CN106831747A - The N- alkylamide WNT pathway inhibitors of five-ring heterocycles substitution - Google Patents
The N- alkylamide WNT pathway inhibitors of five-ring heterocycles substitution Download PDFInfo
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention discloses a kind of N- alkylamide WNT pathway inhibitors of five-ring heterocycles substitution, belong to the compound of regulation Wnt signal path activity, and there is provided the preparation method of such compound, and application of such compound in the medicine for preparing antagonism Wnt signal paths.The N- alkylamide WNT pathway inhibitors of the five-ring heterocycles substitution that the present invention is provided, the Rational drug design based on target, antitumor activity significantly, can be used to develop into the Wnt pathway inhibitors of a new generation, and with great clinical value, market potential is considerable.
Description
Technical field
The present invention relates to a kind of N- alkylamide WNT pathway inhibitors of five-ring heterocycles substitution, belong to tune
The compound of section Wnt signal path activity, and there is provided the preparation method of such compound, and such chemical combination
Thing is used for the application in the medicine for preparing antagonism Wnt signal paths.
Background technology
Wnt signal paths are in life processes such as the differentiation of multicellular organisms axle, histoorgan generation, tumour formation
In play an important roll.The albumen of Wnt gene codes expression is a class secreting type glycoprotein, by 19 members
Composition, by with (Fzd) family proteins of Frizzled on cell membrane and LDH receptor related protein
(LDL receptor related protein, LRP) acceptor is combined, activation typical case Wnt/ β-catenin paths,
Plane pole path, Wnt/Ca2+Signal pathway in the various kinds of cell such as path, regulates and controls including breeding, breaking up, extremely
Various kinds of cell function (Nusse Roel, Varmus Harold E. (1992) .Wnt genes. such as die, migrate, polarizing
Cell,69(7),1073-1087.)。
Found through research report, neurogenic disease, inflammation fibrotic disease, metabolic disease and multiple types
Typical Wnt/ β-catenin signal path β-catenin-TCF/LCF are all related in the pathogenesis of type cancer
Imbalance (Kahn, M. (2014) .Can we safely target the Wnt pathway of the activation of transcription complex
Nature reviews.Nat.Rev.Drug.Discovery,13(7),513-532.).In cancer research field
In, Wnt signals participation tumour early stage source of evidence is isolated in mouse breast cancer to swash because of virus insertion
Oncogene Int1 living；Nearly 10% colorectal cancer, head and neck cancer, lung cancer, oophoroma, melanoma patients
Cancer occurs to be lured with the function mutation of Wnt signals-modulatings element R-spondin families and RNF43/ZNRF3
Lead correlation (B Madan, Z Ke, N Harmston, et al. (2015) .Wnt addiction of genetically
defined cancers reversed by PORCN inhibition.Oncogene,1-11.).However, this kind of trouble
Person clinically there is no targetedly Wnt signal paths small molecule targeted drug to treat at present, and non-selective is thin
Gastrointestinal reaction that born of the same parents' toxin preparation and its combined treatment are brought, marrow hemopoiesis such as suppress at the bad of aspect
Reaction has a strong impact on the life quality of patient.At present, into clinical experimental stage drug candidates also in peace
Full property and clinical stage I/II phases of conceptual drug effect checking, for example, being directed to Wnt signal paths upstream target spot
LGK974 (the ClinicalTrials.gov Identifier of PORCN designs:NCT01351103), ETC-
1922159(ClinicalTrials.gov Identifier:NCT02521844)；For Wnt signal paths downstream
PRI-724 (the ClinicalTrials.gov Identifier of target spot CBP/ β-catenin designs:NCT02413853).
In consideration of it, continuing to develop the medicine can regulate and control with Wnt signal paths, a kind of mechanism of action is searched out bright
Really, the significant compound of drug effect, with important clinical value and social effect.
The content of the invention
Present invention aim at the amide-type WNT paths suppression for providing a kind of novel five-ring heterocycles substitution of structure
Preparation, is modified by the substitution of group, synthesizes and filter out a series of compounds with antitumor activity.
For achieving the above object, this invention takes following technical scheme：
A kind of N- alkylamide WNT pathway inhibitors of five-ring heterocycles substitution, are logical with following structure
The compound and its pharmaceutically acceptable salt of formula：
Wherein, ring A and ring B are each independently selected from aromatic rings or containing the 1-2 heteroatomic virtue of N, O
Fragrant heterocycle；X, Y, Z are each independently selected from CR4、NR5, S atom, the one kind in O atom, and S
Atom exists when different with O atom；N is selected from any integer value in 1~2；R1For substituted or unsubstituted
Aryl, heterocyclic radical, the substituted radical on aryl, heterocyclic radical are selected from halogen, C1-6Alkyl, halo C1-6Alkyl,
C1-6Alkoxy, halo C1-6One or more in alkoxy, hydroxyl, cyano group, amino, acyl group, sulfo group；
R2、R3It is each independently selected from halogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo C1-6
Alkoxy, C3-6Cycloalkyl, C2-6Alkenyl, C2-6Alkynyl, hydroxyl, amino, acyl group, aryl, heterocyclic radical
In one or more；R4、R5It is each independently selected from hydrogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkane
Epoxide, halo C1-6Alkoxy, C3-6One kind in cycloalkyl；Heterocyclic radical is selected from N, O, S hetero atom
3-12 circle heterocycles.
