CN107365323A - Marine natural products Largazole acid amide type analog, preparation method and use - Google Patents
Marine natural products Largazole acid amide type analog, preparation method and use Download PDFInfo
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- C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
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Abstract
The invention belongs to pharmaceutical field, is related to a kind of new marine natural products Largazole acid amide type analog, its preparation method and contains the purposes of the medicine or its composition of the compound as anti-tumor therapeutic agent.The invention provides a kind of compound or its salt represented by leading to formula (I), and shown compound or its salt and the antineoplastic pharmaceutical compositions of pharmaceutical carriers containing treatment effective dose, described compound have the function that the medicine SAHA than Clinical practice has stronger suppression tumor cell proliferation；The medicine can be used for treating solid tumor, cancer, lymthoma, Hodgkin's disease, tumor disease or newborn knurl disease etc..
Description
Technical field
The invention belongs to pharmaceutical field, be related to a kind of acid amide type analog of new marine natural products (i.e. Largazole),
Its preparation method and contain the purposes of the medicine or its composition of the compound as anti-tumor therapeutic agent.
Background technology
It is reported that 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, in China city
Cancer has accounted for cause of the death first place in the resident of town, and therefore, research has important business with finding the efficient anti-tumor medicine of low toxicity
Value.
The antineoplastic developed in the world is numerous, clinically conventional antitumor also to have kind more than 80.With people
Tumor research is deepened continuously, it is understood that the cytotoxic chemotherapeutics of traditional tool is while killing tumor cell
Some to human body can normally it organize, organ and cell such as marrow, alimentary canal, liver, kidneys etc. bring bigger injury, great system
The about clinical practice of these classic chemotherapy medicines.The exploitation of new type antineoplastic medicine at present turns from conventional cell cytotoxic drug
The specificity antineoplastic medicine of abnormal signal system target spot, i.e. molecular targeted therapy medicine into for cancer cell.With right
The continuous understanding of tumor signal network, has developed the molecular targeted agents of some, and enters clinical practice, wherein, organize egg
The hatching egg that white deacetylase (Histone deacetylase, HDACs) plays an important roll to growth of tumour cell regulation and control
In vain.Acetylation of histone transferase (histone acetylases, HATs) and histon deacetylase (HDAC) (histone
Deacetylases, HDACs) it is responsible for regulation and control core histones acetylation and the dynamic equilibrium of deacetylation, so as to ensure human body
The normal function of cell, canceration will not occur.But research confirms that excessive table is presented in HDACs in most tumour cell
Reach, and cause histone to be presented low Acetylation status, the occurrence and development of the unbalance and tumour of acetylation of histone state have close
Cut relation, and it was found that HDACs inhibitor mainly passes through arresting cell cycle, inducing cell apoptosis, angiogenesis inhibiting, induction
Autophagy, the mechanism of action such as synergy are played, the purpose for the treatment of cancer can be reached.
Up to the present oneself the HDACs inhibitor of report is mainly had following several types by structure:1. short-chain fat acids,
Including butyric acid, benzenebutanoic acid and isovaleric acid and its esters；2. hydroximic acid, including trichostatin A (TSA) and Fu Linuota
And its derivative CBHA and MM232 etc. (SAHA)；3. the cyclic tetrapeptide class formation without epoxy ketone group, including FR90I228,
Apicidin and the cyclic tetrapeptide class formation comprising epoxy ketone group, including trapoxin B etc.；4. amide-type, including MS-275, CI-
994 and cso55 etc. (is shown below),
Research finds that in mammalian cell HDACs shares 18 HDAC hypotype, according to saccharomycete HDAC sequences
Homology, be divided into 4 major class：ILei HDAC families include HDAC1, HDAC2, HDAC3 and HDAC8, with saccharomycete Rpd3
Albumen is similar；Class ii HDAC families include HDAC4, HDAC5, HDAC6, HDAC7, HDAC9 and HDAC10, with saccharomycete Hda1
Albumen is similar；Group iii HDAC families and the transcription inhibitory factor Sir2 Sequences similars of saccharomycete；IV class only has HDAC11 mono-
Kind.Wherein the HDAC families of I, II and IV class are Zn2+ dependent form targets, and Group III HDAC is conservative nicotinamide adenine
Dinucleotide (NAD+) dependent form target.
Most of HDACs inhibitor having found is bad for the selectivity of HDACs hypotypes, causes more potential bad
Reaction is gradually exposed, and the activity as Fu Linuota (SAHA) is shown to HDAC1~HDAC9 is substantially suitable, causes as red thin
Born of the same parents' reduction, decrease of platelet and electrocardiographic abnormality etc., this all greatly constrains their clinical efficacy.And with to HDAC with
The discussion that deepens continuously of tumorigenesis research, particularly being constantly revealed to each hypotype 26S Proteasome Structure and Functions of HDACs,
Single hypotype either belongs to of a sort multiple subtype-selective histon deacetylase (HDAC) inhibitors and is playing curative effect and subtracting
Advantage is had more in few side effect.
Mainly have in the HDACs inhibitor medicaments of clinical practice at present：Fu Linuota (vorinostat, SAHA), it
There is higher inhibitory activity to HDAC1, HDAC2, HDAC3, HDAC4, HDAC6, HDAC7, HDAC9 and HDAC10, the compound
It was approved by the fda in the United States for treating T-cell lymphoma,cutaneous, and similar hydroximic acid HDACs inhibitor in 2006
Belinostat was also approved by the FDA in the United States clinical practice in 2014；Romidepsin (romidepsin, FK-228) belongs to
The selective hdac inhibitor of I types, there is preferable selective inhibitory to HDAC I types, it is for HDAC 2 and HDAC 1
Inhibitory activity to compare HDAC4 and HDAC6 inhibitory activity be eager to excel, the disulfide bond in its structure is reduced into sulfydryl in vivo
The combination in metal ion is played afterwards, in the CTTL patient that 2010 are approved by the fda in the United States for clinical treatment；West reaches benzene
Amine, it is that amide-type HDACs inhibitor lists in January, 2015 in China's approval, for treating lymphoma peripheral T cell
(PTCL)。
Marine natural products Largazole is the natural materials research institute by Florida State University
HendrinkLuesch et al. isolated first from marine cyanobacterium Symploca spp. one has in sixteen-ring peptide
Ester structure natural products, and confirm that it is a kind of potent histon deacetylase (HDAC) inhibitor, the especially histone to I types
Deacetylase has fabulous selective inhibitory, can effectively suppress the propagation of tumour cell, preclinical research
Showing the Largazole of suitable dose optionally can kill tumour cell and normal cell is not had an impact
(J.Am.Chem.Soc.2008,130,13506).It is with having romidepsin (romidepsin, the FK- of 16 yuan of macrocyclic structures
228) similar, its thioesters side chain of intracellular hydrolysis, can producing one, to play pharmaceutical activity structure in vivo to FK228 similar
Activated thiol structure, the activated thiol can coordinate to catalysis Zn2+ histon deacetylase (HDAC) in
(Org.Lett.2010,12,1368)。
Largazole is existing largely on it because of its unique structure, good pharmacological activity and special targeting
Synthesis transformation and the relevant report (Nat.Prod.Rep.2012,29,449) of metabolic activity, meanwhile, Largazole free mercaptans
Report (J.Am.Chem.Soc.2011,133,12474) is also disclosed with the X- diffraction crystal structures of HDAC8 compounds.It is right at present
Largazole transformation and modification work are to simplify its structure, improve its pharmaceutical properties, explore its structure-activity relationship mainly to become
Gesture.Because Largazole metabolism unstability may be with trans " C=C " double bond in side chain in the molecule, methyl substituted
The unstable group such as thiazoline quinoline ring or fragment are relevant, therefore carry out structural modification to these unstable structure positions,
Help to develop the antitumor agent that structure is novel, drug effect and pharmaceutical properties are more excellent.
