CN104817490B - Dithiocarbamates compound and preparation method and application - Google Patents
Dithiocarbamates compound and preparation method and application Download PDFInfo
- Publication number
- CN104817490B CN104817490B CN201510243973.2A CN201510243973A CN104817490B CN 104817490 B CN104817490 B CN 104817490B CN 201510243973 A CN201510243973 A CN 201510243973A CN 104817490 B CN104817490 B CN 104817490B
- Authority
- CN
- China
- Prior art keywords
- compound
- pkm2
- nmr
- cell
- dmso
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 0 *C(CCSC(NCc1cccnc1)=S)O Chemical compound *C(CCSC(NCc1cccnc1)=S)O 0.000 description 2
- IIPSXWJFXDXLSD-ZPYFUIHZSA-N C=N/C=C\C=C\CN Chemical compound C=N/C=C\C=C\CN IIPSXWJFXDXLSD-ZPYFUIHZSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/46—Oxygen atoms
- C07D213/50—Ketonic radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention discloses dithiocarbamates compound and preparation method and application, belong to medicinal chemistry art.The compounds of this invention structure is as shown in formula I, research shows the compounds of this invention targeting PKM2, is PKM2 activator, and finds that such compound produces antineoplastic action by preventing PKM2 from entering nucleus, with good antitumor action, and there is good selectivity to tumour cell.Therefore the compounds of this invention can have wide application value as antineoplastic.
Description
Technical field
The present invention relates to compound and preparation method and application, more particularly to novel amino dithiocarbonic acid esters chemical combination
Thing and preparation method and application, such compound is the new PKM2 activators of a class, can belong to medicine as antineoplastic
Thing chemical field.
Background technology
Antineoplastic research is always one of hot fields of whole world drug research.At present, effective antitumour medicine
Thing is a lot, but the low antineoplastic of good drug efficacy, toxic side effect is seldom.Therefore, current antineoplastic research will be solved
Key issue be the antineoplastic for finding that good effect, toxic side effect are low.It had been metabolized using tumour cell and normal cell
Difference in journey, optionally intervenes the key link in tumour cell metabolic process, it is possible to reaches and neither damages normal thin
Born of the same parents, can suppress the purpose of growth of tumour cell again.
In the 1920s, Otto Warburg propose tumour be using glycolysis rather than more efficient oxidative phosphorylation come
Produce energy.The result of this Metabolism regulation is the secretion of higher glucose consumption and lactic acid, and these features are referred to as
Warburg effects are aerobic glycolysis.Nearest tumor metabolic turns into a big focus in tumor research field again, and this causes very
A discovery before morning is attracted attention again, i.e., all cancer cells, no matter what their starting tissue is,
The expression of pyruvate kinase M2 hypotypes (PKM2) is all significantly raised.This finds to orientate PKM2 as treatment of cancer latent rapidly
In target spot.
Pyruvate kinase (PK) is the enzyme for being catalyzed glycolysis final step, and PEP (PEP) is converted into
ADP phosphoric acid is turned to ATP by pyruvic acid simultaneously.PK has 4 kinds of hypotypes in mammal, and their express spectra and regulation may be anti-
The specific function and energy requirement of different tissues where having answered them.These four hypotypes, altogether by 2 gene codes, are PKLR respectively
And PKM, their expression is respectively by the regulation of tissue-specific promoter and adjusting for alternative splicing.PKLR encode PKL and
Two kinds of hypotypes of PKR, it is specific expressed in liver kidney and granulophilocyte respectively.PKM genes produce two kinds by alternative splicing
Variant:A kind of M1, is mainly expressed in skeletal muscle, heart and brain;Another M2, it is initially in increment cell and embryo
It is certified in puberty cell.Wherein M1 hypotypes are the high activity form of sustained activation, and PKM2 can be in low activity and height
Converted between activity.And in tumour cell, PKM2 must gradually replace the PK hypotypes of tissue specificity until it turns into main shape
Formula.The transformation of this hypotype shows that PKM2 certain special properties promote tumour generation.This guess is further by a research
Confirm, the research finds that after the PKM2 in tumour cell is replaced with PKM1, the PK hypotypes of the sustained activation delay xenogenesis
The growth of transplantation tumor.
The research of effects of the PKM2 in cancer abnormal metabolism there has also been substantial progress.Research discovery, its effect
It is many, the effect to metabolism that includes also has the regulating and controlling effect to portion gene.It has been proposed that PKM2 is in increment cell
In be low activity, and it low activity help have accumulated glycometabolism intermediate.It can be used for synthesising biological macromolecular, so that
Promote the growth and increment of cell.And PKM2, except there is the function of glycolytic ferment in endochylema, it is also sent out in nucleus
It is existing.PKM2 nuclear location is probably the NLS sequences due to C-terminal, this sequence with classical NLS be compared to difference arginine with
Lysine is simultaneously few.It has been proposed that PKM2 position shifter mechanism is related to PKM2 and SUMO-E3PIAS3 interaction, the latter promotees
Enter PKM2 sumoylation and nuclear translocation.The function for the PKM2 being mentioned is different.Core PKM2 is stimulated for interleukin-13
Cell death after rear increment and apoptotic stimulus is necessary, but how not clear specific mechanism is.Other are researched and proposed
Core PKM2 can interact with transcription factor such as β-catenin, Oct-4 etc. and activate them, in cell survival and rise in value
Played a role in journey.β-the catenin of the activation-inducing of EGF-R ELISA PKM2 nuclear translocation and c-SRC mediation
Phosphorylation.In core, PKM2 is combined with phosphorylation β-catenin and is promoted its transcriptional activity;Especially, cycling is induced
D1 expression, this cell propagation induced EGF is necessary.And the PKM2 mutant combinations β of catalytic activity inactivation-
Catenin is simultaneously indexable into nucleus, however, it can not activate cycling D1 transcription.One closer to research provide
Fresh evidence demonstrates effects of the PKM2 of glycolysis inactivation in cell propagation.PKM2 dimer is proved in nucleus
Exist as protein kinase, it uses PEP dephosphorylation transcription factors Stat 3.It is interesting that PKM2 mutant is unable to shape
Into the tetramer, thus it is just small as a PK activity, and so it prefers in nucleus, it can be by strengthening Stat there
3 phosphorylation and the increment for promoting cell.In addition, adjusting the report of cell cycle also on core PKM2, there is research to send out recently
Existing, PKM2 helps cell to enter line splitting by phosphorylation Bub2 so as to help the latter's formation compound to navigate to centromere.Total
For, PKM2 kernel function promotes cell propagation.PKM2 these functions are considered as it as the benefit of glycolysis key enzyme
Fill.Different from PKM2, PKM1 is targeted to growth and existence that nucleus does not interfere with cell.Therefore, PKM2 nucleus is lived
Property be likely to be true cause of its high expression in tumour.
Have started to be taken seriously in the world using PKM2 as the research of the anti-cancer agent of target spot in recent years, but studies in China
It is seldom.At present, it has been found that some have the small molecule PKM2 activators of preferably activity, but very limited.And reported
PKM2 activators only show preferable activity in enzyme level, in cellular level all without significant antitumor activity.Unless will
Tumour cell is cultivated in the culture medium for eliminating the nutriments such as serine, and existing activator is just shown to tumour cell
Lethal effect.Our groups take the lead in establishing pyruvate kinase M2 hypotypes (PKM2) activity screen model at home, and to own
Compound library has carried out primary dcreening operation.Therefrom, it has been found that a class formation brand-new PKM2 activators, and find that such swashs first
Dynamic agent also has good antitumor activity in cellular level.And compared with normal cell, it has well to tumour cell
Selectivity.Further, we have synthesized a series of derivative of lead compounds, and it is entered in two levels of enzyme and cell
Row activity rating, discloses its structure-activity relationship, and it is sharp to optimize the new PKM2 for having obtained to be furtherd investigate as drug candidate
Dynamic agent, and preliminary Mechanism Discussion has been carried out to it.It was found that such compound is produced anti-swollen by preventing PKM2 from entering nucleus
The effect of knurl.Our work provides new skeleton, more low-toxicity antitumor drug for the new drug research using PKM2 as target spot
Discovery provide new approaches.
