CN107987031A - 1 nitrogen mustards inhibitor of one kind targeting indoles amine -2,3- dioxygenases and its preparation method and application - Google Patents
1 nitrogen mustards inhibitor of one kind targeting indoles amine -2,3- dioxygenases and its preparation method and application Download PDFInfo
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- CN107987031A CN107987031A CN201711250115.6A CN201711250115A CN107987031A CN 107987031 A CN107987031 A CN 107987031A CN 201711250115 A CN201711250115 A CN 201711250115A CN 107987031 A CN107987031 A CN 107987031A
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- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
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Abstract
The invention discloses one kind to target indoleamine 2,3 dioxygenase, 1 nitrogen mustards inhibitor and its preparation method and application, and the structure of the inhibitor is as shown in general formula I, and the definition of R is as described in claims and specification.Pharmacological evaluation shows that the compound of the present invention not only shows good IDO1 inhibitory activity, but also the anti tumor activity in vitro with wide spectrum.Experiment in vivo shows that compound of the invention can effectively lower internal IDO1 activity, and can significantly delay tumour growth, can be applied to prepare the medicine of the tumor disease of the pathological characteristics of the tryptophan metabolic pathway of IDO1 mediations.
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to 1 nitrogen mustards of one kind targeting indoles amine -2,3- dioxygenase suppresses
Agent and its preparation method and application.
Background technology
Chlormethine series pharmaceuticals are still a kind of important antitumor drug of clinical practice at present, such as Chlorambucil
(Chlorambucil) and melphalan (Melphalan).
The mechanism of action of this series antineoplastic medicament is that it can form the Ethylenimine ion of electron deficient in vivo, so with life
Covalent bond occurs for the group containing abundant electronics in thing macromolecular (such as DNA, RNA or some important enzyme), makes its forfeiture
Activity is broken DNA molecular, so as to reach antitumous effect.Chlormethine series pharmaceuticals are wide, thin to tumour with antitumor spectra
The advantages that born of the same parents' lethality is strong, but also there are the shortcomings of therapeutic efficiency is low, poor selectivity, big toxic side effect.
Indoleamine 2,3-dioxygenase 1 (IDO) is a dioxygenase containing ferroheme, and IDO families include three kinds of enzymes:Color
Propylhomoserin 2,3- dioxygenases (TDO), and two relevant IDO isodynamic enzymes (IDO1, IDO2), it can be passed through using active oxygen
The pyrrole ring of three kinds of possible reaction mechanism catalysis oxidation L-Trps is into N- acetylkynurenines.This is kynurenine pathway
(KP) rate-limiting step, further synthesizes a series of active metabolites, such as melatonin, quinolinic acid, N- first
Base-D-Asp receptor antagonist kynurenic acid and nicotinamide adenine dinucleotide.Many clinical researches find that IDO leads to
Cross consumption tryptophan and blocked the propagation of T lymphocytes, and the prognosis of kinds cancer patient is poor with the IDO tables of tumour cell
It is associated up to amount increase.Therefore, in immunotherapy of tumors, IDO be one can be suppressed by small-molecule drug its activity or
Person blocks the crucial target spot of signal effect downstream.In the past few decades, many potential IDO inhibitors are designed, and close
Into and evaluation, wherein D-1-MT, INCB24360 and NLG919 have been enter into clinical investigation phase at present.
Although it is limited that therapeutic effect can be used alone with human activin immune system in IDO inhibitor.And and radiotherapy, change
Treat or immunization therapy combination may can play more preferable therapeutic effect in invasive tumor Ultras onography is induced.Recent
Clinical data shows that Epacadastat and PD-1 inhibitor Keytruda can greatly improve the response of patient after being combined
Rate.
The research of Mutiple Targets inhibitor of IDO is currently based on almost without report.
The content of the invention
It is an object of the invention to provide 1 nitrogen mustards inhibitor of one kind targeting indoles amine -2,3- dioxygenases.
The first aspect of the present invention, there is provided compound or its pharmaceutically acceptable salt shown in logical formula (I):
R is substituted or unsubstituted group selected from the group below:- aryl-,-aryl-C1-4Alkyl-,-heteroaryl-or-heteroaryl
Base-C1-4Alkyl-, the substitution refers to there is one or more substituents selected from the group below:Hydroxyl, amino, nitro, C1-4Alkane
Base, C1-4Alkoxy, C1-4Haloalkyl.
In another preference, the aryl is phenyl or naphthyl.
In another preference, the heteroaryl is quinolyl, benzimidazolyl, pyridine radicals, purine radicals, indyl, phonetic
Piperidinyl, pyrrole radicals, pyrazolyl, thienyl, isothiazolyl or imidazole radicals.
