CN106518809A - Pyruvate dehydrogenase kinase inhibitor and application thereof - Google Patents

Pyruvate dehydrogenase kinase inhibitor and application thereof Download PDF

Info

Publication number
CN106518809A
CN106518809A CN201510586458.4A CN201510586458A CN106518809A CN 106518809 A CN106518809 A CN 106518809A CN 201510586458 A CN201510586458 A CN 201510586458A CN 106518809 A CN106518809 A CN 106518809A
Authority
CN
China
Prior art keywords
group
unsubstituted
compound
substituted
purposes
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.)
Pending
Application number
CN201510586458.4A
Other languages
Chinese (zh)
Inventor
黄敏
耿美玉
李剑
谢作权
刘毅夫
唐帅
兰小晶
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
East China University of Science and Technology
Shanghai Institute of Materia Medica of CAS
Original Assignee
East China University of Science and Technology
Shanghai Institute of Materia Medica of CAS
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by East China University of Science and Technology, Shanghai Institute of Materia Medica of CAS filed Critical East China University of Science and Technology
Priority to CN201510586458.4A priority Critical patent/CN106518809A/en
Publication of CN106518809A publication Critical patent/CN106518809A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C333/14—Dithiocarbamic acids; Derivatives thereof
    • C07C333/30—Dithiocarbamic acids; Derivatives thereof having sulfur atoms of dithiocarbamic groups bound to other sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention provides a pyruvate dehydrogenase kinase inhibitor and an application thereof, specifically a compound as shown in a formula I described in the specification or pharmaceutically acceptable salts thereof. The compound has excellent effects of inhibiting pyruvate dehydrogenase kinase activity and resisting tumors. The invention also provides a pharmaceutical composition containing the compound provided by the invention and the application thereof in the aspect of inhibiting pyruvate dehydrogenase kinase.