Preferably, it is any compound and its pharmaceutically acceptable salt with following general structure：
Wherein, ring B is selected from aromatic rings or containing the 1-2 heteroatomic aromatic heterocycle of N, O；X、Y、Z
It is each independently selected from CR4、NR5, S atom, the one kind in O atom, and S atom is different with O atom
When exist；N is selected from any integer value in 1~2；R1Substituted or unsubstituted phenyl, heterocyclic radical, phenyl,
Substituted radical on heterocyclic radical is selected from halogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo C1-6
One or more in alkoxy, hydroxyl, cyano group, amino, acyl group, sulfo group；R2、R3Independently of one another
Selected from halogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo C1-6Alkoxy, C3-6Cycloalkanes
One or more in base, hydroxyl, amino, acyl group, phenyl, heterocyclic radical；R4、R5Select independently of one another
From hydrogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo C1-6One kind in alkoxy；Heterocycle
Base is selected from the heteroatomic 3-6 circle heterocycles of N, O, S.
It is furthermore preferred that in general structure (2),It is selected from In one kind；X, Y, Z are each independently selected from CR4、NR5, S atom, O
One kind in atom, and S atom it is different with O atom when exist；N is selected from any integer value in 1~2；
R1ForIn one kind；R2、R3It is each independently selected from
Hydrogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo C1-6Alkoxy, amide groups, C1-6Alkane
One kind in base amide groups, heterocyclic radical；R4、R5It is each independently selected from hydrogen, C1-6Alkyl, halo C1-6
Alkyl, C1-6Alkoxy, halo C1-6One kind in alkoxy；R6Selected from hydrogen, C1-6Alkyl, halo C1-6
Alkyl, C1-6Alkoxy, halo C1-6One kind in alkoxy, amide groups；Heterocyclic radical is miscellaneous selected from N, O
The 3-6 circle heterocycles of atom.
Preferably, aryl is phenyl, naphthyl or anthryl；Described heterocyclic radical is morpholinyl, piperidyl, pyrrole
Piperidinyl, pyrimidine radicals, pyranose, thienyl, furyl, pyrrole radicals, pyrazolyl, imidazole radicals or thiazolyl.
Preferably, halogen is the one kind in fluorine, chlorine, bromine, iodine.
A kind of N- alkylamide WNT pathway inhibitors of five-ring heterocycles substitution, be selected from numbering
The following characteristic compounds of REX-W-1~REX-W-8：
REX-W-1：N- ((5- (2- picoline -4- bases) thiazol-2-yl) methyl)-[1,1'- biphenyl] -4- acid amides；
REX-W-2：N- ((4- methyl -5- (2- picoline -4- bases) thiazol-2-yl) methyl)-[1,1'- biphenyl] -4- acyls
Amine；
REX-W-3：N- ((2- (2- picoline -4- bases) thiazole -5- bases) methyl)-[1,1'- biphenyl] -4- acid amides；
REX-W-4：N- ((3- (2- picoline -4- bases) -1,2,4- oxadiazoles -5- bases) methyl)-[1,1'- biphenyl] -4-
Acid amides；
REX-W-5：N- ((5- (2- picoline -4- bases) -1,2,4- oxadiazoles -3- bases) methyl)-[1,1'- biphenyl] -4-
Acid amides；
REX-W-6：N- ((5- (2- picoline -4- bases) -1,3,4- thiadiazoles -2- bases) methyl)-[1,1'- biphenyl] -4-
Acid amides；
REX-W-7：N- ((4- methyl -2- (2- picoline -4- bases) thiazole -5- bases) methyl)-[1,1'- biphenyl] -4- acyls
Amine；
REX-W-8：N- ((3- (2- picoline -4- bases) -1- hydrogen-pyrazoles -5- bases) methyl)-[1,1'- biphenyl] -4- acyls
Amine.
Foregoing numbering is the compound of REX-W-1~REX-W-8, and structural formula is specific as follows：
" compound " of the present invention, including all stereoisomers, geometric isomer, dynamic isomer
And isotope.
" compound " of the present invention, can be asymmetric, for example, having one or more solids different
Structure body.Unless otherwise indicated, all stereoisomers all include, such as enantiomter and diastereoisomer.
Compound containing asymmetric carbon atom in the present invention, can be with the pure form of optical activity or racemic form quilt
Separate.The pure form of optical activity can be from racemic mixture, or by using chiral raw material
Or chiral reagent synthesis.
" compound " of the present invention, also including tautomeric forms.Tautomeric forms are derived from
One singly-bound and adjacent double bond exchange and together with a migration for proton.