Psammaplin A are a kind of marine natural products for extracting for 1987 to obtain from spongia, are sent out through research
Existing, the natural products has multi-medicament active, and it may be used as natural efficient antibiotic, while a kind of still chitinase
Inhibitor (J.Org.Chem.2003,68,3866-3873).Then, it has also been found that psammaplin A and FK228,
The natural products such as Largazole are equally also a kind of natural pro-drug, its mercaptan structure obtained in vivo by reduction
It compound, can also be combined with the zinc ion in HDAC, there is the selection inhibitory activity of height to HDAC I, by reducing cell
The content of GSH-PX activity reduces the Acetylation Level of histone, and then the acetylation of histone and the deacetylation is reached flat
Weighing apparatus, so as to suppress the hyperplasia of tumour cell (J.Med.Chem.2012,55,1731-1750).
It is worth noting that, Psammaplin A activity mercaptan and FK228 and Largazole activity mercaptan significant differences
It is and the FK228 and Largazole phases by acid amides key connection at the position for being separated by 2 carbon atoms with pharmacophore sulfydryl to be
It is trans double bond (seeing below shown in formula) to answer position, because the amido link has similar trans double bond property due to conjugation,
It can be considered isostere.Based on this, the present invention uses for reference the architectural feature of the two, and relevant architectural feature is merged, devised logical
Formula (I) compound.
The content of the invention
The present invention mesh be to provide a kind of acid amide type analog of new marine natural products (i.e. Largazole), its
Preparation method and contain the purposes of the medicine or its composition of the compound as anti-tumor therapeutic agent.
The invention provides a kind of compound or its salt represented by leading to formula (I)：
Wherein：
R1Selected from H, R3, R3S, R3CO, R3NHCO, R3OCO,(R3O)2P(O)；
It can be double bond either singly-bound connection between 7/8 of logical formula (I)；
When between 7/8 of logical formula (I) being singly-bound connection, the spatial configuration of 7 can be R or S configurations；Work as formula
(I) when being double bond connection between 7/8, R2It is not present；
R2Selected from R3；
R3Selected from C1-C10Alkyl, aromatic radical, either selected from the aromatic radical for being connected to C1-C10 alkyl or be connected to virtue
The combination of the C1-C10 of base alkyl or C1-C10 alkyl and aryl cyclization；
In addition, present invention also offers the preparation method of compound described in logical formula (I), route one is synthesized as follows in this method
Carry out：
In the preparation method of compound described in the logical formula (I) of the present invention,
1st step：
L MALIC ACID (compound 1) and chloraldurate (compound 2) are in the presence of a kind of acid, in suitable solvent and reaction
Under temperature conditionss, react some hours, generate compound 3, described chloraldurate, its dosage be its be compound 1 0.5-
3.0 molar equivalent；Described acid refers to hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid, the tetrafluoro boric acid of various concentrations；Described solvent is
Water, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, ethanol, methanol, acetic acid, acetonitrile, DMF, DMSO or their mixed solvent, or not
Use solvent；Described reaction temperature is -10-100 DEG C；
2nd step：
Compound 3 and 2- (trimethylsilyl) ethanol (compound 4) are in the presence of a kind of alkali and condensing agent, suitable molten
Under the conditions of agent and reaction temperature, react some hours, generate compound 5, described compound 4, its dosage is compound 3
0.5-5.0 molar equivalents；Described alkali refers to potassium carbonate, sodium carbonate, saleratus, sodium acid carbonate, potassium hydroxide, hydroxide
Sodium, pyridine, 4-dimethylaminopyridine, 2,6- lutidines, triethylamine, DIPEA or N-methylmorpholine, its dosage are chemical combination
The 0.01-3.0 molar equivalents of thing 3；Described condensing agent refers to DCC, EDCI, and its dosage is 0.1-3.0 moles of compound 3 and worked as
Amount；Described solvent is tetrahydrofuran, ether, 1,4- dioxane, dichloromethane, chloroform, toluene, ethyl acetate, second
Nitrile, DMF, DMSO or their mixed solvent, described reaction temperature are -10-100 DEG C；
3rd step：
Compound 5 and 2- (triphenyl first sulfydryl) ethamine, under the conditions of suitable solvent and reaction temperature, reaction is some small
When, compound 6 is generated, described compound 2- (triphenyl first sulfydryl) ethamine, its dosage is 0.5-3.0 mole of compound 5
Equivalent；Described solvent be tetrahydrofuran, ether, 1,4- dioxane, dichloromethane, chloroform, toluene, ethyl acetate,
Methanol, ethanol, water, acetonitrile, DMF, DMSO or their mixed solvent, described reaction temperature are -10-100 DEG C；
4th step：
The valine (compound 7) of amido protecting is in the presence of certain alkali and a kind of additive, in suitable solvent and instead
Answer under temperature conditionss, react some hours, activate the carboxyl of valine, then with compound 6, generate compound 8, described change
Compound 7, its dosage are the 0.5-5.0 molar equivalents of compound 6；Described alkali refers to potassium carbonate, sodium carbonate, saleratus, carbon
Sour hydrogen sodium, potassium hydroxide, sodium hydroxide, pyridine, 4-dimethylaminopyridine, 2,6- lutidines, triethylamine, DIPEA, N-
Methyl morpholine or their any combination, its dosage are the 0.01-3.0 molar equivalents of compound 6；Described additive refers to 2,
4,6-Cl3-C6H4COCl, MeOCOCl, EtOCOCl, its dosage are the 0.5-3.0 molar equivalents of compound 6；Described solvent
For tetrahydrofuran, ether, 1,4- dioxane, dichloromethane, chloroform, toluene, ethyl acetate, acetonitrile, DMF, DMSO or
Their mixed solvent, described reaction temperature are -10-100 DEG C；
5th step：
Compound 8 is in the presence of certain alkali, under the conditions of suitable solvent and reaction temperature, reacts some hours, generation
Compound 9, described alkali refer to diethylamine, dimethylamine, nafoxidine, piperidines, morpholine or their any combination, and its dosage is
The 1.0-40 molar equivalents of compound 8；Described solvent is tetrahydrofuran, ether, 1,4- dioxane, dichloromethane, trichlorine
Methane, toluene, ethyl acetate, acetonitrile, DMF, DMSO or their mixed solvent, described reaction temperature are -10-100 DEG C；
6th step：
Compound 9 and a kind of organic acid, i.e. compound 10, in the presence of activator and condensing agent, in suitable solvent and
Under the conditions of reaction temperature, react some hours, generate compound 11, described compound 10, its dosage is the 0.5- of compound 9
2.0 molar equivalent；Described activator refers to HOBT, HATU, HOAT or PyBOC, and its dosage is that the 0.5-2.0 of compound 9 rubs
That equivalent；Described condensing agent refers to DCC or EDCI, and its dosage is the 0.5-2.0 molar equivalents of compound 9；Described solvent
For tetrahydrofuran, ether, 1,4- dioxane, dichloromethane, chloroform, toluene, ethyl acetate, acetonitrile, DMF, DMSO or
Their mixed solvent, described reaction temperature are -10-100 DEG C；
7th step：
Compound 11 is in the presence of certain organic acid, under the conditions of suitable solvent and reaction temperature, reacts some hours,
Generate compound 12, certain described organic acid refer to acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, p-methyl benzenesulfonic acid,
Boron trifluoride, Boron tribromide, hydrogen chloride, perchloric acid, tetrafluoro boric acid, sulfuric acid, its dosage are the 0.01-1.0 of suitable solvent volume
Times or for suitable solvent saturated solution；Described solvent refers to tetrahydrofuran, ether, 1,4- dioxane, dichloromethane, three
Chloromethanes, toluene, ethyl acetate, acetonitrile, DMF, DMSO or their mixed solvent, described reaction temperature are -10-100 DEG C；
8th step：