Description

Pyruvic dehydrogenase kinase inhibitor and its application
Technical field
The invention belongs to pharmaceutical chemistry and pharmacotherapeuticss field, in particular it relates to compound of formula I is pressing down with which Application in terms of pyruvic dehydrogenase kinase processed.
Background technology
China is one of higher country of cancer morbidity in the world, increases 3,070,000 cancer patients every year newly, That is, just there is a people to make a definite diagnosis per 10 seconds.It was predicted that will to the annual cancer patient of the year two thousand thirty China Reach 5,000,000 people, dead number reaches 3,500,000 people, and destroy the economic situation of more people, and thus band Carry out huge medical pressure.Therefore, independently research and develop the new medicine with anticancer effect have it is important Realistic meaning and scientific value.
Most of cancerous cell are characterized with a metabolism conversion, even if the conversion is referred under normal oxygen situation, cancer The glycoxidative glycolysiss for being converted to Cytoplasm dependence of Fructus Vitis viniferae that the metabolism of cell is still relied on by mitochondrion, this is just It is so-called warburg effect.This metabolism route is reduced to Fructus Vitis viniferae is glycoxidative with glucolytic increase Feature, the propagation for cancerous cell provide the advantages such as energy, substrate.Therefore, cancerous cell metabolism is relied on Property destruction be a kind of anticancer strategy likely, true also the way it goes, and increasing research shows target Chance can be provided for the treatment of cancer to the metabolism reconstruct of cancer specific.
Pyruvic dehydrogenase kinase (PDHK) is a kind of cyclophorase, can suppress pyruvate dehydrogenase complex (PDC), it is the glycoxidative crucial control enzyme of Fructus Vitis viniferae.PDHK has four hypotypes, respectively PDHK1～4, Wherein PDHK1 is closely related with the grade malignancy of cancer.PDHK1 is in kinds cancer such as pulmonary carcinoma, head and neck squamous All it is activation in epithelial cancer.PDHK1 is proto-oncogene (C-MYC) and hypoxia inducible factor (hypoxia Inducing factor, HIF) etc. oncogene transcriptional control, the metabolism that cancerous cell is controlled with this and malignant phenotype. Title is had been reported, is suppressed PDHK effectively improve the effect of tumor cell chemotherapy, and this is had height The tumour-specific of degree.
So far, the PDHK inhibitor for mainly having three types is seen in report (Fig. 5), and they pass through different machines System produces suppression to PDHK.AZD7545 and Nov3r contain trifluoromethyl propionic acid amide. group, and they represent The inhibitor combined with the thioctic acid pocket of PDHK by one class.DCA is by the spiral binding with N-terminal Close to inactivate PDHK.Radicicol belongs to ATP competitive type inhibitor, and which is by being connected to PDHK's ATP pockets work.Although the quantity of PDHK inhibitor is gradually increasing, its inhibitor type and mechanism Also do not break through, no medicine enters clinical practice so far.Therefore, this area is effective in the urgent need to developing Pyruvic dehydrogenase kinase activity inhibitor.
The content of the invention
It is an object of the invention to provide it is a kind of suppress pyruvic dehydrogenase kinase activity compound and its should With.
A first aspect of the present invention, there is provided a kind of compound of formula I, its optical isomer, non-raceme, outer The purposes of raceme or its pharmaceutically acceptable salt, they are used for preparing suppression pyruvic dehydrogenase kinase (PDHK) active pharmaceutical composition or preparation,
In formula,
R1And R2It is each independently selected from the following group：Hydrogen, halogen, hydroxyl, cyano group, substituted or unsubstituted C1-C6 Alkyl, substituted or unsubstituted C1-C6Alkoxyl, substituted or unsubstituted C2-C6Alkenyl, replacement or not Substituted C2-C8Alkynyl, R3-R4- group, substituted or unsubstituted C5-C20Aryl and replacement or unsubstituted C5-C20Heteroaryl；
R3It is selected from the group：Substituted or unsubstituted C5-C20Aryl, substituted or unsubstituted C5-C20Heteroaryl；
R4It is selected from the group：Substituted or unsubstituted C1-C6Alkylidene；
Or, R1、R2Substituted or unsubstituted, saturation or undersaturated is collectively forming with adjacent nitrogen-atoms 5-8 circle heterocycles, wherein described 5-8 circle heterocycles have the 1-3 hetero atom being selected from the group：O, S and N, And the 5-8 circle heterocycles have at least one nitrogen heteroatom；
Wherein described replacement refers to the substituent group being selected from the group with one or more：Halogen, C1-C4Alkyl, C1-C4Haloalkyl, C1-C4Alkoxyl, hydroxyl, nitro ,-CN and R5- C (O)-, wherein R5It is selected from the group： H, hydroxyl, C1-C4Alkoxyl, C1-C4Alkyl, C1-C4Haloalkyl and C1-C4Halogenated alkoxy.
In another preference, described pharmaceutical composition or preparation are independently or additionally used for promoting line grain The activation of body pyruvate dehydrogenase complex.
In another preference, described pharmaceutical composition or preparation are independently or additionally used for promoting cell The glycoxidative conversion that the anaerobic glycolysises that matter is relied on are relied on to mitochondrion.
In another preference, described pharmaceutical composition or preparation are additionally operable to suppress tumor cell or are used for Treatment tumor.
In another preference, each R1It is same or different.
In another preference, each R2It is same or different.
In another preference, each R1It is identical, and/or each R2It is identical.
In another preference, R1、R2Substituted or unsubstituted, saturation is collectively forming with adjacent nitrogen-atoms Or undersaturated 5-6 circle heterocycles.
In another preference, described 5-6 circle heterocycles are selected from the group：6 circle heterocycles containing a nitrogen, containing one 6 circle heterocycles and 6 circle heterocycles containing two nitrogen of individual nitrogen and an oxygen.
In another preference, described heterocycle isIn formula, each Ra is independently selected from the following group： Halogen, C1-C4Alkyl, C1-C4Haloalkyl, hydroxyl, nitro, amino or amido；And n is 0-4 Positive integer.
In another preference, Ra is C1-C4Alkyl.
In another preference, Ra is methyl.
In another preference, n is 2 or 3, and preferably n is 2.
In another preference, each Ra is for methyl and n is 2.
In another preference, described heterocycle is the heterocycle of saturation.
In another preference, described heterocycle is selected from the group：Nafoxidine base, piperidyl, morpholinyl, And piperazinyl.
In another preference, described R1And R2It is each independently selected from the following group：It is substituted or unsubstituted C1-C6Alkyl, R3-R4- group, substituted or unsubstituted C5-C20Aryl.
In another preference, described C5-C20Aryl is the phenyl for replacing or replacing.
In another preference, R3For substituted or unsubstituted phenyl.
In another preference, R1And R2It is each independently selected from the following group：Substituted or unsubstituted C1-C2Alkane Base, replacement or unsubstituted C6Aryl.
In another preference, the substituted heterocycle is the saturated rings of 5 yuan or 6 yuan, and optionally has one Individual or multiple substituent groups being selected from the group：Methyl, carboxyl or tert-butyl ester base.
In another preference, the compound of formula I is selected from the group：
In another preference, contain 0.001-99wt% in described pharmaceutical composition, preferably 0.1-90wt%, more The compound of formula I of good ground 1-80wt% or its pharmaceutically acceptable salt, are based on the total weight of the composition.
In another preference, the dosage form of described pharmaceutical composition is peroral dosage form or injection.
In another preference, the peroral dosage form includes tablet, capsule, membrane, granule etc., also Including spacetabs type or available in non-time-release type dosage form.
In another preference, described pharmaceutical composition can also contain other drugs active component, wherein wrap Include the active component such as cisplatin, paclitaxel or antineoplastic antibody etc. for the treatment of tumor.
