CN109134512A

CN109134512A - Laragzole analog, preparation method and the purposes for preparing antitumor agent of C-18 fluoro

Info

Publication number: CN109134512A
Application number: CN201710459174.8A
Authority: CN
Inventors: 雷新胜; 张冰冰; 李英霞
Original assignee: Fudan University
Current assignee: Fudan University
Priority date: 2017-06-16
Filing date: 2017-06-16
Publication date: 2019-01-04
Anticipated expiration: 2037-06-16
Also published as: CN109134512B

Abstract

The invention belongs to pharmaceutical fields, it is related to fluoro analogs, preparation method and the pharmaceutical applications of marine natural products cyclic ester peptide. (i.e. marine natural products Largazole) shown in formula (I), inhibitory activity test through external HDACs, as the result is shown, compound of the present invention has the function of strong, selective inhibition HDACs, further, drug containing the compound of the present invention or combinations thereof object can prepare anti-tumor therapeutic agent.

Description

The Laragzole analogs of C-18 fluoro, preparation method and prepare antitumor agent Purposes

Technical field

The invention belongs to pharmaceutical fields, are related to a kind of new marine natural products cyclic ester peptide. (i.e. marine natural products Largazole fluoro analogs), preparation method and the drug that contains the compound or combinations thereof object are as antineoplaston The purposes of agent.

Background technique

According to data, cancer has become the great disease of the another harm human health after cardiovascular and cerebrovascular disease Disease, since the 1970s, China's pathogenesis of cancer and death toll once ascendant trend always, it is contemplated that arrive the year two thousand twenty tumour year Number of the infected more will be up to 3,000,000 person-times, and year death toll can also reach 2,500,000 person-times, the cancer in China town dweller Cause of the death first place is accounted for, therefore, research and the efficient tumor therapeutic agent of discovery low toxicity have important clinic and commercial value.

Current anti-tumor drug developed in the world is numerous, and clinically used antitumor have more than 80 kinds.With people couple Tumor research deepens continuously, and makes it was recognized that the cytotoxic chemotherapeutics of traditional tool, in killing tumor cell It is deepened continuously to tumor research with people, is made it was recognized that the cytotoxic chemotherapeutics of traditional tool simultaneously, It, also can the bands such as normal tissues certain to human body, organ and cell such as marrow, alimentary canal, liver, kidney while killing tumor cell Carry out bigger injury, these all greatly constrain the clinical application of these classic chemotherapy drugs.New type antineoplastic medicine at present Exploitation is turning to the specificity antineoplastic for being directed to abnormal signal system target spot in cancer cell from conventional cell cytotoxic drug Drug, i.e. molecular targeted therapy medicine.With the continuous understanding to tumor signal network, some molecular targeted medicines have been developed Object, and clinical application is entered, achieve important achievement.Wherein, histon deacetylase (HDAC) (Histone deacetylase, HDACs) regulate and control a kind of albumen played a significant role to growth of tumour cell.Acetylation of histone transferase (histone Acetylases, HATs) and the responsible regulation core group of histon deacetylase (HDAC) (histone deacetylases, HDACs) To guarantee the normal function of human body cell canceration will not occur for the dynamic equilibrium of histone acetylation and deacetylation.But Research confirms that overexpression is presented in HDACs in most tumour cell, and causes histone that low Acetylation status, group is presented The occurrence and development of the unbalance and tumour of histone acetylation state have this substantial connection, and it was found that HDACs inhibitor mainly leads to Arresting cell cycle is crossed, induces cell apoptosis, angiogenesis inhibiting, induction autophagy, play the effects of synergistic effect mechanism, It can achieve the purpose for the treatment of cancer.

Up to the present oneself it is found that HDACs inhibitor be mainly the following type: 1. short chain fatty acids by structure Class, including butyric acid, benzenebutanoic acid and isovaleric acid and its esters；2. hydroximic acid, including trichostatin A (TSA) and Fu Linuo His (SAHA) and its derivative CBHA and MM232 etc.；3. the cyclic tetrapeptide class formation of epoxy ketone group, including FR90I228 are free of, Apicidin and cyclic tetrapeptide class formation, including trapoxin B comprising epoxy ketone group etc.；4. amides, including MS-275, CI- 994 and cso55 etc. (is shown below).

Research finds that HDACs in mammalian cells shares the hypotype of 18 HDAC, according to saccharomycete HDAC sequence Homology, be divided into 4 major class: ILei HDAC family includes HDAC1, HDAC2, HDAC3 and HDAC8, with saccharomycete Rpd3 albumen is similar；Class ii HDAC family includes HDAC4, HDAC5, HDAC6, HDAC7, HDAC9 and HDAC10, with yeast Bacterium Hda1 albumen is similar；The transcription inhibitory factor Sir2 Sequences similar of group iii HDAC family and saccharomycete；Section IV class only has HDAC11 is a kind of.Wherein the HDAC family of I, II and IV class is Zn2+ dependent form target, and Group III HDAC is conservative Buddhist nun gram acyl Amine adenine dinucleotide (NAD+) dependent form target.

Practice display, current HDACs inhibitor is not mostly good enough for the selectivity of HDACs hypotype, has exposed more Potential adverse effect, as Fu Linuota (SAHA) to HDAC1~HDAC9 show activity it is substantially suitable, cause such as red blood cell Reduction, decrease of platelet and electrocardiographic abnormality etc., this all greatly constrains their clinical efficacy.And with to HDAC and swollen Tumor occurs, discussions that deepen continuously of developmental research, especially being constantly revealed to each hypotype structure and function of HDACs, singly A hypotype either belongs to of a sort multiple subtype-selective histon deacetylase (HDAC) inhibitors and is playing curative effect and reduction Advantage is had more in side effect.