The content of the invention
It is an object of the invention to provide dithiocarbamates compound and preparation method and application.
In order to achieve the above object, the technological means that uses of the present invention for:
Dithiocarbamates compound provided by the present invention with structure shown in formula I or its is pharmaceutically acceptable
Salt,
Wherein R1Selected from aryl, substituted aryl, fragrant heterocyclic radical or substituted aroma heterocyclic radical.
In the present invention, it is preferred to, R1One kind in group is constituted selected from following group:(1) phenyl;(2) through C1-3Alkane
Epoxide, halogen, C1-3Alkylhalide group, nitro, benzyloxy, hydroxyl or the phenyl of cyano group substitution;(3) furyl, pyridine radicals, thienyl,
Pyrrole radicals, thiazolyl, indyl, cumarin base, azaindolyl or 3- imidazopyridyls.
In the present invention, it is preferred to, R1Selected from phenyl, 3,4- dichlorophenyls, 4- fluorophenyls, 2- furyls, 4- chlorphenyls,
4- methoxyphenyls, 4- benzyloxy-phenyls, 4- nitrobenzophenones, 4- hydroxy phenyls, 4- cyano-phenyls, 2- chlorphenyls, 2- methoxyl groups
Phenyl, 4- trifluoromethyls, 3,4,5- trimethoxyphenyls, 3,4- difluorophenyls, 3- pyridine radicals, 2- thienyls, 2- pyrroles
Base, 2- thiazolyls, 3- indyls, 3- cumarins base, 3- azaindolyls or 3- imidazopyridyls.
The method of compound or its pharmaceutically acceptable salt described in preparing, it is characterised in that the change of described formula I
Compound can be prepared by the following method:
Wherein, R1For phenyl.
The method of compound or its pharmaceutically acceptable salt described in preparing, it is characterised in that the change of described formula I
Compound can be prepared by the following method:
Wherein, R1For 3,4- dichlorophenyls, 4- fluorophenyls, 2- furyls, 4- chlorphenyls, 4- methoxyphenyls, 4- benzyloxies
Base phenyl, 4- nitrobenzophenones, 4- hydroxy phenyls, 4- cyano-phenyls, 2- chlorphenyls, 2- methoxyphenyls, 4- trifluoromethyls,
3,4,5- trimethoxyphenyls, 3,4- difluorophenyls, 3- pyridine radicals, 2- thienyls, 2- pyrrole radicals, 2- thiazolyls, 3- indyls,
3- cumarins base, 3- azaindolyls or 3- imidazopyridyls.
In the present invention, it is preferred to, the compound of structure can be prepared as follows shown in formula II:
(1) R is worked as1For 3,4- dichlorophenyls, 4- fluorophenyls, 2- furyls, 4- chlorphenyls, 4- methoxyphenyls, 4- benzyloxies
Base phenyl, 4- nitrobenzophenones, 4- hydroxy phenyls, 4- cyano-phenyls, 2- chlorphenyls, 2- methoxyphenyls, 4- trifluoromethyls,
3,4,5- trimethoxyphenyls, 3,4- difluorophenyls, 3- pyridine radicals, 2- thienyls, 2- pyrrole radicals, 2- thiazolyls, 3- indyls
Or during 3- cumarin bases,
The compound of the structure of formula III is with paraformaldehyde in catalyst CF3COOH·(iPr)2React, generate under NH effects
The compound of the structure of formula II;
(2) R is worked as1During for 3- azaindolyls,
7- azaindoles and chloroacetic chloride are in AlCl3In the presence of, react the compound of the structure of production II;
(3) R is worked as1During for 3- imidazopyridyls,
PA is first reacted with DMF dimethylacetal, the intermediate product of generation again with chlorine
Acetone is reacted, the compound of the structure of production II.
It should be noted that route of synthesis described above is to illustrate the preparation of the compounds of this invention, and prepares and determine
This is not limited only to, i.e., other synthetic methods are equally possible, methods described refers to the synthetic method in skilled person's general knowledge.
If desired, the compounds of this invention can be changed into their officinal salt using methods known in the art.
It is a further object to provide the purposes of the compounds of this invention.
Inventor experiments prove that, the compounds of this invention targeting PKM2, be PKM2 activator, and find should
Class compound produces antineoplastic action by preventing PKM2 from entering nucleus, with good antitumor action, and right
Tumour cell has good selectivity.
Therefore, the present invention proposes the compound or its pharmaceutically acceptable salt and is preparing pyruvate kinase M2 hypotypes
Application in activator.Wherein, described pyruvate kinase M2 subtype agonists, which have, prevents pyruvate kinase M2 hypotypes from entering
The effect of nucleus.And
The compound or its application of salt pharmaceutically received in antineoplastic is prepared.Wherein, it is described antitumor
Medicine is for treating colon cancer, cervical carcinoma or the medicine of lung cancer.And
The compound or its application of salt pharmaceutically received in the activator of glycolytic pathway is prepared.
The preparation method of the compound of table 1 is set forth in detail in a particular embodiment of the present invention:
Target compound:
Table 1
Brief description of the drawings
Fig. 1 is the western testing result figures that compound 22 adds PKM2 in nucleus and cytoplasm after cell;Wherein,
Mock is the control group for being not added with compound, and NZT is the activator reported;
Fig. 2 is the arresting cell cycle figure of compound 22;Wherein, the dose-dependant of (A) compound 22 must be by cell block in G2/
M phases, the structure of (B) compound 22, (C) drug-treated group (1 μM, 5 μM) accounts for the whole cell cycle with the DMSO control group G2/M phases
Ratio.
Embodiment
The invention will now be further described with reference to specific embodiments, advantages of the present invention and feature will be with description and
It is apparent.But embodiment is only exemplary, does not constitute any limitation to the scope of the present invention.Those skilled in the art should
It should be appreciated that, the details and form of technical solution of the present invention can be repaiied without departing from the spirit and scope of the invention
Change or replace, but these modifications and replacement are each fallen within protection scope of the present invention.
The explanation of abbreviation appeared in the present invention:
P petroleum ethers
E ethyl acetate
The synthesis of the 3- pyridylmethyls dithiocarbonic acid of embodiment 1-(2- benzoyls) ethyl ester (compound 1)
3- aminomethyl-pyridines (541mg, 5mmol) are dissolved in 25mL DCM, TEA (506mg, 5mmol) are added, at room temperature
10min is stirred, CS is added2(457mg, 6mmol), reacts 20min at room temperature, adds 3- chlorophenyl acetones (843mg, 5mmol), room
The lower reaction 5h of temperature, directly decompression is spin-dried for solvent, column chromatography (P:E=1:2) white solid, yield 77.2%, are obtained.Fusing point:82-
84℃。
1H NMR (400MHz, DMSO) δ 10.50 (s, 1H), 8.70-8.32 (m, 2H), 7.97 (d, J=7.4Hz, 2H),
7.66 (ddd, J=10.8,8.5,4.4Hz, 2H), 7.53 (t, J=7.1Hz, 2H), 7.37 (dd, J=7.7,4.8Hz, 1H),
4.86 (d, J=5.3Hz, 2H), 3.50 (dt, J=11.8,4.7Hz, 4H)
13C NMR(100MHz,DMSO)δ198.72,197.82,149.56,148.90,136.65,135.96,133.90,
133.40,129.25,128.37,123.98,47.58,38.65,29.32.
