CN106916101A - Double target spot inhibitor of NAMPT/HDAC and preparation method thereof - Google Patents

Double target spot inhibitor of NAMPT/HDAC and preparation method thereof Download PDF

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CN106916101A
CN106916101A CN201710082432.5A CN201710082432A CN106916101A CN 106916101 A CN106916101 A CN 106916101A CN 201710082432 A CN201710082432 A CN 201710082432A CN 106916101 A CN106916101 A CN 106916101A
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aminophenyls
methyl
benzamide
yls
triazol
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CN106916101B (en
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盛春泉
李宝力
董国强
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Poly (shanghai) Biological Technology Co Ltd
Second Military Medical University SMMU
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Poly (shanghai) Biological Technology Co Ltd
Second Military Medical University SMMU
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    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
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Abstract

The invention discloses double target spot inhibitor of a kind of NAMPT/HDAC and preparation method thereof；This pair of target spot inhibitor is amide derivatives and its pharmaceutically acceptable salt, shown in its general structure such as formula (I)：(I).Pharmacological evaluation shows, derivative of the present invention or salt, and very strong inhibitory activity is respectively provided with to Nampt and histon deacetylase (HDAC), and with stronger anti tumor activity in vitro and outstanding internal tumor killing effect.Present invention also offers said derivative and its preparation method of pharmaceutically acceptable salt, and the application in Nampt inhibitor, histon deacetylase (HDAC) inhibitor and antineoplastic is prepared.

Description

Double target spot inhibitor of NAMPT/HDAC and preparation method thereof
Technical field
The invention belongs to pharmaceutical technology field；There are a specifically related to class the double target spots of the NAMPT/HDAC of antitumor activity to press down Preparation and its pharmaceutical formulation treatment malignant tumour and with differentiation and proliferation relevant disease medicine in terms of application.
Background technology
Mutiple Targets medicine can simultaneously adjust the multiple links in tumor disease network system, be not likely to produce drug resistance, right The gross effect of each target spot effect is more than single effect sum, reaches optimal therapeutic effect.Additionally, individual molecule possesses letter relatively Single absorption, distribution, it is metabolized and discharge process, greatly reduces drug-drug interactions (Peters, J., et Al.J.Med.Chem.2013,56,8955-8971).FDA successively have approved multiple multiple receptor tyrosine kinases inhibitor listings, Including Sorafenib (sorafenib), Dasatinib (dasatinib) and Lapatinib (lapatinib) etc., many targets are indicated Point medicine has become the new direction of oncotherapy and medicament research and development.
Acetylation/the deacetylation of histone is the important regulative mode of alteration of chromosome structure and gene expression, thin Played a significant role in the life processes such as born of the same parents' apoptosis, energetic supersession, transcription and translation.The acetylation of histone and deacetylation are repaiied Decorations process is main by acetylation of histone enzyme (histone acetylases, HATs) and histon deacetylase (HDAC) (histone Deacetylases, HDACs) co-catalysis completion.It is thin in tumours such as prostate cancer, stomach cancer, breast cancer, colon cancer and leukaemia In born of the same parents, HDACs abnormal expressions are raised, and small-molecule drug research and development are carried out for HDAC, have become current antineoplastic target treatment Focus.Two classes are broadly divided into by structure type hdac inhibitor：Hydroxamic acid and amide-type.Representation compound is respectively Vorinostat (SAHA) and CI-994.SAHA is clinically used for treating hematologic cancers through U.S. FDA approval entrance；CI-994 is current Carrying out clinical II phases experimental study.Additionally, still there is multiple hdac inhibitors to carry out clinical trial.However, single target Lack effective treatment to the combinations on solid tumors of HDAC.HDAC has functions that synergistic antitumor, example with multiple tumor targets Such as tubulin (Tubulin) and heat shock protein 90 (Hsp90), develop the Mutiple Targets medicine based on HDAC anti-as improving Tumor efficiency, the effective means for reducing tumor drug resistance.