Mainly have in the HDACs inhibitor medicaments of clinical application at present: Fu Linuota (vorinostat, SAHA), it There is higher inhibitory activity to HDAC1, HDAC2, HDAC3, HDAC4, HDAC6, HDAC7, HDAC9 and HDAC10, the chemical combination Object was approved by the fda in the United States for treatment T-cell lymphoma,cutaneous, and similar hydroximic acid HDACs inhibitor in 2006 Belinostat was also approved by the FDA in the United States clinical application in 2014；Romidepsin (romidepsin, FK-228) belongs to The selective hdac inhibitor of I type has preferable selective inhibitory to HDAC I type, it is for HDAC 2 and HDAC 1 inhibitory activity will compare being eager to excel for HDAC4 and HDAC6 inhibitory activity, and the disulfide bond in structure is reduced into mercapto in vivo It plays after base in the combination of metal ion, the CTTL patient of clinical treatment was approved by the fda in the United States in 2010；West It is that amides HDACs inhibitor is listed in January, 2015 in China's approval, for treating lymphoma peripheral T cell up to aniline (PTCL)。

Marine natural products Largazole is the natural materials research institute Hendrink by Florida State University Luesch et al. isolated for the first time from marine cyanobacterium Symploca spp. one has sixteen-ring peptide lactones structure day Right product, and confirm that it is a kind of potent histon deacetylase (HDAC) inhibitor, the especially histone deacetylase to I type Changing enzyme has fabulous selective inhibitory, can effectively inhibit the proliferation of tumour cell, preclinical research shows that closing The Largazole of suitable dosage selectively can kill tumour cell and not have an impact to normal cell (J.Am.Chem.Soc.2008,130,13506).It with 16 yuan of macrocyclic structures romidepsin (romidepsin, FK- 228) similar, it hydrolyzes its thioesters side chain and can generate one and play the similar activation of pharmaceutical activity structure in vivo with FK228 Mercaptan structure, the activated thiol can coordinate to catalysis Zn2+ histon deacetylase (HDAC) in (Org.Lett.2010,12, 1368)。

Largazole is because of its unique structure, good pharmacological activity and special targeting, and one is it is found that report Road has just started the upsurge to its structural modification carried out, up to the present has and largely lives about its synthesis transformation and metabolism Property relevant report (Nat.Prod.Rep.2012,29,449), meanwhile, Largazole free mercaptan and HDAC8 compound X- diffraction crystal structure also discloses report (J.Am.Chem.Soc.2011,133,12474).But about Largazole fluoro class Do not go deep into like the research of object, a large amount of new drug development can often increase it the study found that introducing F element in bioactive molecule Active and internal metabolic stability, reason are: the size of 1. fluorine atoms and hydrogen atom very close to, after introducing molecular size and Shape is almost without changing；2. the introducing of fluorine atom makes nonpolar carbon-carbon double bond (C=C) produce polarity；The last 3. is negative Electrical F atom can participate in forming hydrogen bond；4. the introducing of fluorine atom can produce strong lipophilicity effect, it is particularly advantageous for through thin After birth；5. introducing a F atom in double bond can be more more stable than common C=C double bond, stronger to the tolerance of enzyme.Thus exist In bioactive molecule exploitation, fluorine atom is especially introduced on olefinic double bonds, often generates unexpected effect.

Although Largazole is an anti-tumor therapeutic agent because having been found, further structural modification is to improve it Inhibit HDACs effect, reduce its toxicity and physicochemical property is still necessary.Status based on the prior art, present invention People is quasi- to provide a kind of Largazole fluoro analogs with antitumor action, preparation method and the medicine containing the compound Purposes of object or combinations thereof object as anti-tumor therapeutic agent.

Summary of the invention

The purpose of the present invention is the statuses based on the prior art, quasi- to provide a kind of Largazole with antitumor action A kind of fluoro analogs, and in particular to fluoro of new marine natural products cyclic ester peptide. (i.e. marine natural products Largazole) Analog, preparation method and the drug that contains the compound or combinations thereof purposes of the object as anti-tumor therapeutic agent.

The present invention provides a kind of logical formula (I) compound represented or its salt:

Wherein:

R¹Selected from H, R³, R³S, R³CO, R³NHCO；

R²Selected from H, Me, Et, R³S, R³SS, SH, CH₂SR³, CH₂SSR³, CH₂SH, R³O, Bn, or the Bn replaced；

R³Selected from hydrogen, C₁-C₁₀Alkyl, aromatic radical, wherein C₁-C₁₀Alkyl chain on can be embedded in one or more oxygen or Nitrogen-atoms；Or C₁-C₁₀An aromatic radical can be embedded on alkyl chain；Or R³Also selected from C₁-C₁₀Alkyl and aryl at The combination of ring；

R¹With R²A ring can also be formed；

In addition, route progress is synthesized as follows the present invention provides the preparation method of compound described in logical formula (I):

Wherein,

Step 6: the alcohol 6 of S- configuration prepares the fluoroolefin ester 7 of the heterocycle containing thiazoles accordingly through condensation reaction, it is described Condensation reaction refer to the alcohol 6 of S- configuration, under the conditions of suitable solvent and reaction temperature, under alkali and acid activators effect, with Amino acid reaction with amino protecting group, prepares the fluoroolefin ester 7 of the heterocycle containing thiazoles of respective configuration, wherein described Alkali can be diisopropylethylamine (DIPEA), 4- diformazan methylamino piperidine (DMAP)；The activator be acyl chlorides, HOBT, HOAT, EDCI or DCC；Wherein the solvent is the non-proton organic solvents such as tetrahydrofuran, ether, methylene chloride, DMF, The reaction temperature is -10-100 DEG C；

Step 7: ester 7 prepares the big of respective configuration through hydrolysis, deprotection reaction, intramolecular condensation ring closure reaction Cycle compound 8；The hydrolysis refers to: under alkaline condition, in polar solvent, selective methyl esters water occurs for ester 7 Solution, it is neutralized to obtain corresponding intermediate acid；The alkaline condition refers to alkali such as KOH, NaOH, LiOH, Ba (OH)₂Or Bu₃SnOH etc.；The polar solvent refer to 1,2- dichloroethanes, THF, 1,4- dioxane, DMF, DMSO, methanol, ethyl alcohol, In isopropanol, water equal solvent or the mixed solvent of above-mentioned solvent combination；The reaction condition includes reaction temperature, preferably Reaction temperature is -10-100 DEG C；

The deprotection reaction refers to: the corresponding intermediate acid that ester 7 is obtained through hydrolysis, then anti-through Deprotection Corresponding carboxylic organic amine compound should be prepared；The deprotection reaction refers to corresponding intermediate acid second level amine Compound makees organic base such as: diethylamide, morpholine, piperidines, organic solvent for example methylene chloride, 1,2- dichloroethanes, THF, It, such as -10-100 DEG C of control reaction temperature, can be in Isosorbide-5-Nitrae-dioxane, DMF, DMSO, methanol, ethyl alcohol or isopropanol equal solvent Amino protecting group in intermediate is selectively removed, corresponding carboxylic aminated compounds is prepared；