In another preference, the substitution refers to there is one or more substituents selected from the group below:Amino, C1-4Alkane
Base, C1-4Alkoxy.
In another preference, R is:
Wherein n positions 0,1,2 or 3.
In another preference, the compound is:
3- (double (2- chloroethyls) amino)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines base) -1,2,
5- oxadiazoles -3- methyl) amino) ethyl) benzamide,
2- (3- (double (2- chloroethyls) amino) phenyl)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines
Base) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) acetamide,
3- (3- (double (2- chloroethyls) amino) phenyl)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines
Base) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) propionamide,
4- (double (2- chloroethyls) amino)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines base) -1,2,
5- oxadiazoles -3- methyl) amino) ethyl) benzamide,
2- (4- (double (2- chloroethyls) amino) phenyl)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines
Base) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) acetamide,
3- (4- (double (2- chloroethyls) amino) phenyl)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines
Base) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) propionamide,
4- (4- (double (2- chloroethyls) amino) phenyl)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines
Base) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) butyramide,
2- amino -3- (4- (double (2- chloroethyls) amino) phenyl)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls
Base carbonamidine base) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) propionamide or
4- (5- (double (2- chloroethyls) amino) -1- methyl isophthalic acid H- benzos [d] imidazoles -2- methyl)-N- (2- ((4- (N- (3-
Bromo- 4- fluorophenyls)-N'- hydroxy formamidines base) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) butyramide.
In another preference, the compound is any compound prepared by embodiment 1-9.
In another preference, the pharmaceutically acceptable salt is the acid that the compound shown in logical formula (I) is formed with acid
Addition salts, it is described acid for hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, naphthalene sulfonic acids, citric acid,
Tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or butanedioic acid, fumaric acid, salicylic acid, phenylacetic acid or tussol.
The second aspect of the present invention, there is provided the preparation method of the compound described in first aspect, comprises the following steps:
(i) chemical combination shown in condensation reaction acquisition formula IV occurs for the compound shown in Formula II and the compound shown in formula III
Thing;
(ii) compound shown in formula IV obtains the compound shown in the logical formula (I) described in claim 1 through hydrolysis,
Wherein, R is defined as described above.
In another preference, in step i), the compound shown in compound and formula III shown in Formula II is in 2- (7- oxygen
Change benzotriazole)-N, N, N', under the action of N'- tetramethylurea hexafluorophosphoric acid esters HATU is as condensing agent, adds N, N- bis- is different
Propylethylamine DIPEA and dimethylformamide DMF, room temperature reaction obtain the compound shown in compound formula IV overnight.
In another preference, step ii) in, the compound shown in formula IV hydrolyzes under the action of NaOH.
The third aspect of the present invention, there is provided a kind of pharmaceutical composition, comprising:
Compound or its pharmaceutically acceptable salt described in claim 1;With
Pharmaceutically acceptable carrier.
The fourth aspect of the present invention, there is provided compound or its pharmaceutically acceptable salt or the 3rd described in first aspect
The application of pharmaceutical composition described in aspect, is used for:(i) 1 inhibitor of indoles amine -2,3- dioxygenase is prepared;Or prepared by (ii)
Treat the medicine of tumour.
The tumour has the pathological characteristics of the tryptophan metabolic pathway of the mediation of indoles amine -2,3- dioxygenase 1.
The treatment includes the lethal effect to tumour cell, and delays tumour growth in mouse tumor model.
The compound of the present invention, not only shows good IDO1 inhibitory activity, but also the extracorporeal anti-tumor with wide spectrum
Activity.Experiment in vivo shows that the compounds of this invention can effectively lower internal IDO1 activity, and can significantly delay to swell
Knurl is grown, and can be applied to the tumor disease of the pathological characteristics of the tryptophan metabolic pathway of IDO1 mediations.Such compound is made
For the difunctional antitumor drug based on IDO1 reported first, there is further R and D value, be expected to become one
Class can target IDO1 simultaneously can direct killing cancer cell antitumor drug.
It is to be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment)
It can be combined with each other between each technical characteristic of body description, so as to form new or preferable technical solution.As space is limited, exist
This no longer tires out one by one states.
Embodiment
Present inventor has found a kind of double oxygenations of targeting indoles amine -2,3- first by depth studying extensively
1 nitrogen mustards inhibitor of enzyme, not only shows good IDO1 inhibitory activity, but also the anti tumor activity in vitro with wide spectrum.
On the basis of this, the present invention is completed.