Present invention additionally comprises the atom of all isotopes, either in intermediate or last compound.Same position
The atom of element is included with identical atomicity but different quality number.For example, the isotope of hydrogen includes deuterium
And tritium.
Compound containing aforementioned formula structure, term used herein has following implication：
Term " halogen ", refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
Term " cyano group ", refers to-CN.
Term " hydroxyl ", refers to-OH.
Term " alkyl ", refers to the saturated hydrocarbons group of the straight or branched being made up of carbon atom and hydrogen atom, such as
C1-20Alkyl, preferably C1-6Alkyl, such as methyl, ethyl, propyl group (including n-propyl and isopropyl),
Butyl (including normal-butyl, isobutyl group, sec-butyl or tert-butyl group), amyl group (including n-pentyl, isopentyl,
Neopentyl), n-hexyl, 2- methylhexyls etc..The alkyl can be non-substituted or by one or many
Individual substitution base is replaced, and substitution base includes but is not limited to alkyl, alkoxy, cyano group, hydroxyl, carbonyl, carboxylic
Base, aryl, heteroaryl, amino, halogen, sulfonyl, sulfinyl, phosphoryl.
Term " amino ", refers to-NH2,-NH (alkyl) and-N (alkyl)2, the implication of alkyl is as previously described.
The structure type of-NH (alkyl) isSpecific example includes but is not limited to-NHCH3、-NHCH(CH3)2、
-NHC2H5Deng；- N (alkyl)2Structure type beSpecific example includes but is not limited to-N (CH3)2、
-N(CH3)C2H5Deng.
Term " aryl ", refer to the pi-electron system with total conjugated full carbon is monocyclic or fused rings, usual tool
There is 6-14 carbon atom, preferably with 6-12 carbon atom, most preferably with 6 carbon atoms.Aryl can be with
Be it is non-substituted or by one or more substitution bases replace, substitution base include but is not limited to alkyl, alcoxyl
Base, cyano group, hydroxyl, carbonyl, carboxyl, aryl, aralkyl, amino, halogen, sulfonyl, sulfenyl
Base, phosphoryl.The example of non-substituted aryl includes but is not limited to phenyl, naphthyl and anthryl.
Term " heterocyclic radical ", refers to the monocyclic or fused rings with 3-12 (integer) annular atoms, wherein have 1,
2 or 3 annular atoms are C selected from one or more in N, O, remaining annular atom, and with total conjugated
π-electron system.Heterocyclic radical can be saturation or unsaturated group, or it is non-substituted,
Or replaced by one or more substitution bases, substitution base includes but is not limited to alkyl, alkoxy, cyano group, hydroxyl
Base, carbonyl, carboxyl, aryl, aralkyl, amino, halogen, sulfonyl, sulfinyl, phosphoryl.
The example of non-substituted heterocyclic radical includes but is not limited to pyrrole radicals, indyl, pyrrolidinyl, imidazole radicals, pyrrole
Oxazolyl, tetrazole radical, pyridine radicals, quinolyl, isoquinolyl, piperidyl, pyrimidine radicals, pyrazinyl, piperazine
Base, furyl, pyranose, morpholinyl.
Present invention also offers a kind of pharmaceutical composition, comprising foregoing compound or its can pharmaceutically connect
The salt received is used as active ingredient, and one or more pharmaceutically acceptable carrier.
" pharmaceutical composition " of the present invention, refers to one or more compound or its salt of the invention and at this
The system of the carrier for bioactive compound to be delivered to organism (such as people) generally received in field
Agent.The purpose of pharmaceutical composition is advantageous for that organism is administered and conveys.
Term " pharmaceutically acceptable carrier ", refer to active ingredient co-administered and be conducive to activity into
The material of part administration, including but not limited to State Food and Drug Administration's license is acceptable for people
Or any glidant of animal (such as domestic animal), sweetener, diluent, preservative, dyestuff/colouring agent, rectify
Taste reinforcing agent, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent,
Solvent or emulsifying agent.For example include but is not limited to calcium carbonate, calcium phosphate, various sugared and each kind of starch, fiber
Plain derivative, gelatin, vegetable oil and polyethylene glycol.
Pharmaceutical composition of the present invention, can be configured to solid-state, semisolid, liquid or gaseous state preparation, such as
Tablet, pill, capsule, pulvis, granule, paste, emulsion, suspending agent, solution, suppository,
Injection, inhalant, gel, microballoon and aerosol etc..
Pharmaceutical composition of the present invention, can be manufactured using method well known in the art, and such as conventional is mixed
Legal, dissolution method, granulation, dragee method processed, levigate method, emulsion process, freeze-drying etc..
The method of administration of compound of the present invention or its pharmaceutically acceptable salt or its pharmaceutical composition,
Including but not limited to oral, rectum, saturating mucous membrane, through enteral administration, or local, percutaneous, suction, stomach
Outward, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.Preferably
Method of administration is to be administered orally.