The intramolecular condensation ring closure reaction refers to: ester 7 accordingly contains carboxylic through prepared by hydrolysis, deprotection reaction The organic amine compound of base, then the macrocyclic compound that the fluoroolefin through intramolecular condensation ring closure reaction preparation respective configuration replaces 8, the intramolecular condensation ring closure reaction refers to: through carboxylic organic aminated made from hydrolysis, deprotection reaction Object is closed in the presence of condensing agent, any combination of the condensing agent such as HATU, HOAT, HOBt, DIPEA or former three, Suitable organic solvent is such as: methylene chloride, 1,2- dichloroethanes, THF, 1,4- dioxane, DMF, DMSO or acetonitrile equal solvent In, such as -10-100 DEG C of control reaction temperature, the macrocyclic compound 8 of the fluoroolefins of respective configuration can be prepared；

Step 8: the macrocyclic compound 8 of the fluoroolefins of respective configuration is anti-through the elimination reaction of sulfhydryl protected base, acylation The fluoroolefin of Largazole should be prepared similar to object 9, that is, lead to compound described in formula (I):

The elimination reaction of the sulfhydryl protected base refers to macrocyclic compound 8, in organic solvent such as methylene chloride, 1,2- In dichloroethanes, THF, Isosorbide-5-Nitrae-dioxane, DMF, DMSO or acetonitrile equal solvent, such as -10- in preferred range of reaction temperature 100 DEG C, under being acted on alone or synergistically through tri isopropyl silane and trifluoroacetic acid, the removing of sulfhydryl protected base occurs, is dissociated Thiol intermediate；

The acylation reaction refers to macrocyclic compound 8, and the elimination reaction through sulfhydryl protected base is made in free mercaptan Mesosome, in organic solvent such as methylene chloride, 1,2- dichloroethanes, THF, Isosorbide-5-Nitrae-dioxane, DMF, DMSO or acetonitrile equal solvent In, such as -10-100 DEG C in preferred range of reaction temperature, in the presence of alkali, acylation reaction occurs with acylating reagent and synthesizes For the fluoroolefin of Largazole similar to object, the alkali includes inorganic base or organic base, such as NaHCO₃、KHCO₃、K₂CO₃、 Na₂CO3、Cs₂CO₃Or triethylamine, diisopropyl ethyl amine, pyridine, DMAP etc., the acylating agent refer to the alkane of C1-10 Base acyl chlorides, aryl-acyl chlorides, C1-10 alkoxy carbonyl chlorine, C1-10 alkylamino radical phosgene, aryl-acyl chlorides, aryloxy phosgene, Arylamine group phosgene；

Wherein in described above, related functional group, chemical reagent or solvent code name are related to, referring to international name Rule or generic model, related functional group, chemical reagent or solvent code name are defined as follows:

Ac:Acetyl；

Bn:Benzyl；

Boc:tert-Butoxycarbonyl；

Cbz:Benzyloxycarbonyl；

DIBALH:Diisobutylaluminium hydride；

DCE:Dichloromethane；

DCM:Dichloromethane；

DIPEA:Diisopropylethyamine；

DME:1,2-Ethanedioldimethylether；

DMAP:4-Dimethylamino pyridine；

DMF:N, N-Dimethylformamide；

DMP:Dess-Martin periodinane；

DMSO:Dimethylsulfoxide；

DPPA:Diphenylphosphonic azide；

DMPU:1,3-Dimethyl-3,4,5,6-tetrahydro-2 (1H)-pyrimidinone；

EA:Ethyl Acetate；

EDCI:Dimethylaminopropyl-N '-enthylcarbodiimide hydrochloride；

Fmoc-Cl:9-Fluorenylmethylchloroformate；

Fmoc:9-Fluorenylmethylformyl；

HATU:2- (7-Aza-1H-benzotriazole-1-yl) -1,1,3,3-tetramethyluronium

Hexafluorophosphate；

HOAT:1-Hydroxy-7-azabenzotriazole；

HOBT:1-Hydroxybenzotriazole；

LDA:Lithium diisopropylamide；

MeCN:Acetonitrile；

NaHMDS:Sodiumbis (trimethylsilyl) amide；

Py:Pridine；

THF:Tetrahydrofuran；

TIPS:Triisopropylsilane；

TFA:Trifluoroacetic acid；

TMSOTf:Trimethylsilyltrifluoromethanesulfonate；

Tol:Toluene.

The inhibitory activity that the present invention has carried out external HDACs to the part of compounds is tested, and investigates it respectively to 6 kinds Commercially available HDACs (such as: HDAC1,2,3,6,8 and inhibitory activity 10), and make comparisons with Largazole；As a result it shows Show, compound of the present invention has the function of strong, selective inhibition HDACs；Representative compound is to HDACs IC₅₀Value is as shown in table 1；

Table 1

The present invention also provides the drug ingedient that the compound and more than one adjuvant form, wherein drug ingedients In containing compound described in general formula, it is further described that drug ingedient is for inhibiting mammalian cell proliferation, i.e., to swollen The mammal of tumor takes drug described in the general formula for the treatment of effective dose, and the tumour that wherein mammal suffers from includes entity Tumor, cancer, lymthoma, Hodgkin's disease, tumor disease, newborn tumor disease etc..

The present invention provides a kind of pharmaceutical compositions, general formula compound of the present invention or its salt containing treatment effective dose And pharmaceutical carriers, purposes in the preparation of antitumor drugs.In other words, the present invention also provides the above compounds containing effective dose Composition, the salt of compound shown in formula of of the invention (I) can be free form and acid addition salt or carboxylate Form.The example of acid addition salt include inorganic acid salt such as: sulfate, nitrate, hydrobromate, hydriodate, phosphate, Or acylate for example tartrate, acetate, mesylate, benzene sulfonate, toluene fulfonate, citrate, maleate, Fumarate, lactate etc..

Specific embodiment

With reference to embodiments for further describing the present invention, but these embodiments are not intended to limit the scope of the invention.