A second aspect of the present invention, there is provided compound, its optical isomer shown in a kind of Formulas I, non-racemization The purposes of body, racemic modification or its pharmaceutically acceptable salt, they be used for prepare suppress tumor cell or The pharmaceutical composition or preparation of tumor is treated, also, described compound of formula I is selected from the group：
In another preference, described tumor is selected from the group：Pulmonary carcinoma, breast carcinoma, colon cancer.
A third aspect of the present invention, there is provided a kind of suppression pyruvic dehydrogenase kinase of external non-therapeutic is lived The method of property, including step：
A () is by the compound of formula I described in pyruvic dehydrogenase kinase and first aspect present invention, its optical siomerism Body, non-raceme, racemic modification or its pharmaceutically acceptable salt are contacted, so as to suppress acetone acid The activity of dehydrogenase kinase.
In another preference, in step (a), by compound of formula I, its optical isomer, non-raceme, Racemic modification or its pharmaceutically acceptable salt are added in cell culture system, so that itself and acetone acid Dehydrogenase kinase is contacted.
In another preference, described cell is normal cell or tumor cell.
In another preference, described cell is mammalian cell.
In another preference, described cell is people's cell.
A fourth aspect of the present invention, there is provided a kind of method of suppression pyruvic dehydrogenase kinase, described side Method includes：(i) to need object apply first aspect present invention described in compound of formula I, its optical isomer, Non- raceme, racemic modification or its pharmaceutically acceptable salt.
In another preference, described object includes people and non-human mammal (as rodent and spirit are long dynamic Thing).
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and below (such as embodiment) Can be combined with each other between each technical characteristic of middle specific descriptions, so as to constitute new or preferred technical side Case.As space is limited, here is no longer tired out one by one and is stated.
Description of the drawings
Fig. 1 shows inhibitory action of the compound 5 to PDHA1 phosphorylations in three kinds of tumor cells.
Fig. 2 shows effect of the compound 5 to A549 grape cell Sugar intakes.
Fig. 3 shows the effect that the ATP intracellular to A549 of compound 5 is generated.
Fig. 4 shows impact of the compound 5 to human lung cancer A549 Nude Mice volume.
Fig. 5 shows known representativeness PDHK inhibitor.
Specific embodiment
Through extensively and in depth studying, the present inventor have unexpectedly discovered that compound of formula I can be significantly first Suppress pyruvic dehydrogenase kinase activity.Experiment shows that the compound of formula I can be taken off by suppressing acetone acid Hydrogen kinase enzyme (PDHK), activation mitochondrion pyruvate dehydrogenase complex (PDC) promote what Cytoplasm was relied on The glycoxidative conversion that anaerobic glycolysises are relied on to mitochondrion, the final propagation for suppressing tumor cell.Here basis On, complete the present invention.
Term
Group
Term " C1-C6Alkyl " refers to the straight or branched alkyl with 1-6 carbon atom, for example methyl, ethyl, Propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group or similar group.
Term " C1-C6Alkoxyl " refers to the straight or branched alkoxyl with 1-6 carbon atom, such as methoxyl group, Ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy or class Like group.
Term " cycloalkyl " refers to that 3 to 8 yuan of full carbon is monocyclic, 5 yuan/6 yuan or 6 yuan/6 yuan fused rings or multi-ring thick of full carbon Ring group, wherein one or more rings can contain one or more double bonds, but neither one ring has had The pi-electron system of full conjugate.Examples of cycloalkyl has cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, hexamethylene Dialkylene, adamantyl, cycloheptyl alkyl, cycloheptatriene base etc..
Term " 5-7 unit monocycles " refers to monocyclic (only one ring structure) with 5-7 units, described monocyclic to be Saturation or unsaturation ring, such as cycloalkyl, cycloalkenyl group, aromatic ring.
Term " carbocyclic ring " finger ring skeleton is all the saturation or unsaturation ring of carbon atom, and wherein one or more rings can With containing one or more double bonds.
At least there is a heteroatomic saturation being selected from the group or unsaturation on term " heterocycle " finger ring skeleton Ring：N, S, O or P, wherein one or more rings can contain one or more double bonds.
Term " aromatic ring " refers to the aromatic ring of the pi-electron system with conjugation, including isocyclic aryl, heteroaryl.
Term " heteroaryl " refers to 1 hetero atom that as annular atom aryl of remaining annular atom for carbon is miscellaneous Atom includes oxygen, sulfur, nitrogen.The ring can be 5 yuan or 6 yuan or 7 yuan of rings.The example bag of heteroaryl groups Include but be not limited to furyl, thienyl, benzofuranyl, benzothienyl, pyridine radicals, pyrroles, N- alkane Base pyrrole radicals.
Term " alkoxyl " refers to-O- (alkyl).Representative example includes methoxyl group, ethyoxyl, propoxyl group, fourth Epoxide etc..
Term " halogen " refers to fluorine, chlorine, bromine, iodine.Term " halo " refer to fluoro, chloro, bromine It is generation, iodo.
Herein, except special instruction part, term " replacement " refers to one or more the hydrogen atom quilts on group The substituent group being selected from the group replaces：C1-C10Alkyl, C3-C10Cycloalkyl, C1-C10Alkoxyl, halogen, hydroxyl Base, carboxyl (- COOH), C1-C10Aldehyde radical, C2-C10Acyl group, C2-C10Ester group, amino, phenyl；It is described Phenyl include unsubstituted phenyl or the substituted-phenyl with 1-3 substituent group, the substituent group is selected from：Halogen Element, C1-C10Alkyl, cyano group, OH, nitro, C3-C10Cycloalkyl, C1-C10Alkoxyl, amino.
Compound of formula I
As used herein, term " the compounds of this invention ", or " compound " refer to compound shown in Formulas I or Its raceme, correspondence isomer or its pharmaceutically acceptable salt.It should be understood that the term is also including above-mentioned The mixture of component.
In formula, each group is as defined above.
In formula,
R1And R2It is each independently selected from the following group：Hydrogen, halogen, hydroxyl, cyano group, substituted or unsubstituted C1-C6 Alkyl, substituted or unsubstituted C1-C6Alkoxyl, substituted or unsubstituted C2-C6Alkenyl, replacement or not Substituted C2-C8Alkynyl, R3-R4- group, substituted or unsubstituted C5-C20Aryl and replacement or unsubstituted C5-C20Heteroaryl；
R3It is selected from the group：Substituted or unsubstituted C5-C20Aryl, substituted or unsubstituted C5-C20Heteroaryl；
R4It is selected from the group：Substituted or unsubstituted C1-C6Alkylidene；
Or, R1、R2Substituted or unsubstituted, saturation or undersaturated is collectively forming with adjacent nitrogen-atoms 5-8 circle heterocycles, wherein described 5-8 circle heterocycles have the 1-3 hetero atom being selected from the group：O, S and N, And the 5-8 circle heterocycles have at least one nitrogen heteroatom；
Wherein described replacement refers to the substituent group being selected from the group with one or more：Halogen, C1-C4Alkyl, C1-C4Haloalkyl, C1-C4Alkoxyl, hydroxyl, nitro ,-CN and R5- C (O)-, wherein R5It is selected from the group： H, hydroxyl, C1-C4Alkoxyl, C1-C4Alkyl, C1-C4Halogenated alkoxy and C1-C4Halogenated alkoxy.
The particularly preferred compound of formula I of one class is prepared compound, especially compound 4-10 in embodiment, More preferably it is compound 5 and 6.
In the present invention, the pharmaceutically acceptable salt also including compound of formula I.Term is " pharmaceutically acceptable Salt " refer to the compounds of this invention with acid or the salt for being suitable as medicine that formed of alkali.Pharmaceutically acceptable salt Including inorganic salt and organic salt.The preferred salt of one class is the salt that the compounds of this invention is formed with acid.Suitably form salt Acid include but is not limited to：The mineral acids such as hydrochloric acid, hydrobromic acid, Fluohydric acid., sulphuric acid, nitric acid, phosphoric acid, first Acid, acetic acid, propanoic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, wine The organic acid such as stone acid, citric acid, picric acid, methanesulfonic acid, benzene methanesulfonic acid, benzenesulfonic acid；And aspartic acid, The acidic amino acids such as glutamic acid.