In recent years, important means and row that medicament research and development has become antineoplastic discovery are carried out for metabolism target spot Effective strategy.Nampt (nicotinamidephosphoribosyltransferase, NAMPT) It is then wherein great representational metabolism class target spot.NAMPT is catalyzed niacinamide (nicotinamide, NAM) generation niacinamide list Nucleotides (nicotinaminde mononucleotide, NMN), the water of the required energy matter NAD of regulation and control mammalian cell It is flat, it is the rate-limiting enzyme of NAD constructive ways, vital effect is played in cellular physiological events.Research shows, NAMPT with The occurrence and development of tumour are closely related, have become a very important novel targets in antineoplastic research：1) tumour Cell has NAD consumption and metabolic rate very high, and tumor cell ratio normal cell is stronger to the dependence of NAD, it is easier to receive To the influence of NAMPT inhibitor；2) NAD participates in the conjunction of kinds of tumors required material as required coenzyme in tumour cell Into, and, NAD can significantly reduce active oxygen radical (reactive oxygen species, ROS) level in environment, protect Shield tumour cell；3) NAMPT is played an important role in angiogenesis, induction of vascular endothelial growth factor generation.Have at present The NAMPT inhibitor for studying report has FK866 and CHS-828, and both of which has been enter into clinical research.Clinical data shows, both Dose-dependent thrombopenia and gastrointestinal side effect are there is, still needing further to improve.
The content of the invention
It is an object of the invention to provide the double target spot inhibitor of HDAC/NAMPT and its medicine of a class amide-type high-efficiency low-toxicity Acceptable salt on；It is a further object of the present invention to provide the double target spot inhibitor of such HDAC/NAMPT and its can pharmaceutically connect The preparation method of the salt received；The third object of the present invention is to provide the double target spot inhibitor of such HDAC/NAMPT and its pharmaceutically may be used Application of the salt of receiving in NAMPT inhibitor, hdac inhibitor and antineoplastic is prepared.
The purpose of the present invention is achieved through the following technical solutions：
The first aspect of the present invention, is to provide a kind of amide derivatives and its pharmaceutically acceptable salt, the compound General structure such as formula (I) shown in：
Wherein, A groups are selected from any one in (1)~(4)：
(1) phenyl or substituted-phenyl
Substitution base on substituted-phenyl phenyl ring can be located at ortho position, meta and the contraposition of phenyl ring, can be monosubstituted, it is also possible to Be it is polysubstituted, substitution base be selected from it is following any one or a few：
A, halogen atom (including F, Cl, Br, I),
B, 1-6 the straight chained alkyl or the 3-6 branched alkyl of carbon atom of carbon atom, (preferred, the 1-6 carbon is former The straight chained alkyl of son includes methyl, ethyl, propyl group, normal-butyl, n-pentyl, n-hexyl；The branched alkyl of the 3-6 carbon atom Including isopropyl, isobutyl group, the tert-butyl group, isopentyl, tertiary pentyl),
C, hydroxyl, cyano group, cyano methyl, amino, nitro, trifluoromethyl, trifluoromethoxy, methoxyl group, ethyoxyl, the third oxygen Base, isopropoxy, butoxy, acetyl group；
(2) pyridine radicals or substituted pyridinyl
Replace base to can be located at that pyridine ring is any to may replace position on substituted pyridines, can be monosubstituted, or take more Generation, substitution base be selected from it is following any one or a few：
A, halogen atom (including F, Cl, Br, I),