The synthesis for the Largazole fluoro analogs that 1 benzyl of embodiment replaces

The first step, the preparation of compound 2:

The anhydrous of three beneze methane thiol of compound (1.28g, 4.62mmol) and 20ml is added in 100ml dry reaction flask Methylene chloride, is stirred at room temperature dissolution, is added triethylamine (0.9ml, 6.50mmol), be then added dropwise methacrylaldehyde (0.43ml, 6.50mmol), reaction 1h (TLC tracking) is stirred at room temperature.Stop stirring, be spin-dried for solvent, obtain white crude, does not do further pure Change, is directly used in the preparation of compound 2.R_f=0.13 (PE:EA=40:1)¹H-NMR(400MHz,CDCl3):δ9.56 (brs, 1H), 7.23-7.43 (m, 15H), 2.47 (t, J=7.0Hz, 2H), 2.37 (t, J=6.7Hz, 2H)

The preparation of second step compound 3:

PPh is added in 100ml dry reaction flask₃(3.15g, 12.0mmol), two ethyl bromide fluorides (0.83ml, 6.0mmol) and the anhydrous THF of 30ml, stirring and dissolving at room temperature, quickly instill the diethyl zinc of 1.0M hexane solution (12.0ml, 12.0mmol), it after mixture stirring 10min, rapidly joins dissolved with compound 2 (1.0g, 3.0mmol), reaction is overnight.It is added The dehydrated alcohol of 10ml is quenched, and solid is precipitated, and after stirring 10min, is concentrated under reduced pressure, 100ml anhydrous ether is added, is stirred at room temperature 30min, through diatomite drainage, washed with ether, filtrate is concentrated, residue silica gel column chromatography (elution requirement: PE/EA=40:1), White solid is obtained, wherein E formula structure 0.325g, yield 26%；Z formula structure 0.730g, yield 58%.Z formula structure:

R_f=0.35 (PE/EA=40:1)¹H-NMR(400MHz,CDCl₃):δ7.40(m,6H),7.25(m,6H), 7.18 (m, 3H), 5.75 (dt, J=20.9,7.9Hz, 1H), 4.23 (q, J=7.1Hz, 2H), 2.56 (m, 2H), 2.26 (t, J =7.2Hz, 2H), 1.29 (t, J=7.1Hz, 3H)¹³C-NMR(150MHz,CDCl₃):δ 160.58(d,²J_C-F= 34.5Hz),147.91(d,¹J_C-F=252Hz), 144.65,129.48,127.81,126.60,121.24 (d,²J_C-F= 19.6Hz),66.71,61.28,31.30,24.55(d,³J_C-F=5.1Hz), 14.00.¹⁹F-NMR(376MHz,CDCl₃):δ- 121.29(d,22.6Hz).ESI-MS(M/Z):443.6[M+Na]⁺. HRMS-ESI(M/Z):[M+Na]⁺Calcd.for C₂₆H₂₅FO₂SNa:443.1452, found:443.1452. E formula structure:

R_f=0.27 (PE/EA=40:1)¹H-NMR(400MHz,CDCl₃):δ7.41(m,6H),7.28(m,6H), 7.22 (m, 3H), 5.97 (dt, J=32.8,7.2Hz, 1H), 4.25 (q, J=7.1Hz, 2H), 2.25 (m, 4H), 1.31 (t, J =7.1Hz, 3H)¹³C-NMR(150MHz,CDCl₃):δ155.83(d,²J_C-F=34.5Hz), 143.62 (d,¹J_C-F= 256.5Hz),139.93,124.82,123.19,121.99,113.57(d,²J_C-FF=11.4 Hz), 62.15,56.85, 25.79,18.90,9.39.¹⁹F-NMR(376MHz,CDCl₃): δ -128.95 (d, J=32.8Hz) .ESI-MS (M/Z): 443.6[M+Na]⁺.HRMS-ESI(M/Z):[M+Na]⁺Calcd.for C₂₆H₂₅FO₂SNa:443.1452,found: 443.1454.

The preparation of third step compound 4:

Compound Z-3 (4.028g, 9.60mmol) is added in 500ml dry reaction flask, argon gas protection is lower to be added 100ml Dry toluene, stirring and dissolving.- 78 DEG C are cooled to, the diisobutyl aluminium hydride (22.0ml, 33.5mmol) of 1.5M is added dropwise, is dripped After adding, thermotonus 1h is kept, 50ml methanol is carefully added into and is quenched, restores to room temperature, the saturation winestone of 100ml is added Sour sodium potassium, is stirred overnight at room temperature.Liquid separation is stood, water phase extracts (100ml × 2) with EA, merges organic phase, and saturated sodium-chloride is washed, Anhydrous sodium sulfate dries, filters, and concentration, residue is obtained through silica gel column chromatography (elution requirement: PE/DCM/EA=35:5:1) Compound 4, wherein the 4 of compound Z- configuration, are white solid 2.74g, yield 76%.R_f=0.35 (PE/DCM/EA=35: 5:1).¹H-NMR(400MHz,CDCl₃): δ 9.13 (d, J=18.2Hz, 1H), 7.43 (m, 6H), 7.27 (m, 9H), 5.75 (dt, J=32.1,7.2Hz, 1H), 2.35 (m, 4H)¹³C-NMR (100 MHz, DMSO-d6): δ 183.49 (d, J= 24.9Hz), 156.48 (d, J=261Hz), 146.88,144.53,129.54,128.71 (d, J=10.2Hz), 127.99 (d, J=10.1Hz), 127.29,126.86,67.09,30.22,24.01.¹⁹F-NMR(376MHz,CDCl₃):δ-132.15 (dd, J=32.1,18.2Hz) .ESI-MS (M/Z): 399.6 [M+Na]⁺.HRMS-ESI(M/Z):[M+Na]⁺Calcd.for C₂₄H₂₁FOSNa: 399.1189,found:399.1192.

The preparation of 4th step compound 5:

4 (1.12g, 4.46mmol) of compound Z- configuration are added in 250ml dry reaction flask, argon gas protection is lower to be added Anhydrous methylene chloride 50ml, stirring and dissolving.The lower dropwise addition titanium tetrachloride of ice salt bath (0.82ml, 7.43 mmol), is stirred to react 0.5h, at crocus suspension.- 40 DEG C are cooled to, is added dropwise DIPEA (1.23ml, 7.43mmol), and react at such a temperature 2h；- 90 DEG C are down to, the anhydrous methylene chloride solution about 20ml dissolved with compound 67 (1.44g, 3.71mmol) is slowly added dropwise, and Thermotonus 3h is kept, the saturated ammonium chloride solution that 20ml is added is quenched, and restores to room temperature.20ml water is added, stands liquid separation, Water phase extracts (20ml × 3) with methylene chloride, merges organic phase, and saturated sodium-chloride is washed, and anhydrous sodium sulfate dries, filters, concentration, Residue obtains two yellow isomeric compounds 5, (1.027g is received 5S through silica gel column chromatography (elution requirement: PE/EA=8:1) Rate 44%) and compound 5R (0.956g, yield 40%).