For being administered orally, can be by by reactive compound and pharmaceutically acceptable load well known in the art
Body mixes to prepare the pharmaceutical composition.These carriers can make compound of the invention be formulated into tablet,
Pill, lozenge, sugar-coat agent, capsule, liquid, gel, slurry agent, suspending agent etc., for suffering from
The oral administration of person.For example, for the pharmaceutical composition being administered orally, can in the following way obtain tablet：
Active component is merged with one or more solid carrier, if desired by gained granulating mixture, and such as
Fruit needs to add a small amount of excipient processing resulting mixture or particle, to form tablet or label.Label can be with
The coating material of optionally suitable enteric is combined, and is processed into the coating for being more beneficial for organism (such as people) absorption
Dosage form.
Antagonism is being prepared present invention also offers a kind of foregoing compound or its pharmaceutically acceptable salt
Application in the medicine of Wnt signal paths.
Preferably, pharmaceutical applications be for treating cancer, including non-small cell lung cancer, Anaplastic large cell drench
Bar knurl, inflammatory myofibroblastic tumor, nasopharyngeal carcinoma, breast cancer, colorectal cancer, diffuse large B cell lymph
Knurl, liver cancer, stomach cancer, cancer of the esophagus, cancer of pancreas, oophoroma, body tissue's cellular proliferative disorder and nerve are female thin
Born of the same parents' knurl.
In the present invention, the N- alkylamides of a series of five-ring heterocycles substitution that inventor obtains to synthesis
WNT pathway inhibitors, from the inhibitory activity of Molecular level mensuration Wnt path STF reporter genes, find
Part of compounds has significant inhibitory activity to Wnt paths；Additionally, also having carried out zebra fish phenotypic screen
Experiment, is tested and the development suppression experiment of body axle by the tail Regeneration of cutting to zebra fish, finds part chemical combination
Thing antitumor activity in vivo is notable.
Compared with prior art, the N- alkylamide WNT paths of the five-ring heterocycles substitution that the present invention is provided
Inhibitor, the Rational drug design based on target is modified by the substitution of group, obtains a series of structures
Novel compound；And STF Reporter Gene Experiments, the experiment of zebra fish phenotypic screen are combined, optimal screening goes out
A series of compounds with antitumor activity.Therefore, the Wnt paths that can be used to develop into a new generation suppress
Agent, has great clinical value, city for the disease that targeted therapy or prevention are mediated by Wnt paths
Field potentiality are considerable.
Brief description of the drawings
Fig. 1 is AB type zebra fish bodies axle development suppression figure after treatment 48h
Fig. 2 is AB type zebra fish bodies axle development suppression dose-effect graph of a relation (mean ± sd) after treatment 48h
Fig. 3 is that AB type zebra fish cuts tail Regeneration figure after processing 7dpf
Fig. 4 is that AB type zebra fish cuts tail Regeneration dose-effect relationship figure (mean ± sd) after processing 7dpf
Specific embodiment
The following is specific embodiment of the invention, technical scheme is further described, but
Protection scope of the present invention is not limited to these embodiments.Every change or equivalent without departing substantially from present inventive concept
Replacement is included within protection scope of the present invention.
In the target compound preparation method that the present invention is provided, liquid chromatogram uses WatersSymmetry C18
Chromatographic column.Thin-layer chromatography uses GF254 (0.25 millimeter).Nuclear magnetic resonance chromatogram (NMR) uses Bruker-400
Nmr determination；Liquid matter is used in conjunction (LC/MS) and uses Waters ZQ mass detector (pillars：
WatersSymmetryC18, millimeter, 5 microns, 35 DEG C), using ESI (+) ion mode.
Additionally, all operations for being related to oxidizable or facile hydrolysis raw material are all carried out under nitrogen protection.Remove
Non- to be otherwise noted, the raw material that the present invention is used all is marketable material, need not be further purified and can directly use.
Embodiment 1, N- ((3- (2- picoline -4- bases) -1,2,4- oxadiazoles -5- bases) methyl)-[1,1'- biphenyl] -4-
Acid amides【Numbering is REX-W-4】Preparation
Synthetic route is as follows：
Step one：The preparation of compound 1-2
Respectively by compound 1-1 (5.0g, 36.1mmol), trimethyl aluminium hexane solution (36.1ml, 2N),
Tetra-triphenylphosphine palladium (0.9g, 0.7mmol) is dissolved in the dry Isosorbide-5-Nitrae-dioxane solutions of 100ml,
4 hours of temperature rising reflux, reaction adds 1N watery hydrochloric acid that reaction is quenched after terminating, and is extracted with ethyl acetate,
Saturated common salt wash, anhydrous sodium sulfate drying, after concentration with silicagel column purify, obtain compound 1-2 (2.5g,
57.6%).
MSm/z[ESI]：119.1[M+1].
Step 2：The preparation of compound 1-3
By compound 1-2 (2.5g, 20.8mmol), triethylamine (8.6ml, 62.4mmol), hydroxylamine hydrochloride
(2.9g, 41.6mmol) is dissolved in the ethanol of 50ml 95%, stirred at reflux condition 2 hours, reaction
Ethanol is concentrated away after end, is extracted with ethyl acetate, saturated common salt washing, anhydrous sodium sulfate drying is dense
Purified with silicagel column after contracting, obtain compound 1-3 (2.9g, 93.4%).