Term
The term " substitution " of theory of the present invention, it is intended that one or more hydrogen on any specified atom or ring are substituted, preceding
The normal chemical valency for being no more than specified atom is carried, and substitutes and produces stable compound.In another preference, the substitution
Be it is monosubstituted, two substitution, three substitution or four substitution.During with two or more substituent, each substituted radical can be identical or different.
Except as otherwise noted, term " alkyl " herein the part individually or as another group in use, bag
Include straight chain and side chain " alkyl ", such as methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, isobutyl group.Term " aryl " is single
Solely or during a part as another group, the monocyclic and bicyclic aromatic group for containing 6~10 carbon in loop section is referred to.Term
" heteroaryl " represents to be selected from the heteroatomic aromatic ring groups of N, O, S comprising 1-4, without limitation including pyrazolyl, thienyl,
Pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, furyl, pyrrole radicals, oxazolyl, isoxazolyls, imidazole radicals, thiazolyl, different thiophene
Oxazolyl, quinazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl and purine radicals.Phrase " pharmaceutically acceptable "
For herein referring to such compound, material, composition and/or formulation, they are adapted to use within a reasonable range of medical judgment
Contacted in humans and animals body tissue, and without excessive toxicity, irritation, allergic reaction or other problems or complication, and in
Rational interests/Hazard ratio matches.
" pharmaceutically acceptable carrier " refers to:One or more biocompatible solids or liquid filler or gelatinous mass,
They are suitable for people's use and it is necessary to have enough purity and sufficiently low toxicity." compatibility " referred to herein as composition
Middle each component energy and the active ingredient of the present invention and they between mutually admix, and significantly reduce the drug effect of active ingredient.
Pharmaceutically acceptable carrier part example have cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose sodium,
Cellulose ethanoate etc.), gelatin, talcum, kollag (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soya-bean oil,
Sesame oil, peanut oil, olive oil etc.), polyalcohol (such as propane diols, glycerine, mannitol, sorbierite), emulsifying agent (such as
), wetting agent (such as lauryl sodium sulfate), colouring agent, flavor enhancement, stabilizer, antioxidant, preservative, apirogen water.
With reference to specific embodiment, the present invention is further explained.It is to be understood that these embodiments are merely to illustrate the present invention
Rather than limit the scope of the invention.The reagents and materials used in the present invention are commercially available or can be prepared by literature method.Under
The experimental method of actual conditions is not specified in row embodiment, usually according to normal condition, or according to the bar proposed by manufacturer
Part.
Embodiment 1:3- (double (2- chloroethyls) amino)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines
Base) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) benzamide synthesis
A, 3- (double (2- chloroethyls) amino)-N- (2- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- carbonyls -4,5- dihydro -1,
2,4- oxadiazoles -3- methyl) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) benzamide preparation
Compound 3- (4- ((2- aminoethyls)) amino -1,2,5- oxadiazoles -3- methyl) -4- (the bromo- 4- fluorophenyls of 3-) -1,
- 5 (4H) -one hydriodate (0.20g, 0.4mmol) of 2,4- oxadiazoles and 3- (double (2- chloroethyls) amino) benzoic acid (0.11g,
0.4mmol) it is dissolved in DMF, adds HATU (0.15g, 0.4mmol) and DIPEA (0.18mL, 1mmol), be stirred overnight at room temperature
Afterwards, reaction solution is poured into frozen water, and ethyl acetate extraction, saturated sodium-chloride water solution is washed, and anhydrous sodium sulfate drying, is concentrated to give thick production
Thing, (eluant, eluent is purified via silica gel column chromatography:Methylene chloride/methanol=120:1–100:1) white solid 3- (double (2- chlorine are obtained
Ethyl) amino)-N- (2- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- carbonyl -4,5- dihydros -1,2,4- oxadiazoles -3- methyl) -
1,2,5- oxadiazoles -3- methyl) amino) ethyl) benzamide 0.13g, yield 52%.
B, 3- (double (2- chloroethyls) amino)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines base) -1,
2,5- oxadiazoles -3- methyl) amino) ethyl) and benzamide preparation
Compound 3- (double (2- chloroethyls) amino)-N- (2- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- carbonyls -4,5- two
Hydrogen -1,2,4- oxadiazoles -3- methyl) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) benzamide (0.1g, 0.16mmol)
Be dissolved in methanol (10mL), add 2M NaOH (0.5mL), when stirring 2 is small under the conditions of 40 DEG C after, the detection of TCL contact plates has been reacted
Entirely, reaction solution concentration is evaporated remaining methanol, adds a small amount of water, 2M HCl tune pH to 7, has solid precipitation after standing, suction filtration arrives
White solid 3- (double (2- chloroethyls) amino)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines base) -1,2,
5- oxadiazoles -3- methyl) amino) ethyl) benzamide 0.07g, yield 70%.