Wherein compound 5S:

R_f=0.19 (PE/EA=4:1)¹H-NMR(400MHz,CDCl₃):δ7.29(m,20H),5.33(m,1H), 4.86 (dd, J=36.8,7.1Hz, 1H), 4.63 (brs, 1H), 3.67 (m, 1H), 3.47 (dd, J=17.9,8.8 Hz, 1H), 3.36 (dd, J=11.2,7.2Hz, 1H), 3.21 (m, 1H), 3.03 (m, 1H), 2.95 (d, J=4.1 Hz, 1H), 2.87 (d, J =11.6Hz, 1H), 2.19 (m, 4H)¹³C-NMR(150MHz,CDCl₃):δ 201.27,172.02,158.60(d,¹J_C-F= 257.2Hz),144.87,136.32,129.60,129.45,128.97, 127.88,127.34,126.63,104.96(d,³J_C-F=12.9Hz), 68.32,66.63,42.81,36.79,32.18,31.52,22.72.¹⁹F-NMR(376MHz, CDCl₃): δ -129.15 (dd, J=32.1,18.2Hz) .ESI-MS (M/Z): 650.4 [M+Na]⁺.HRMS-ESI(M/Z):[M+ Na]⁺Calcd.for C₃₆H₃₄FNO₂S₃Na: 650.1628,found:650.1621.

The preparation of 5th step compound 6:

Be added in 50ml dry reaction flask the substitution of compound described in reaction equation as above thiazole amine (0.603g, 1.636mmol), the anhydrous methylene chloride of DMAP (0.520g, 4.253mmol) and 20ml, stirs and evenly mixs 5min at room temperature.It is added dropwise Dissolved with the anhydrous methylene chloride solution about 10ml of compound 5S (1.027g, 1.636mmol), be stirred to react at room temperature 1h (TLC with Track).Stop stirring, concentration, residue obtains white solid 0.759g through silica gel column chromatography (elution requirement: PE/EA=1:2), receives Rate 65%.R_f=0.26 (PE/ EA=1:1)(c=0.4, CHCl₃).¹H-NMR(400MHz,CDCl₃):δ 7.89 (s, 1H), 4.79 (m, 2H), 4.68 (m, 2H), 4.49 (brs, 1H), 3.87 (d, J=11.4Hz, 1H), 3.79 (s, 3H), 3.27 (d, J=11.4Hz, 1H), 2.56 (m, 2H), 2.15 (m, 5H), 1.63 (s, 3H)¹³C-NMR (100MHz, DMSO-d6): δ 173.62,171.49,167.63,162.78,158.92 (d, J=257.4Hz), 148.20,144.83, (129.58,127.91,126.67,122.56,104.67 d, J=12.3Hz), 84.49,67.09,66.87,66.62, (53.01,41.54,40.80,39.72,31.49,24.02,22.70 d, J=3.5Hz)¹⁹F-NMR(376MHz,CDCl₃): δ -124.95 (dd, J=36.2,20.3Hz) .ESI-MS (M/Z): 712.4 [M+Na]⁺.HRMS-ESI(M/Z):[M+Na]⁺ Calcd.for C₃₆H₃₆FN₃O₄S₃Na: 712.1744,found:712.1748.

The preparation of 6th step compound 7:

50mL is added in compound Fmoc-L-Phe-OH (0.079g, 0.20mmol), DMAP (0.014g, 0.11mmol) In the stand up reaction bottle of dried and clean, it is filled with argon gas protection, the anhydrous methylene chloride of 15mL, ice bath are added with one-shot injector Lower stirring and dissolving, is down to 0 DEG C, respectively with one-shot injector be added dropwise 2,4,6- trichloro-benzoyl chlorides (0.04mL, 0.25mmol) and DIPEA (0.05mL, 0.3mmol) keeps thermotonus 1h.Compound 6 (0.280g, 0.406mmol) is dissolved in the nothing of 5mL Reaction system is instilled after water THF solution, is restored to room temperature reaction 6h, stops stirring, concentration, crude product is through silica gel column chromatography (elution Condition: PE/EA=1:1), obtain white solid 0.063g, yield 60%.

R_f=0.26 (PE/EA=1:1)(c=0.097, CHCl₃).1HNMR(600MHz, CDCl3)δ 7.89 (s, 1H), 7.76 (d, J=7.5Hz, 2H), 7.53 (t, J=7.2Hz, 2H), 7.39 (d, J=7.4Hz, 8H), 7.33- 7.25 (m, 9H), 7.19 (dd, J=16.7,7.7Hz, 6H), 7.04 (d, J=6.9Hz, 2H), 6.60 (s, 1H), 5.77- 5.57 (m, 1H), 5.26 (d, J=7.5Hz, 1H), 4.81 (dt, J=36.0,7.0 Hz, 1H), 4.70-4.61 (m, 2H), 4.52 (dd, J=12.9,6.3Hz, 1H), 4.45-4.27 (m, 2H), 4.18 (t, J=6.8Hz, 1H), 3.86 (d, J= 11.3Hz, 1H), 3.78 (s, 3H), 3.25 (d, J=11.3Hz, 1H), 3.03 (m, J=48.0,13.9,6.1Hz, 2H), 2.66 (m, J=19.6,14.9,6.5Hz, 2H), 2.18 (t, J=6.5Hz, 3H), 2.15-2.07 (m, 2H), 1.63 (s, 4H).¹³C NMR(151MHz,CDCl3)δ 172.56(s),169.70(s),167.54(s),167.03(s),162.15(s), 154.99 (d, J=11.5Hz), 154.46 (d, J=14.7Hz), 152.56 (d, J=74.3Hz), 147.53 (d, J= 54.5Hz), 144.14 (s), 143.09 (d, J=14.9Hz), 140.69 (s), 134.75 (s), 128.94 (s), 128.73 (s), 127.94 (s), 127.29 (s), 127.11 (s), 126.50 (d, J=7.5Hz), 126.07 (s), 124.44 (d, J= 7.6Hz), 121.71 (s), 119.37 (s), 109.04 (d, J=12.3Hz), 83.92 (s), 69.32 (d, J=29.3Hz), 66.25 (d, J=46.7Hz), 54.26 (s), 52.28 (s), 46.50 (s), 40.89 (s), 40.41 (s), 37.41 (s), 37.18 (s),30.43(s),23.36(s),22.31(s)..¹⁹F-NMR(376MHz,CDCl₃): δ -126.27 (dd, J= 35.4,21.1Hz).ESI-MS(M/Z):1059.2[M+H]⁺.HRMS-ESI(M/Z):[M+Na]⁺Calcd. for C₆₀H₅₅FN₄O₇S₃Na:1081.3109,found:1081.3126.