Pyruvic dehydrogenase kinase
Pyruvic dehydrogenase kinase is Pyruvate Dehydrogenase Kinase (PDHK), is a kind of line grain Body enzyme, can suppress pyruvate dehydrogenase complex (PDC), be the glycoxidative crucial control enzyme of Fructus Vitis viniferae, can To prevent conversion of pyruvate as S-acetyl-coenzyme-A, and the latter is the substrate of tricarboxylic acid cycle.The activation energy of PDHK Cause glycolysiss and disconnection glycoxidative downstream.Four hypotypes have been confirmed the existence of in human cell PDHK is respectively PDHK1～4, and wherein PDHK1 is closely related with the grade malignancy of cancer.PDHK1 exists Kinds cancer such as pulmonary carcinoma, is all activation in head and neck squamous cell carcinoma.PDHK1 is proto-oncogene (C-MYC) With the oncogene transcriptional control such as hypoxia inducible factor (hypoxia inducing factor, HIF), controlled with this The metabolism of cancerous cell and malignant phenotype.It is general in human cancer cell that one newest research also discloses PDHK1 For the tyrosine kinase institute phosphorylation of various tumorigenesis, and this is to promoting the warburg effect and tumour growth to be all Critically important.Title is had been reported, suppresses PDHK effectively improve the effect of tumor cell chemotherapy, and This has the tumour-specific of height.Except above-mentioned metabolism anticancer mechanism, also there are some researches show the activation of PDC Cause active oxygen stress (reactive oxygen species, ROS) increase and inducing tumor cell apoptosis.No By the generation for being glucose metabolism intervention or ROS, all show that selective activation PDC can be with induced tumor The apoptosis of cell.Therefore, suppression PDHK can be used as the target spot of killing tumor cell, the common table of these evidences The lifting of clear target PDHK treating cancer opportunities.
Preparation method
Reactions steps are prepared in the present invention using method well known to those skilled in the art in prior art, it is right The response parameter of each step is not particularly limited.Those skilled in the art can be according to different final expections Compound, the reactant of each step reaction to being related in reaction equation, reaction condition etc. are suitably made adjustment.
In the present invention, a kind of preparation method of formula A compound includes step：
Secondary amine (R will be replaced1R2NH), Carbon bisulfide, inorganic strong alkali (potassium hydroxide or sodium hydroxide or Lithium hydrate Deng) soluble in water, 40-60 DEG C is heated to, stirring reaction 10-20 hour.Then add in right amount in reaction system Methanol and sodium nitrite, and be cooled to 0 DEG C.Inorganic acid is slowly added dropwise into reaction system with vigorous stirring (concentrated hydrochloric acid or concentrated sulphuric acid etc.), separates out a large amount of solids after completion of dropping, sucking filtration, filter cake ethyl alcohol recrystallization are obtained Title compound.
In a representational preference, the reaction condition includes:
(a)R1NHR2(50mmol),CS2(51mmol),H2O (200mL), KOH (110mol), 50 DEG C；
(b)NaNO2(3g),CH3OH (3mL), HCl 37% (10mL), 0 DEG C.
Compositionss and application process
Present invention also offers a kind of compositionss for suppressing pyruvic dehydrogenase kinase.Described compositionss Including (but being not limited to)：Pharmaceutical composition, food compositions, dietary supplement, beverage composition for treating dental erosion etc..
In the present invention, described pharmaceutical composition can be directly used for disease treatment, for example, for antitumor The treatment of aspect.When using pharmaceutical preparation of the present invention, other therapeutic agents, such as antitumor can be also used simultaneously Medicine etc..
Present invention also offers a kind of pharmaceutical composition, it contain the compounds of this invention of safe and effective amount and Pharmaceutically acceptable carrier or excipient.This kind of carrier includes (but being not limited to)：Saline, buffer, Portugal Grape sugar, water, glycerol, ethanol, powder, and combinations thereof.Pharmaceutical preparation should be matched with administering mode.
By taking pharmaceutical composition as an example, the compositionss of the present invention can be made into injection form, for example, use physiology salt Water or the aqueous solution containing glucose and other adjuvant are prepared by conventional method.Such as tablet and capsule Etc pharmaceutical composition, can be prepared by conventional method.Pharmaceutical composition such as injection, solution, piece Agent and capsule are preferably aseptically manufactured.The drug regimen of the present invention can also be made into powder for being atomized Suction.The dosage of active component is therapeutically effective amount, such as daily about 1 microgram/kg body weight-about 5 milligram / kg body weight.Additionally, cell pyruvic dehydrogenase kinase inhibitor of the present invention can also be together with other therapeutic agents Use.
For the pharmaceutical composition of the present invention, the object needed for being applied to by way of routine is (such as people and non- People mammal).Representational method of application includes (but being not limited to)：Orally, injection, Neulized inhalation etc..
During using pharmaceutical composition, it is in mammal, the wherein safety by the medicament administration of safe and effective amount Effective dose typically at least about 10 micrograms/kg body weight, and in most of the cases it is no more than about 8 milligrams/thousand Gram body weight, preferably the dosage is the mg/kg body weight of about 10 micrograms/kg body weight-about 1.Certainly, specifically Dosage is also contemplated that the factors such as route of administration, patient health situation, these be all skilled practitioners technical ability scope it Interior.
Main advantages of the present invention are：
(1) can be used to prepare the new compound of pyruvic dehydrogenase kinase inhibitor there is provided a class；
(2) such compound results is simple, and preparation technology is succinct, low production cost；
(3) such compound inside and outside antitumor mechanism is clear and definite, drug effect is notable.
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate The present invention rather than restriction the scope of the present invention.The experiment side of unreceipted actual conditions in the following example Method, generally according to normal condition, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise Percentage ratio and number are calculated by weight.
Embodiment 1 pair (diformazan thiocarbamic acid) changes two magisters of sulfur
50mmol methylamines (aqueous solution), 51mmol Carbon bisulfide, 110mmol potassium hydroxide are dissolved in into 200 millis 50 DEG C of maintenances 12 hours are heated in rising water, then addition 3mL methanol, 3 grams of nitrous acid in reaction system Sodium, and it is cooled to 0 DEG C.10mL concentrated hydrochloric acid is slowly added dropwise into system with vigorous stirring, after completion of dropping, The solid ethyl alcohol recrystallization of precipitation, obtains title compound, 3.0 grams of yellow solids, yield 50%.
1H-NMR(400MHz,CDCl3)δ3.64(s,6H),3.61(s,6H)；HRMS (EI) m/z is calculated Value:C6H12N2S4(M+) 239.9883, measured value：239.9886.
Embodiment 2 pairs (diethyl thiocarbamic acid) changes two magisters of sulfur
In addition to changing methylamine into ethamine, remaining needed raw material, reagent and preparation method are obtained with embodiment 1 3.3 grams of white solids (compound 2), yield is 45%.
1H-NMR(400MHz,CDCl3) δ 4.03 (q, J=6.8Hz, 8H), 1.48 (t, J=6.8Hz, 6H), 1.31 (t, J=6.8Hz, 6H)；HRMS (EI) m/z value of calculation:C10H20N2S4(M+), 296.0509, measured value： 296.0513。
Embodiment 3 pairs (1- pyrrolidinyl thiocarbonyls) changes two magisters of sulfur
In addition to changing methylamine into nafoxidine, remaining needed raw material, reagent and preparation method with embodiment 1, 5.1 grams of white solids (compound 3) are obtained, yield is 70%.
1H-NMR(400MHz,CDCl3)δ4.00-3.95(m,8H),2.18-2.15(m,4H),2.06-2.01(m, 4H)；HRMS (EI) m/z value of calculation:C10H16N2S4(M+), 292.0196, measured value：292.0201.