B, 1-6 the straight chained alkyl or the 3-6 branched alkyl of carbon atom of carbon atom, (preferred, the 1-6 carbon is former The straight chained alkyl of son includes methyl, ethyl, propyl group, normal-butyl, n-pentyl, n-hexyl；The branched alkyl of the 3-6 carbon atom Including isopropyl, isobutyl group, the tert-butyl group, isopentyl, tertiary pentyl),
C, hydroxyl, cyano group, cyano methyl, amino, nitro, trifluoromethyl, trifluoromethoxy, methoxyl group, ethyoxyl, the third oxygen Base, isopropoxy, butoxy, acetyl group；
(3) five-ring heterocycles or substituted five-membered heterocycle (five-ring heterocycles refer to furans, thiophene, pyrrole radicals because)
Substitution base on five-ring heterocycles can be located at it is any may replace position, can be monosubstituted, or polysubstituted, take Dai Ji be selected from it is following any one or a few：
A, halogen atom (including F, Cl, Br, I),
B, 1-6 the straight chained alkyl or the 3-6 branched alkyl of carbon atom of carbon atom, (preferred, the 1-6 carbon is former The straight chained alkyl of son includes methyl, ethyl, propyl group, normal-butyl, n-pentyl, n-hexyl；The branched alkyl of the 3-6 carbon atom Including isopropyl, isobutyl group, the tert-butyl group, isopentyl, tertiary pentyl),
C, hydroxyl, cyano group, cyano methyl, amino, nitro, trifluoromethyl, trifluoromethoxy, methoxyl group, ethyoxyl, the third oxygen Base, isopropoxy, butoxy, acetyl group；
(4) five yuan or the parallel base and bicyclic heterocycles base of hexatomic ring composition；
E groups are selected from the one kind in following group：
X group is selected from the one kind in following group：
Wherein, R1 refer to it is monosubstituted or polysubstituted, selected from it is following any one or a few：
A.H,
B. halogen atom (F, Cl, Br, I),
G.1-6 the straight chained alkyl of individual carbon atom or the 3-6 branched alkyl of carbon atom, (preferred, the 1-6 carbon original The straight chained alkyl of son includes methyl, ethyl, propyl group, normal-butyl, n-pentyl, n-hexyl；The branched alkyl of the 3-6 carbon atom Including isopropyl, isobutyl group, the tert-butyl group, isopentyl, tertiary pentyl),
H. hydroxyl, cyano group, cyano methyl, amino, nitro, trifluoromethyl, trifluoromethoxy, methoxyl group, ethyoxyl, the third oxygen Base, isopropoxy, butoxy, acetyl group；
Y is carbon atom or nitrogen-atoms；
Z group is selected from any one in a~d：
a.H
B. halogen atom (F, Cl, Br, I)
C. phenyl ring or hexa-member heterocycle
D. five-ring heterocycles (including pyrroles, furans, thienyl group)
Preferably, described five yuan or hexatomic ring are constituted parallel base and bicyclic heterocycles base, comprising：
Preferably, described pharmaceutically acceptable salt, be preferably：Hydrochloride, hydrobromate, sulfate, acetate, Lactate, tartrate, tannate, citrate, trifluoroacetate, malate, maleate, succinate, to toluene Sulfonate or mesylate；
Preferably, described pharmaceutically acceptable salt, without the crystallization water, or the crystallization containing one or more molecules Water.
It is furthermore preferred that the crystallization water of the described pharmaceutically acceptable salt containing 0.5-3.0 molecules.
Hdac inhibitor and the double target spot inhibitor of HDAC/NAMPT and its pharmaceutical formulation with differentiation and antiproliferative activity, Part preferred compound of the present invention includes, but are not limited to following：
N- (2- aminophenyls) -4- (3- (6- fluorine pyridin-3-yl) methyl) ghiourea group) benzamide
N- (2- aminophenyls) -4- (3- (pyridin-3-yl methyl) urea groups) benzamide
N- (2- aminophenyls) -4- (3- (pyridin-3-yl) acrylamido) benzamide
N- (2- aminophenyls) -4- (3- (6- chloropyridine -3- bases) methyl) ghiourea group) benzamide
N- (2- aminophenyls) -4- (3- (6- chloropyridine -3- bases) methyl) urea groups) benzamide