Embodiment 2:2- (3- (double (2- chloroethyls) amino) phenyl)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'-
Hydroxy formamidine base) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) acetamide synthesis
According to the method for embodiment 1,3- is replaced with 2- (3- (double (2- chloroethyls) amino) phenyl) acetic acid in step
(double (2- chloroethyls) amino) benzoic acid, in stepb with 2- (3- (double (2- chloroethyls) amino) phenyl)-N- (2- ((4- (4-
(the bromo- 4- fluorophenyls of 3-) -5- carbonyl -4,5- dihydros -1,2,4- oxadiazoles -3- methyl) -1,2,5- oxadiazoles -3- methyl) ammonia
Base) ethyl) acetamide replace 3- (double (2- chloroethyls) amino)-N- (2- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- carbonyl -4,
5- dihydros -1,2,4- oxadiazoles -3- methyl) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) benzamide obtains 2- (3-
(double (2- chloroethyls) amino)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines base) -1,2,5- oxadiazoles -3-
Methyl) amino) ethyl) acetamide 0.12g, yield 77%.
Embodiment 3:3- (3- (double (2- chloroethyls) amino) phenyl)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'-
Hydroxy formamidine base) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) propionamide synthesis
According to the method for embodiment 1,3- is replaced with 3- (3- (double (2- chloroethyls) amino) phenyl) propionic acid in step
(double (2- chloroethyls) amino) benzoic acid, in stepb with 3- (3- (double (2- chloroethyls) amino) phenyl)-N- (2- ((4- (4-
(the bromo- 4- fluorophenyls of 3-) -5- carbonyl -4,5- dihydros -1,2,4- oxadiazoles -3- methyl) -1,2,5- oxadiazoles -3- methyl) ammonia
Base) ethyl) propionamide replace 3- (double (2- chloroethyls) amino)-N- (2- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- carbonyl -4,
5- dihydros -1,2,4- oxadiazoles -3- methyl) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) benzamide obtains 3- (3-
(double (2- chloroethyls) amino) phenyl) (((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines base) -1,2,5- dislikes two to 2- to-N-
Azoles -3- methyl) amino) ethyl) propionamide 0.23g, yield 85%.
Embodiment 4:4- (double (2- chloroethyls) amino)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines
Base) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) benzamide synthesis
According to the method for embodiment 1,3- (double (2- chlorine are replaced with 4- (double (2- chloroethyls) amino) benzoic acid in step
Ethyl) amino) benzoic acid, in stepb with 4- (double (2- chloroethyls) amino)-N- (2- ((4- (4- (the bromo- 4- fluorophenyls of 3-)-
5- carbonyl -4,5- dihydros -1,2,4- oxadiazoles -3- methyl) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) benzamide generation
For 3- (double (2- chloroethyls) amino)-N-, ((((4- (the bromo- 4- fluorophenyls of 3-) -5- carbonyl -4,5- dihydros -1,2,4- dislike two to 4- to 2-
Azoles -3- methyl) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) benzamide obtains 4- (double (2- chloroethyls) amino)-N-
(2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines base) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) benzoyl
Amine 0.08g, yield 64%.
Embodiment 5:2- (4- (double (2- chloroethyls) amino) phenyl)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'-
Hydroxy formamidine base) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) acetamide synthesis
According to the method for embodiment 1,3- is replaced with 2- (4- (double (2- chloroethyls) amino) phenyl) acetic acid in step
(double (2- chloroethyls) amino) benzoic acid, in stepb with 2- (4- (double (2- chloroethyls) amino) phenyl)-N- (2- ((4- (4-
(the bromo- 4- fluorophenyls of 3-) -5- carbonyl -4,5- dihydros -1,2,4- oxadiazoles -3- methyl) -1,2,5- oxadiazoles -3- methyl) ammonia
Base) ethyl) acetamide replace 3- (double (2- chloroethyls) amino)-N- (2- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- carbonyl -4,
5- dihydros -1,2,4- oxadiazoles -3- methyl) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) benzamide obtains 2- (4-
(double (2- chloroethyls) amino) phenyl) (((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines base) -1,2,5- dislikes two to 2- to-N-
Azoles -3- methyl) amino) ethyl) acetamide 0.16g, yield 79%.