Embodiment 4 pairs (piperidino thiocarbonyl) changes two magisters of sulfur
In addition to changing methylamine into piperidines, remaining needed raw material, reagent and preparation method are obtained with embodiment 1 4.0 grams of white solids (compound 4), yield is 50%.
Embodiment 5 pairs (4- morpholinothio carbonyls) changes two magisters of sulfur
In addition to changing methylamine into morpholine, remaining needed raw material, reagent and preparation method are obtained with embodiment 1 5.6 grams of white solids (compound 5), yield is 72%.
1H-NMR(400MHz,CDCl3) δ 4.31 (br s, 8H), 3.85 (t, J=5.0Hz, 8H)；HRMS(EI) M/z value of calculation:C10H16N2O2S4(M+), 324.0095, measured value：324.0099.
Embodiment 6 pairs [4- (cis- 2,6- thebaines) base thiocarbonyl] changes two magisters of sulfur
Outside changing methylamine into cis- 2,6- thebaines, remaining needed raw material, reagent and preparation method are with real Example 1 is applied, 5.7 grams of white solids (compound 6) are obtained, yield is 60%.
1H-NMR(400MHz,CDCl3)δ5.30(br s,2H),4.82(br s,2H),3.77(br s,4H),3.09 (br s,2H),294(br s,2H)；HRMS (EI) m/z value of calculation:C14H24N2O2S4(M+), 380.0721, measurement Value：380.0723
Embodiment 7 pairs (1- is to carboxylic acid piperidin base thiocarbonyl) changes two magisters of sulfur
In addition to methylamine is changed into carboxylic acid piperidin, remaining needed raw material, reagent and preparation method with embodiment 1, 5.4 grams of yellow solids (compound 7) are obtained, yield is 53%.
1H-NMR(400MHz,DMSO-d6):δ=4.91 (br s, 2H), 4.68 (br s, 2H), 4.91 (br s, 2H),3.65-3.60(m,4H),2.74-2.64(m,2H),1.98(br s,4H),1.63(br s,4H)；HRMS (ESI)(m/z):[M+Na]+Value of calculation:C14H20N2O4S4Na,431.0198；Measured value：431.0221.
Embodiment 8 pairs [4- (1-Boc- piperazines) base thiocarbonyl] changes two magisters of sulfur
In addition to methylamine to be changed into 1-Boc- piperazines, remaining needed raw material, reagent and preparation method with embodiment 1, 4.7 grams of gray solids (compound 8) are obtained, yield is 36%.
1H-NMR(400MHz,DMSO-d6)δ4.22(br s,8H),3.51(br s,8H),1.42(s,18H)； HRMS (EI) m/z value of calculation:C20H34N4O4S4(M+), 522.1463, measured value：522.1465.
Embodiment 9 pairs (methylphenylamine base thiocarbonyl) changes two magisters of sulfur
In addition to changing methylamine into methylphenylamine, the same embodiment of remaining needed raw material, reagent and preparation method 1,7.5 grams of yellow solids (compound 9) are obtained, yield is 82%.
1H-NMR(400MHz,CDCl3):δ7.52-7.43(m,10H),3.82(s,6H)；HRMS(EI) (m/z):(M+) value of calculation:C16H16N2S4,364.0196；Measured value：364.0205.
Embodiment 10 pairs (N- methylbenzylamine base thiocarbonyls) changes two magisters of sulfur
In addition to methylamine to be changed into N- methylbenzylamines, the same embodiment of remaining needed raw material, reagent and preparation method 1,7.8 grams of yellow solids (compound 10) are obtained, yield is 80%.
1H NMR(400MHz,CDCl3):δ7.40-7.26(m,10H),5.40(s,2H),5.28(s,2H), 3.53(s,6H)；HRMS(m/z):(M+) value of calculation:C18H20N2S4,392.0509；Measured value： 392.0516.
Biological assessment
Impacts of the 11 compound 1-10 of embodiment to pyruvic dehydrogenase kinase (PDHK1) kinase activity
1st, experimental technique
(1) immobilized substrate：Substrate PDHE1 (0.5 μ g/well) is diluted with carbonate buffer solution (Na2CO3-NaHCO3, 9.6) pH be fixed (100 μ L/well), puts 37 DEG C of shaking tables, 110rpm, Gu Determine 3h.Then, wash three times without potassium PBST, each 5min is patted dry.
(2) enzymatic reaction：100 μ L HEPES reaction systems：50mM HEPES (pH 7.5), 10mM MgCl2, 1mM EGTA, 10 μM of ATP, 0.1 μ g enzymes；Put 37 DEG C of shaking tables, 110rpm, 1h reaction. Wash three times without potassium PBST, each 5min is patted dry.
(3) one anti-incubations：Phosphorylation PDHE1 (S293) antibody is diluted with PBST, and dilution ratio is 1:400, often Hole adds 100 μ L antibody diluents, puts 37 DEG C of shaking tables, and 110rpm is incubated 1h.Then PBST is washed three times, Pat dry.
(4) two anti-incubations：Anti-rabbit HRP bis- resists, with PBST with 1：2000 dilutions, add 100 μ L antibody per hole Diluent, puts 37 DEG C of shaking tables, and 110rpm is incubated 1h.Then TBST is washed three times, is patted dry.
(5) develop the color：The 100 μ l/well of OPD nitrite ions of 2mg/ml are added (with containing 0.03%H2O20.1M lemons Lemon acid-sodium citrate buffer solution (pH 5.4) dilutes).
(6) 2M H are added2SO450 μ l/well stopped reactions, are declined orifice plate microplate reader SPECTRA with wavelengthtunable 190 readings of MAX, wavelength is 490nm.
(7) interpretation of result
IC50 values are adopted the random bundled software of microplate reader and are tried to achieve with the recurrence of four parametric methods.
2nd, experimental result
To the suppression situation of pyruvic dehydrogenase kinase (PDHK1), the experiment by more than is carried out compound (1-10) Determine, the IC for measuring50Value is shown in Table 1.Compound 1 and 5 couples of other members of pyruvic dehydrogenase kinase family suppress The IC of PDHK2-4 kinase activities50Value is shown in Table 2.As a result show, compound (1-10) has to PDHK1 kinases Certain inhibitory action, wherein 1,4,5, No. 6 compound activities of compound are preferable, respectively less than 100nM. Compound (1, have an inhibitory action 5) to PDHK2,3, but to PDHK4 unrestraints effect (>10μM).
1. compound of table (1-10) suppresses the IC of PDHK1 activity50Value
2. compound of table (1,5) suppresses the IC of PDHK2-4 activity50Value
The impact that 12 compound of embodiment is bred to kinds of tumor cells
1st, experimental technique
Tumor cell in exponential phase is seeded to 96 well culture plates by proper density, per 100 μ L of hole System, after cell attachment, adds the compound of 10 μ L variable concentrations, each concentration to set three multiple holes.Change After compound effect 72h, cell training liquid is discarded, 10% (w/v) trichloroacetic acid (100 μ L/ holes) is added in 4 DEG C of fixations 1h, subsequently with distilled water flushing five times.Reverse side is placed into baking oven and is dried, and takes out cooling, adds 100 per hole μ L SRB solution (4mg/mL SRB powder is dissolved in 1% glacial acetic acid), after placing 15min, uses under room temperature 1% glacial acetic acid rinses five times fully to remove SRB not protein bound with plate bottom.Reverse side is placed into baking oven dry It is dry, cooling is taken out, 150 μ L of 10mM Tris solution is added per hole, is determined under 560nm wavelength with microplate reader OD values.Suppression ratio of the compound to growth of tumour cell is calculated as follows：
IC50Value is adopted the random bundled software of microplate reader and is tried to achieve with the recurrence of four parametric methods.
2nd, experimental result
Compound (1-10) the results are shown in Table 3 to lung carcinoma cell H1299 Proliferation Abilities.As a result show, compound 1-6 Have
Preferable inhibited proliferation, compound 7-10 activity are weaker.Compound 5 is to kinds of tumor cells A549, EBC-1, MDA-MB-468 and HCT-15 Proliferation Ability the results are shown in Table 4.As a result show, chemical combination Thing 5 has preferable inhibited proliferation to kinds of tumor cells.
3. compound of table (1-10) is to H1299 cell inhibitory effect IC50
IC of 4. compound 5 of table to kinds of tumor cells Proliferation Ability50
Impact of 13 compound 5 of embodiment in kinds of tumor cells to PDHK inhibitory action
Cell is inoculated in into six orifice plates, Jing after processing, degrees of fusion reaches 80% or so, collects cell, with cold PBS Wash twice, add 1 × sds gel sample-loading buffer cell lysis 5min.Cell pyrolysis liquid is heated in boiling water bath After 10 minutes, it is centrifuged 10 minutes in 4 DEG C of 12000rpm, takes supernatant, abandon precipitation.
Protein sample is placed in variable concentrations SDS- polyacrylamide gel, slow in Tris- glycine-SDS electrophoresis Rush after being separated with 80V electrophoresis to albumen Marker in liquid, separated with 120V electrophoresis about 2h.Use half xerography Albumen is transferred to nitrocellulose filter from gel by mark method or wet robin, is shifted by desirable proteins molecular size range 1-2.5h.Albumen transfer situation and protein band position is determined with the dyeing of Ponceaux dyeing liquor, according to albumen The corresponding purpose band of Marker molecular weight cuttings, is then closed with confining liquid (TBST containing 3%BSA) room temperature 1h, with 4 DEG C of overnight incubations of corresponding antibody (being diluted with the TBST of 3%BSA).With TBST cleaning mixture room temperatures Washing 3 times, each 10min.The two of addition horseradish peroxidase-labeled anti-(1：2000 use 3%BSA TBST dilution), be incubated at room temperature 1h.Then washed three times with TBST, each 10min.According to exposure intensity After selecting suitable luminescence reagent incubation, chromogenic assay is carried out with full automatic gel Image analysis system.