N- (2- aminophenyls) -4- (3- (6- fluorine pyridin-3-yl) methyl) urea groups) benzamide
N- (2- aminophenyls) -4- (3- (6- aminopyridine -3- bases) methyl) ghiourea group) benzamide
N- (2- aminophenyls) -4- (3- (6- aminopyridine -3- bases) methyl) urea groups) benzamide
The tert-butyl group (5- ((3- (4- ((2- aminophenyls) carbamyl) phenyl) urea groups) methyl) pyridine -2- bases) amino first Acid esters
N- (2- aminophenyls) -4- (3- (5- fluorine pyridin-3-yl) methyl) urea groups) benzamide
N- (2- aminophenyls) -4- (3- (6- picoline -3- bases) methyl) urea groups) benzamide
N- (2- aminophenyls) -4- (3- (4- luorobenzyls) ghiourea group) benzamide
N- (2- aminophenyls) -4- (3- (3- luorobenzyls) ghiourea group) benzamide
N- (2- aminophenyls) -4- (3- (2- luorobenzyls) ghiourea group) benzamide
N- (2- aminophenyls) -4- (3- (3- chlorobenzyls) ghiourea group) benzamide
N- (2- aminophenyls) -4- (3- (3- bromobenzyls) ghiourea group) benzamide
N- (2- aminophenyls) -4- (3- (benzo [d] [1,3] dioxole -5- ylmethyls) ghiourea group) benzoyl Amine
N- (2- aminophenyls) -4- (3- (3- aminobenzyls) ghiourea group) benzamide
4- (3- ((1H- benzos [d] imidazoles -2- bases) methyl) ghiourea group)-N- (2- aminophenyls) benzamide
N- (2- aminophenyls) -4- (2,3- bis- chloro- 3- (pyridin-3-yl) acrylamido) benzamide
N- (4- ((2- aminophenyls) carbamoyl) benzyl) thieno [3,2-c] pyridine-2-carboxamide
N- (4- ((2- aminophenyls) carbamyl) benzyl) -1H- pyrroles [2,3-c] pyridine-2-carboxamide
N- (4- ((2- aminophenyls) carbamyl) benzyl) -1H- pyrrolo-es [3,2-c] pyridine-2-carboxamide
N- (4- ((2- aminophenyls) carbamyl) benzyl) -1H- pyrrolo-es [2,3-b] pyridine-2-carboxamide
N- (4- ((2- aminophenyls) carbamoyl) benzyl) imidazo [1,5-a] pyridine -6- formamides
N- (4- ((2- aminophenyls) carbamoyl) benzyl) -1H- pyrazolos [4,3-b] pyridine -6- formamides
N- (4- ((2- aminophenyls) carbamoyl) benzyl) imidazoles [1,2-a] pyridine -7- formamides
N- (2- aminophenyls) -4- ((4- (pyridin-3-yl) -1H-1,2,3- triazol-1-yls) methyl) benzamide
N- (2- aminophenyls) -4- (2- (4- (pyridin-3-yl) -1H-1,2,3- triazol-1-yls) methyl) benzamide
N- (2- aminophenyls) -4- ((4- (pyridin-4-yl) -1H-1,2,3- triazol-1-yls) methyl) benzamide
N- (2- aminophenyls) -4- ((4- (6- chloropyridine -3- bases) -1H-1,2,3- triazol-1-yls) methyl) benzamide
N- (2- aminophenyls) -4- ((4- (3- aminophenyls) -1H-1,2,3- triazol-1-yls) methyl) benzamide
N- (2- aminophenyls) -4- ((4- (tolyl) -1H-1,2,3- triazol-1-yls) methyl) benzamide
4- ((4- (4- acetylphenyls) -1H-1,2,3- triazol-1-yls) methyl)-N- (2- aminophenyls) benzamide
N- (2- aminophenyls) -4- ((4- (thiophene -2- bases) -1H-1,2,3- triazol-1-yls) methyl) benzamide
N- (4- ammonia-[1,1 '-biphenyl] -3- bases) -4- ((5- (pyridin-3-yl) -1H-1,2,3- triazol-1-yls) methyl) Benzamide
N- (4- amino-[1,1 '-biphenyl] -3- bases) -4- ((5- (3- aminophenyls) -1H-1,2,3- triazol-1-yls) first Base) benzamide
N- (4- amino-[1,1 '-biphenyl] -3- bases) -4- ((5- (3- hydroxy phenyls) -1H-1,2,3- triazol-1-yls) first Base) benzamide
4- ((5- (4- acetylphenyls) -1H-1,2,3- triazol-1-yls) methyl)-N- (4- amino-[1,1 '-biphenyl] - 3- yls) benzamide
N- (2- aminophenyls) -4- ((4- (4- (3- (pyridin-3-yl methyl) -1H-1,2,3- triazol-1-yls) methyl) benzene Formamide
N- (2- aminophenyls) -4- ((4- (4- ((pyridin-3-yl methyl) carbamyl) phenyl) -1H-1,2,3- triazoles - 1- yls) methyl) benzamide
N- (2- aminophenyls) -8- (4- (pyridin-3-yl) -1H-1,2,3- triazol-1-yls) caprylamide
N- (2- aminophenyls) -8- (4- (3- aminophenyls) -1H-1,2,3- triazol-1-yls) caprylamide
N- (4- amino-[1,1 '-biphenyl] -3- bases) -8- (4- (pyridin-3-yl) -1H-1,2,3- triazol-1-yls) decoyl Amine
N- (4- amino-[1,1 '-biphenyl] -3- bases) -8- (4- (3- aminophenyls) -1H-1,2,3- triazol-1-yls) decoyl Amine
N- (4- amino-[1,1 '-biphenyl] -3- bases) -8- (4- (3- hydroxy phenyls) -1H-1,2,3- triazol-1-yls) decoyl Amine