Compound 12 is in the presence of certain alkali and condensing agent, and under the conditions of suitable solvent and reaction temperature, reaction is some
Hour, the compound 13 of big ring is generated, certain described alkali refers to potassium carbonate, sodium carbonate, saleratus, sodium acid carbonate, hydrogen-oxygen
Change potassium, sodium hydroxide, pyridine, 4-dimethylaminopyridine, 2,6- lutidines, triethylamine, DIPEA, N-methylmorpholine or
Their any combination, its dosage are the 1-10 molar equivalents of compound 12；Described condensing agent refer to HOBT, HATU, HOAT,
PyBOC, DCC, EDCI or its any combination, its dosage is the 1.0-5.0 molar equivalents of compound 12；Described solvent refers to four
Hydrogen furans, ether, 1,4- dioxane, dichloromethane, chloroform, toluene, ethyl acetate, acetonitrile, DMF, DMSO or they
Mixed solvent, described reaction temperature be -10-100 DEG C；
9th step：
In logical formula (I), work as R2For hydrogen when, if desired for thiazoline ring carry out aromatisation generation thiazole ring, then can lead to
Cross the realization of the 9th step experimental implementation.I.e.：
Compound 13 (i.e. 7 be R or S configurations compound 13b or compound 13c：R2=H, 7,8- positions are singly-bound)
In the presence of certain organic base and halo agent, under the conditions of suitable solvent and reaction temperature, react some hours, generate aromatisation
Product (i.e. compound 13d：R2=H, 7,8- positions are double bond), certain described organic base refers to DBU, pyridine, 4-N, N- bis-
Dimethylaminopyridine, 2,6- lutidines, triethylamine, DIPEA, N-methylmorpholine or their any combination, its dosage are
1-10 times of compound 13b or compound 13c；Described halo agent refers to NIS (N- N-iodosuccinimides), NBS (N- bromos
Succimide), NCS (N- chlorosuccinimides), BrCCl3Or its any combination, its dosage is compound 13b or chemical combination
Thing 13c 1.0-5.0 molar equivalents；Described solvent refers to tetrahydrofuran, ether, 1,4- dioxane, dichloromethane, trichlorine
Methane, toluene, ethyl acetate, acetonitrile, DMF, DMSO or their mixed solvent, described reaction temperature are -10-100 DEG C；
10th step：
Compound 13 is in the presence of certain organic acid and reducing agent, under the conditions of suitable solvent and reaction temperature, reaction
Some hours, generate compound 14, certain described organic acid refers to acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, right
Toluenesulfonic acid, boron trifluoride, Boron tribromide, hydrogen chloride, perchloric acid, tetrafluoro boric acid, sulfuric acid, its dosage are that its dosage is suitable molten
0.01-1.0 times or the saturated solution for suitable solvent of agent volume；Described reducing agent refers to i-Pr3SiH or Et3SiH, it is used
Amount is the 1.0-5.0 molar equivalents of compound 12；Described solvent refers to tetrahydrofuran, ether, 1,4- dioxane, dichloromethane
Alkane, chloroform, toluene, ethyl acetate, acetonitrile, DMF, DMSO or their mixed solvent, described reaction temperature are -10-
100℃；
11st step：
Compound 14 is in the presence of certain alkali and acyl chlorides or acid anhydrides or alkylating agent, in suitable solvent and reaction temperature condition
Under, some hours are reacted, generate the compound 15 of big ring, certain described alkali refers to potassium carbonate, sodium carbonate, saleratus, carbon
Sour hydrogen sodium, potassium hydroxide, sodium hydroxide, pyridine, 4-dimethylaminopyridine, 2,6- lutidines, triethylamine, DIPEA, N-
Methyl morpholine or their any combination, its dosage are the 1-10 molar equivalents of compound 13；Described acyl chlorides or acid anhydrides or hydrocarbon
Agent refers to R3I, R3SS(O)R3, R3COCl, R3NHCOCl, R3OCOCl, (R3O)2P (O) Cl, wherein R3Alkane selected from C1-C10
Base, aromatic radical, the aromatic radical or R for being connected to C1-C10 alkyl3Alkyl or C1- selected from the C1-C10 for being connected to aryl
The combination of C10 alkyl and aryl cyclization, described acyl chlorides or acid anhydrides or alkylating agent dosage are 1.0-10 moles of compound 13
Equivalent；Described solvent refers to tetrahydrofuran, ether, 1,4- dioxane, dichloromethane, chloroform, toluene, acetic acid second
Ester, acetonitrile, DMF, DMSO or their mixed solvent, described reaction temperature are -10-100 DEG C；
The present invention is in described above, the relevant functional group, chemical reagent or the solvent code name that are related to, with reference to international life
Name rule or generic model, relevant 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.
Present invention also offers the drug ingedient being made up of described compound and more than one adjuvant, wherein medicine into
Containing the compound described in formula in point, the drug ingedient is used to suppress mammalian cell proliferation, that is, gives with tumour
Mammal takes the medicine described in the formula for the treatment of effective dose, and the tumour that wherein mammal suffers from includes solid tumor, cancer,
Lymthoma, Hodgkin's disease, tumor disease, newborn knurl disease etc..
Present invention also offers a kind of pharmaceutical composition, and it contains the compound of the formula of the present invention for the treatment of effective dose
Or its salt and pharmaceutical carriers, and purposes of the pharmaceutical composition in antineoplastic is prepared.In other words, lead in of the invention
The salt of compound shown in formula (I) can be the form of free form and acid addition salt or carboxylate.The example of acid addition salt
Including inorganic acid salt such as：Sulfate, nitrate, hydrobromate, hydriodate, phosphate etc., or acylate such as tartaric acid
Salt, acetate, mesylate, benzene sulfonate, toluene fulfonate, citrate, maleate, fumarate, lactate etc..
Embodiment
It is used to further describe the present invention with reference to embodiments, but these embodiments are not intended to limit the scope of the invention.
The compound 15a of embodiment 1 synthesis
1st step：
Compound 1 (5g, 37.3mmol) is added in the single-necked flask of 100mL dried and cleans, adds the concentrated sulfuric acid (30mL), will
Device, which is placed in ice-water bath, is cooled to 0 DEG C, adds chloraldurate (6.17mg, 37.3mmol), recovers to continue to stir to room temperature environment
Mix reaction 10 hours.TLC monitoring reactions are complete, stop reaction.Reaction solution is poured into 100mL frozen water along wall, liquid separation, aqueous phase is used
DCM extracts (100mL × 3), merges organic phase, washes (100mL), and saturated common salt washing (100mL × 1), anhydrous sodium sulfate is done
It is dry, filtering, remove solvent under reduced pressure and obtain compound as white solid 9.4g, the yield 95% of compound 3.1H NMR(400MHz,
CDCl3) δ 5.90 (s, 1H), 4.90 (s, 1H), 3.14 (dd, J1=20Hz, J2=4.0Hz, 1H), 3.06 (dd, J1=20Hz,
J2=4.0Hz, 1H) .ESI-MS (m/z):285[M+Na]+.m.p.:70.8-71.8℃.
2nd step：
Compound 3 (1.06g, 4mmol), 2- (trimethylsilyl) ethanol (chemical combination are added in the single port bottle of 100mL dried and cleans
Thing 4,0.29mL, 2mmol), DMAP (25mg, 0.2mmol), the anhydrous DCM dissolvings of 50mL are added, device is placed in ice-water bath and dropped
Temperature is added drop-wise in above-mentioned reaction solution after EDCI (767mg, 4mmol) is dissolved in the anhydrous DCM of 10mL, recovered to room temperature ring to 0 DEG C
Continue stirring reaction and stay overnight in border.TLC monitoring reactions are complete, remove solvent under reduced pressure, and residue is dissolved (200mL) with EA, washing
(50mL × 3), saturated common salt washing (50mL), anhydrous sodium sulfate drying, filtering, remove solvent, silica gel column chromatography separation under reduced pressure
Purified product, obtain oily compound 602mg, the yield 83% of compound 5.1H NMR(400MHz,CDCl3) δ 5.91 (d, J=
4.0Hz, 1H), 4.84-4.86 (m, 1H), 4.22-4.27 (m, 2H), 3.04 (dd, J1=16, J2=4.0Hz, 1H), 2.95
(dd, J1=16Hz, J2=4.0Hz, 1H), 1.00-1.04 (m, 2H), 0.05 (s, 9H) .ESI-MS (M/Z):385[M+Na]+.