As a result as shown in figure 1, in three kinds of tumor cells (A549, MDA-MB-468 and HCT-15), changing After compound effect 24h, under 0.3 μM of concentration, the phosphorylation in PDHA1S293 and S232 sites is just had Certain inhibitory action.This prompting, the compounds of this invention can activate pyruvate dehydrogenase complex (PDC) with And the glycoxidative conversion that the anaerobic glycolysises of promotion Cytoplasm dependence are relied on to mitochondrion.
Additionally, experimental result is also shown that increase with concentration, inhibitory action strengthens, and presents preferably amount Effect relation.
Impact of 14 compound 5 of embodiment to grape cell Sugar intake
Cell in exponential phase is seeded to into 6 well culture plates by proper density, it is per hole 2ml, adherent Afterwards, add the compound or DMSO effect 12h of variable concentrations.Attached cell 2 is washed with the PBS of pre-cooling It is secondary, after PBS is exhausted, aloof from politics and material pursuits sugar training liquid (25mM Glucose) of 1mL depletion of blood is added in every hole, is added not Remake with the compound or DMSO of concentration and use 12h.Training liquid is drawn in 1.5ml EP pipes, Buffer is obtained A, is put on ice for preserving.Carefully exhaust remaining cell training liquid, washs attached cell 2 with the PBS of pre-cooling It is secondary, after PBS is exhausted, 200 μ L lysates are added in every hole, be placed in 4 DEG C of cracking 10min.To split Solution liquid is drawn in 1.5ml EP pipes, and 4 DEG C of 12,000g are centrifuged 15min.Precipitation is abandoned, supernatant is moved into new In EP pipes, Buffer B are obtained.A certain amount of Buffer A are taken, (biotechnology is built up in Nanjing to be had with glucose testing kit Limit company) glucose assays are carried out, calculate the concentration of glucose A that liquid is trained in every hole.Meanwhile, measure is fresh not to be added Entered the concentration of glucose C of the aloof from politics and material pursuits sugar training liquid of depletion of blood of cell.A certain amount of cell pyrolysis liquid is taken, BCA albumen is used Quantification kit (green skies biotechnology research institute) is quantitative, calculates the protein concentration B in every hole.With (C-A)/B Draw the glucose amount absorbed by per unit albumen.
As a result as shown in Fig. 2 after effect 24h, compound 5 has significant increase to the glucose uptake of A549 Effect, and there is a certain amount to imitate relation.In A549 cells, compound has aobvious to the phosphorylation of PDHA1 The inhibitory action of work, and the phosphorylation degree of PDHA1 is in negatively correlated with its activity level.As a result table Bright compound can be active with the PDHA1 in active cell, and then enables to enter mitochondrial acetone acid more Many catalysis become acetyl-CoA, so as to have lasting activation to the path of mitochondrion aerobic phosphorylation. What acetone acid was utilized increases can cause its upstream breakdown of glucose to be accelerated, and further result in cell and glucose is taken the photograph Take increase.
Impact of 15 compound 5 of embodiment to intracellular ATP concentration
6 well culture plates will be seeded in the cell of exponential phase by proper density, per hole 2ml, it is adherent after, Add the compound or DMSO effect 24h of variable concentrations.Attached cell 2 times is washed with the PBS of pre-cooling, will After PBS exhaustions, 200 μ L lysates are added in every hole, be placed in 4 DEG C of cracking 10min.Lysate is inhaled Enter in 1.5ml EP pipes, 4 DEG C of 12000g are centrifuged 15min.Precipitation is abandoned, supernatant is moved in new EP pipes. Take a certain amount of cell pyrolysis liquid, with ATP Colorimetric/Fluorometric Assay Kit (Biovision, USA ATP measure is carried out), ATP concentration amounts A in every hole are calculated.A certain amount of cell pyrolysis liquid is taken, BCA is used Protein quantification test kit (green skies biotechnology research institute) is quantitative, calculates the protein concentration B in every hole.With A/B draws the ATP amounts contained by per unit albumen.
As a result as shown in figure 3, after effect 24h, the ATP concentration intracellular to A549 of compound 5 has significantly Increasing action, and there is good dose-effect relationship.One glucose can synthesize through oxidative phosphorylation path 36 ATP, but 4 ATP can only be synthesized through aerobic glycolysiss path.So, when oxidative phosphorylation path After being activated, the generation of intracellular ATP can increase.As a result show that compound 5 can activate oxidative phosphorylation Path.
Growth inhibition effect of 16 compound 5 of embodiment to nude mouse subcutaneous transplantation tumor
Using nude mouse (BALB/c), female, 4-5 week old, 17 ± 2g of body weight are biological purchased from Beijing China Fukang Science and Technology Co., Ltd..Every group of number of animals：6.Animal used in this experiment strictly observes animal Raise and use ethical standard.Nude mouse is raised under the conditions of without special pathogen, substitutes illumination one per 12h It is secondary, feedstuff and water it is sterilized after can use.Specific experiment step is as follows：Take the A549 in exponential phase Cell, by 5 × 106A cell/subcutaneous vaccination right side of mice axillary fossa, with slide gauge determine tumor major diameter (A) and Minor axis (B), and thus calculate gross tumor volume (Tumor volume, TV) V=A × B × B/2.Treat gross tumor volume Grow to 100-200mm3Afterwards animal is grouped immediately.Compound 540mg/kg groups, 80mg/kg groups and CMCC solvent controls, daily intraperitoneal administration once, final volume be 200 μ L, successive administration 21 days.It was administered Cheng Zhong, measured transplanted tumor diameter once per two days, while weighing Mouse Weight.After administration terminates, will be all The disconnected neck of mice put to death, and take out tumor tissue.
Relative tumour volume (Relative tumor volume, RTV) is calculated according to the result of measurement, calculates public Formula is RTV=Vt/V0, wherein, V0For (d during random packet0) measurement gained gross tumor volume, VtFor each Gross tumor volume during measurement.Antitumor activity evaluation index is：Relative tumor rate of increase T/C (%), calculates public Formula is as follows：T/C (%)=(TRTV/CRTV) × 100%, TRTVFor administration group RTV, CRTVFor negative control group RTV；Tumor volume growth inhibition rate GI%, computing formula are as follows： GI%=[1- (TVt-TV0)/(CVt-CV0)] × 100%, TVtFor the tumor volume that administration group is measured every time, TV0For Tumor volume when administration group is grouped at random, CVtFor the tumor volume that matched group is measured every time, CV0For matched group with Tumor volume when machine is grouped.Tumor-like hyperplasia, computing formula are as follows：Tumor-like hyperplasia=(Wc-Wt)/Wc× 100%, WcFor matched group knurl weight, WtFor administration group knurl weight.
As a result as shown in figure 4, at the end of administration (d21), compound 5 has significantly suppress human lung cancer A549 naked little The effect that Mus transplanted tumor increases, Relative tumor rate of increase T/C (%) under 80mg/kg dosage are 39.83% (P<0.001), the T/C values under 40mg/kg dosage are 52.40% (P<0.001).
The all documents referred in the present invention are all incorporated as reference in this application, just as each document It is individually recited such as reference.In addition, it is to be understood that after the above-mentioned teachings for having read the present invention, Those skilled in the art can be made various changes or modifications to the present invention, and these equivalent form of values equally fall within this Shen Please appended claims limited range.