The 3- pyridylmethyls dithiocarbonic acid of embodiment 2-[2- (3,4- dichloro-benzoyls)] ethyl ester (compound 2)
Synthesis
3,4- dichloroacetophenones (756mg, 4mmol) are dissolved in 10mL DMF, addition paraformaldehyde (240mg,
8mmol), catalyst CF3COOH·(iPr)2NH (860mg, 4mmol), reacts 12h at 80 DEG C, is cooled to room temperature, adds water
50mL, is extracted with ethyl acetate (10mL × 3), merges organic phase, anhydrous sodium sulfate drying, concentration, column chromatography (P:E=20:
1) grease intermediate (2-1), yield 27.5%, are obtained.3- aminomethyl-pyridines (324mg, 3mmol) are dissolved in 20mL DCM
In, TEA (303mg, 3mmol) is added, 5min is stirred at room temperature, CS is added2(274mg, 3.6mmol), reacts 10min, adds
Intermediate 2-1, reacts 5h at room temperature, removes solvent, column chromatography (P under reduced pressure:E=2:1) white solid, yield 56.3%, are obtained.
Fusing point:139.3-140.2℃.
Intermediate 2-1
1H NMR(400MHz,CDCl3)δ8.14-7.78(m,1H),7.81-7.60(m,1H),7.60-7.37(m,1H),
7.15-6.93 (m, 1H), 6.39 (dd, J=17.1,1.4Hz, 1H), 6.06-5.70 (m, 1H)
13C NMR(100MHz,CDCl3)δ187.61,136.61,135.80,132.35,130.51,130.37,
129.79,129.67,126.69.
Product 2
1H NMR (400MHz, DMSO) δ 10.52 (q, J=5.3Hz, 1H), 8.77-8.28 (m, 2H), 8.37-8.05 (m,
1H), 7.92 (dd, J=4.9,3.5Hz, 1H), 7.79 (td, J=8.3,4.1Hz, 1H), 7.75-7.58 (m, 1H), 7.60-
7.26(m,1H),5.09-4.70(m,2H),3.74-3.39(m,4H).
13C NMR(100MHz,DMSO)δ197.18,196.51,149.08,148.40,136.21,135.47,132.88,
131.85,131.06,129.81,127.92,123.46,47.11,38.41,28.64.
HRMS calcd.For C16H15Cl2N2OS2 +[M+H]+384.9997,found:384.9989.
The synthesis of the 3- pyridylmethyls dithiocarbonic acid of embodiment 3-[2- (the fluoro- benzoyls of 4-)] ethyl ester (compound 3)
Using 4- fluoro acetophenones as raw material, with reference to the synthetic route synthesising target compound of embodiment 2.Intermediate 3-1 is oil
Shape thing, yield 46.1%;Product 3 is white solid, yield 35.4%, fusing point:127.4-128.1℃.
Intermediate 3-1
1H NMR(400MHz,CDCl3) δ 8.11-7.83 (m, 2H), 7.14 (dt, J=10.6,9.6Hz, 3H), 6.58-
6.23(m,1H),6.12-5.77(m,1H).
13C NMR(100MHz,CDCl3)δ188.31,165.96,163.43,132.63,132.60,130.98,
130.34,130.25,129.29,114.85,114.64.
Product 3
1H NMR (400MHz, DMSO) δ 10.60 (t, J=5.5Hz, 1H), 8.81-8.35 (m, 2H), 8.33-7.92 (m,
2H), 7.93-7.56 (m, 1H), 7.46-7.17 (m, 3H), 4.85 (d, J=5.6Hz, 2H), 3.72-3.40 (m, 4H)
13C NMR(100MHz,DMSO)δ197.73,197.32,166.84,164.34,149.57,148.85,135.98,
133.44,131.45,131.36,123.94,116.35,116.13,47.53,45.79,38.65.
HRMS calcd.For C16H16FN2OS2 +[M+H]+335.0683,found:384.0680.
The synthesis of the 3- pyridylmethyls dithiocarbonic acid of embodiment 4-[2- (2- furanylcarbonyls)] ethyl ester (compound 4)
Using 2- acetyl furans as raw material, with reference to the synthetic route synthesising target compound of embodiment 2.Intermediate 4-1 is oil
Shape thing, yield 36.5%;Product 4 is white solid, yield 63.5%, fusing point:122.9-123.6℃.
Intermediate 4-1
1H NMR(400MHz,CDCl3)δ7.77-7.56(m,1H),7.31-7.24(m,1H),7.19-6.96(m,1H),
6.72-6.42(m,2H),6.00-5.73(m,1H).
13C NMR(100MHz,CDCl3)δ177.97,152.91,146.95,131.32,129.38,118.27,
112.45.
Product 4
1H NMR (400MHz, DMSO) δ 10.51 (t, J=5.5Hz, 1H), 8.82-8.26 (m, 2H), 7.99 (dd, J=
1.6,0.6Hz, 1H), 7.69 (dt, J=7.8,1.9Hz, 1H), 7.60-7.18 (m, 2H), 6.71 (dd, J=3.6,1.7Hz,
1H), (t, J=6.8Hz, the 2H) of 4.85 (d, J=5.6Hz, 2H), 3.49 (t, J=6.8Hz, 2H), 3.26
13C NMR(100MHz,DMSO)δ197.54,186.94,152.05,149.55,148.88,148.35,135.96,
133.38,123.96,119.10,113.02,47.58,38.15,29.01.
HRMS calcd.For C14H15N2O2S2 +[M+H]+307.0570,found:307.0563.
The synthesis of the 3- pyridylmethyls dithiocarbonic acid of embodiment 5-[2- (the chloro- benzoyls of 4-)] ethyl ester (compound 5)
Using 4- chloro-acetophenones as raw material, with reference to the synthetic route synthesising target compound of embodiment 2.
Because substituent is different so that raw material MIBK and the intermediate Michael acceptors formed are difficult to separate, therefore only
It is to carry out rough column chromatography to remove paraformaldehyde, is not precisely separated, directly carries out the next step.Product 5 is solid for white
Body, two step yields 21.7%, fusing point:113.7-113.9℃.
1H NMR (400MHz, DMSO) δ 10.52 (t, J=5.2Hz, 1H), 8.77-8.34 (m, 2H), 8.22-7.93 (m,
2H), 7.70 (dt, J=7.8,1.8Hz, 1H), 7.68-7.52 (m, 2H), 7.36 (dd, J=7.8,4.8Hz, 1H), 4.85 (d,
J=5.3Hz, 2H), 3.62-3.40 (m, 4H)
13C NMR(100MHz,DMSO)δ197.75,197.74,149.57,148.88,138.80,135.97,135.31,
133.40,130.30,129.34,123.95,47.58,38.72,29.23.
HRMS calcd.For C16H16ClN2OS2 +[M+H]+351.0387,found:351.0380.
The 3- pyridylmethyls dithiocarbonic acid of embodiment 6-[2- (4- methoxv-benzoyls)] ethyl ester (compound 6)
Synthesis
Using 4- methoxyacetophenones as raw material, with reference to the synthetic route synthesising target compound of embodiment 2.Product 6 is white
Color solid, two step yields 54.1%, fusing point:135.5-135.8℃.
1H NMR (400MHz, DMSO) δ 10.49 (t, J=5.2Hz, 1H), 8.50 (dd, J=19.5,2.4Hz, 2H),
7.94 (d, J=8.8Hz, 2H), 7.70 (d, J=7.8Hz, 1H), 7.36 (dd, J=7.7,4.8Hz, 1H), 7.03 (d, J=
8.8Hz, 2H), 4.86 (d, J=5.5Hz, 2H), 3.84 (s, 3H), 3.44 (ddd, J=17.6,12.1,5.6Hz, 4H)
13C NMR(100MHz,DMSO)δ197.91,196.99,163.74,149.56,148.89,135.96,133.42,
130.71,129.67,123.96,114.40,56.00,47.57,38.21,29.50.
HRMS calcd.For C17H19N2O2S2 +[M+H]+347.0883,found:347.0876.
The 3- pyridylmethyls dithiocarbonic acid of embodiment 7-[2- (4- benzyloxies-benzoyl)] ethyl ester (compound 7)
Synthesis
Using 4- benzyloxy acetophenones as raw material, with reference to the synthetic route synthesising target compound of embodiment 2.Product 7 is white
Color solid, two step yields 22.0%, fusing point:148.3-148.9℃.