3rd step：
Addition 2- triphenyl first mercaptoethylmaines (2.39g, 6.6mmol) in 100mL single port bottles, compound 5 (1.75g,
5.5mmol), the dissolving of 50mL absolute ethyl alcohols is added, stirring reaction is stayed overnight in room temperature environment, and TLC monitoring reactions are complete, remove under reduced pressure
Solvent, silica gel column chromatography separating purification product (DCM/MeOH=70/1), obtain oily liquids compound 2.06g, the yield of compound 6
90%.1H NMR(400MHz,CDCl3) δ 7.30-7.53 (m, 15H), 7.05 (t, J=4.0Hz, 1H), 4.47-4.49 (m,
1H), 4.30-4.34 (m, 2H), 4.00 (d, J=4.0Hz, 1H), 3.14-3.28 (m, 2H), 3.02 (dd, J1=16Hz, J2=
4.0Hz, 1H), 2.73 (dd, J1=16Hz, J2=8.0Hz, 1H), 2.51 (t, J=4.0Hz, 2H), 1.11 (t, J=8.0Hz,
2H),0.15(s,9H).ESI-MS(m/z):536.7[M+H]+.
4th step：
Fmoc-L-Valine (compound 7,2.79g, 8.21mmol) is added in 50mL single port bottles, adds the anhydrous DCM of 20mL
Dissolving, device is placed in ice-water bath and is cooled to 0 DEG C, DIPEA (2.72mL, 16.5mmol) is added dropwise, 2,4,6- benzoyls are added dropwise
Chlorine (1.72mL, 11.0m mol), is added dropwise, and is kept for 0 DEG C continue stirring reaction 1.5 hours, by compound 6 (2.89g,
5.48mmol) and DMAP (736mg, 6.02mmol) is dissolved in the anhydrous DCM of 10mL in the rear above-mentioned reaction solution of instillation, is recovered to room temperature
Environment continues stirring reaction 3 hours, and TLC monitoring reactions are complete, add DCM (100mL), wash (30mL × 3), saturated aqueous common salt
Wash (30mL × 1), anhydrous sodium sulfate drying, filter, remove solvent, silica gel column chromatography separating purification product (elution requirement under reduced pressure：
PE/EA=5/1), white solid powder shape compound 3.08g, the yield 66% of compound 8 are obtained.1H NMR(400MHz,CDCl3)δ
7.91 (d, J=8.0Hz, 2H), 7.69 (t, J=4.0Hz, 2H), 7.30-7.56 (m, 19H), 6.82 (t, J=4.0Hz, 1H),
5.63-5.65 (m, 1H), 5.28 (d, J=4.0Hz, 1H), 4.48-4.59 (m, 2H), 4.36-4.39 (m, 1H), 4.27-4.32
(m, 2H), 3.14-3.19 (m, 2H), 3.19 (dd, J1=16Hz, J2=4.0Hz, 1H), 2.90 (dd, J1=16Hz, J2=
8.0Hz, 1H), 2.49-2.55 (m, 2H), 2.33-2.42 (m, 1H), 1.09 (t, J=8.0Hz, 2H), 1.08 (d, J=
8.0Hz, 2H), 1.02 (d, J=8.0Hz, 3H) .ESI-MS (m/z):879.4[M+Na]+.
5th step：
Compound 8 (1.33g, 1.55mmol) is added in 100ml single port bottles, the dissolving of 20mL anhydrous acetonitriles is added, is added dropwise two
Ethylamine solution (0.8mL, 7.8mmol), reaction 3 hours is stirred at room temperature, TLC monitoring reactions are complete, remove solvent, silicagel column under reduced pressure
Chromatography purified product, obtain oily liquids compound 660mg, the yield 68% of compound 9.1H NMR(400MHz,CDCl3)δ
7.19-7.39 (m, 15H), 6.52 (t, J=8.0Hz, 1H), 5.46-5.49 (m, 1H), 4.10-4.20 (m, 2H), 3.29 (d, J
=4.0Hz, 1H), 3.01-3.11 (m, 2H), 2.79-2.94 (m, 2H), 2.38 (t, J=8.0Hz, 2H), 1.97-2.06 (m,
1H), 0.95-0.98 (m, 2H), 0.93 (d, J=8.0Hz, 3H), 0.86 (d, J=4.0Hz, 3H), 0.02 (s, 9H) .ESI-MS
(M/Z):635.3[M+H]+.
6th step：
Compound 10a (1.53g, 2.40mmol), compound 9 (715mg, 2mmol), HOBT are added in 100mL single port bottles
(325mg, 2.40mmol), the anhydrous DCM dissolvings of 20mL are added, after EDCI (461mg, 2.4mmol) is dissolved in the anhydrous DCM of 10mL
Instill in above-mentioned reaction solution, stirring reaction 3 hours in room temperature environment, TLC monitoring reactions are complete, remove solvent, residue under reduced pressure
Dissolved with 200mL EA, saturated sodium bicarbonate solution is washed (50mL × 3), and saturated common salt washing (50mL × 1), anhydrous sodium sulfate is done
It is dry, filtering, remove solvent under reduced pressure, silica gel column chromatography separating purification product, obtain white solid powder shape compound 1.5g, compound
11a yields 77%.1H NMR(600MHz,CDCl3) δ 7.96 (s, 1H), 7.26-7.48 (m, 15H), 7.16 (t, J=6.0Hz,
1H), 5.60 (dd, J1=12, J2=6.0Hz, 1H), 5.36 (s, 1H), 4.71 (d, J=6.0Hz, 2H), 4.30 (dd, J1=
6.0Hz, J2=6.0Hz, 1H), 3.74 (d, J=12Hz, 1H), 3.27-3.33 (m, 1H), 3.14 (d, J=6.0Hz, 1H),
3.07 (dd, J1=18Hz, J2=6.0Hz, 1H), 2.97-3.02 (m, 1H), 2.77 (dd, J1=18Hz, J2=12Hz, 1H),
2.58 (dt, J1=6.0Hz, J2=12Hz, 1H), 2.46 (dt, J1=6.0Hz, J2=12Hz, 1H), 2.32-2.37 (m,
1H), 1.58 (s, 3H), 1.54 (s, 9H), 1.05 (dd, J1=12Hz, J2=6.0Hz, 2H), 0.10 (s, 9H)13C NMR
(150MHz,CDCl3)δ178.01,172.00,171.51,171.31,170.10,166.42,157.48,150.41,
145.56,131.47,129.80,128.61,123.57,86.73,82.42,86.73,82.42,72.71,68.60,66.21,
60.14,44.24,42.60,40.39,38.85,33.34,31.78,30.18,25.67,21.13,19.59,19.15.
ESI-MS(m/z):996.4[M+Na]+.m.p.:62.5-64.6℃.
7th step：
Compound 11a (293mg, 0.3mmol) is added in 25mL single port bottles, the anhydrous DCM dissolvings of 15mL is added, device is put
0 DEG C is cooled in ice-water bath, TFA (DCM/TFA=5/1) is added dropwise, recovers to continue stirring reaction 12 hours to room temperature, TLC prisons
It is complete to survey reaction, removes solvent under reduced pressure, residue is removed under reduced pressure after being dissolved with 50mL toluene, is repeated twice, and it is anhydrous to add 50mL
Ether separates out a large amount of compound as white solid immediately, the compound as white solid 12a obtained after filtration drying, is directly used in next
Step reaction.