The preparation of 7th step compound 8:

Compound 7 (0.37g, 0.35mmol) is added in the reaction flask of 100mL clean dried, the THF/ of 45mL is added H₂The mixed solvent of O=4:1, stirring and dissolving are down to 0 DEG C, and the THF/H of the LiOH of 0.1 M of 5.25mL is added dropwise₂O=4:1's is mixed Solution to be closed, thermotonus 1h is kept, the dilute hydrochloric acid solution acidification of the 0.1M of 5mL is added in TLC detection reaction after reaction, EA extracts (100mL × 3), and 50mL saturated common salt washing, anhydrous sodium sulfate dries, filters, and is concentrated, crude product is through silica gel column chromatography (elution requirement: EA:MEOH:AcOH=20:1:1), obtains white solid 0.256g.Obtained product is dissolved in clean dried In 50mL stand up reaction bottle, it is filled with argon gas protection, the anhydrous methylene chloride of 15mL is added with one-shot injector, is stirred at room temperature Two different amine (1.50mL, 14.561mmol) are added dropwise with one-shot injector in 5min, and overnight, TLC detection is reacted, instead for reaction at room temperature It after answering, is concentrated under reduced pressure, 10mL dry toluene is added, be concentrated under reduced pressure, be repeated twice, to remove the different amine of extra two.It will be thick Product are protected with argon gas, and HATU (0.157 g, 0.412mmol) and HOAT (0.057g, 0.416mmol) is added, with disposable injection The anhydrous methylene chloride solution of 400mL is added in device, is added dropwise DIPEA (0.13mL, 0.786mmol), reacts 30h at room temperature.TLC Detection reaction, is concentrated after reaction, and crude product crosses short column of silica gel (elution requirement: first PE/EA=2:1, rear EA are rinsed), obtains white Color solid 30mg, three step total recoverys 11%.

R_f=0.15 (PE/EA=2:3)(c=0.021, CHCl₃)¹H NMR(600MHz, CDCl3)δ 7.61 (s, 1H), 7.38 (d, J=7.6Hz, 6H), 7.27 (dd, J=11.0,4.3Hz, 6H), 7.20 (t, J=7.3Hz, 3H), 7.13 (d, J=7.7Hz, 1H), 6.94-6.70 (m, 5H), 6.15 (d, J=8.3Hz, 1H), 5.71 (m, J=18.9, 10.1,1.9Hz, 1H), 5.05 (d, 12Hz, 1H), 5.00 (dt, 36Hz, 7.5Hz, 1H), 4.88 (m, 1H), 4.17 (dd, J= 17.4,2.8Hz, 1H), 4.08 (d, J=11.3Hz, 1H), 3.25 (d, j=11.3Hz, 1H), 3.20 (dd, J=14.0, 23Hz, 1H), 3.06 (dd, J=14.0,5.9Hz, 1H), 2.99 (dd, J=16.4,10.2Hz, 1H), 2.62 (dd, J= 16.4,2.1Hz, 1H), 2.17 (dt, J=11.0,4.0 Hz, 2H), 2.10 (dt, J=14.4,7.2Hz, 2H), 1.79 (s, 3H).¹³C NMR(150MHz,CDCl3)δ 173.67(s),168.89(s),168.16(s),166.97(s),163.73(s), 155.33 (s), 153.63 (s), 147.26 (s), 144.78 (s), 135.11 (s), 129.60 (d, J=8.8Hz), 127.88 (d, J=7.6Hz), 126.65 (s), 125.93 (s), 123.68 (s), 109.17 (d, J=12.5Hz), 84.19 (s), 70.18 (d, J=30.9 Hz), 66.61 (s), 54.19 (s), 42.46 (s), 40.98 (s), 37.70 (s), 37.46 (s), 31.12 (s), 24.98 (s), 22.88 (d, J=3.8Hz)¹⁹F-NMR(376MHz,CDCl₃): δ -124.43 (dd, J= 36.2,20.3Hz). ESI-MS(M/Z):827.2[M+Na]⁺.HRMS-ESI(M/Z):[M+Na]⁺Calcd.for C₄₄H₄₁FN₄O₄S₃Na:827.2166,found:827.2166.

The preparation of step 8 compound 9:

Compound 8 (49mg, 0.061mmol) is added in 50mL clean dried stand up reaction bottle, argon gas protection is filled with, uses The anhydrous methylene chloride of 10mL, stirring and dissolving 30min under ice-water bath is added in one-shot injector.It is added dropwise at 0 DEG C with one-shot injector Tri isopropyl silane (25ul, 0.12mmol) then instills trifluoroacetic acid (0.27mL, 3.7mmol).Naturally it is warmed to room temperature anti- 1h is answered, TLC detection reaction is concentrated under reduced pressure, and crude product Flash silica column chromatographs (EA), obtains white solid 20mg, yield 59%.

R_f=0.42 (PE/EA=2:3)¹HNMR(600MHz,CDCl3)δ7.66(s,1H),7.19(m, 2H),6.84 (m, 5H), 6.15 (s, 1H), 5.78 (dd, J=17.9,9.4Hz, 1H), 5.16 (dt, J=36.3,7.5 Hz, 1H), 5.04 (dd, J=17.4,8.2Hz, 1H), 4.93 (m, 1H), 4.27 (d, J=17.1Hz, 1H), 4.11 (d, J=11.2Hz, 1H), 3.26 (d, J=11.3Hz, 1H), 3.22 (dd, J=14.0,3.0Hz, 1H), 3.12-3.08 (m, 1H), 3.07 (d, J= 5.9Hz, 1H), 2.67 (d, J=14.8Hz, 1H), 2.54 (dd, J=14.4,7.1Hz, 1H), 2.40 (m, 2H), 1.83 (s, 3H).ESI-MS(M/Z):563.0[M+H]⁺.HRMS-ESI (M/Z):[M+H]⁺Calcd.for C₂₅H₂₇FN₄O₄S₃H: 563.1251,found:563.1254.

The mercaptan (0.033g, 0.06mmol) is added in the stand up reaction bottle of 50mL clean dried, with disposable The anhydrous methylene chloride of 10mL is added in syringe, stirs 30min under ice-water bath, instills Et with micro syringe at 0 DEG C₃N(16uL, 0.070mmol) with caprylyl chloride (51uL, 0.3mmol), restore to room temperature.Reaction 4h is stirred at room temperature, TLC tracing detection is anti- It answers, 2mL methanol quenching reaction is added after reaction, the ethyl acetate dissolution of 50mL is added in concentration, and saturated sodium bicarbonate is washed (10mL × 1) is washed (10mL × 1), and saturated sodium-chloride is washed, and anhydrous sodium sulfate dries, filters, concentration, residue silica gel column layer Analyse (elution requirement: MeOH:CH₂Cl₂=1:200), obtain white amorphous solid 13mg, yield 61%.