1H NMR (400MHz, DMSO) δ 8.72-8.36 (m, 2H), 7.92 (dd, J=9.4,2.3Hz, 2H), 7.69 (dt,
J=7.8,1.9Hz, 1H), 7.38 (dqd, J=9.6,8.7,4.3Hz, 6H), 7.11 (d, J=8.9Hz, 2H), 5.19 (s,
2H),4.85(s,2H),3.76-3.26(m,4H).
13C NMR(100MHz,DMSO)δ197.84,197.04,162.81,149.46,148.83,136.86,136.00,
133.44,130.71,129.80,128.96,128.49,128.21,124.00,115.21,69.97,47.39,38.18,
29.48.
HRMS calcd.For C23H23N2O2S2 +[M+H]+423.1196,found:423.1194.
The conjunction of the 3- pyridylmethyls dithiocarbonic acid of embodiment 8-[2- (4- nitro-benzoyls)] ethyl ester (compound 8)
Into
Using 4- nitro-acetophenones as raw material, with reference to the synthetic route synthesising target compound of embodiment 2.Product 8 is yellowish
Color solid, two step yields 26.8%, fusing point:153.0-154.1℃.
1H NMR (400MHz, DMSO) δ 8.69-8.43 (m, 2H), 8.34 (d, J=8.9Hz, 2H), 8.25-8.09 (m,
2H), 7.71 (dd, J=7.8,1.7Hz, 1H), 7.38 (dd, J=7.8,4.8Hz, 1H), 4.86 (s, 2H), 3.54 (d, J=
15.1Hz,4H).
13C NMR(100MHz,DMSO)δ197.52,197.06,149.96,148.95,148.34,140.58,135.53,
132.89,129.32,123.84,123.51,46.92,38.83,28.54.
HRMS calcd.For C16H16N3O3S2 +[M+H]+362.0628,found:362.0625.
The conjunction of the 3- pyridylmethyls dithiocarbonic acid of embodiment 9-[2- (4- hvdroxv-benzovls)] ethyl ester (compound 9)
Into
Using 4-hydroxyacetophenone as raw material, with reference to the synthetic route synthesising target compound of embodiment 2.Product 9 is white
Solid, two step yields 11.1%, fusing point:166.7-167.2℃.
1H NMR (400MHz, DMSO) δ 8.75-8.35 (m, 2H), 7.85 (d, J=8.7Hz, 2H), 7.81-7.60 (m,
1H), 7.38 (dd, J=7.7,4.8Hz, 1H), 6.87 (d, J=8.7Hz, 2H), 4.85 (s, 2H), 3.88-3.19 (m, 4H)
13C NMR(100MHz,DMSO)δ197.38,196.29,161.99,148.94,148.33,135.50,132.95,
130.46,127.89,123.53,115.18,46.86,37.48,29.03.
HRMS calcd.For C16H17N2O2S2 +[M+H]+333.0726,found:333.0718.
The 3- pyridylmethyls dithiocarbonic acid of embodiment 10-[2- (4- cyano-benzoyls)] ethyl ester (compound 10)
Synthesis
Using 4- cyano-acetophenones as raw material, with reference to the synthetic route synthesising target compound of embodiment 2.Product 10 is white
Solid, two step yields 16.9%, fusing point:146.7-147.5℃.
1H NMR (400MHz, DMSO) δ 10.51 (t, J=5.5Hz, 1H), 8.64-8.41 (m, 2H), 8.11 (d, J=
8.5Hz, 2H), 8.00 (d, J=8.5Hz, 2H), 7.69 (d, J=7.8Hz, 1H), 7.36 (dd, J=7.7,4.8Hz, 1H),
4.85 (d, J=5.6Hz, 2H), 3.52 (s, 4H)
13C NMR(100MHz,DMSO)δ198.22,197.65,149.56,148.90,139.70,135.98,133.37,
133.31,129.03,123.97,118.59,115.82,47.60,39.11,29.09.
HRMS calcd.For C17H16N3OS2 +[M+H]+342.0729,found:342.0723.
The conjunction of the 3- pyridylmethyls dithiocarbonic acid of embodiment 11-[2- (the chloro- benzoyls of 2-)] ethyl ester (compound 11)
Into
Using 2- chloro-acetophenones as raw material, with reference to the synthetic route synthesising target compound of embodiment 2.Product 11 is solid for white
Body, two step yields 7.45%, fusing point:78.0-78.6℃.
1H NMR (400MHz, DMSO) δ 10.53 (t, J=5.4Hz, 1H), 8.84-8.32 (m, 2H), 7.67 (dd, J=
9.9,7.8Hz, 2H), 7.58-7.33 (m, 4H), 4.85 (d, J=5.6Hz, 2H), 3.44 (dt, J=12.9,6.7Hz, 4H)
13C NMR(100MHz,DMSO)δ201.11,197.53,149.54,148.91,138.53,135.94,133.37,
132.94,130.98,130.07,129.67,127.95,123.97,47.57,42.47,29.04.
HRMS calcd.For C16H16ClN2OS2 +[M+H]+351.0387,found:351.0382.
The 3- pyridylmethyls dithiocarbonic acid of embodiment 12-[2- (2- methoxv-benzoyls)] ethyl ester (compound 12)
Synthesis
Using 2- methoxyacetophenones as raw material, with reference to the synthetic route synthesising target compound of embodiment 2.Product 12 is white
Color solid, two step yields 1.4%, fusing point:96.2-97.0℃.
1H NMR (400MHz, DMSO) δ 10.47 (t, J=5.5Hz, 1H), 8.62-8.41 (m, 2H), 7.69 (dt, J=
7.8,1.8Hz, 1H), 7.64-7.46 (m, 2H), 7.36 (dd, J=7.6,4.7Hz, 1H), 7.17 (d, J=8.3Hz, 1H),
7.11-6.97 (m, 1H), 4.85 (d, J=5.6Hz, 2H), 3.86 (s, 3H), 3.58-3.32 (m, 4H)
13C NMR(100MHz,DMSO)δ199.94,197.88,158.92,149.53,148.88,135.93,134.54,
133.42,130.04,127.49,123.96,120.96,113.01,56.28,47.54,43.61,29.44.
HRMS calcd.For C17H19N2O2S2 +[M+H]+347.0883,found:347.0877.
The 3- pyridylmethyls dithiocarbonic acid of embodiment 13-[2- (4- trifluoromethvl-benzovls)] ethyl ester (compound
13) synthesis
Using 4- trifluoromethyl acetophenones as raw material, with reference to the synthetic route synthesising target compound of embodiment 2.Product 13 is
Yellow solid, two step yields 10.4%, fusing point:135.8-136.6℃.
1H NMR (400MHz, DMSO) δ 10.51 (t, J=5.5Hz, 1H), 8.69-8.43 (m, 2H), 8.16 (d, J=
8.1Hz, 2H), 7.90 (d, J=8.3Hz, 2H), 7.71 (d, J=1.8Hz, 1H), 7.37 (dd, J=7.8,4.8Hz, 1H),
4.85 (d, J=5.6Hz, 2H), 3.53 (s, 4H)
13C NMR(100MHz,DMSO)δ198.27,197.68,149.56,148.90,139.65,135.97,133.38,
132.96,129.24,126.23,123.97,109.89,47.59,39.08,29.10.
HRMS calcd.For C17H16F3N2OS2 +[M+H]+385.0651,found:385.0644.
The 3- pyridylmethyls dithiocarbonic acid of embodiment 14-[2- (3,4,5- trimethoxies-benzoyl)] ethyl ester (is changed
Compound 14) synthesis
With 3,4,5- trimethoxy acetophenones for raw material, with reference to the synthetic route synthesising target compound of embodiment 2.Product
14 be white solid, two step yields 45.7%, fusing point:85.6-86.8℃.