8th step：
It is transferred in another 500ml single port bottles, adds after compound as white solid 12a is dissolved in the anhydrous DCM of 10mL
DIPEA (0.3mL, 1.8mmol) is added dropwise after the dilution of 300ml anhydrous acetonitriles, at room temperature stirring reaction 10 minutes, by HATU
(229mg, 0.6mmol) and HOBT (82mg, 0.6mmol) are added dropwise in above-mentioned reaction solution after being dissolved in 10mL anhydrous acetonitriles, room
The lower stirring reaction of temperature 16 hours, TLC monitoring reactions are complete, remove solvent under reduced pressure, residue is dissolved in 200ml EA, 50mL saturations
Sodium bicarbonate solution is washed (50mL × 3), saturated common salt washing (50mL × 1), anhydrous sodium sulfate drying, filtering, is removed under reduced pressure molten
Agent, silica gel column chromatography separating purification product (elution requirement：EA), white solid 144mg, compound 13a yields 64% are obtained.1H
NMR(400MHz,CDCl3) δ 7.72 (s, 1H), 7.57 (t, J=4.0Hz, 1H), 7.41 (d, J=8.0Hz, 1H), 7.16-
7.30 (m, 15H), 6.54 (t, J=8.0Hz, 1H), 5.46 (t, J=4.0Hz, 1H), 5.30 (s, 1H), 5.00 (dd, J1=
16, J2=4.0Hz, 1H), 4.53 (dd, J1=8.0, J2=4.0Hz, 1H), 4.07 (dd, J1=20Hz, J2=8.0Hz,
1H), 3.92 (d, J=12Hz, 1H), 3.32 (d, J=12Hz, 1H), 3.20-3.29 (m, 1H), 3.06-3.17 (m, 2H),
2.72-2.80 (m, 1H), 2.36 (t, J=8.0Hz, 2H), 2.01-2.13 (m, 2H), 1.69 (s, 3H), 0.84 (d, J=
4.0Hz, 3H), 0.70 (d, J=8.0Hz, 3H) [α]20 D:+ 0.256 (c=0.39, CHCl3).
ESI-HRMS calcd for C39H41N5O5S3[M+H]+:778.2162found:778.2168.
10th step：
Compound 13a (144mg, 0.2mmol) is added in 50mL single port bottles, the anhydrous DCM dissolvings of 20mL is added, device is put
0 DEG C is cooled in ice-water bath, adds tri isopropyl silane (0.082mL, 0.4 mmol), adds trifluoroacetic acid (1mL, 0.2M
in S1), stirring reaction 1.5 hours, TLC monitorings reaction at room temperature completely, is depressurized and just removes solvent, silica gel column chromatography separation product
(elution requirement：EA), white solid powder shape compound 72mg, 14a yield 70% is obtained.1H NMR(600MHz,CDCl3)δ7.77
(s, 1H), 7.75 (s, 1H), 7.25 (d, J=6.0Hz, 1H), 6.75 (brs, 1H), 5.57 (t, J=6.0Hz, 1H), 5.16
(dd, J1=12Hz, J2=6.0Hz, 1H), 4.57 (dd, J1=12Hz, J2=6.0Hz, 1H), 4.39-4.51 (m, 1H),
4.32 (dd, J1=18Hz, J2=6.0Hz, 1H), 3.91 (dd, J1=24, J2=12Hz, 2H), 3.52-3.58 (m, 1H),
3.89 (d, J=6.0Hz, 1H), 3.33-3.36 (m, 2H), 3.25 (dd, J1=12Hz, J2=6.0Hz, 1H), 2.82 (dd, J1
=12Hz, J2=6.0Hz, 1H), 2.64-2.70 (m, 1H), 2.45-2.51 (m, 2H), 2.10-2.14 (m, 2H), 1.81 (s,
3H), 0.85 (d, J=6.0Hz, 3H), 0.74 (d, J=6.0Hz, 3H)13C NMR(150MHz,CDCl3)δ172.79,
169.56,168.10,168.30,147.19,124.52,84.42,84.26,71.87,60.45,58.34,43.15,42.66,
41.47,38.46,33.03,32.00,29.75,29.43,24.73,24.48,19.21,17 .27,14.23 (d, J=13.5)
[α]20 D:- 6.061 (c=0.132, CHCl3)
ESI-HRMS calcd for C20H27N5O5S3[M+H]+:514.1247found:514.1245.
11st step：
Compound 14a (29mg, 0.057mmol) and DCM (20mL) is added in 25mL single-necked flasks, device is placed in ice bath
In be cooled to 0 DEG C, triethylamine solution (0.016mL, 0.114mmol) is added dropwise, adds caprylyl chloride (0.068mL, 0.339mmol),
Stirring reaction 2 hours at room temperature, TLC monitoring reactions are complete, and device is again placed in be cooled to 0 DEG C in ice-water bath, adds 10mL
Reaction is quenched in methanol solution, removes solvent under reduced pressure, and residue is dissolved in 150mlLDCM, saturated sodium bicarbonate solution wash (30mL ×
3) (30mL × 1), is washed, anhydrous sodium sulfate drying, filtering, removes the solvent, (elution of silica gel column chromatography separating purification product under reduced pressure
Condition：EA), compound as white solid 23mg, 15a yield 63% is obtained.1H NMR(600MHz,CDCl3)δ7.76(s,1H),7.66
(brs, 1H), 7.24 (d, J=6.0Hz 1H), 6.62 (brs, 1H), 5.54 (s, 1H), 5.15 (d, J=12Hz, 1H), 4.58-
4.60 (m, 1H), 4.32 (d, J=12Hz, 1H), 3.94 (d, J=12Hz, 1H), 3.40-3.41 (m, 2H), 3.36 (d, J=
12Hz, 1H), 3.24 (d, J=12Hz, 1H), 2.90-2.97 (m, 2H), 2.79 (d, J=12Hz, 1H), 2.50 (t, J=
12Hz, 2H), 2.13-2.14 (m, 1H), 1.83 (s, 3H), 1.62 (d, J=6.0Hz, 2H), 1.26-1.33 (m, 8H), 0.88
(t, J=6.0Hz, 3H), 0.86 (d, J=6.0Hz, 3H), 0.74 (d, J=6.0Hz, 3H)13C NMR(150MHz,CDCl3)δ
173.27,169.85,168.63,168.08,72.23,58.64,44.55,43.57,41.94,40.04,38.72,33.49,
32.00,30.10,29.28,28.47,25.97,25.06,22.98,19.56,17.61,14.45.[α]20 D:- 2.607 (c=
0.537,CHCl3).ESI-HRMS calcd for C28H41N5O6S3[M+H]+640.2292found:640.2293。
Embodiment 2 compound 15b and 15c synthesis
Intermediate 9 prepared by method and experimental procedure 1-5 according to embodiment 1, then according to the method and reality of embodiment 1
Test step 6-11 prepare compounds 13b and compound 13c：
6th step：
Method 1
In the round-bottomed flask of 100mL dried and cleans add compound 9 (413mg, 1.2mmol), compound 10bc (890mg,
1.4mmol) and HOBT (190mg, 1.4mmol), anhydrous DCM (20mL) dissolvings are added, EDCI (269mg, 1.4mmol) is dissolved in
Instilled after in anhydrous DCM in above-mentioned reaction solution, drop finishes, and stirring reaction is stayed overnight at room temperature, and TLC monitoring reactions are complete, remove under reduced pressure
Solvent, residue are dissolved in EA (200mL), and saturated sodium bicarbonate solution is washed (50mL × 3), are washed (50mL), unsaturated carbonate hydrogen
Sodium solution is washed (50mL × 2), anhydrous sodium sulfate drying, removes solvent, silica gel column chromatography separating purification product (elution bar under reduced pressure
Part：PE/EA=4/3), it is dried in vacuo, obtains white foam solid compound 842mg, compound 11bc yield 73%.ESI-MS
(m/z):960.4[M+H]+。
Method 2
In the single port bottle of 100mL dried and cleans add compound 9 (550mg, 1.6mmol), compound 10bc (996mg,
1.6mmol) and HATU (761mg, 2mmol), dry DMF (50mL) dissolving is added, DIPEA (0.8mL, 4.8mmol), drop is added dropwise
Finish, continue stirring reaction at room temperature 2 hours, TLC monitoring reactions are complete, remove solvent, silica gel column chromatography separating purification production under reduced pressure
Thing, obtain solid white foam shape compound 863mg, compound 11bc yield 56%.ESI-MS(m/z):960.4[M+H]+.