Embodiment 6:3- (4- (double (2- chloroethyls) amino) phenyl)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'-
Hydroxy formamidine base) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) propionamide synthesis
According to the method for embodiment 1,3- is replaced with 3- (4- (double (2- chloroethyls) amino) phenyl) propionic acid in step
(double (2- chloroethyls) amino) benzoic acid, in stepb with 3- (4- (double (2- chloroethyls) amino) phenyl)-N- (2- ((4- (4-
(the bromo- 4- fluorophenyls of 3-) -5- carbonyl -4,5- dihydros -1,2,4- oxadiazoles -3- methyl) -1,2,5- oxadiazoles -3- methyl) ammonia
Base) ethyl) propionamide replace 3- (double (2- chloroethyls) amino)-N- (2- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- carbonyl -4,
5- dihydros -1,2,4- oxadiazoles -3- methyl) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) benzamide obtains 3- (4-
(double (2- chloroethyls) amino) phenyl) (((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines base) -1,2,5- dislikes two to 2- to-N-
Azoles -3- methyl) amino) ethyl) propionamide 0.11g, yield 69%.
Embodiment 7:4- (4- (double (2- chloroethyls) amino) phenyl)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'-
Hydroxy formamidine base) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) butyramide synthesis
According to the method for embodiment 1,3- is replaced with 4- (4- (double (2- chloroethyls) amino) phenyl) butyric acid in step
(double (2- chloroethyls) amino) benzoic acid, in stepb with 4- (4- (double (2- chloroethyls) amino) phenyl)-N- (2- ((4- (4-
(the bromo- 4- fluorophenyls of 3-) -5- carbonyl -4,5- dihydros -1,2,4- oxadiazoles -3- methyl) -1,2,5- oxadiazoles -3- methyl) ammonia
Base) ethyl) butyramide replace 3- (double (2- chloroethyls) amino)-N- (2- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- carbonyl -4,
5- dihydros -1,2,4- oxadiazoles -3- methyl) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) benzamide obtains 4- (4-
(double (2- chloroethyls) amino) phenyl) (((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines base) -1,2,5- dislikes two to 2- to-N-
Azoles -3- methyl) amino) ethyl) butyramide 0.04g, yield 71%.
Embodiment 8:2- amino -3- (4- (double (2- chloroethyls) amino) phenyl)-N- (2- ((4- (N- (bromo- 4- fluorobenzene of 3-
Base)-N'- hydroxy formamidines base) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) and propionamide synthesis
According to the method for embodiment 1, in step with 2- amino -3- (4- (double (2- chloroethyls) amino) phenyl) propionic acid
Instead of 3- (double (2- chloroethyls) amino) benzoic acid, in stepb with 2- amino -3- (4- (double (2- chloroethyls) amino) benzene
Base) (((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- carbonyl -4,5- dihydros -1,2,4- oxadiazoles -3- methyl) -1,2,5- is disliked 2--N-
Diazole -3- methyl) amino) ethyl) propionamide replaces 3- (double (2- chloroethyls) amino)-N- (2- ((4- (4- (bromo- 4- fluorobenzene of 3-
Base) -5- carbonyl -4,5- dihydros -1,2,4- oxadiazoles -3- methyl) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) benzoyl
Amine obtains 2- amino -3- (4- (double (2- chloroethyls) amino) phenyl)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls
Carbonamidine base) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) propionamide 0.02g, yield 54%.
Embodiment 9:4- (5- (double (2- chloroethyls) amino) -1- methyl isophthalic acid H- benzos [d] imidazoles -2- methyl)-N- (2-
((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines base) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) butyramide
Synthesis
According to the method for embodiment 1, in step with 4- (5- (double (2- chloroethyls) amino) -1- methyl isophthalic acid H- benzos
[d] imidazoles -2- methyl) butyric acid replaces 3- (double (2- chloroethyls) amino) benzoic acid, in stepb with 4- (5- (double (2- chloroethenes
Base) amino) -1- methyl isophthalic acid H- benzos [d] imidazoles -2- methyl)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-) -5- carbonyl -4,
5- dihydros -1,2,4- oxadiazoles -3- methyl) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) butyramide replaces 3- (double (2-
Chloroethyl) amino)-N- (2- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- carbonyl -4,5- dihydros -1,2,4- oxadiazoles -3- first
Base) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) benzamide obtain 4- (5- (double (2- chloroethyls) amino) -1- methyl -
1H- benzos [d] imidazoles -2- methyl) (((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines base) -1,2,5- dislikes two to 2- to-N-
Azoles -3- methyl) amino) ethyl) butyramide 0.03g, yield 66%.
Compound in embodiment 1-91HNMR、13CNMR and MS data refer to table 1, and sequence number 1-9 corresponds to for embodiment 1-9
Compound number.