R_f=0.42 (DCM/EA=3:1)(c=0.025, CHCl₃).¹HNMR(150MHz, CDCl3)δ 7.64 (s, 1H), 7.14 (d, J=7.7Hz, 2H), 7.00-6.74 (m, 5H), 6.15 (d, J=8.0 Hz, 1H), 5.76 (dd, J =19.2,9.9Hz, 1H), 5.12 (dt, J=36.3Hz, 7.5Hz, 1H), 5.06 (d, J=9.0Hz, 1H), 4.92 (t, J= 8.1Hz, 1H), 4.92 (t, J=8.1Hz, 1H), 4.24 (dd, J=17.4,2.1 Hz, 1H), 4.10 (d, J=11.2Hz, 1H), 3.23 (d, J=11.2Hz, 1H), 3.21 (d, J=2.8Hz, 1H), 3.06 (m, 2H), 2.88 (t, J=7.1Hz, 2H), 2.66 (d, J=16.0Hz, 1H), 2.53 (t, J=7.5 Hz, 2H), 2.36 (dd, J=14.4,7.2Hz, 2H), 1.83 (s, 3H), 1.64 (dd, J=14.0,7.0Hz, 3H), 1.27 (m, 8H), 0.89 (dd, J=9.0,4.6Hz, 3H)¹³C NMR (150MHz,CDCl3)δ 198.61(s),173.12(s),168.27(s),167.47(s),166.35(s),163.04(s), 146.63 (d, J=28.5Hz), 134.52 (s), 129.03 (s), 127.22 (s), 125.29 (s), 123.03 (s), 107.82 (d, J=23.4 Hz), 83.63 (s), 69.52 (d, J=30.9Hz), 53.57 (s), 43.52 (s), 41.84 (s), 40.37 (s), 37.00 (d, J=18.3Hz), 30.98 (s), 29.07 (s), 28.27 (s), 27.27 (s), 24.99 (s), 24.35 (s), 23.20 (s), 21.95 (s), 13.45 (d, J=8.6Hz)¹⁹F-NMR(376MHz,CDCl₃): δ -124.76 (dd, J= 36.1,19.3Hz).ESI-MS(M/Z):689.2[M+H]⁺.HRMS-ESI(M/Z):[M+H]⁺Calcd.for C₃₃H₄₁FN₄O₅S₃:689.2296,found:689.2302.。

The synthesis for the Largazole fluoro analogs mercaptan that 2 methylthiomethyl of embodiment replaces

The Largazole fluoro analogs replaced as described in Example 1 with experimental procedure preparation methylthiomethyl Synthesis replaces Fmoc-L-Phe-OH with corresponding Fmoc-L-MeS-OH in testing the 6th step.3 methylthiomethyl of embodiment The synthesis of substituted Largazole fluoro analogs

The Largazole fluoro analogs replaced as described in Example 1 with experimental procedure preparation methylthiomethyl Synthesis is tested in the 8th step in embodiment 1, and the Largazole fluoro that the methylthiomethyl made from embodiment 2 replaces is similar Object mercaptan is raw material.

Embodiment 4 goes the synthesis of the Largazole fluoro analogs of isopropyl

The Largazole fluoro analogs replaced according to the method for embodiment 1 with experimental procedure preparation methylthiomethyl Synthesis, test the 6th step in, replace Fmoc-L-Phe-OH with corresponding Fmoc-L-Gly-OH.

5 test experiments of embodiment

The inhibitory activity that the present invention has carried out external HDACs to the part of compounds is tested, and investigates it respectively to 6 kinds Commercially available HDACs (such as: HDAC1,2,3,6,8 and inhibitory activity 10), and make comparisons with Largazole；

The test philosophy of inhibitory activity: fluorophor 4- amino -7- cumarin is coupled on the peptide fragment of acetylation (Lys- Ac-AMC), fluorophor does not generate transmitting light under excitation light at this time.Using Lys-Ac-AMC as substrate, HDAC deacetylate Structure afterwards is exactly the reaction site of trypsase specific recognition, so the AMC separate out after integrated enzyme reaction, under excitation light Transmitting light can be generated；

Compound ira vitro inhibits HDAC activity test, and specific step is as follows: HDAC albumen is purchased from BPS Bioscience Company, reaction buffer system are the Tris-HCl solution (pH 7.0) of improvement.All small molecule compounds are molten by 100%DMSO Solution is prepared.It is formulated in buffer by a certain concentration as enzyme solutions for HDAC1,2,3,6, HDAC；Trypsase and coupling The acetylation peptide fragment substrate of fluorophor is formulated in buffer by a certain concentration as substrate solution.Compound presses design concentration The reacting hole in 384 orifice plates is added, 15uL HDAC enzyme solutions are then added in reacting hole, in incubation at room temperature 15 minutes, then adds Enter 10uL substrate solution to start to react, after incubation at room temperature 1 hour, with microplate reader measurement fluorescence intensity, (launch wavelength 355nM inhales Receive wavelength 460nM)；Result data is analyzed by GraphPadPrism software；

It is formulated in buffer by a certain concentration as enzyme solutions for HDAC8,10, HDAC；It is coupled the second of fluorophor Acylated peptide fragment substrate is formulated in buffer by a certain concentration as substrate solution.384 orifice plates are added by design concentration in compound In reacting hole, then in reacting hole be added 15uL HDAC enzyme solutions, incubation at room temperature 15 minutes, then be added 10uL substrate Solution starts to react, and after incubation at room temperature 4 hours, adds the trypsin solution of 15uL, continues after being incubated for 90min at 37 DEG C Fluorescence intensity (launch wavelength 355 nM, absorbing wavelength 460nM) is measured with microplate reader；Result data passes through GraphPadPrism Software analysis；

IC of the representative compound to HDACs₅₀Value is as shown in table 1, the results show that compound of the present invention has The effect of strong, selective inhibition HDACs.

Table 1

Claims

1. the compound or its salt of logical formula (I):

Wherein:

R¹Selected from H, R³, R³S, R³CO, R³NHCO；

R³Selected from hydrogen, C₁-C₁₀Alkyl, aromatic radical, wherein C₁-C₁₀Alkyl chain on can be embedded in one or more oxygen or nitrogen former Son；Or C₁-C₁₀An aromatic radical can be embedded on alkyl chain；Or R³Also selected from C₁-C₁₀Alkyl and aryl cyclization Combination；

Or in which

R¹With R²Form a ring；

Shown in salt be free form and acid addition salt or carboxylate form.