7th step：
Compound 11bc (288mg, 0.3mmol) is added in the single-necked flask of 50mL dried and cleans, adds anhydrous DCM
(15ml) is dissolved, and device is placed in ice-water bath and is cooled to 0 DEG C, and trifluoroacetic acid solution (3mL) is slowly added dropwise, and drop finishes, and recovers extremely
Room temperature continues stirring reaction 12 hours, and TLC monitoring reactions are complete, remove solvent and unnecessary trifluoroacetic acid under reduced pressure, add toluene
Solution (25mL × 3) dissolution residual substance, remove solvent under reduced pressure, add absolute ether (15mL), there is compound as white solid precipitation,
Incline supernatant, is repeated twice, vacuum drying white powdery solids compound 249mg, compound 12bc yields 95%.
ESI-MS(m/z):782.2[M+Na]+.
8th step：
After compound 12bc (437mg, 0.5mmol) is dissolved in the anhydrous DCM of 10mL, another dried and clean is transferred to
In 1000mL single port bottles, after adding anhydrous acetonitrile (500mL) dilution, DIPEA (0.5mL, 3.0mmol) is added dropwise, stirs at room temperature
Reaction 10 minutes, is added dropwise to after HATU (381mg, 1.0mmol) HOBT (136mg, 1.0mmol) is dissolved in 10mL anhydrous acetonitriles
In above-mentioned reaction solution, stirring reaction 16 hours, TLC monitorings reaction at room temperature completely, removes solvent under reduced pressure, residue is dissolved in
In 200mlEA, 50mL saturated sodium bicarbonate solutions are washed (50mL × 3), and saturated common salt washing (50mL × 1), anhydrous sodium sulfate is done
It is dry, filtering, remove solvent, silica gel column chromatography separating purification product (elution requirement under reduced pressure：EA), compound as white solid is obtained
186mg, compound 13b and 13c total recovery 50%, the two ratio is about 1：1, isolated and purified by preparation HPLC, can be with
Respectively obtain compound 13b and 13c.ESI-MS(m/z):764.2[M+Na]+.
10th step：
Compound 13b or 13c (144mg, 0.2mmol) are added in 50mL single port bottles, adds the anhydrous DCM dissolvings of 20mL, will
Device, which is placed in ice-water bath, is cooled to 0 DEG C, adds tri isopropyl silane (0.082mL, 0.4mmol), add trifluoroacetic acid (1mL,
0.2M in S1), stirring reaction 1.5 hours, TLC monitorings reaction at room temperature completely, is depressurized and just removes solvent, silica gel column chromatography separation
Product (elution requirement：EA), white solid powder shape compound, compound 14b or 14c yield 70% are obtained.ESI-MS(m/
z):500.1[M+H]+.
11st step：
Compound 14b or 14c (29mg, 0.057mmol) and DCM (20mL) are added in 25mL single-necked flasks, device is put
Be cooled to 0 DEG C in ice bath, triethylamine solution (0.016mL, 0.114mmol) be added dropwise, add caprylyl chloride (0.068mL,
0.339mmol), stirring reaction 2 hours, TLC monitorings reaction completely, device are again placed in be cooled to 0 in ice-water bath at room temperature
DEG C, add 10mL methanol solutions and reaction is quenched, remove solvent under reduced pressure, residue is dissolved in 150mlLDCM, saturated sodium bicarbonate
Solution is washed (30mL × 3), is washed (30mL × 1), anhydrous sodium sulfate drying, filtering, removes solvent, silica gel column chromatography separation under reduced pressure
Purified product (elution requirement：EA), compound as white solid 23mg, 15b or 15c yield 63% is obtained.ESI-MS(m/z):626.2
[M+H]+。
The compound 15d of embodiment 3 synthesis
As described in Example 2 with experimental procedure prepare compound 13a and 13b mixture, then using 13a/13b as original
Material, passes through following steps prepare compound 15d：
9th step：
Compound 13a/13b (223mg, 0.3mmol) is added in the single port bottle of 25mL dried and cleans, it is molten to add anhydrous DCM
Solution, device is placed in ice-water bath and is cooled to 0 DEG C, DBU solution (0.224mL, 1.5mmol) is added dropwise, by BrCCl3(0.15ml,
Anhydrous DCM (5mL) 1.5mmol) is dissolved in instill afterwards in above-mentioned reaction solution, drop finishes, and recovers to continue stirring reaction 7 hours to room temperature,
TLC monitoring reactions are complete, remove solvent, column chromatographic isolation and purification product (elution requirement under reduced pressure：PE/EA=1/8), it is dried in vacuo
Compound as white solid 50mg, compound 13d yields 23%.1H NMR(400MHz,CDCl3)δ8.08(s,1H),7.90(s,
1H), 7.83 (d, J=12Hz, 1H), 7.58 (t, J=8.0Hz, 1H), 7.17-7.38 (m, 15H), 7.10 (t, J=4.0Hz,
1H), 5.10 (d, J=4.0Hz, 1H), 4.70 (d, J=8.0Hz, 2H), 4.37 (brs, 1H), 3.02-3.09 (m, 2H), 288
(dd, J1=16Hz, J2=4.0Hz, 1H), 2.84 (dd, J1=12Hz, J2=4.0 Hz, 1H), 2.32-2.40 (m, 2H),
2.26-2.31 (m, 1H), 1.01 (t, J=4.0Hz, 6H) .ESI-MS (m/z):762.2[M+Na]+.
10th step：
Compound 13b or 13c (144mg, 0.2mmol) are added in 50mL single port bottles, adds the anhydrous DCM dissolvings of 20mL, will
Device, which is placed in ice-water bath, is cooled to 0 DEG C, adds tri isopropyl silane (0.082mL, 0.4mmol), add trifluoroacetic acid (1mL,
0.2M in S1), stirring reaction 1.5 hours, TLC monitorings reaction at room temperature completely, is depressurized and just removes solvent, silica gel column chromatography separation
Product (elution requirement：EA), white solid powder shape compound, compound 14d yield 65% are obtained.ESI-MS(m/z):
498.1[M+H]+.
11st step：
Compound 14d (29mg, 0.057mmol) and DCM (20mL) is added in 25mL single-necked flasks, device is placed in ice bath
In be cooled to 0 DEG C, triethylamine solution (0.016mL, 0.114mmol) is added dropwise, adds caprylyl chloride (0.068mL, 0.339mmol),
Stirring reaction 2 hours at room temperature, TLC monitoring reactions are complete, and device is again placed in be cooled to 0 DEG C in ice-water bath, adds 10mL
Reaction is quenched in methanol solution, removes solvent under reduced pressure, and residue is dissolved in 150mlLDCM, saturated sodium bicarbonate solution wash (30mL ×
3) (30mL × 1), is washed, anhydrous sodium sulfate drying, filtering, removes the solvent, (elution of silica gel column chromatography separating purification product under reduced pressure
Condition：EA), compound as white solid 23mg, 15d yield 57% is obtained.ESI-MS(m/z):624.2[M+H]+。
The test case of embodiment 4
Part of compounds srb assay of the present invention is to EBC-1 (human lung carcinoma cell line, c-Met gene magnifications), EBC-1/
SR (human lung carcinoma cell line, c-Met gene magnifications, SGX-523 persisters) and NCI-H3122 (human lung carcinoma cell line, EML4-ALK
(variant1) influence of its cell proliferation (72 hours) ability), is investigated respectively, and is made with the medicine SAHA with Clinical practice
Compare.