MSm/z[ESI]：152.1[M+1].
Step 3：The preparation of compound 1-4
Respectively by compound 1-3 (2.9g, 19.4mmol), BOC- glycine (3.4g, 19.4mmol),
N, N- diisopropylethylamine (10.1ml, 58.2mmol), 2- (7- azos BTA)-N, N, N', N'- tetramethyl
Base urea hexafluorophosphoric acid ester (8.8g, 23.3mmol) is dissolved in the dry DMFs of 100ml,
It is warming up to 100 DEG C to be stirred overnight, reaction terminates, to adding frozen water 150ml that reaction is quenched in system, to use acetic acid
Ethyl ester is extracted, and saturated common salt washing, anhydrous sodium sulfate drying is purified after concentration with silicagel column, obtains chemical combination
Thing 1-4 (2.9g, 52.1%).
MSm/z[ESI]：291.1[M+1].
Step 4：The preparation of compound 1-5
Compound 1-4 (2.9g, 10.1mmol) is dissolved in the dry dichloromethane of 50ml, it is slow to add
Enter trifluoroacetic acid 10.0ml, be stirred at room temperature 2 hours, reaction is concentrated after terminating, and is purified with silicagel column, is changed
Compound 1-5 (1.8g, 95.2%).
MSm/z[ESI]：191.1[M+1].
Step 5：The preparation of compound R EX-W-4
Respectively by compound 1-5 (1.8g, 9.6mmol), 4- Phenylbenzoic acids (1.9g, 9.6mmol), N, N-
Diisopropylethylamine (5.0ml, 28.8mmol), 2- (7- azos BTA)-N, N, N', N'- tetramethylurea six
Fluorophosphoric acid ester (4.4g, 11.5mmol) is dissolved in the dry dimethyl sulfoxides of 50ml, is stirred at room temperature 2 hours,
Reaction terminates, to frozen water 200ml is added in system, to be extracted with ethyl acetate, saturated common salt washing, anhydrous sulphur
Sour sodium is dried, and is purified with silicagel column after concentration, obtains target compound REX-W-4 (1.3g, 35.9%).
1H-NMR(400MHz,DMSO-d6):δ=9.47 (t, J=5.6Hz, 1H), 8.66 (d, J=5.2
Hz, 1H), 8.01 (d, J=8.0Hz, 2H), 7.79-7.84 (m, 3H), 7.71-7.77 (m, 3H), 7.48-
(s, the 3H) of 7.54 (m, 2H), 7.39-7.45 (m, 1H), 4.87 (d, J=5.6Hz, 2H), 2.57
Embodiment 2, N- ((5- (2- picoline -4- bases) -1,2,4- oxadiazoles -3- bases) methyl)-[1,1'- biphenyl] -4- acyls
Amine【Numbering is REX-W-5】Preparation
Synthetic route is as follows：
Step one：The preparation of compound 1-2
Hydroxylamine hydrochloride (2.7g, 38.4mmol), sodium carbonate (10.6g, 96.0mmol) are dissolved in respectively
In 100ml water, compound 1-1 (5.0g, 32.0mmol) is added drop-wise in system and stirred under condition of ice bath
4 hours, reaction was extracted with ethyl acetate after terminating, saturated common salt washing, anhydrous sodium sulfate drying, after concentration
Purified with silicagel column, obtain compound 1-2 (4.0g, 66.0%).
MSm/z[ESI]：190.1[M+1].
Step 2：The preparation of compound 1-3
Respectively by compound 1-2 (4.0g, 21.1mmol), 2- picoline -4- formic acid (2.9g, 21.1mmol),
N, N- diisopropylethylamine (11.0ml, 63.3mmol), 2- (7- azos BTA)-N, N, N', N'- tetramethyl
Base urea hexafluorophosphoric acid ester (9.7g, 11.5mmol) is dissolved in the dry dimethyl sulfoxides of 150ml, and room temperature is stirred
Mix 2 hours, reaction terminates, to frozen water 200ml is added in system, to be extracted with ethyl acetate, saturated aqueous common salt
Wash, anhydrous sodium sulfate drying, purified with silicagel column after concentration, obtain compound 1-3 (1.1g, 19.6%).
MSm/z[ESI]：291.1[M+1].
Step 3：The preparation of compound 1-4
Compound 1-3 (1.1g, 3.8mmol) is dissolved in the dry dichloromethane of 30ml, is slowly added to
Trifluoroacetic acid 10.0ml, is stirred at room temperature 2 hours, and reaction is concentrated after terminating, and is purified with silicagel column, obtains chemical combination
Thing 1-5 (1.8g, 91.8%).
MSm/z[ESI]：191.1[M+1].