1H NMR (400MHz, DMSO) δ 10.52 (s, J=5.0Hz, 1H), 8.49 (dd, J=11.1,10.2Hz, 2H),
7.70 (d, J=7.8Hz, 1H), 7.37 (dd, J=7.6,4.9Hz, 1H), 7.23 (d, J=28.6Hz, 2H), 4.86 (d, J=
5.4Hz,2H),3.85(s,6H),3.74(s,3H),3.61-3.40(m,4H).
13C NMR(100MHz,DMSO)δ197.39,197.18,152.76,149.07,148.41,141.95,135.48,
132.91,131.54,123.47,105.44,60.12,56.02,47.09,38.10,29.09.
HRMS calcd.For C19H23N2O4S2 +[M+H]+407.1094,found:407.1087.
The 3- pyridylmethyls dithiocarbonic acid of embodiment 15-[2- (3,4 ,-difluoro-benzoyl)] ethyl ester (compound
15) synthesis
With 3,4- difluoro acetophenones for raw material, with reference to the synthetic route synthesising target compound of embodiment 2.Product 15 is white
Color solid, two step yields 24.4%, fusing point:128.8-129.7℃.
1H NMR (400MHz, DMSO) δ 10.51 (s, J=4.9Hz, 1H), 8.62-8.35 (m, 2H), 7.99 (t, J=
8.2Hz, 1H), 7.86 (d, J=2.1Hz, 1H), 7.70 (d, J=7.8Hz, 1H), 7.56 (d, J=5.1Hz, 1H), 7.42-
(tt, J=8.4,4.2Hz, the 4H) of 7.28 (m, 1H), 4.86 (d, J=5.4Hz, 2H), 3.49
13C NMR(100MHz,DMSO)δ207.24,196.61,151.12,149.66,149.45,149.03,148.57,
136.05,135.79,134.14,133.38,123.94,117.83,47.51,38.80,29.18.
HRMS calcd.For C16H15F2N2OS2 +[M+H]+353.0588,found:353.0581.
The conjunction of the 3- pyridylmethyls dithiocarbonic acid of embodiment 16-[2- (3- picolinoyls)] ethyl ester (compound 16)
Into
Using 3- acetylpyridines as raw material, with reference to the synthetic route synthesising target compound of embodiment 2.Product 16 is yellow
Solid, two step yields 10.0%, fusing point:95.1-95.9℃.
1H NMR (400MHz, DMSO) δ 10.52 (t, J=5.3Hz, 1H), 9.13 (t, J=4.3Hz, 1H), 8.80 (dd,
J=4.7,1.4Hz, 1H), 8.50 (dd, J=20.1,2.4Hz, 2H), 8.30 (dd, J=6.1,1.8Hz, 1H), 7.70 (d, J
=7.8Hz, 1H), 7.56 (dd, J=7.8,4.8Hz, 1H), 7.36 (dd, J=7.7,4.8Hz, 1H), 4.86 (d, J=
5.5Hz, 2H), 3.53 (t, J=4.3Hz, 4H)
13C NMR(100MHz,DMSO)δ198.32,197.71,154.06,149.62,149.56,148.89,135.97,
135.92,133.39,131.90,124.38,123.97,47.61,39.00,29.05.
HRMS calcd.For C15H16N3OS2 +[M+H]+318.0729,found:318.0725.
The conjunction of the 3- pyridylmethyls dithiocarbonic acid of embodiment 17-[2- (2- Thenoyls)] ethyl ester (compound 17)
Into
Using 2- acetyl thiophenes as raw material, with reference to the synthetic route synthesising target compound of embodiment 2.Product 17 is white
Solid, two step yields 52.8%, fusing point:135.3-136.2℃.
1H NMR (400MHz, DMSO) δ 10.49 (t, J=5.3Hz, 1H), 8.56-8.45 (m, 2H), 8.02 (dd, J=
4.9,1.1Hz, 1H), 7.96 (dd, J=3.8,1.1Hz, 1H), 7.69 (dt, J=7.8,1.8Hz, 1H), 7.37 (ddd, J=
7.8,4.8,0.7Hz, 1H), 7.24 (dd, J=4.9,3.8Hz, 1H), 4.85 (d, J=5.6Hz, 2H), 3.51 (t, J=
6.5Hz, 2H), 3.39 (dd, J=10.3,3.6Hz, 2H)
13C NMR(100MHz,DMSO)δ197.62,191.68,149.56,148.90,143.72,135.95,135.52,
134.04,133.38,129.28,123.97,47.59,38.89,29.38.
HRMS calcd.For C14H15N2OS3 +[M+H]+323.0341,found:323.0339.
The conjunction of the 3- pyridylmethyls dithiocarbonic acid of embodiment 18-[2- (2- pyrroyl groups)] ethyl ester (compound 18)
Into
Using 2- acetyl pyrroles as raw material, with reference to the synthetic route synthesising target compound of embodiment 2.Product 18 is white
Solid, two step yields 18.4%, fusing point:128.7-129.3℃.
1H NMR (400MHz, DMSO) δ 11.85 (s, 1H), 10.47 (t, J=5.3Hz, 1H), 8.57-8.39 (m, 2H),
7.69 (d, J=7.8Hz, 1H), 7.36 (dd, J=7.7,4.8Hz, 1H), 7.09 (s, 1H), 6.97 (s, 1H), 6.22-6.13
(m, 1H), 4.86 (d, J=5.5Hz, 2H), 3.50 (t, J=6.8Hz, 2H), 3.18 (t, J=6.9Hz, 2H)
13C NMR(100MHz,DMSO)δ197.81,187.76,149.55,148.88,135.95,133.42,131.83,
126.09,123.96,117.18,110.33,47.55,37.55,29.85.
HRMS calcd.For C14H16N3OS2 +[M+H]+306.0729,found:306.0724.
The conjunction of the 3- pyridylmethyls dithiocarbonic acid of embodiment 19-[2- (2- thiazoles formoxyl)] ethyl ester (compound 19)
Into
Using 2- acetylthiazoles as raw material, with reference to the synthetic route synthesising target compound of embodiment 2.Product 19 is yellowish
Color solid, two step yields 9.2%, fusing point:114.0-114.9℃.
1H NMR(400MHz,CDCl3)δ9.12-8.96(m,1H),8.51-8.36(m,2H),8.02-7.93(m,1H),
7.70 (dd, J=7.1,4.2Hz, 2H), 7.28-7.20 (m, 1H), 5.03-4.89 (m, 2H), 3.77-3.62 (m, 4H)
13C NMR(100MHz,CDCl3)δ198.21,191.90,166.19,149.20,148.81,144.87,
136.32,132.58,126.59,123.76,48.09,38.91,29.00.
HRMS calcd.For C13H14N3OS3 +[M+H]+324.0294,found:324.0290.
The conjunction of the 3- pyridylmethyls dithiocarbonic acid of embodiment 20-[2- (3- indoles formoxyl)] ethyl ester (compound 20)
Into
Using 3- acetylindoles as raw material, with reference to the synthetic route synthesising target compound of embodiment 2.Product 20 is white
Solid, two step yields 5.6%, fusing point:156.6-157.4℃.
1H NMR (400MHz, DMSO) δ 11.96 (s, 1H), 10.45 (t, J=5.5Hz, 1H), 8.56-8.45 (m, 2H),
8.33 (d, J=3.1Hz, 1H), 8.25-8.13 (m, 1H), 7.75-7.63 (m, 1H), 7.47 (dd, J=6.7,1.7Hz, 1H),
7.37 (dd, J=7.8,4.8Hz, 1H), 7.26-7.12 (m, 2H), 4.86 (d, J=5.6Hz, 2H), 3.55 (t, J=6.9Hz,
2H), 3.29 (t, J=7.0Hz, 2H)
13C NMR(100MHz,DMSO)δ198.09,193.35,149.56,148.87,137.06,135.92,134.52,
133.45,125.75,123.95,123.28,122.25,121.72,116.48,112.60,47.53,38.77,30.01.
HRMS calcd.For C18H18N3OS2 +[M+H]+356.0886,found:356.0883.