2. the preparation method of the compound of logical formula (I) described in claim 1, which is characterized in that route is synthesized as follows:

Wherein,

Step 6: the alcohol 6 of S- configuration prepares the fluoroolefin ester 7 of the heterocycle containing thiazoles accordingly, the contracting through condensation reaction It closes reaction and refers to the alcohol 6 of S- configuration under the conditions of suitable solvent and reaction temperature, under alkali and acid activators effect, and have ammonia The amino acid of base protecting group reacts, and prepares the fluoroolefin ester 7 of the heterocycle containing thiazoles of respective configuration；

Step 7: big cyclisation of the ester 7 through hydrolysis, deprotection reaction, intramolecular condensation ring closure reaction preparation respective configuration Close object 8；The hydrolysis refers to: under alkaline condition, in polar solvent, selective methyl esters hydrolysis, warp occur for ester 7 It neutralizes and obtains corresponding intermediate acid；Reaction condition includes reaction temperature；

The deprotection reaction refers to: the corresponding intermediate acid that ester 7 is obtained through hydrolysis, then through deprotection reaction system Standby corresponding carboxylic organic amine compound；

The intramolecular condensation ring closure reaction refers to: ester 7 prepares corresponding carboxylic through hydrolysis, deprotection reaction Organic amine compound, then the macrocyclic compound 8 that the fluoroolefin through intramolecular condensation ring closure reaction preparation respective configuration replaces；

Step 8: the macrocyclic compound 8 of the fluoroolefins of respective configuration is through the elimination reaction of sulfhydryl protected base, acylation reaction system The fluoroolefin of standby Largazole is similar to object 9, i.e., compound described in logical formula (I).

3. the preparation method of the compound of logical formula (I) as described in claim 2, which is characterized in that wherein,

Step 6: wherein the alkali is diisopropylethylamine (DIPEA), 4- diformazan methylamino piperidine (DMAP)；The work Agent is acyl chlorides, HOBT, HOAT, EDCI or DCC；The solvent is non-proton organic solvent, is selected from tetrahydrofuran, second Ether, methylene chloride or DMF, the reaction temperature are -10-100 DEG C；

Step 7: the alkaline condition refers to alkali such as KOH, NaOH, LiOH, Ba (OH)₂Or Bu₃SnOH；The polarity is molten Agent refers to 1,2- dichloroethanes, THF, 1,4- dioxane, DMF, DMSO, methanol, ethyl alcohol, isopropanol or water or the solvent group The mixed solvent of conjunction；The reaction temperature is -10-100 DEG C；

The deprotection reaction refers to that corresponding intermediate acid second level aminated compounds makees organic base such as: diethylamide, Quinoline, piperidines etc., in organic solvent such as methylene chloride, 1,2- dichloroethanes, THF, Isosorbide-5-Nitrae-dioxane, DMF, DMSO, methanol, second In alcohol or isopropanol equal solvent, such as -10-100 DEG C of control reaction temperature, amino protecting group in intermediate is selectively removed, Prepare corresponding carboxylic aminated compounds；

The intramolecular condensation ring closure reaction refers to: through carboxylic organic amine made from hydrolysis, deprotection reaction Compound is in the presence of condensing agent, any combination of the condensing agent such as HATU, HOAT, HOBt, DIPEA or former three, Suitable organic solvent such as: in methylene chloride, 1,2- dichloroethanes, THF, Isosorbide-5-Nitrae-dioxane, DMF, DMSO or acetonitrile, control Such as -10-100 DEG C of reaction temperature processed, prepare the macrocyclic compound 8 of the fluoroolefins of respective configuration；

Step 8: the elimination reaction of the sulfhydryl protected base refers to macrocyclic compound 8 in organic solvent such as methylene chloride, 1,2- In dichloroethanes, THF, Isosorbide-5-Nitrae-dioxane, DMF, DMSO or acetonitrile equal solvent, such as -10- in preferred range of reaction temperature 100 DEG C, under being acted on alone or synergistically through tri isopropyl silane and trifluoroacetic acid, the removing of sulfhydryl protected base occurs, is dissociated Thiol intermediate；

The acylation reaction refers to that free thiol intermediate is made through the elimination reaction of sulfhydryl protected base in macrocyclic compound 8, In organic solvent such as methylene chloride, 1,2- dichloroethanes, THF, Isosorbide-5-Nitrae-dioxane, DMF, DMSO or acetonitrile solvent, reaction - 10-100 DEG C of temperature, in the presence of alkali, it is similar that the acylation reaction synthesis fluoroolefin of Largazole occurs with acylating reagent Object, the alkali include inorganic base or organic base, such as NaHCO₃、KHCO₃、K₂CO₃、Na₂CO3、Cs₂CO₃Or it is triethylamine, two different Ethylamine, pyridine or DMAP；The acylating agent is the alkyl acyl chloride, aryl-acyl chlorides, C1-10 alkoxy carbonyl of C1-10 Chlorine, C1-10 alkylamino radical phosgene, aryl-acyl chlorides, aryloxy phosgene or arylamine group phosgene.

4. the compound or its salt of logical formula (I) according to claim 1: it is characterized in that, the compound is:

Wherein:

R¹Selected from H, R³CO, wherein R³Selected from C₇Alkyl；

R²Selected from H, Me, Et, MeS, SH, CH₂SMe, CH₂SH, MeO, Bn, or the Bn replaced；

It is prepared by following synthetic routes:

5. the compound or its salt of logical formula (I) according to claim 1: it is characterized in that, the compound is:

Wherein:

R¹Selected from H, R³CO, i.e. R³Selected from C₇Alkyl；

R²Selected from H, Me, Et, MeS, CH₂SMe, MeO, Bn；

Route preparation is synthesized as follows:

6. by compound or its salt described in claim 1, which is characterized in that the acid addition salt includes inorganic acid salt salt Such as: sulfate, nitrate, hydrobromate, hydriodate, phosphate or acylate such as tartrate, acetate, methylsulphur Hydrochlorate, benzene sulfonate, toluene fulfonate, citrate, maleate, fumarate, lactate.

7. a kind of pharmaceutical composition, which is characterized in that compound or its salt described in its claim 1 for containing treatment effective dose And pharmaceutical carriers.

8. the purposes of compound or its salt described in claim 1 in the preparation of antitumor drugs.

9. purposes according to claim 8, which is characterized in that the tumour is the solid tumor that mammal suffers from, cancer, leaching Bar tumor or Hodgkin's disease or tumor disease or newborn tumor disease.