1 target compound of table1HNMR, 13CNMR and MS data
Embodiment 10:The compounds of this invention tests (IC to IDO1 inhibitory activity50)。
The indole ring generation N'- formylkynurenines of IDO1 catalytic oxidative cracking L-Trps.In the potassium phosphate phosphorus of 50mM
In sour potassium buffer solution (pH 6.5), the anti-sepsis acid of 20mM, 3.5 μM of methylene blues, 0.2mg/mL catalases, substrate are added
The inhibitor of 2mM tryptophans and various concentrations.
Inhibiting rate of the testing compound various concentrations to IDO1 enzymes is calculated according to the above method, uses Prism
GraphPad softwares calculate IC50。
Experimental result:The IC of the compounds of this invention50It is worth (part of compounds list concentration inhibiting rate) as shown in table 2, testization
Compound waits until outstanding inhibitory activity in showing, and wherein compound 1 shows optimal Inhibiting enzyme activity.
2 target compound IDO1 inhibitory activity of table
Embodiment 11:The compounds of this invention tests (EC in cellular level to IDO1 inhibitory activity50)。
Cellular level inhibitory activity measure uses HeLa cell culture mediums as DMEM in high glucose, penicillin containing 50U/mL, 50U/
ML streptomysins.It is 6 × 10 that 96 orifice plates, which add concentration per hole,3The 100 μ L of HeLa cell suspensions of a/mL, put 37 DEG C, 5%CO2Culture
In case.24 it is small when after, the culture containing IFN-γ (Sangon Biotech#C600039,50ng/mL) and various concentrations compound
Base (200 μ L) add, be incubated 48 it is small when after, take 140 μ L of supernatant liquid into another 96 orifice plate, add 10 μ L 6.1N trifluoroacetic acids,
It is that the formylkynurenine generated is fully converted to kynurenin that 30 minutes are heated at 50 DEG C, and then 12000rpm centrifuges 10 points
Clock, takes 100 μ L of supernatant liquid and the acetic acid solution of isometric 2% (w/v) paradime thylaminobenzaldehyde to mix colour developing, finally using enzyme
Mark instrument detects absorbance under 490nM.
Effective inhibiting rate of testing compound various concentrations is calculated according to the above method, it is soft with Prism GraphPad
Part calculates EC50。
Experimental result:The EC of the compounds of this invention50Value is as shown in table 3, and test result shows that majority of compounds all shows
Go out the cytoactive of nanomolar range, the overall activity for being better than its molecular level, wherein compound 4 shows optimal cellular water
Flat IDO inhibitory activity.
3 target compound cellular level IDO inhibitory activity of table
Embodiment 12:Anti tumor activity in vitro test (the IC of the compounds of this invention50)。
Five kinds of Cytostatic to tumor cell aptitude tests are carried out to the compound of the present invention, test method is using routine
CCK8 methods.It will be digested for the tumour cell of exponential phase (LLC, CT-26, A549, HCT116 and HT-29) with pancreatin, so
It is with culture medium (DMEM+10%FBS or PRMI1640+10%FBS) that cell dilute suspension is thin into single cell suspension, adjustment afterwards
Born of the same parents' density is 6-10 × 104A/mL, 100 μ L are added per hole and are inoculated in 96 orifice plates, put 37 DEG C, 5%CO2Culture 24 in incubator
Hour, it is being separately added into the compound of various concentrations, parallel three multiple holes of each concentration, and experimental group and control group are set, after
It is continuous be incubated 48 it is small when after, add 10 μ L CCK8 solution to every hole, then at 37 DEG C lucifuge be incubated 1-4 it is small when after, with complete with MK-2
Automatic microplate reader surveys 450nm OD values.Calculation of half inhibitory concentration IC50。
Experimental result:The compounds of this invention is to tumour cell half-inhibition concentration IC50Value is as shown in table 4, and test result is shown
Show that a series of this nitrogen mustard derivatives shows the antitumor activity of wide spectrum, its IC50Value is between 1~40 μm of ol, and benign medicine
INC824360 does not have cytotoxic activity substantially.
The half-inhibition concentration IC of 4 target compound cells against tumor cells of table50(unit:μmol/L)
Embodiment 13:The compounds of this invention is to mouse junction cancer tumor model therapeutic effect research
Cell line:Mouse colonic cell (CT-26).