Step 4：The preparation of compound R EX-W-5
Respectively by compound 1-5 (1.8g, 3.5mmol), 4- Phenylbenzoic acids (0.8g, 4.2mmol), N, N-
Diisopropylethylamine (1.8ml, 10.5mmol), 2- (7- azos BTA)-N, N, N', N'- tetramethylurea six
Fluorophosphoric acid ester (1.6g, 4.2mmol) is dissolved in the dry dimethyl sulfoxides of 50ml, is stirred at room temperature 2 hours,
Reaction terminates, to frozen water 100ml is added in system, to be extracted with ethyl acetate, saturated common salt washing, anhydrous sulphur
Sour sodium is dried, and is purified with silicagel column after concentration, obtains compound R EX-W-5 (235.7mg, 18.2%).
MSm/z[ESI]：371.1[M+1].
1H-NMR(400MHz,DMSO-d6):δ=9.29 (t, J=6.0Hz, 1H), 8.76 (d, J=5.2
Hz,1H),7.96-8.03(m,3H),7.85-7.89(m,1H),7.79-7.83(m,2H),7.73-7.77
(m, 2H), 7.48-7.53 (m, 2H), 7.40-7.45 (m, 1H), 4.73 (d, J=6.0Hz, 2H), 2.63 (s,
3H).
The zebra fish phenotypic screen of embodiment 3 is tested
Zebra fish is a kind of vertebrate, and 85% is up to human genome homology, has approximate with the mankind
Tissue organ function and signal transduction pathway, and with egg laying amount is high, blastoprolepsis, embryo it is transparent etc. solely
Special advantage so that zebra fish is applied successfully to human diseases research and live body medicament high flux screening.Wnt
Signal path is widely present in invertebrate and vertebrate, is that a class is highly conserved during evolution
Signal path, participate in organism in regulation and control about cell growth, apoptosis, self-renewing and lifetime because table
Reach, maintain the physiological function (Wolfram such as normal embryonic development and tissue repair regeneration in organism
Goessling,Trista E.North,Sabine Loewer,et al.(2009).Genetic Interaction of PGE2
and Wnt Signaling Regulates Developmental Specification of Stem Cells and
Regeneration.Cell,136(6):1136-1147.).Wnt signal paths are lacked of proper care with cancer and also close phase occur
Close, such as all contain in 80%~90% colorectal cancer and have an impact Wnt signal path Gene As denomatous
Polyposis Coli (APC) function mutation (Hans Clevers, Roel Nusse. (2012) .Wnt/ β-Catenin
Signaling and Disease.Cell,149(6):1192-1205.)。
Research shows that phenotype of the zebra fish in terms of the development of body axle and Regeneration and Repair is close with Wnt signal paths
Correlation (Xiaolei Wang, Jesung Moon, Michael E.Dodge, et al. (2013) .The
Development of Highly Potent Inhibitors for Porcupine.Journal of Medicinal
Chemistry,56,2700-2007.)。
Therefore, the conservative using Wnt signal paths between different plant species and zebra fish phenotypic screen side
The advantage in face, we investigate compound normal AB types zebra fish body axle is developed and Regeneration and Repair influence, come
Inquire into the compound active power of anti-Wnt signal paths in vivo.
Experiment (one) compound suppresses experiment to the development of AB type zebra fish bodies axle
Method：The AB type zebra fish fish-eggs for choosing 3hpf (hours post fertilization) carry out body axle development
Phenotypic assay, by tested final concentration, administration group and solvent control group are carried out in the range of 100 μM~0.001 μM
Random packet, every group of 20 AB fish-eggs are added in 6 orifice plates, per hole 3mL fish and water, DMSO concentration
≤ 1% (v/v).AB fish-eggs after agent-feeding treatment are incubated to during 48hpf as 28.5 DEG C of biochemical cultivation cases and carry out
IMAQ, each group juvenile fish body shaft length px values are measured using the software analysis of NIS-Elements D 3.1
(pixels).According to various concentrations compound to the inhibiting rate of each group juvenile fish body axle development growth, use
GraphPad Prism6.0 carry out nonlinear fitting and calculate each compound in AB type zebra fish bodies axle developmentally
IC50Value.
Computing formula is；
As a result：A series of compounds such as REX-W-4 prepared by the embodiment of the present invention, to AB type zebra fish bodies
The determination of activity that axle development suppresses the results are shown in Table one；Body axle after REX-W-4 treatment AB type zebra fish 48hpf
Development holddown is shown in Fig. 1, and dose-effect relationship (mean ± sd) is shown in Fig. 2.
The determination of activity that the embodiment compound of table one suppresses to the development of AB type zebra fish bodies axle
| Compounds | Emax (%) | |
| LGK-974 (comparison medicine) | 0.5831 | 97.1 |
| REX-W-4 | 0.3605 | 93.0 |
| REX-W-5 | 3.42 | 72.9 |
Note：IC50To calculate 50% inhibiting rate concentration, Emax is maximal percentage inhibition
Further, present invention selection compound R EX-W-4 carries out zebra fish and cuts tail regeneration phenotypic assay reinspection.
