d, J=8.3Hz, 2H), 6.56 (dd, J=
8.5,2.1Hz, 1H), 6.49 (d, J=2.1Hz, 1H), 5.55 (dd, J=32.3,9.7Hz, 2H), 4.63 (dd, J=12.0,
6.0Hz, 1H), 3.92 (s, 2H), 3.87 (s, 3H), 3.71 (s, 3H), 1.39 (d, J=6.0Hz, 3H), 1.35 (d, J=
6.0Hz, 3H) .MS (ESI), m/z=654 [M+H]+。
2- (4- ((4R, 5S) -4,5- bis- (4- chlorphenyls) -2- (2- isopropoxy -4- methoxyphenyls) -4,5- dihydros -
- 1 carbonyl of 1H- imidazoles) -2- oxypiperazin -1- bases) acetic acid (14) synthesis
To the THF/MeOH/H of compound 13 (160mg, 245 μm of ol)2O=4:1:In 1 (5mL) solution, hydroxide is added
Acquired solution is simultaneously stirred overnight by lithium monohydrate (49.5mg, 1.179mmol).It by evaporation of the solvent, is diluted with water, with 10%
HCl is adjusted to pH=5, is extracted with DCM, uses Na2SO4It is dry, it filters and is evaporated to dryness under a high vacuum.Residue is loaded into
Quick column (SiO2, DCM to DCM/MeOH=100:5 to 100:10 to 100:15 to 100:20) on, compound 14 is obtained
(136mg) is white solid.
1H NMR(400MHz,CDCl3) δ 7.59 (d, J=8.5Hz, 1H), 7.05 (dd, J=18.1,8.4Hz, 4H),
6.89 (dd, J=25.5,8.1Hz, 4H), 6.61-6.52 (m, 1H), 6.46 (s, 1H), 5.58 (dt, J=23.5,11.6Hz,
2H), 4.60 (dt, J=12.3,6.2Hz, 1H), 3.84 (s, 3H), 3.42 (d, J=13.2Hz, 3H), 3.30 (s, 2H), 3.00
(s, 2H), 1.35 (dd, J=15.4,6.0Hz, 6H) .MS (ESI), m/z=639 [M+H]+
2- (4- ((4R, 5S) -4,5- bis- (4- chlorphenyls) -2- (2- isopropoxy -4- methoxyphenyls) -4,5- dihydros -
1H- imidazoles -1- carbonyls) -2- oxypiperazin -1- bases)-N- (1- (4- ((4S, 5R) -4,5- bis- (4- chlorphenyls) -2- (2- isopropyls
Oxygroup -4- methoxyphenyls) -4,5-- dihydro -1H- imidazoles -1- carbonyls) -2- oxypiperazin -1- bases) -2- oxos -7,10,13-
Trioxa -3-azahexadecan-16- bases) acetamide (product 15a) synthesis
Compound 14 (127mg, 0.20mM), DCC (82mg, 0.40mM) and HOBt (30.4mg, 0.20mM) are dissolved in nothing
4,7,10- tri- oxygen -1,13- tridecane diamines are slowly added dropwise after ice bath stirring 30min under nitrogen protection in water dichloromethane (10mL)
The dichloromethane solution of (21.8mg, 0.10mM), is stirred at room temperature 3h.After reaction, it filters and removes solid, filtrate saturation chlorine
Change sodium washing (3 × 20mL), anhydrous sodium sulfate drying is recovered under reduced pressure solvent, carries out column chromatography, gradient elution (ethyl acetate/first
Alcohol=9:1~4:1) white solid 15a, is obtained, structure is as follows：
1H NMR(400MHz,CDCl3)1H NMR(400MHz,CDCl3)δ7.83(s,1H),7.62(s,1H),7.15–
7.00 (m, 8H), 6.91 (d, J=21.1Hz, 8H), 6.45 (dd, J=33.4,14.6Hz, 4H), 6.11 (dd, J=17.3,
10.6Hz, 2H), 5.86 (d, J=10.3Hz, 2H), 5.54 (s, 4H), 4.62 (s, 2H), 4.16 (d, J=11.9Hz, 2H),
3.95 (s, 2H), 3.87 (d, J=15.9Hz, 6H), 3.62-3.48 (m, 16H), 3.28 (s, 6H), 3.13 (s, 4H), 1.72
(d, J=6.2Hz, 6H), 1.41-1.32 (m, 12H) .MS (ESI), m/z=1448 [M+H]+。
2- (4- { [(4R, 5S) -4,5- bis- (4- chlorphenyls) -2- (2- isopropoxy -4- methoxyphenyls) -4,5- dihydros -
1H- imidazoles -1- bases] carbonyl } -2- oxypiperazin -1- bases)-N- { 2- [2- (2- { [(4- { [(the 4- chlorobenzenes of (4S, 5R) -4,5- bis-
Base) -2- (2- isopropoxy -4- methoxyphenyls) -4,5- dihydro -1H- imidazoles -1- bases] carbonyl } -2- oxypiperazin -1- bases)
Acetyl group] amino ethyoxyl) ethyoxyl] ethyl acetamide (product 15b) synthesis
Compound 14 (120mg, 0.19mM), DCC (78mg, 0.38mM) and HOBt (29mg, 0.19mM) are dissolved in anhydrous
It is bis- (ethamine) after ice bath stirring 30min 2,2 '-(ethylene dioxies) to be slowly added dropwise under nitrogen protection in dichloromethane (10mL)
The dichloromethane solution of (13.5mg, 0.10mM), is stirred at room temperature 3h.After reaction, it filters and removes solid, filtrate saturation chlorine
Change sodium washing (3 × 20mL), anhydrous sodium sulfate drying is recovered under reduced pressure solvent, carries out column chromatography, gradient elution (ethyl acetate/first
Alcohol=9:1~4:1) white solid 15b, is obtained, structure is as follows：
1H NMR(400MHz,CDCl3) δ 7.62 (s, 2H), 7.00 (ddd, J=39.0,17.1,7.1Hz, 16H), 6.46
(ddd, J=20.5,18.5,4.6Hz, 4H), 5.54 (s, 4H), 4.71-4.51 (m, 2H), 3.88 (dd, J=24.8,
21.1Hz, 9H), 3.55 (dd, J=14.6,6.6Hz, 9H), 3.40 (s, 4H), 3.30-2.99 (m, 8H), 1.46-1.19 (m,