The 3- pyridylmethyls dithiocarbonic acid of embodiment 21-[2- (3- cumarins formoxyl)] ethyl ester (compound 21)
Synthesis
Using 3- acetyl butylcoumariii as raw material, with reference to the synthetic route synthesising target compound of embodiment 2.Product 21 is white
Color solid, two step yields 5.2%, fusing point:127.8-128.7℃.
1H NMR (400MHz, DMSO) δ 10.49 (t, J=5.5Hz, 1H), 8.75-8.68 (m, 1H), 8.54-8.42 (m,
2H), 7.98 (dd, J=7.8,1.2Hz, 1H), 7.74 (ddd, J=22.0,12.9,4.6Hz, 2H), 7.50-7.34 (m, 3H),
4.85 (d, J=5.6Hz, 2H), 3.58-3.37 (m, 4H)
13C NMR(100MHz,DMSO)δ197.72,196.12,158.81,155.08,149.56,148.89,147.89,
135.96,135.11,133.38,131.33,125.44,124.25,123.97,118.64,116.60,47.60,42.43,
28.96.
HRMS calcd.For C19H17N2O3S2 +[M+H]+385.0675,found:385.0672.
The 3- pyridylmethyls dithiocarbonic acid of embodiment 22-[2- (the miscellaneous indoles formoxyls of 3-N)] ethyl ester (compound 22)
Synthesis
The key of reaction is the preparation of 3- acetyl group azaindole (22-I).7- azaindoles (590mg, 5mmol) is molten
In 80mL DCM, AlCl is added3(3.39g, 25mmol), is slowly added to chloroacetic chloride (3.4mL, 47.8mmol), at room temperature instead
10h is answered, is placed reaction liquid into ice bath, methanol 20mL is slowly added to and reaction is quenched, reaction solution is concentrated, is added into residue
30mL water, PH~4 or so, EtOAc (15mL × 5) extractions, anhydrous sodium sulfate drying, concentration, column chromatography for separation are adjusted with 1N NaOH
(P:E=1:1) white solid (22-I), yield 82.5%, are obtained.Using 22-I as raw material, closed with reference to the synthetic route of embodiment 2
Into target compound.Product 22 is white solid, two step yields 4.9%, fusing point:147.8-148.2℃.
22-I
1H NMR(400MHz,CDCl3)δ13.11-12.78(m,1H),8.79-8.69(m,1H),8.47-8.37(m,
1H),8.15-7.98(m,1H),7.36-7.28(m,1H),2.64-2.52(m,3H).
13C NMR(100MHz,CDCl3)δ193.43,149.21,143.54,132.43,131.83,118.96,
118.44,116.79,27.15.
Product 22
1H NMR (400MHz, DMSO) δ 12.50 (s, 1H), 10.47 (t, J=5.5Hz, 1H), 8.56-8.43 (m, 4H),
8.33 (dd, J=4.7,1.6Hz, 1H), 7.74-7.65 (m, 1H), 7.37 (dd, J=7.7,4.8Hz, 1H), 7.26 (dd, J=
7.9,4.7Hz, 1H), 4.86 (d, J=5.6Hz, 2H), 3.55 (t, J=6.8Hz, 2H), 3.31 (d, J=7.0Hz, 2H)
13C NMR(100MHz,DMSO)δ197.99,193.64,149.56,149.41,148.88,144.72,135.94,
134.90,133.43,130.00,123.97,118.59,118.05,115.13,47.55,38.67,29.79.
HRMS calcd.For C17H17N4OS2 +[M+H]+357.0838,found:357.0832.
The 3- pyridylmethyls dithiocarbonic acid of embodiment 23-[2- (3- imidazopyridines formoxyl)] ethyl ester (compound
23) synthesis
The key of reaction is the synthesis of raw material 3- acetyl imidazoles and pyridine (23-I).By PA (1.88g,
20mmol) it is dissolved in 3.82gN, dinethylformamide dimethylacetal, reacts 24h at 105 DEG C, be concentrated under reduced pressure, adds 35mL
Ethanol, chlroacetone (2.08g, 22.7mmol), reacts 24h at room temperature, continues to be concentrated under reduced pressure, column chromatography for separation (P:E=2:1),
Obtain yellow solid (23-I), yield 70.0%.Using 23-I as raw material, with reference to the synthetic route synthesis target chemical combination of embodiment 2
Thing.Product 23 is white solid, two step yields 14.0%, fusing point:164.8-165.6℃.
23-I
1H NMR(400MHz,CDCl3)δ9.73-9.47(m,1H),8.46-8.27(m,1H),7.88-7.69(m,1H),
7.56-7.42(m,1H),7.25-6.94(m,1H),2.86-2.35(m,3H).
13C NMR(100MHz,CDCl3)δ187.25,148.80,143.43,128.96,128.71,123.96,
117.69,114.98,27.16.
Product 23
1H NMR (400MHz, DMSO) δ 10.51 (t, J=5.1Hz, 1H), 9.54 (d, J=6.8Hz, 1H), 8.64 (s,
1H), 8.50 (dd, J=10.4,8.8Hz, 3H), 7.85 (d, J=8.9Hz, 1H), 7.70 (d, J=7.7Hz, 1H), 7.38 (d,
J=5.0Hz, 1H), 7.29 (t, J=6.7Hz, 1H), 4.86 (d, J=5.0Hz, 2H), 3.59 (t, J=6.8Hz, 2H), 3.40
(t, J=6.8Hz, 2H)
13C NMR(100MHz,DMSO)δ197.14,187.57,149.06,148.40,143.81,135.45,132.89,
132.63,129.61,128.04,123.48,123.03,117.44,115.60,47.09,38.33,29.28.
HRMS calcd.For C17H17N4OS2 +[M+H]+357.0838,found:357.0832.
Agonist activity evaluation of the compounds of this invention of test example 1 to PKM2
Experimental procedure:
PKM2 activity is detected by lactic dehydrogenase (LDH) coupled reaction system, passes through subtracting for detection substrate NADH contents
Few vigor to judge PKM2 catalytic action, it is known that substrate NADH can launch 340nm fluorescence by after ultraviolet excitation, and 340nm is glimmering
Light decrement is directly proportional to NADH decrements.Therefore PKM2 activity is just detected by the decrement of NADH in the unit interval.
By reaction system (final concentrations of the 44ul containing substrate:50mM Tris-Cl pH 8.0,200mM KCl,15mM MgCl2,0.1mM
PEP, 4.0mM ADP and 0.2mM NADH) 96 orifice plates are added, add 1 μ l compounds and 5 μ l enzymatic mixture (final concentrations:
10nM hPKM2and 1μM of LDH).It is incubated after 20min, 96 orifice plates is put into the (Molecular of FlexStation 3
Devices in), NADH readings is detected every 30s, 3~6min is detected altogether.Result is recorded, output is made with GraphPad prism
Effect relation curve obtains compound AC50Result.
Evaluation of result:
The present invention has synthesized 23 thio-compounds of amino two, and have detected its agonist activity to PKM2, experimental result
It is shown in Table 2.It can be seen that, the activity of these compounds is all below 10 μM, wherein No. 22 compounds have reached 1 μM, has to PKM2
There is stronger agonist activity.And from the point of view of maximum exciting rate, these compounds have reached more than 50% mostly.Wherein No. 22 changes
Compound has reached 182%.
Agonist activity measurement result of the compounds of this invention of table 2 to PKM2
a:%FBP represents maximum exciting rate and the ratio of the exciting rates (normalizing to 100%) of FBP, and wherein FBP is in PKM2
Source property activator.