Pass through step：Cell in exponential phase is seeded to 96 well culture plates by proper density, per the μ L of hole 90, culture
After overnight, the medicine effect 72h of various concentrations is added, each concentration sets three wells, and sets the Vehicle controls and nothing of respective concentration
Cell zeroing hole.After effect terminates, attached cell inclines nutrient solution, adds 10% (w/v) trichloroacetic acid (100 μ L/ holes) in 4 DEG C
Fixed 1h, then with distilled water flushing five times, after drying at room temperature, added per hole SRB solution (Sigma, St.Louis, MO,
U.S.A) the 100 μ L that (4mg/mL, are dissolved in 1% glacial acetic acid), after being incubated dyeing 15min at room temperature, rinsed five times and washed with 1% glacial acetic acid
Remove uncombined SRB, after drying at room temperature, the 190 ELIASA measure of μ L, SpectraMax of 10mM Tris solution 100 is added per hole
Optical density (OD values) under 560nm wavelength.
The IC that testing compound is bred to EBC-1 cells50Value is as shown in table 1, to the IC of EBC-1/SR cells propagation50Value
As shown in table 2, the IC that compound is bred to NCI-H3122 cells50Value is as shown in table 3.As a result show, chemical combination of the present invention
Thing has the function that the medicine SAHA than Clinical practice has stronger suppression tumor cell proliferation.
Inhibited proliferation of the compound of table 1. to EBC-1 cells
Proliferation inhibition rate (%) of the compound of table 2. to EBC-1/SR cells
Proliferation inhibition rate (%) of the compound of table 3. to NCI-H3122 cells
Claims (8)
1. the compound or its salt shown in logical formula (I)：
Wherein：
R1Selected from H, R3, R3S, R3CO, R3NHCO, R3OCO,(R3O)2P(O)；
It is double bond either singly-bound connection between 7/8 of logical formula (I)；
When between 7/8 of logical formula (I) being singly-bound connection, the spatial configuration of 7 is R or S configurations；When 7/8 of logical formula (I)
Between be double bond connection when, R2It is not present；
R2Selected from H, R3；
R3Selected from C1-C10Alkyl, aromatic radical, or selected from being connected to the aromatic radical of C1-C10 alkyl or be connected to the C1- of aryl
The combination of C10 alkyl or C1-C10 alkyl and aryl cyclization.
2. the preparation method of compound described in logical formula (I), it is characterised in that carried out by synthetic route one：
Including step,
1st step：
L MALIC ACID (compound 1) and chloraldurate (compound 2) are in the presence of a kind of acid, in suitable solvent and reaction temperature
Under the conditions of, react some hours, generate compound 3, described chloraldurate, its dosage is that it is that the 0.5-3.0 of compound 1 rubs
That equivalent；Described acid refers to hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid, the tetrafluoro boric acid of various concentrations；Described solvent is water, four
Hydrogen furans, Isosorbide-5-Nitrae-dioxane, ethanol, methanol, acetic acid, acetonitrile, DMF, DMSO or their mixed solvent, or without molten
Agent；Described reaction temperature is -10-100 DEG C；
2nd step：
Compound 3 and 2- (trimethylsilyl) ethanol (compound 4) in the presence of a kind of alkali and condensing agent, in suitable solvent and
Under the conditions of reaction temperature, react some hours, generate compound 5, described compound 4, its dosage is the 0.5- of compound 3
5.0 molar equivalent；Described alkali refers to potassium carbonate, sodium carbonate, saleratus, sodium acid carbonate, potassium hydroxide, sodium hydroxide, pyrrole
Pyridine, 4-dimethylaminopyridine, 2,6- lutidines, triethylamine, DIPEA or N-methylmorpholine, its dosage are compounds 3
0.01-3.0 molar equivalents；Described condensing agent refers to DCC, EDCI, and its dosage is the 0.1-3.0 molar equivalents of compound 3；Institute
The solvent stated be tetrahydrofuran, ether, 1,4- dioxane, dichloromethane, chloroform, toluene, ethyl acetate, acetonitrile,
DMF, DMSO or their mixed solvent, described reaction temperature are -10-100 DEG C；
3rd step：
Compound 5 and 2- (triphenyl first sulfydryl) ethamine, under the conditions of suitable solvent and reaction temperature, react some hours, raw
Into compound 6, described compound 2- (triphenyl first sulfydryl) ethamine, its dosage is the 0.5-3.0 molar equivalents of compound 5；
Described solvent be tetrahydrofuran, ether, 1,4- dioxane, dichloromethane, chloroform, toluene, ethyl acetate, methanol,
Ethanol, water, acetonitrile, DMF, DMSO or their mixed solvent, described reaction temperature are -10-100 DEG C；
4th step：
The valine of the amido protecting of compound 7 is in the presence of alkali and a kind of additive, in suitable solvent and reaction temperature condition
Under, some hours are reacted, activate the carboxyl of valine, then with compound 6, generate compound 8, described compound 7, it is used
Amount is the 0.5-5.0 molar equivalents of compound 6；Described alkali refers to potassium carbonate, sodium carbonate, saleratus, sodium acid carbonate, hydrogen-oxygen
Change potassium, sodium hydroxide, pyridine, 4-dimethylaminopyridine, 2,6- lutidines, triethylamine, DIPEA, N-methylmorpholine or
Their any combination, its dosage are the 0.01-3.0 molar equivalents of compound 6；Described additive refers to 2,4,6-Cl3-
C6H4COCl, MeOCOCl, EtOCOCl, its dosage are the 0.5-3.0 molar equivalents of compound 6；Described solvent is tetrahydrochysene furan
Mutter, ether, 1,4- dioxane, dichloromethane, chloroform, toluene, ethyl acetate, acetonitrile, DMF, DMSO or theirs is mixed
Bonding solvent, described reaction temperature are -10-100 DEG C；
5th step：
Compound 8 is in the presence of alkali, under the conditions of suitable solvent and reaction temperature, reacts some hours, generates compound 9,
Described alkali refers to diethylamine, dimethylamine, nafoxidine, piperidines, morpholine or their any combination, and its dosage is compound 8
1.0-40 molar equivalents；Described solvent is tetrahydrofuran, ether, 1,4- dioxane, dichloromethane, chloroform, first
Benzene, ethyl acetate, acetonitrile, DMF, DMSO or their mixed solvent, described reaction temperature are -10-100 DEG C；
6th step：
Compound 9 and a kind of organic acid, i.e. compound 10, in the presence of activator and condensing agent, in suitable solvent and reaction
Under temperature conditionss, react some hours, generate compound 11, described compound 10, its dosage is the 0.5-2.0 of compound 9
Molar equivalent；Described activator refers to HOBT, HATU, HOAT or PyBOC, and its dosage is 0.5-2.0 moles of compound 9 and worked as
Amount；Described condensing agent refers to DCC or EDCI, and its dosage is the 0.5-2.0 molar equivalents of compound 9；Described solvent is four
Hydrogen furans, ether, 1,4- dioxane, dichloromethane, chloroform, toluene, ethyl acetate, acetonitrile, DMF, DMSO or they
Mixed solvent, described reaction temperature be -10-100 DEG C；
7th step：
Compound 11 under the action of an acid, under the conditions of suitable solvent and reaction temperature, is reacted some hours, generates compound
12, certain described acid refers to acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, p-methyl benzenesulfonic acid, boron trifluoride, tribromide
Boron, hydrogen chloride, perchloric acid, tetrafluoro boric acid, sulfuric acid, its dosage are 0.01-1.0 times of suitable solvent volume or are suitable solvent
Saturated solution；Described solvent refers to tetrahydrofuran, ether, 1,4- dioxane, dichloromethane, chloroform, toluene, acetic acid
Ethyl ester, acetonitrile, DMF, DMSO or their mixed solvent, described reaction temperature are -10-100 DEG C；
8th step：
Compound 12 is in the presence of alkali and condensing agent, under the conditions of suitable solvent and reaction temperature, reacts some hours, generation
The compound 13 of big ring, certain described alkali refer to potassium carbonate, sodium carbonate, saleratus, sodium acid carbonate, potassium hydroxide, hydrogen-oxygen
Change sodium, pyridine, 4-dimethylaminopyridine, 2,6- lutidines, triethylamine, DIPEA, N-methylmorpholine or theirs is any
Combination, its dosage is the 1-10 molar equivalents of compound 12；Described condensing agent refer to HOBT, HATU, HOAT, PyBOC, DCC,
EDCI or its any combination, its dosage is the 1.0-5.0 molar equivalents of compound 12；Described solvent refers to tetrahydrofuran, second
Ether, 1,4- dioxane, dichloromethane, chloroform, toluene, ethyl acetate, acetonitrile, DMF, DMSO or their mixing are molten
Agent, described reaction temperature are -10-100 DEG C；
9th step：
In logical formula (I), work as R2For hydrogen when, aromatisation generation thiazole ring is carried out to thiazoline ring, it is real to pass through the 9th step experimental implementation
It is existing, i.e.,：
Compound 13 (i.e. 7 be R or S configurations compound 13b or compound 13c：R2=H, 7,8- positions are singly-bound) in organic base
In the presence of halo agent, under the conditions of suitable solvent and reaction temperature, some hours are reacted, generate the product of aromatisation (i.e.