Experiment (two) compound cuts the experiment of tail Regeneration to AB type zebra fish
Choosing the AB type zebra fish juvenile fish of 3dpf (days post fertilization) carries out cutting tail fin modeling treatment,
By tested final concentration, administration group and solvent control group are grouped at random in the range of 10 μM~0.001 μM,
Every group of 15 juvenile fish are added in 6 orifice plates, per hole 3mL fish and water, DMSO concentration≤1% (v/v).Agent-feeding treatment
AB fish-eggs afterwards are incubated to IMAQ is carried out during 7dpf as 28.5 DEG C of biochemical cultivation cases, are utilized
The software analysis of NIS-Elements D 3.1 measurement each group juvenile fish tail fin regenerates length px values (pixels).According to not
With the inhibiting rate that concentration compound regenerates to each group juvenile fish tail fin, non-thread is carried out with GraphPad Prism6.0
Property each compound of the Fitting Calculation AB type zebra fish cut tail regeneration on IC50Value.
Computing formula is；
As a result：REX-W-4 compounds prepared by the embodiment of the present invention, tail regeneration suppression is cut to AB type zebra fish
The determination of activity of system the results are shown in Table two；REX-W-4 treatment 3dpf cuts tail modeling AB types zebra fish to 7dpf
Tail fin Regeneration is shown in Fig. 3, and dose-effect relationship (mean ± sd) is shown in Fig. 4.
The embodiment compound of table two cuts the determination of activity of tail Regeneration to AB type zebra fish
| Compounds | Emax (%) | |
| LGK-974 (comparison medicine) | 0.4624 | 92.8 |
| REX-W-4 | 0.0773 | 93.5 |
Embodiment 4Super-Top-Flash (STF) reporter gene assay
A series of compounds such as compound L GK-974 (comparison medicine), REX-W-4 (embodiment) are using steady
Surely the HEK293T-STF cell lines of transfection STF reporter genes are with L-Wnt3a secretory cells strain co-cultivation side
Formula determines its inhibitory activity to Wnt signal paths, and the activity uses IC50This index represents, IC50
I.e. the Luciferase activity inhibiteds 50% of STF reporter gene expressions when compound concentration.
A series of compounds such as REX-W-4 prepared by the embodiment of the present invention, using the Wnt of CrownBio companies
Reporter gene platform is measured, and measurement result is shown in Table three.Result shows, the compound that the present invention is provided from
There is preferable Wnt signal paths inhibitory activity on molecular level.
The determination of activity that the embodiment compound of table three suppresses to Wnt path STF reporter genes
| Compounds | |
| LGK-974 (comparison medicine) | 0.65 |
| REX-W-4 | 3.0 |
| REX-W-5 | 29.37 |
Claims (9)
1. a kind of N- alkylamide WNT pathway inhibitors of five-ring heterocycles substitution, are with following structure
The compound and its pharmaceutically acceptable salt of formula：
Wherein, ring A and ring B are each independently selected from aromatic rings or containing the 1-2 heteroatomic virtue of N, O
Fragrant heterocycle；
X, Y, Z are each independently selected from CR4、NR5, S atom, the one kind in O atom, and S atom
Exist when different with O atom；
N is selected from any integer value in 1~2；
R1Be substituted or unsubstituted aryl, heterocyclic radical, the substituted radical on aryl, heterocyclic radical be selected from halogen,
C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo C1-6Alkoxy, hydroxyl, cyano group, amino,
One or more in acyl group, sulfo group；
R2、R3It is each independently selected from halogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo
C1-6Alkoxy, C3-6Cycloalkyl, C2-6Alkenyl, C2-6Alkynyl, hydroxyl, amino, acyl group, aryl, heterocycle
One or more in base；
R4、R5It is each independently selected from hydrogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo
C1-6Alkoxy, C3-6One kind in cycloalkyl；
Described heterocyclic radical is selected from the heteroatomic 3-12 circle heterocycles of N, O, S.
2. the N- alkylamide WNT pathway inhibitors that five-ring heterocycles according to claim 1 replace,
It is characterized in that：It is any compound and its pharmaceutically acceptable salt with following general structure：
Wherein, ring B is selected from aromatic rings or containing the 1-2 heteroatomic aromatic heterocycle of N, O；
X, Y, Z are each independently selected from CR4、NR5, S atom, the one kind in O atom, and S atom
Exist when different with O atom；
N is selected from any integer value in 1~2；
R1Substituted or unsubstituted phenyl, heterocyclic radical, substituted radical on phenyl, heterocyclic radical be selected from halogen,
C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo C1-6Alkoxy, hydroxyl, cyano group, amino,
One or more in acyl group, sulfo group；
R2、R3It is each independently selected from halogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo
C1-6Alkoxy, C3-6One or more in cycloalkyl, hydroxyl, amino, acyl group, phenyl, heterocyclic radical；
R4、R5It is each independently selected from hydrogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo
C1-6One kind in alkoxy；
Described heterocyclic radical is selected from the heteroatomic 3-6 circle heterocycles of N, O, S.