Inhibitory action evaluation of the compounds of this invention of test example 2 to different tumor cell proliferations
Experimental procedure:
Mtt assay detects cytoactive, prepares MTS solution and MTS working solutions;Cell is inoculated in (5 × 10 in 96 orifice plates3
The μ L of individual cell/100), in 37 DEG C, 5%CO212h is incubated with the incubator of 95% air ambient;Every piece of 96 orifice plates set blank pair
According to group, administration group, administration group is separately added into final concentration of 0.625 μM, 1.25 μM, 2.5 μM, 5 μM, 10 μM, 20 μM of compound
Solution, parallel 3 holes of each concentration, is placed in incubator and is incubated 48h;MTS working solutions are added, is placed in incubator and is incubated 4h, in ripple
OD values are determined at long 490nm.Cell survival rate is calculated according to the following formula:Cell survival rate (%)=ODAdministration group/ODBlank control group×
100%.Repeat experiment 3 times.
Evaluation of result:
The activator reported does not have significant antiproliferative effect in cellular level, except acellular is with without serine, paddy ammonia
The medium culture of acid amides.But the compound of the present invention shows stronger effect in cellular level.The present invention have chosen
10 preferable compounds of enzymatic activity are carried out in the tumor cell line of tri- kinds of PKM2 height expression of HCT116, Hela and H1299
The detection of mtt assay cytoactive.Due to positive control of the unsuitable PKM2 activators as cellular level, therefore this hair
The bright taxol that have selected carrys out the accuracy of confirmatory experiment as control.The activity data of the measured taxol of experiment is with having reported
Activity quite, illustrate that the model testing degree of accuracy of the invention is also possible with sensitivity.As a result as shown in Table 3, it is of the invention
The field of activity of compound is between 0.64-5.6 μM.Wherein, Hela cells are most sensitive to these compounds, most of IC50Value
NM grades are reached.In order to further explore the selectivity of this kind of compound on tumor cell, the present invention is also to normal pulmonary branches tracheae
Epithelial cell BEAS-2B has carried out Activity determination.It can see from table 3, most compounds are shown to tumour cell
Selectivity.These results show the potential antineoplastic as new tumor-selective of this series compound.This
Also with PKM2 target spots the characteristics of is consistent.Normal cell is more likely to high activity pyruvate kinase form, therefore excitement PKM2 is not
Normal cell can be damaged.
The compounds of this invention of table 3 suppresses the IC of HCT116, Hela and H1299 cell growth50(μM)
Wherein BEAS-2B is normal lung bronchial epithelial cell.
The compounds of this invention of test example 3 suppresses PKM2 and enters nucleus
1) strike after low PKM2, then compound 22 is added in cell, the activity decrease of compound illustrates that compound is strictly
Target PKM2's.
Experimental procedure:PKM2 genes in low HCT116 cells are struck with slow virus system, shPKM2-1 and shPKM2-2 is obtained
Two plants of cells, this two plants of cells and normal cell, the work with mtt assay detection compound to cell are handled with No. 22 compounds respectively
Property.
Evaluation of result:As can be found from Table 4, after having struck PKM2 low, the activity of compound is reduced to 8 μM of left sides by 2.5 μM
The right side, illustrates that the activity of the compound is to rely on PKM2 paths, also illustrate the compound it is fine must be targeted to PKM2 this
Individual target spot.
The comparison active in the cell in normal HCT116 cells and after having struck PKM2 low of the compound 22 of table 4
2) compound 22 is added in cell, it is suppressed that PKM2's enters core in cell.
Experimental procedure:Serum free medium is changed to while adding chemical combination during normal culture HCT16 cells to density about 60%
Thing 22, final concentration of 10 μM.Cell is received after four hours, PBS is washed one time, utilize Puli's Lay caryoplasm separating kit separating nucleus
Cytoplasm, the amount of PKM2 in endochylema is detected with western, nucleus applied sample amount is that 200ug cytoplasm applied sample amounts are 150ug.
Evaluation of result:Separated by caryoplasm, can become apparent from that the PKM2 being distributed in core with endochylema must be observed, can from Fig. 1
To see, give after No. 22 medicines, PKM2 is barely perceivable in core.NZT is that the activator reported is represented in Fig. 1, can
Enter core to see that existing activator can not suppress PKM2.This result illustrates the mechanism of action of the compound and conventional activator
Difference, is to enter core by suppressing PKM2, and then suppresses its protein kinase activity that rush propagation correlation is played in core, so as to reach
Antineoplastic action.
3) added in HCT116 cells after compound 22, cell is substantially arrested in the G2/M phases.
Experimental procedure:With 1,000,000 or so HCT16 cells of 6cm culture dishes kind, 36-48h is incubated.Made after being digested with pancreatin
Into single cell suspension, rinsed 1-2 times with precooling PBS, then add 1ml PBS to be resuspended.Add (- 20 DEG C) absolute ethyl alcohol of precooling, 4
It is DEG C fixed overnight or -20 DEG C long-term to preserve.Fixer is removed in centrifugation, is finally previously added 5ml PBS, is contributed to centrifugation, is abandoned
Clearly.5ml PBS are resuspended, soak 15min-30min, and supernatant is abandoned in centrifugation.475 μ l PBS are resuspended, and add 1.5ml EP pipes, plus
Enter 25 μ 20 × RNAse of l A, 37 DEG C of incubation 30min.5 μ l PI dye liquors are added, 4 degree of lucifuges are incubated 30min, and dye liquor is removed in centrifugation,
Plus the μ l of PBS 500 are resuspended, cell sieve, upper machine testing are crossed.
Evaluation of result:By various concentrations compound 22, (1 μM, 5 μM) adds in HCT116 cells, carries out cell detection.From
Fig. 2 can see, and No. 22 compounds can must be arrested in the G2/M phases by cell is obvious.Compared with DMSO negative control groups, with 1 μM
With the HCT116 cells of 5 μM of drug-treateds, the ratio of G2/M phases adds 22.74% and 59.75% (Fig. 2, C) respectively.
Claims (9)
1. dithiocarbamates compound or its pharmaceutically acceptable salt with structure shown in formula I,
Wherein R1Selected from phenyl, 2- furyls, 4- nitrobenzophenones, 4- hydroxy phenyls, 4- cyano-phenyls, 2- chlorphenyls, 2- methoxyl groups
Phenyl, 3- pyridine radicals, 2- thiazolyls or 3- azaindolyls.
2. the method for the compound or its pharmaceutically acceptable salt described in preparation claim 1, it is characterised in that described formula
I compound is prepared by the following method:
Wherein, R1For phenyl.
3. the method for the compound or its pharmaceutically acceptable salt described in preparation claim 1, it is characterised in that described formula
I compound is prepared by the following method:
Wherein, R1For 2- furyls, 4- nitrobenzophenones, 4- hydroxy phenyls, 4- cyano-phenyls, 2- chlorphenyls, 2- methoxyphenyls,
3- pyridine radicals, 2- thiazolyls or 3- azaindolyls.
4. method according to claim 3, it is characterised in that the compound of structure is prepared as follows shown in formula II:
(1) R is worked as1For 2- furyls, 4- nitrobenzophenones, 4- hydroxy phenyls, 4- cyano-phenyls, 2- chlorphenyls, 2- methoxyphenyls,
When 3- pyridine radicals or 2- thiazolyls,
The compound of the structure of formula III is with paraformaldehyde in catalyst CF3COOH·(iPr)2Reacted under NH effects, production II
The compound of structure;
(2) R is worked as1During for 3- azaindolyls,
7- azaindoles and chloroacetic chloride are in AlCl3In the presence of, reaction generation 3- acetyl group azaindoles, 3- acetyl group azepines Yin
Diindyl is with paraformaldehyde in catalyst CF3COOH·(iPr)2Reacted under NH effects, the compound of the structure of production II.
5. compound described in claim 1 or its pharmaceutically acceptable salt are in pyruvate kinase M2 subtype agonists are prepared
Using.
6. application according to claim 5, it is characterised in that described pyruvate kinase M2 subtype agonists, which have, to be prevented
Pyruvate kinase M2 hypotypes enter the effect of nucleus.
7. compound described in claim 1 or its application of salt pharmaceutically received in antineoplastic is prepared.
8. application according to claim 7, it is characterised in that the antineoplastic is to be used to treat colon cancer, uterine neck
The medicine of cancer or lung cancer.