The structural formula and nucleus n-ness spectrum data of the invention described above preferred compound are as shown in table 1：
Table 1, the structural formula of preferred compound of the present invention and nucleus n-ness spectrum data
The second aspect of the present invention, is to provide the preparation side of above-mentioned amide derivatives and its pharmaceutically acceptable salt Method；
Reaction process leads to (including the synthesis of compound A1-20 of method one：)
When general structure isAnd X2For O or S, R are-NH-CH2- A ,-CH=CH-A orA is that phenyl, amino substituted-phenyl, halogen substituted phenyl, pyridine radicals, the straight chained alkyl of 1-6 carbon atom replace pyrrole Piperidinyl, the branched alkyl substituted pyridinyl of 3-6 carbon atom, halogen substituted pyridinyl, amino substituted pyridinyl,When, methods described is as follows：
(wherein, R2 is hydrogen, halogen, amino or t-butoxycarbonyl amino)
Reagent and condition：(a) Raney Ni, hydrogen, ammoniacal liquor methanol solution, room temperature, 12 hours, yield 21-89%；(b) CDIor TCDI, dichloromethane, room temperature, 2 hours, yield 85-95%；(c) tetrahydrofuran, room temperature, 12 hours, yield 62- 81%；(d) dichloromethane, room temperature or 70 degree, 2 hours, yield 60%；(e) tetrahydrofuran, room temperature, 12 hours, yield 70%； (f) o-phenylenediamine, HBTU, triethylamine, DMF, room temperature, 3 hours, yield 43-75%.
Cyano compound 1 is catalyzed through Raney Ni, and hydrogen reducing obtains amino-compound 2a in ammoniacal liquor methanol solution.To ammonia Yl benzoic acid 3 reacts and obtains intermediate 4 at room temperature with CDI or TCDI.The room temperature reactions in tetrahydrofuran of compound 2a or 2c and 4 Obtain intermediate 5 within 12 hours.Compound 2b and 3 is condensed to yield intermediate 5 in dichloromethane.Intermediate 5 in DMF with adjacent benzene Diamines room temperature reaction 4 hours, target compound A1-20 is obtained through column chromatography.
Reaction process leads to method two (synthesis containing compound B-11-7)：
When general structure isAnd A is When, methods described is as follows：
Reagent and condition：(a) R-COOH, EDC, DMAP, DMF, room temperature, 3 hours, yield 31-69%；(b) lithium hydroxide, Tetrahydrofuran/methanol/water, room temperature, 24 hours, yield 82-97%；(c) o-phenylenediamine, HBTU, triethylamine, DMF, room temperature, 4 is small When, yield 37-75%.
4- amine methyl toluate 7, through EDC/DMAP catalyzing and condensings, obtains intermediate 8 with various carboxylic acids.In tetrahydrochysene furan Mutter/methanol/water mixed solvent system in, intermediate 8 obtains corresponding carboxylic acid compound 9 through lithium hydrate.Compound 9 exists Reacted at ambient temperature with o-phenylenediamine 3 hours in DMF, column chromatography obtains target compound B1-7.
Reaction process leads to method three (synthesis containing compound C1-14)：
When general structure isAnd n=1 or 2, A are pyridine radicals, halogen substitution Pyridine radicals, amino substituted pyridinyl, 1-6 carbon atom straight chain alkyl-substituted phenyl, acetyl group substituted-phenyl, thienyl,When Z is hydrogen atom or phenyl, methods described is as follows：
Reagent and condition：(a) trimethyl silicane ethyl-acetylene, triphenyl phosphorus palladium, cupric iodide, triethylamine, room temperature, 1 hour；(b) Potassium carbonate, methyl alcohol, room temperature, 0.5 hour, two step yield 32-81%；(c) sodium azide, room temperature, 8 hours, yield 64-85%； (d) intermediate 13 or RCN, copper sulphate, sodium ascorbate, nitrogen protection, room temperature, overnight, yield 64-87%；(e) hydroxide Lithium, tetrahydrofuran/methanol/water, room temperature, 24 hours, yield 71-92%；(f) o-phenylenediamine or [1,1 '-biphenyl] -3,4- bis- Amine, HBTU, triethylamine, room temperature, 3 hours, yield 27-72%.