18H) .MS (ESI), m/z=1376 [M+H]+。
Reaction process is as follows：
Experimental example 1
In order to test the compounds of this invention effect, inventor's effect to compound 15a and 15b in A549 cells respectively
Carry out experiment test.
Specific experimental method is as follows：Respectively A549 cells are handled with 5 μM or 20 μM of compounds 15a and 15b 12 hours；Together
When, the sample for being not added with compound is prepared as negative control.
After processing, by cell cracking and immunoblotting assay is carried out to monitor the horizontal variation of endogenous MDM2 and p53.
WesternBolt experimental results are as shown in figure 3, by Fig. 3 experimental results it is found that compound 15a and 15b is thin in A549
After being intervened with 5 μM of concentration 12h in born of the same parents, p53 albumen starts to raise, and MDM2 starts to weaken, and dry to a concentration of 20 μM of concentration 12h
Prognosis, p53 albumen raise obviously, and MDM2 albumen obviously weakens.
Meanwhile compared with negative control, A549 cells, which are exposed to any one of two kinds of compounds, causes MDM2 horizontal
It reduces.Increasing the concentration of two kinds of compounds causes MDM2 levels to reduce increase.This observation indicate that, 15a and 15b may
Induce the degradation of MDM2 in living cells.Importantly, it was noted that horizontal raising and the MDM2 levels drop of endogenous p53
Result low, that p53 stablizes when this may be MDM2 degradations.These results and our design and it is expected consistent, it was demonstrated that pass through
Cause MDM2 degradations with HOMO-PROTAC to target the feasibility of p53-MDM2 approach.
Although illustrate and describing the present invention with specific embodiment, it will be appreciated that without departing substantially from the present invention's
Many other change and modification can be made in the case of spirit and scope.It is, therefore, intended that in the following claims
Including belonging to all such changes and modifications in the scope of the invention.
Claims (10)
1. a kind of induction MDM2 self degradations E3 ubiquitin ligase dimer amide micromoleculars PROTACs, which is characterized in that knot
Structure is as follows：
Wherein, in compound (I), L1For the linear or branched alkyl group of the C1-C30 of with or without substituent group, L1In it is arbitrary
Carbon atom is optional to be replaced by hetero atom；
L2、L3It is independently the linear chain or branched chain alkylidene of the C1-C12 of with or without substituent group, with or without
It is the C3-C12 cycloalkylidenes of substituent group or the C3-C12 heterocycloalkylene groups of with or without substituent group, heteroarylene, miscellaneous
Atom replaces alkyl chain or amino acid residue；
R1、R2、R3、R4Be independently the alkyl of the linear chain or branched chain of the C1-C30 of with or without substituent group, carry or
Without the aryl of the C1-C30 of substituent group, the alkylaryl of the linear chain or branched chain of the C1-C30 of with or without substituent group,
Or the aryl alkyl of the linear chain or branched chain of the C1-C30 of with or without substituent group；
X1、X2、X3、X4It is independently halogen.
2. induction MDM2 self degradations E3 ubiquitin ligase dimer amide micromoleculars according to claim 1
PROTACs, which is characterized in that in compound (I), L1For the linear chain or branched chain alkane of the C1-C30 of with or without substituent group
Base, L1At least one of carbon atom replaced by oxygen atom；
L2、L3It is independently the C3-C12 heterocycloalkylene groups of with or without substituent group；
R1、R2、R3、R4Be independently the alkyl of the linear chain or branched chain of the C1-C12 of with or without substituent group, carry or
Without the aryl of the C1-C12 of substituent group, the alkylaryl of the linear chain or branched chain of the C1-C12 of with or without substituent group,
Or the aryl alkyl of the linear chain or branched chain of the C1-C12 of with or without substituent group；
X1、X2、X3、X4It is independently chlorine, bromine or iodine.