9. compound described in claim 1 or its application of salt pharmaceutically received in the activator of glycolytic pathway is prepared.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510243973.2A CN104817490B (en) | 2015-05-13 | 2015-05-13 | Dithiocarbamates compound and preparation method and application |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510243973.2A CN104817490B (en) | 2015-05-13 | 2015-05-13 | Dithiocarbamates compound and preparation method and application |
Publications (2)
Publication Number | Publication Date |
---|---|
CN104817490A CN104817490A (en) | 2015-08-05 |
CN104817490B true CN104817490B (en) | 2017-10-13 |
Family
ID=53727995
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201510243973.2A Active CN104817490B (en) | 2015-05-13 | 2015-05-13 | Dithiocarbamates compound and preparation method and application |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN104817490B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110683975B (en) * | 2019-10-23 | 2021-04-09 | 成都理工大学 | Synthesis method of dialkyl amino alkyl dithioformate |
Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4202832A (en) * | 1977-05-02 | 1980-05-13 | Hoffmann-La Roche Inc. | Thiocarbamoylthio fatty acids |
CN1727332A (en) * | 2004-07-27 | 2006-02-01 | 北京大学 | Compound in category of aryl methylamino dithio formic ether, preparation method and application |
WO2010118063A2 (en) * | 2009-04-06 | 2010-10-14 | Agios Pharmaceuticals, Inc. | Therapeutic compositions and related methods of use |
CN102234271A (en) * | 2010-04-21 | 2011-11-09 | 北京大学 | Aryl (alkyl) amino dithio formate compounds, and preparation method and application thereof |
WO2012092442A1 (en) * | 2010-12-29 | 2012-07-05 | Agios Pharmaceuticals, Inc. | Therapeutic compounds and compositions |
CN102657647A (en) * | 2012-04-06 | 2012-09-12 | 澳门大学 | Application of IC-4 in antiangiogenesis |
CN103508930A (en) * | 2012-06-25 | 2014-01-15 | 北京大学 | Bis(aminodithioformate)-1,3-propane diester compound, and synthesis method, pharmaceutical composition and use thereof |
WO2014074848A1 (en) * | 2012-11-08 | 2014-05-15 | Agios Pharmaceuticals, Inc. | Therapeutic compounds and compositions and their use as pkm2 modulators |
WO2014139325A1 (en) * | 2013-03-15 | 2014-09-18 | Agios Pharmaceuticals, Inc. | Therapeutic compounds and compositions |
CN104370936A (en) * | 2014-09-28 | 2015-02-25 | 苏州维泰生物技术有限公司 | Novel pyruvate kinase M2 activator and its synthetic method |
-
2015
- 2015-05-13 CN CN201510243973.2A patent/CN104817490B/en active Active
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4202832A (en) * | 1977-05-02 | 1980-05-13 | Hoffmann-La Roche Inc. | Thiocarbamoylthio fatty acids |
CN1727332A (en) * | 2004-07-27 | 2006-02-01 | 北京大学 | Compound in category of aryl methylamino dithio formic ether, preparation method and application |
WO2010118063A2 (en) * | 2009-04-06 | 2010-10-14 | Agios Pharmaceuticals, Inc. | Therapeutic compositions and related methods of use |
CN102234271A (en) * | 2010-04-21 | 2011-11-09 | 北京大学 | Aryl (alkyl) amino dithio formate compounds, and preparation method and application thereof |
WO2012092442A1 (en) * | 2010-12-29 | 2012-07-05 | Agios Pharmaceuticals, Inc. | Therapeutic compounds and compositions |
CN102657647A (en) * | 2012-04-06 | 2012-09-12 | 澳门大学 | Application of IC-4 in antiangiogenesis |
CN103508930A (en) * | 2012-06-25 | 2014-01-15 | 北京大学 | Bis(aminodithioformate)-1,3-propane diester compound, and synthesis method, pharmaceutical composition and use thereof |
WO2014074848A1 (en) * | 2012-11-08 | 2014-05-15 | Agios Pharmaceuticals, Inc. | Therapeutic compounds and compositions and their use as pkm2 modulators |
WO2014139325A1 (en) * | 2013-03-15 | 2014-09-18 | Agios Pharmaceuticals, Inc. | Therapeutic compounds and compositions |
CN104370936A (en) * | 2014-09-28 | 2015-02-25 | 苏州维泰生物技术有限公司 | Novel pyruvate kinase M2 activator and its synthetic method |
Non-Patent Citations (1)
Title |
---|
Discovery of novel dithiocarbamic acid ester HGWJ11C with significant anticancer action;Bin Liu,等;《Journal of Chinese Pharmaceutical Sciences》;20141029;第23卷(第10期);第681-687页 * |
Also Published As
Publication number | Publication date |
---|---|
CN104817490A (en) | 2015-08-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5640006B2 (en) | Condensed heterocyclic inhibitors of histone deacetylases and / or cyclin-dependent kinases | |
EP2349999B1 (en) | Allosteric protein kinase modulators | |
US8309721B2 (en) | HSP90 inhibitory carbazole derivatives, compositions containing same and use thereof | |
US20150259351A1 (en) | Modulators of methyl modifying enzymes, compositions and uses thereof | |
CN1413213A (en) | Azaindoles | |
JP2005539001A (en) | Substituted thienyl hydroxamic acids as histone deacetylase inhibitors | |
JP2007522142A (en) | Benzimidazole-substituted thiophene derivatives having activity against IKK3 | |
WO2005080330A1 (en) | Heteroarylphenylurea derivative | |
CN1070173C (en) | Benzoylaguanidine derivatives as medicaments | |
Zhou et al. | Design, synthesis of 4, 5-diazafluorene derivatives and their anticancer activity via targeting telomeric DNA G-quadruplex | |
CN107207489A (en) | It is used as the acylamino- thiadiazoles derivative of nadph oxidase inhibitor | |
CN104557863B (en) | A kind of new Nampt inhibitor and its synthetic method and application | |
CN102417483A (en) | 2-phenyl-1H-benzimidazole-4-formic ether derivative serving as PARP (Poly(ADP-Ribose)Polymerase) inhibiting agent | |
US6018046A (en) | Pyridocarbazole derivatives having cGMP-PDE inhibitory activity | |
EP3398942B1 (en) | Substituted oxadiazole chemical compound and composition containing said chemical compound and use thereof | |
CN103242273B (en) | 2-arylbenzofuran-7-methanamide compound, preparation method and application thereof | |
KR20150125716A (en) | Novel sulfonamide trpa1 receptor antagonists | |
Nakhi et al. | Transition metal free hydrolysis/cyclization strategy in a single pot: synthesis of fused furo N-heterocycles of pharmacological interest | |
JP2016508135A (en) | Novel pyrazole-substituted imidazopyrazine as casein kinase 1D / E inhibitor | |
CN104837835A (en) | VEGFR3 inhibitors | |
CN104817490B (en) | Dithiocarbamates compound and preparation method and application | |
CN104069092A (en) | Use of 2-(substituted phenylamino) benzoic acid and ester compound thereof in preparation of FTO (Fat Mass and Obesity-Associated Protein) inhibitor | |
CN101973935B (en) | Preparation method and application of N-substituted-3,5-dibenzal piperidine-4-one | |
CN114014814A (en) | N-benzyl-4-phenylphthalazin-1-amine derivative, preparation method thereof and medicine for treating RECQL4 specific expression | |
AU2019279441B2 (en) | Novel compound and pharmaceutical composition comprising same |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
EXSB | Decision made by sipo to initiate substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
TR01 | Transfer of patent right |
Effective date of registration: 20230421 Address after: No. 341, 11th Floor, Building 1, No. 158 West Fourth Ring North Road, Haidian District, Beijing, 100142 Patentee after: Beijing Tianchi Kaiyuan Technology Co.,Ltd. Address before: 100191 Peking University Health Science Center, Haidian District, Xueyuan Road, 38, Beijing Patentee before: Peking University |
|
TR01 | Transfer of patent right |