Compound 11 reacts to obtain compound 12 with trimethyl silicane ethyl-acetylene, in the basic conditions the de- trimethyl silicon substrate system of room temperature Obtain compound 13.Bromide 14 obtains intermediate 15 through sodium azide substitution.Intermediate 15 and 13 or other alkynyl compounds are sent out Raw click reactions obtain product 16.Intermediate 16 is hydrolyzed in the basic conditions, is condensed with o-phenylenediamine or 4- phenyl o-phenylenediamine It is final to obtain targeted and thing C1-14.
Reaction process leads to method four (synthesis containing compound D1-5)：
When formula isAnd R ' be amino, hydroxyl or hydrogen atom, X3During for N or CH, Z for hydrogen atom or phenyl, methods described is as follows：
Reagent and condition：(a) sodium azide, DMF, 85 degree, 6 hours；(b) o-phenylenediamine or [1,1 '-biphenyl] -3,4- bis- Amine, HBTU, triethylamine, room temperature, 3 hours；(c) copper sulphate, sodium ascorbate, the tert-butyl alcohol: water=5: 1, room temperature, nitrogen, 24 is small When.
Compound 18 obtains intermediate 19,19 with o-phenylenediamine or 4- phenyl o-phenylenediamines in HBTU with reaction of sodium azide Intermediate 20 is obtained with the lower generation condensation reaction of triethylamine catalysis.Intermediate 20 occurs with the aryl ethane containing different substituents Click reactions obtain compound D1-5.
The third aspect of the present invention, is to provide above-mentioned amide derivatives and its pharmaceutically acceptable salt is preparing cigarette Use in the double target spot inhibitor of amidophosphoric acid phosphoribosynltransferase inhibitor, histon deacetylase (HDAC) inhibitor or HDAC/NAMPT On the way.
Compound of the invention is tested through NAMPT and HDAC1 activity suppressions, it was demonstrated that majority of compounds has preferable NAMPT and HDAC1 inhibitory activity, A2, A3, C1, C2, C9, C13, C14, D1, D2, D3 there is balance to press down NAMPT and HDAC1 System activity.
Antineoplastic is being prepared present invention also offers above-mentioned amide derivatives and its pharmaceutically acceptable salt In purposes.
Preferably, described tumour is liver cancer, lung cancer, intestinal cancer, oophoroma, prostate cancer, stomach cancer, lymph cancer etc..
Compound of the invention is tested through antitumor activity, it was demonstrated that there is majority of compounds preferable extracorporeal anti-tumor to live Property, preferred compound has outstanding tumor growth in vivo inhibitory activity.
Compared with prior art, the present invention has the advantages that：
The present invention is by the double target spot inhibitor of pharmacophore convergence strategy reasonable construction amide-type HDAC/NAMPT, and it is right to obtain NAMPT and HDAC1 has the efficient small molecule of balance inhibitory activity, realizes significantly improving for internal drug effect；For further investigation and Exploitation new construction types of anti-tumor medicine opens new approach, there is provided new strategy.
Brief description of the drawings
The detailed description made to non-limiting example with reference to the following drawings by reading, further feature of the invention, Objects and advantages will become more apparent upon：
Fig. 1 is human body intestinal cancer HCT116 nude mice knurl Volume Changes schematic diagrames；Wherein, (A) gross tumor volume broken line graph；(B) give Medicine terminates rear tumour internal anatomy.
Specific embodiment
With reference to embodiment, the present invention is described in detail.Following examples will be helpful to those skilled in the art The present invention is further understood, but the invention is not limited in any way.It should be pointed out that to one of ordinary skill in the art For, without departing from the inventive concept of the premise, can also make certain adjustments and improvements.These belong to guarantor of the invention Shield scope.Percentage of the present invention goes out outside special instruction, is weight percentage.