Compound 13d：R2=H, 7,8- positions are double bond), certain described organic base refer to DBU, pyridine, 4-dimethylaminopyridine,
2,6- lutidines, triethylamine, DIPEA, N-methylmorpholine or their any combination, its dosage are compound 13b or change
Compound 13c 1-10 molar equivalents；Described halo agent refers to NIS (N- N-iodosuccinimides), NBS (N- bromo succinyl
Imines), NCS (N- chlorosuccinimides), BrCCl3Or its any combination, its dosage is compound 13b or compound 13c
1.0-5.0 molar equivalent；Described solvent refers to tetrahydrofuran, ether, 1,4- dioxane, dichloromethane, chloroform, first
Benzene, ethyl acetate, acetonitrile, DMF, DMSO or their mixed solvent, described reaction temperature are -10-100 DEG C；
10th step：
Compound 13 is in the presence of certain organic acid and reducing agent, and under the conditions of suitable solvent and reaction temperature, reaction is some
Hour, generate compound 14, certain described organic acid refer to acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, to toluene
Sulfonic acid, boron trifluoride, Boron tribromide, hydrogen chloride, perchloric acid, tetrafluoro boric acid, sulfuric acid, its dosage are that its dosage is suitable solvent system
0.01-1.0 times long-pending or the saturated solution for suitable solvent；Described reducing agent refers to i-Pr3SiH or Et3SiH, its dosage are
The 1.0-5.0 molar equivalents of compound 12；Described solvent refer to tetrahydrofuran, ether, 1,4- dioxane, dichloromethane,
Chloroform, toluene, ethyl acetate, acetonitrile, DMF, DMSO or their mixed solvent, described reaction temperature are -10-100
℃；
11st step：
Compound 14 is in the presence of certain alkali and acyl chlorides or acid anhydrides or alkylating agent, under the conditions of suitable solvent and reaction temperature,
Some hours are reacted, generate the compound 15 of big ring, certain described alkali refers to potassium carbonate, sodium carbonate, saleratus, bicarbonate
Sodium, potassium hydroxide, sodium hydroxide, pyridine, 4-dimethylaminopyridine, 2,6- lutidines, triethylamine, DIPEA, N- methyl
Morpholine or their any combination, its dosage are the 1-10 molar equivalents of compound 13；Described acyl chlorides or acid anhydrides or alkylating agent
Refer to R3I, R3SS(O)R3, R3COCl, R3NHCOCl, R3OCOCl, (R3O)2P (O) Cl, wherein R3Alkyl, virtue selected from C1-C10
Perfume base, the alkyl for being connected to alkyl or C1-C10 of the aromatic radical of C1-C10 alkyl either selected from the C1-C10 for being connected to aryl
With the combination of aryl cyclization, described acyl chlorides or acid anhydrides or alkylating agent dosage are the 1.0-10 molar equivalents of compound 13；It is described
Solvent refer to tetrahydrofuran, ether, 1,4- dioxane, dichloromethane, chloroform, toluene, ethyl acetate, acetonitrile,
DMF, DMSO or their mixed solvent, described reaction temperature are -10-100 DEG C.
3. lead to the compound or its salt shown in formula (I) according to claim 1, it is characterised in that in the logical formula (I)：R1Choosing
From H, R3S, R3CO, R3NHCO, R3OCO；
It is double bond either singly-bound connection between 7/8；When between 7/8 being singly-bound connection, the spatial configuration of 7 is R or S
Configuration；When between 7/8 being double bond connection, R2It is not present；
R2Selected from H, R3；
R3Selected from C1-C10Alkyl.
4. lead to the compound or its salt shown in formula (I) according to claim 8, it is characterised in that described compound is：
R1Selected from H, C7H15CO；
It is double bond either singly-bound connection between 7/8；When between 7/8 being singly-bound connection, the spatial configuration of 7 is R or S
Configuration；When between 7/8 being double bond connection, R2It is not present；
R2Selected from H, CH3。
5. the drug ingedient that a kind of compound and more than one adjuvant form, it is characterised in that wherein contain in drug ingedient
The compound shown in formula described in claim 1.
6. the drug component drug composition described in claim 5 is preparing the purposes in suppressing mammal tumor medicine, described
Tumour be solid tumor, cancer, lymthoma, Hodgkin's disease, tumor disease or newborn knurl disease.
A kind of 7. antineoplastic pharmaceutical compositions, it is characterised in that its contain compound shown in the logical formula (I) for the treatment of effective dose or
Its salt and pharmaceutical carriers, the salt of the compound are the forms of free form and acid addition salt or carboxylate.
8. the antineoplastic pharmaceutical compositions as described in claim 5, it is characterised in that described acid addition salt is selected from sulfuric acid
Salt, nitrate, hydrobromate, hydriodate or phosphate, or tartrate, acetate, mesylate, benzene sulfonate, toluene
Sulfonate, citrate, maleate, fumarate or lactate.
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| CN111440199A (en) * | 2020-03-11 | 2020-07-24 | 中国药科大学 | Macrocyclic glutaminase G L S1 inhibitor or pharmaceutically acceptable salt thereof, and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010009334A1 (en) * | 2008-07-17 | 2010-01-21 | Colorado State University Research Foundation | Method for preparing largazole analogs and uses thereof |
| CN104529842A (en) * | 2014-12-22 | 2015-04-22 | 泰州施美康多肽药物技术有限公司 | Intermediate of depsipeptide type histone deacetylase inhibitors and preparation method of intermediate |
| CN103601742B (en) * | 2013-10-30 | 2016-01-20 | 中国科学院广州生物医药与健康研究院 | A kind of Largazole analogue, its preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010009334A1 (en) * | 2008-07-17 | 2010-01-21 | Colorado State University Research Foundation | Method for preparing largazole analogs and uses thereof |
| CN103601742B (en) * | 2013-10-30 | 2016-01-20 | 中国科学院广州生物医药与健康研究院 | A kind of Largazole analogue, its preparation method and application thereof |
| CN104529842A (en) * | 2014-12-22 | 2015-04-22 | 泰州施美康多肽药物技术有限公司 | Intermediate of depsipeptide type histone deacetylase inhibitors and preparation method of intermediate |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111440199A (en) * | 2020-03-11 | 2020-07-24 | 中国药科大学 | Macrocyclic glutaminase G L S1 inhibitor or pharmaceutically acceptable salt thereof, and preparation method and application thereof |
| CN111440199B (en) * | 2020-03-11 | 2023-02-24 | 中国药科大学 | Macrocyclic glutaminase GLS1 inhibitor or pharmaceutically acceptable salt thereof, and preparation method and application thereof |
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