Experimental animal:Eight week old Babl/C female mices purchase Shanghai Slac Experimental Animal Co., Ltd., quality certification number:
SCXK-2013-0016。
Mouse tumor model is established, is grouped and is administered:CT-26 cells are injected in mouse forelimb oxter, and every injection 6 ×
105A cell.Gross tumor volume reaches 50mm3When start to be administered, this experiment mice is divided into 5 groups, every group 6.Take orally and give respectively
Carboxymethyl cellulose (0.5%CMC), 5 (100mg/ of INCB24360 (100mg/kg), compound 1 (100mg/kg) and compound
kg).It is taken twice daily, successive administration 14 days.Every 4 days monitoring tumor volume changes, gross tumor volume calculate public in therapeutic process
Formula:(width2× length)/2.
Experimental result:Preferred compound vivo tumor model therapeutic effect is for example as shown in table 5, and compound 1 and 5 is shown
Preferable internal antitumor activity, the internal tumour inhibiting rate of wherein compound 1 are better than benign medicine INCB24360.
5 gross tumor volume of table
Group | Mean tumour volume mm3 |
Blank group | 3352.17 |
INCB24360 groups | 1808.43 |
1 group of compound | 1419.32 |
5 groups of compound | 1792.73 |
Embodiment 14:Influence of the compounds of this invention for IDO1 activity in Mice Body
Experimental animal:Eight week old C57BL/6 female mices purchase Shanghai Slac Experimental Animal Co., Ltd., the quality certification
Number:SCXK-2013-0018.
Internal IDO inhibitory activity can be reacted by kynurenin (Kyn) changes of contents.This experiment mice totally 5, gives
When fasting 4 is small before medicine, after Oral administration of compounds 1 (100mg/kg), mouse is put to death in different time points, is worn by eye socket
Thorn blood sampling, adds the sample cell containing EDTA-3K, 4 DEG C, after 3000rpm centrifuges 15min, takes supernatant Cord blood.Then by 60
μ L blood plasma mixes vortex with 240 μ L (containing the internal standard thing 50ng/mL) trifluoroacetic acid of methanol -1% 5 minutes, 5800rpm centrifugations 10min
Afterwards, take 50 μ L of supernatant to be used for sample introduction after mixing with isometric water to analyze, detecting kyn by LC-MS/MS (API 6500) contains
Amount.
Experimental result:Compound 1 is as shown in table 6 to IDO1 Activity Results in Mice Body, and test result shows that compound 1 exists
After administration between 0.5h to 8h, Kyn concentration illustrates compound 1 in vivo relative to significantly decreasing before administration in blood
It can suppress IDO1 activity, the internal antitumor activity of compound 1 is by immune-mediated.
Kynurenin (Kyn) content (unit in 6 blood of table:nmol/L)
Suppress to live test result indicates that the compounds of this invention shows preferable IDO1 on molecule and cellular level
Property, the wherein IC of compound 150And EC50Respectively 0.13 ± 0.02 μM and 0.27 ± 0.059 μM.This kind of compound is suppressing body
In outer tumor cell proliferation experiment, the antitumor activity of wide spectrum, its half-inhibition concentration IC are shown50Between 5 to 30 μM.Change
Compound 1 and 5 can effectively suppress the growth of tumour in mouse junction cancer tumor model, and the vivo efficacy of compound 1 is better than
Benign medicine INCB24360, and the content of kynurenin in Mice Body can be effectively reduced.The compound of the present invention is as one
The mustargen analog derivative of class targeting indoles amine -2,3- dioxygenase 1 not only has a good Inhibiting enzyme activity, but also in vitro and body
Preferable antitumor activity is inside shown, for the tumour of the pathological characteristics of tryptophan metabolic pathway mediated with IDO
Disease, it has good antitumor drug Development volue as new difunctional hybrid molecule.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To be made various changes or modifications to the present invention, such equivalent forms equally fall within the model that the application the appended claims are limited
Enclose.
Claims (10)
1. compound or its pharmaceutically acceptable salt shown in logical formula (I):
R is substituted or unsubstituted group selected from the group below:- aryl-,-aryl-C1-4Alkyl-,-heteroaryl-or-heteroaryl-
C1-4Alkyl-, the substitution refers to there is one or more substituents selected from the group below:Hydroxyl, amino, nitro, C1-4Alkyl,
C1-4Alkoxy, C1-4Haloalkyl.
2. compound as claimed in claim 1, it is characterised in that the aryl is phenyl or naphthyl.
3. compound as claimed in claim 1, it is characterised in that the heteroaryl is quinolyl, benzimidazolyl, pyridine
Base, purine radicals, indyl, pyrimidine radicals, pyrrole radicals, pyrazolyl, thienyl, isothiazolyl or imidazole radicals.