Claims (10)

1. a kind of compound of formula I, its optical isomer, non-raceme, racemic modification or its pharmaceutically may be used The purposes of the salt of acceptance, it is characterised in that suppress pyruvic dehydrogenase kinase (PDHK) activity for preparing Pharmaceutical composition or preparation,
In formula,
R1And R2It is each independently selected from the following group：Hydrogen, halogen, hydroxyl, cyano group, substituted or unsubstituted C1-C6 Alkyl, substituted or unsubstituted C1-C6Alkoxyl, substituted or unsubstituted C2-C6Alkenyl, replacement or not Substituted C2-C8Alkynyl, R3-R4- group, substituted or unsubstituted C5-C20Aryl and replacement or unsubstituted C5-C20Heteroaryl；
R3It is selected from the group：Substituted or unsubstituted C5-C20Aryl, substituted or unsubstituted C5-C20Heteroaryl；
R4It is selected from the group：Substituted or unsubstituted C1-C6Alkylidene；
Or, R1、R2Substituted or unsubstituted, saturation or undersaturated is collectively forming with adjacent nitrogen-atoms 5-8 circle heterocycles, wherein described 5-8 circle heterocycles have the 1-3 hetero atom being selected from the group：O, S and N, And the 5-8 circle heterocycles have at least one nitrogen heteroatom；
Wherein described replacement refers to the substituent group being selected from the group with one or more：Halogen, C1-C4Alkyl, C1-C4Haloalkyl, C1-C4Alkoxyl, hydroxyl, nitro ,-CN and R5- C (O)-, wherein R5It is selected from the group： H, hydroxyl, C1-C4Alkoxyl, C1-C4Alkyl, C1-C4Haloalkyl and C1-C4Halogenated alkoxy.
2. purposes as claimed in claim 1, it is characterised in that described pharmaceutical composition or preparation are also used In suppression tumor cell or for treating tumor.
3. purposes as claimed in claim 1, it is characterised in that R1、R2With the common shape of adjacent nitrogen-atoms Into substituted or unsubstituted, saturation or undersaturated 5-6 circle heterocycles.
4. purposes as claimed in claim 3, it is characterised in that described 5-6 circle heterocycles are selected from the group：Contain 6 circle heterocycles of one nitrogen, 6 circle heterocycles and 6 circle heterocycles containing two nitrogen containing a nitrogen and an oxygen.
5. purposes as claimed in claim 1, it is characterised in that described heterocycle isIn formula, Each Ra is independently selected from the following group：Halogen, C1-C4Alkyl, C1-C4Haloalkyl, hydroxyl, nitro, amino, Or amido；And n is the positive integer of 0-4.
6. purposes as claimed in claim 5, it is characterised in that each Ra is methyl and n is 2.
7. purposes as claimed in claim 1, it is characterised in that R1And R2It is each independently selected from the following group： Substituted or unsubstituted C1-C2Alkyl, replacement or unsubstituted C6Aryl.
8. purposes as claimed in claim 1, it is characterised in that the compound of formula I is selected from the group：
9. a kind of compound shown in Formulas I, its optical isomer, non-raceme, racemic modification or its medicine The purposes of acceptable salt on, it is characterised in that for preparing the medicine for suppressing tumor cell or treatment tumor Compositions or preparation,
Wherein, described compound of formula I is selected from the group：
10. a kind of external non-therapeutic suppress pyruvic dehydrogenase kinase activity method, it is characterised in that Including step：
A () is by pyruvic dehydrogenase kinase and the compound of formula I described in claim 1, its optical isomer, non- Raceme, racemic modification or its pharmaceutically acceptable salt are contacted, so as to suppress pyruvic dehydrogenase The activity of kinases.
CN201510586458.4A 2015-09-15 2015-09-15 Pyruvate dehydrogenase kinase inhibitor and application thereof Pending CN106518809A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510586458.4A CN106518809A (en) 2015-09-15 2015-09-15 Pyruvate dehydrogenase kinase inhibitor and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510586458.4A CN106518809A (en) 2015-09-15 2015-09-15 Pyruvate dehydrogenase kinase inhibitor and application thereof