Embodiment 1, N- (2- aminophenyls) -4- (3- (6- fluorine pyridin-3-yl) methyl) ghiourea group) benzamide preparation (A1)
1.1 prepare intermediate 2：The fluoro- 3- aminomethyl-pyridines of 6-
In 2mol/L ammonia/methanol solution that the fluoro- nicotinonitriles of 6- (300mg, 2.46mmol) is dissolved in (30mL), add Raney Ni (0.5g), H2Room temperature reaction 12 hours under atmosphere.Rear reaction solution diatomite has been reacted to filter, methyl alcohol flushing (5mL × 2), filtrate is evaporated, and through silica gel column chromatography, (dichloromethane: methyl alcohol=100: 4) isolates and purifies, obtain yellow oily solid residue 262mg, yield is 85%.1H-NMR(DMSO-d6, 300MHz) and δ：8.11-6.84 (m, 3H), 3.86 (s, 2H), 1.47 (s, 2H).
1.2 prepare intermediate 4：4- isothiocyano benzoic acid
Triethylamine (1.4mL, 194mmol) is dissolved in dichloromethane (12mL), and thio-carbonyldiimidazole is added under ice bath (2.11g, 11.85mmol) and PABA (1.25g, 11.57mmol), stirs 1 hour under ice bath.Concentrated hydrochloric acid (3mL, Prepared mixed solution in n-hexane (12mL) 33.60mmol) is dropped to, the mixed solution is slowly added dropwise into reaction solution, room Temperature stirring 3 hours.Placed reaction liquid into after having reacted in ice bath, filtering, filter cake washing (5mL × 2) obtains pale solid 1.93g, yield is 93%.1H-NMR(DMSO-d6, 300MHz) and δ：13.20 (br s, 1H), 7.52 (d, J=8.7Hz, 2H), 7.97 (d, J=8.7Hz, 2H)
1.3 prepare intermediate 5：4- (3- ((6- fluorine pyridin-3-yl) methyl) ghiourea group) benzoic acid
The fluoro- 3- aminomethyl-pyridines (133mg, 1.06mmol) of 6- and 4- isothiocyanos benzoic acid (189mg, 1.06mmol) are molten In dry THF (10mL), reacted 12 hours under room temperature condition, reacted rear solvent evaporated and obtained yellow solid 0.26g, yield 81%.1H-NMR(DMSO-d6, 300MHz) and δ：10.24 (s, 1H), 8.75 (s, 1H), 8.36-8.34 (m, 2H), 7.87 (d, J= 8.5Hz, 2H), 7.63-7.58 (m, 3H), 4.80 (d, J=5.4Hz, 2H) .ESI-MS (m/s)：287.12[M+1].
1.4 prepare target product A1
4- (3- ((6- fluorine pyridin-3-yl) methyl) ghiourea group) benzoic acid (90mg, 0.30mmol) is dissolved in and dries DMF (5mL), addition o-phenylenediamine (32mg, 0.30mmol), HBTU (114mg, 0.30mmol), triethylamine (41 μ L, 0.30mmol), Room temperature reaction 4 hours.Reaction solution is poured into water (40mL) after reaction, crude product is filtrated to get.Crude product is through column chromatography (dichloromethane : methyl alcohol=100: 3) obtain white powder 59mg, yield 51%.1H-NMR(DMSO-d6, 300MHz) and δ：9.95 (s, 1H), 9.56 (s, 1H), 8.46 (s, 1H), 8.22 (s, 1H), 8.04-7.88 (m, 3H), 7.58 (d, J=8.3Hz, 2H), 7.24-7.10 (m, 2H), 6.96 (t, J=7.1Hz, 1H), 6.85-6.72 (m, 1H), 6.58 (t, J=7.3Hz, 1H), 4.99-4.72 (m, 4H) .ESI-MS(m/s)：396.38 [M+1], 394.17 [M-1]
Other A series compound A2-20 preparation methods are with reference to embodiment 1.