3. induction MDM2 self degradations E3 ubiquitin ligase dimer amide micromoleculars according to claim 2
PROTACs, which is characterized in that in compound (I), L1For R5-O-R6, R7-O-R8-O-R9Or R10-O-R11-O-R12-O-R13；
Wherein, R5-R13It is independently the linear or branched alkyl group of the C1-C6 of with or without substituent group；
L2、L3It is independently substituted or non-substituted piperazine；
R1、R2、R3、R4It is independently the alkyl of the linear chain or branched chain of the C1-C12 of with or without substituent group；
X1、X2、X3、X4It is independently chlorine or bromine.
4. induction MDM2 self degradations E3 ubiquitin ligase dimer amide micromoleculars according to claim 2
PROTACs, which is characterized in that compound (I) is：
5. the induction MDM2 self degradation E3 ubiquitin ligase dimer amide micromoleculars described in any one of claim 1-4
The preparation method of PROTACs, which is characterized in that the preparation method includes the following steps：
(a) piperazine -2- ketone replaces after radical protection, is then deprotected, and obtains
(b) 2,4- 4-dihydroxy benzaldehydes replace, and obtain
(c) 4- halogenated benzaldehydes are reacted with ammonium acetate, are then obtained with strong sulfuric acid response
(d) compound (ii) is reacted with compound (iv), products therefrom hydrolyzes after being reacted with compound (i), obtains
(e) compound (vii) and H2N-L4-NH2(viii) it reacts, obtains product；
Wherein, R14For the linear or branched alkyl group of the C1-C6 of with or without substituent group；
R15、R16It is independently the alkyl of the linear chain or branched chain of the C1-C30 of with or without substituent group, with or without
The aryl of the C1-C30 of substituted base, the alkylaryl of the linear chain or branched chain of the C1-C30 of with or without substituent group, or
The aryl alkyl of the linear chain or branched chain of the C1-C30 of with or without substituent group；
X5、X6It is independently halogen；
L4For the linear or branched alkyl group of the C1-C30 of with or without substituent group, L4In optional miscellaneous of arbitrary carbon atom
Atom is replaced.
6. preparation method according to claim 5, which is characterized in that R14For the C1-C6 of with or without substituent group
Straight chained alkyl；
And/or R15、R16It is independently the alkyl of the linear chain or branched chain of the C1-C12 of with or without substituent group, carries
Or the aryl of the C1-C12 without substituent group, the alkyl virtue of the linear chain or branched chain of the C1-C12 of with or without substituent group
The aryl alkyl of the linear chain or branched chain of the C1-C12 of base or with or without substituent group；
And/or X5、X6It is independently chlorine, bromine or iodine；
And/or L4For the linear or branched alkyl group of the C1-C30 of with or without substituent group, L4At least one of carbon atom
Replaced by oxygen atom.
7. preparation method according to claim 6, which is characterized in that R14For the C1-C3 of with or without substituent group
Straight chained alkyl；
And/or R15、R16It is independently the alkyl of the linear chain or branched chain of the C1-C12 of with or without substituent group；
And/or X5、X6It is independently chlorine or bromine；
And/or L4For R17-O-R18, R19-O-R20-O-R21Or R22-O-R23-O-R24-O-R25；
Wherein, R5-R13It is respectively provided with or the linear or branched alkyl group of C1-C6 without substituent group.
8. preparation method according to claim 5, which is characterized in that step (c) includes the following steps：
4- halogenated benzaldehydes are obtained by the reaction with ammonium acetateProduct and dense sulphur
Acid is obtained by the reaction (iv)；
Wherein, X7、X8It is independently halogen.
9. the induction MDM2 self degradation E3 ubiquitin ligase dimer amide micromoleculars described in any one of claim 1-4
Applications of the PROTACs in preparing tumor therapeutic agent.
10. including the induction MDM2 self degradation E3 ubiquitin ligase dimer amides described in any one of claim 1-4
The drug or pharmaceutical composition of small molecule PROTACs.
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| CN103347874A (en) * | 2010-12-13 | 2013-10-09 | 诺瓦提斯公司 | Dimeric iap inhibitors |
| WO2017185036A1 (en) * | 2016-04-22 | 2017-10-26 | Dana Farber Cancer Institute, Inc. | Bifunctional molecules for degradation of egfr and methods of use |
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| CN103347874A (en) * | 2010-12-13 | 2013-10-09 | 诺瓦提斯公司 | Dimeric iap inhibitors |
| WO2017185036A1 (en) * | 2016-04-22 | 2017-10-26 | Dana Farber Cancer Institute, Inc. | Bifunctional molecules for degradation of egfr and methods of use |
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| CN110563706A (en) * | 2019-08-29 | 2019-12-13 | 中国人民解放军第二军医大学 | MDM2 protein degradation targeting chimera and preparation method and application thereof |
| CN110563706B (en) * | 2019-08-29 | 2021-11-09 | 中国人民解放军第二军医大学 | MDM2 protein degradation targeting chimera and preparation method and application thereof |
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