Publications (1)

Publication Number Publication Date
CN106518809A true CN106518809A (en) 2017-03-22

Family

ID=58348577

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510586458.4A Pending CN106518809A (en) 2015-09-15 2015-09-15 Pyruvate dehydrogenase kinase inhibitor and application thereof

Country Status (1)

Country Link
CN (1) CN106518809A (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107356461A (en) * 2017-05-17 2017-11-17 华中科技大学 Applications of the BCKDK as biomarker in tumor diagnosis kit is prepared
CN107922366A (en) * 2016-03-23 2018-04-17 华东理工大学 Pyruvic dehydrogenase kinase inhibitor and its application
CN109400509A (en) * 2018-10-24 2019-03-01 科迈化工股份有限公司 Promotor TBzTD and its synthesis technology
CN111116439A (en) * 2019-12-31 2020-05-08 鹤壁中昊新材料科技有限公司 Synthesis process of N, N '-dialkyl-N, N' -diphenyl thiuram disulfide
CN111349033A (en) * 2018-12-20 2020-06-30 杜剑平 Derivative broad-spectrum antitumor drug based on disulfiram structure and preparation method thereof
US20230174474A1 (en) * 2021-12-02 2023-06-08 Batterjee Medical College Disulfiram derivatives as aldh1a1 and magl inhibitors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101506211A (en) * 2006-04-04 2009-08-12 加利福尼亚大学董事会 Kinase antagonists
WO2015040425A1 (en) * 2013-09-23 2015-03-26 Vernalis (R&D) Limited Resorcinol n-aryl amide compounds, for use as pyruvate dehydrogenase kinase inhibitors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101506211A (en) * 2006-04-04 2009-08-12 加利福尼亚大学董事会 Kinase antagonists
WO2015040425A1 (en) * 2013-09-23 2015-03-26 Vernalis (R&D) Limited Resorcinol n-aryl amide compounds, for use as pyruvate dehydrogenase kinase inhibitors

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
GHALI BRAHEMI 等: "Exploring the Structural Requirements for Inhibition of the Ubiquitin E3 Ligase Breast Cancer Associated Protein 2 (BCA2) as a Treatment for Breast Cancer", 《J. MED. CHEM》 *
GORENSHTEIN, B. I等: "Effect of disulfiram and cyamidum on pyruvate dehydrogenase activity", 《VESTSI AKADEMII NAVUK BSSR, SERYYA BIYALAGICHNYKH NAVUK》 *
JARMILA NAVRÁTILOVÁ等: "Acidic pH of Tumor Microenvironment Enhances Cytotoxicity of the Disulfiram/Cu 2+ Complex to Breast and Colon Cancer Cells", 《CHEMOTHERAPY》 *
LINCAN DUAN等: "Inhibitory effect of Disulfiram/copper complex on non-small cell lung cancer cells", 《BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS》 *
RHUSHIKESH A. KULKARNI等: "Thiuram Disulfides as Pseudo-irreversible Inhibitors of Lymphoid Tyrosine Phosphatase", 《CHEMMEDCHEM》 *
菅记涌等: "丙酮酸脱氢酶激酶的研究进展", 《基础医学与临床》 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107922366A (en) * 2016-03-23 2018-04-17 华东理工大学 Pyruvic dehydrogenase kinase inhibitor and its application
CN107356461A (en) * 2017-05-17 2017-11-17 华中科技大学 Applications of the BCKDK as biomarker in tumor diagnosis kit is prepared
CN109400509A (en) * 2018-10-24 2019-03-01 科迈化工股份有限公司 Promotor TBzTD and its synthesis technology
CN111349033A (en) * 2018-12-20 2020-06-30 杜剑平 Derivative broad-spectrum antitumor drug based on disulfiram structure and preparation method thereof
CN111116439A (en) * 2019-12-31 2020-05-08 鹤壁中昊新材料科技有限公司 Synthesis process of N, N '-dialkyl-N, N' -diphenyl thiuram disulfide
CN111116439B (en) * 2019-12-31 2023-03-14 鹤壁中昊新材料科技有限公司 Synthesis process of N, N '-dialkyl-N, N' -diphenyl thiuram disulfide
US20230174474A1 (en) * 2021-12-02 2023-06-08 Batterjee Medical College Disulfiram derivatives as aldh1a1 and magl inhibitors
US11753371B2 (en) * 2021-12-02 2023-09-12 Batterjee Medical College Disulfiram derivatives as ALDH1A1 and MAGL inhibitors

Similar Documents

Publication Publication Date Title
CN106518809A (en) Pyruvate dehydrogenase kinase inhibitor and application thereof
CN105237504B (en) Nitrogenous analog derivative of myricetin and its preparation method and application
CN106967005B (en) A kind of compound that can inhibit IDO, Its Preparation Method And Use
CN102432663B (en) Celastrol derivative and preparation method thereof and application of celastrol derivative to preparation of antitumor medicine
CN103946231B (en) Oleanolic acid amidated derivative, and its preparation method and application
CN107286077A (en) A kind of selective C-KIT kinase inhibitors
CN103570630A (en) Heterocyclic nitrogen derivative and application thereof in medicines
CN103193691B (en) Sulfonamides compound, pharmaceutical composition and its preparation method and application
JP2016515547A (en) Triazine compounds with anti-chicken coccidiosis
JP2010502586A (en) Anti-cancer use of caffeic acid and derivatives
CN102552908B (en) Pharmaceutical composition containing artemisinin, artemisinin derivatives and Bcl-2 inhibitor and application thereof
CN103360317B (en) Bicycle substituted pyrazolone azo analog derivative, Preparation Method And The Use
CN106565763B (en) Axial substituted silicon phthalocyanine complex sensitive pH and preparation method thereof and application in medicine
Liu et al. HTBPI, an active phenanthroindolizidine alkaloid, inhibits liver tumorigenesis by targeting Akt
CN102285944B (en) Benzoselenadiazole derivatives with antitumor and antioxidation activities, and preparation and application thereof
CN106749478A (en) 1,4 pH sensitive Di-substituted phthalocyanine Zn complexes and preparation method thereof and in application pharmaceutically
CN103110621A (en) Applications of tea double-chlorine carboxamide and tea double-bromine carboxamide or like in preparation of products for prevention and treatment of diseases such as cancer
CN101475532B (en) 1,5- diheterocyclic-1,4- pentadiene-3-keto derivative , and preparation and use thereof
CN101230045A (en) Aromatic triazin derivatives and uses thereof
WO2015064764A1 (en) Aryloyl(oxy or amino)pentafluorosulfanylbenzene compound, pharmaceutically acceptable salt thereof, and prodrugs thereof
CN105541810B (en) A kind of Coumarins NEDD8 activation enzyme inhibitor and the preparation method and application thereof
CN110152001A (en) Purposes of small molecule compound and combinations thereof
CN104800204A (en) Morusin anti-tumor application
CN107922366A (en) Pyruvic dehydrogenase kinase inhibitor and its application
JP2016500649A (en) Condensation product of theanine derivative and carboxylic acid coumarin derivative, its intermediate, preparation method, and use thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication
RJ01 Rejection of invention patent application after publication

Application publication date: 20170322