3. the N- alkylamide WNT pathway inhibitors that five-ring heterocycles according to claim 2 replace,
It is characterized in that：In described general structure (2),It is selected from In one kind；
X, Y, Z are each independently selected from CR4、NR5, S atom, the one kind in O atom, and S atom
Exist when different with O atom；
N is selected from any integer value in 1~2；
R1ForIn one kind；
R2、R3It is each independently selected from hydrogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo
C1-6Alkoxy, amide groups, C1-6One kind in alkylamidoalkyl, heterocyclic radical；
R4、R5It is each independently selected from hydrogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo
C1-6One kind in alkoxy；
R6Selected from hydrogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo C1-6Alkoxy, acid amides
One kind in base；
Described heterocyclic radical is selected from the heteroatomic 3-6 circle heterocycles of N, O.
4. the N- alkylamides WNT of the five-ring heterocycles substitution according to any one of claims 1 to 3 leads to
Road inhibitor, it is characterised in that：Described aryl is phenyl, naphthyl or anthryl；Described heterocyclic radical for
Quinoline base, piperidyl, pyridine radicals, pyrimidine radicals, pyranose, thienyl, furyl, pyrrole radicals, pyrazolyl,
Imidazole radicals or thiazolyl.
5. the N- alkylamides WNT of the five-ring heterocycles substitution according to any one of claims 1 to 3 leads to
Road inhibitor, it is characterised in that：Described halogen is the one kind in fluorine, chlorine, bromine, iodine.
6. a kind of N- alkylamide WNT pathway inhibitors of five-ring heterocycles substitution, characterize selected from following
Compound：
N- ((5- (2- picoline -4- bases) thiazol-2-yl) methyl)-[1,1'- biphenyl] -4- acid amides；
N- ((4- methyl -5- (2- picoline -4- bases) thiazol-2-yl) methyl)-[1,1'- biphenyl] -4- acid amides；
N- ((2- (2- picoline -4- bases) thiazole -5- bases) methyl)-[1,1'- biphenyl] -4- acid amides；
N- ((3- (2- picoline -4- bases) -1,2,4- oxadiazoles -5- bases) methyl)-[1,1'- biphenyl] -4- acid amides；
N- ((5- (2- picoline -4- bases) -1,2,4- oxadiazoles -3- bases) methyl)-[1,1'- biphenyl] -4- acid amides；
N- ((5- (2- picoline -4- bases) -1,3,4- thiadiazoles -2- bases) methyl)-[1,1'- biphenyl] -4- acid amides；
N- ((4- methyl -2- (2- picoline -4- bases) thiazole -5- bases) methyl)-[1,1'- biphenyl] -4- acid amides；
N- ((3- (2- picoline -4- bases) -1- hydrogen-pyrazoles -5- bases) methyl)-[1,1'- biphenyl] -4- acid amides.
7. a kind of pharmaceutical composition, comprising compound such as defined in claim 1 or its is pharmaceutically acceptable
Salt is used as active ingredient, and one or more pharmaceutically acceptable carrier.
8. a kind of as compound or its pharmaceutically acceptable salt defined in claim 1 are preparing antagonism Wnt
Application in the medicine of signal path.
9. application as claimed in claim 8, it is characterised in that：For treating cancer, including non-small cell
Lung cancer, primary cutaneous type, inflammatory myofibroblastic tumor, nasopharyngeal carcinoma, breast cancer, Colon and rectum
Cancer, Diffuse Large B-Cell Lymphoma, liver cancer, stomach cancer, cancer of the esophagus, cancer of pancreas, oophoroma, body tissue
Cellular proliferative disorder and neuroblastoma.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11091447B2 (en) | 2020-01-03 | 2021-08-17 | Berg Llc | UBE2K modulators and methods for their use |
| WO2023122152A1 (en) * | 2021-12-22 | 2023-06-29 | Praxis Precision Medicines, Inc. | Kcnt1 inhibitors and methods of use |
| CN118496159A (en) * | 2024-07-18 | 2024-08-16 | 广州医科大学附属市八医院 | Application of compound in preparation of medicine with liver fibrosis preventing and/or treating effect |
-
2015
- 2015-12-07 CN CN201510889158.3A patent/CN106831747A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11091447B2 (en) | 2020-01-03 | 2021-08-17 | Berg Llc | UBE2K modulators and methods for their use |
| WO2023122152A1 (en) * | 2021-12-22 | 2023-06-29 | Praxis Precision Medicines, Inc. | Kcnt1 inhibitors and methods of use |
| CN118496159A (en) * | 2024-07-18 | 2024-08-16 | 广州医科大学附属市八医院 | Application of compound in preparation of medicine with liver fibrosis preventing and/or treating effect |
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Effective date of registration: 20180223 Address after: Suzhou City, Jiangsu Province, Suzhou Industrial Park 215123 Xinghu Street No. 218 building 511 unit B2 Applicant after: Suzhou CIGNA Dimensional Medical Technology Co Ltd Address before: Hangzhou City, Zhejiang province Xiaoshan District 311202 North Street Jincheng Road No. 1038, room 817 Applicant before: Hangzhou Leisuo Pharmaceutical Co., Ltd. |
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