4. compound as claimed in claim 1, it is characterised in that the substitution refers to there is one or more selected from the group below
Substituent:Amino, C1-4Alkyl, C1-4Alkoxy.
5. compound as claimed in claim 1, it is characterised in that R is:
Wherein n positions 0,1,2 or 3.
6. compound as claimed in claim 1, it is characterised in that the compound is:
(((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines base) -1,2,5- is disliked 2- 3- (double (2- chloroethyls) amino)-N-
Diazole -3- methyl) amino) ethyl) benzamide,
2- (3- (double (2- chloroethyls) amino) phenyl)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines base)-
1,2,5- oxadiazoles -3- methyl) amino) ethyl) acetamide,
3- (3- (double (2- chloroethyls) amino) phenyl)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines base)-
1,2,5- oxadiazoles -3- methyl) amino) ethyl) propionamide,
(((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines base) -1,2,5- is disliked 2- 4- (double (2- chloroethyls) amino)-N-
Diazole -3- methyl) amino) ethyl) benzamide,
2- (4- (double (2- chloroethyls) amino) phenyl)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines base)-
1,2,5- oxadiazoles -3- methyl) amino) ethyl) acetamide,
3- (4- (double (2- chloroethyls) amino) phenyl)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines base)-
1,2,5- oxadiazoles -3- methyl) amino) ethyl) propionamide,
4- (4- (double (2- chloroethyls) amino) phenyl)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines base)-
1,2,5- oxadiazoles -3- methyl) amino) ethyl) butyramide,
2- amino -3- (4- (double (2- chloroethyls) amino) phenyl)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl first
Amidino groups) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) propionamide or
(((((3- is bromo- by N- by 4- by 2- by-N- by 4- (5- (double (2- chloroethyls) amino) -1- methyl isophthalic acid H- benzos [d] imidazoles -2- methyl)
4- fluorophenyls)-N'- hydroxy formamidines base) -1,2,5- oxadiazoles -3- methyl) amino) ethyl) butyramide.
7. compound as claimed in claim 1, it is characterised in that the pharmaceutically acceptable salt is shown in logical formula (I)
Compound with acid formed acid-addition salts, it is described acid for hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzene sulfonic acid, to toluene sulphur
Acid, naphthalene sulfonic acids, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or butanedioic acid, fumaric acid, salicylic acid, phenyl second
Acid or tussol.
8. the preparation method of compound as claimed in claim 1, it is characterised in that the preparation method comprises the following steps:
(i) compound shown in condensation reaction acquisition formula IV occurs for the compound shown in Formula II and the compound shown in formula III;
(ii) compound shown in formula IV obtains the compound shown in the logical formula (I) described in claim 1 through hydrolysis,
Wherein, R is defined as described above.
9. a kind of pharmaceutical composition, it is characterised in that described pharmaceutical composition includes:
Compound or its pharmaceutically acceptable salt described in claim 1;With
Pharmaceutically acceptable carrier.
10. the application of the compound or its pharmaceutically acceptable salt described in claim 1, it is characterised in that be used for:(i) make
Standby 1 inhibitor of indoles amine -2,3- dioxygenase;Or
(ii) medicine for the treatment of tumour is prepared.
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Cited By (2)
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CN108530444A (en) * | 2018-06-11 | 2018-09-14 | 中国药科大学 | A kind of novel NAMPT and IDO double inhibitors and preparation method thereof and medical usage |
CN109438321A (en) * | 2018-11-15 | 2019-03-08 | 南京友怡医药科技有限公司 | A kind of tryptophan derivative and its preparation method and application |
Citations (1)
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CN101212967A (en) * | 2005-05-10 | 2008-07-02 | 因塞特公司 | Modulators of indoleamine 2,3-dioxygenase and methods of using the same |
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2017
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CN101212967A (en) * | 2005-05-10 | 2008-07-02 | 因塞特公司 | Modulators of indoleamine 2,3-dioxygenase and methods of using the same |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108530444A (en) * | 2018-06-11 | 2018-09-14 | 中国药科大学 | A kind of novel NAMPT and IDO double inhibitors and preparation method thereof and medical usage |
CN108530444B (en) * | 2018-06-11 | 2021-08-24 | 药康众拓(江苏)医药科技有限公司 | Novel NAMPT and IDO dual inhibitor and preparation method and medical application thereof |
CN109438321A (en) * | 2018-11-15 | 2019-03-08 | 南京友怡医药科技有限公司 | A kind of tryptophan derivative and its preparation method and application |
CN109438321B (en) * | 2018-11-15 | 2021-12-17 | 南京友怡医药科技有限公司 | Tryptophan derivative and preparation method and application thereof |
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