Embodiment 2, N- (4- ((2- aminophenyls) carbamoyl) phenyl) imidazole [1,2-a] pyridine -7- formamide systems Standby (B7)
2.1 prepare intermediate 8：4- ((imidazo [1,2-a] pyridine -7- formamides) methyl) methyl benzoate
By imidazo [1,2-a] pyridine -6- formic acid (200mg, 1.00mmol), EDC (230mg, 1.20mmol) and DMAP (146mg, 1.20mmol) is dissolved in dry DMF (5mL), is stirred 0.5 hour under room temperature condition.Add Aminomethylbenzoic Acid Methyl esters (165mg, 1.00mmol), continues to stir 2 hours.Reaction solution is poured into ten times of water of amount after having reacted, there is solid to analyse Go out.Solid is filtered, column chromatography obtains intermediate 120mg after filter cake drying, and yield is 37%.1H-NMR(DMSO-d6, 300MHz)δ：9.21 (t, J=5.7Hz, 1H), 9.16 (s, 1H), 8.08 (s, 1H), 7.90 (d, J=8.3Hz, 2H), 7.73- (s, the 3H) .ESI-MS (m/s) of 7.60 (m, 3H), 7.44 (d, J=8.4Hz, 2H), 4.57 (d, J=5.8Hz, 2H), 3.84： 310.51 [M+1], 300.23 [M-1]
2.2 prepare intermediate 9：4- ((imidazo [1,2-a] pyridine -7- formamides) methyl) benzoic acid
4- ((imidazo [1,2-a] pyridine -7- formamides) methyl) methyl benzoate (120mg.0.387mmol) is dissolved in THF∶MeOH∶H2During O is the mixed solvent of 3: 2: 1 (6mL).LiOH (28mg, 1.16mmol) is added, 24 are reacted under room temperature condition Hour.Rear solvent evaporated is reacted, residue adds water (10mL), adjusted pH value to 3-4 with watery hydrochloric acid, there is white solid to separate out, mistake Filter cake drying, obtains white solid product 111mg after filter, and yield is 97%.1H-NMR(DMSO-d6, 300Hz) and δ：12.92(s Br, 1H), 9.22 (t, J=5.7Hz, 1H), 9.17 (s, 1H), 8.08 (s, 1H), 7.91 (d, J=8.3Hz, 2H), 7.72- (d, J=5.7Hz, the 2H) .ESI-MS (m/s) of 7.60 (m, 3H), 7.45 (d, J=8.3Hz, 2H), 4.57：296.42 [M+1], 294.19[M-1].
2.3 prepare target product B7
4- ((imidazo [1,2-a] pyridine -7- formamides) methyl) benzoic acid (111mg, 0.38mmol), o-phenylenediamine (45mg, 0.41mmol), HBTU (157mg, 0.41mmol) are dissolved in dry DMF (3mL), dropwise addition triethylamine (60 μ L, 0.41mmol), reaction 4 hours is then stirred at room temperature.After question response is complete, in the water that reaction solution is poured into (30mL), acetic acid second Ester extracts (30mL × 3), anhydrous sodium sulfate drying.Extract is evaporated, residue column chromatography (dichloromethane: methyl alcohol=100: 3) Obtain white powdery solids 56mg, yield 39%.1H-NMR(DMSO-d6, 300MHz) and δ：9.62 (s, 1H), 9.22 (t, J= 6.1Hz, 1H), 9.17 (s, 1H), 8.08 (s, 1H), 7.94 (d, J=8.4Hz, 2H), 7.77-7.57 (m, 3H), 7.45 (d, J =8.2Hz, 2H), 7.15 (d, J=7.6Hz, 1H), 6.95 (t, J=6.9Hz, 1H), 6.76 (d, J=7.1Hz, 1H), 6.58 (t, J=7.4Hz, 1H), 4.57 (d, J=4.6Hz, 2H)13C-NMR(DMSO-d6, 150MHz) and δ：165.57,164.76, 144.84,143.55,143.38,143.26,134.37,133.68,129.15,128.27,127.80,127.63,127.15, 126.94,124.97,123.79,123.66,120.24,119.59,116.74,116.60,116.40,114.92,110.07, 49.06,42.96.ESI-MS (m/s)：386.38 [M+1], 384.30 [M-1]
Other B series compound B1-6 preparation methods are with reference to embodiment 2.
Embodiment 3, N- (2- aminophenyls) -4- ((4- (pyridin-3-yl) -1H-1,2,3- triazol-1-yls) methyl) benzene first Acid amides is prepared (C1)
3.1 prepare intermediate 15：4- azido-methyl methyl benzoates
4- bromomethyl-benzoic acid methyl esters (342mg, 1.5mmol) are dissolved in and dry DMF (5mL), are stirred at room temperature down and are slowly added to NaN3 (195mg, 3mmol).Then, place reaction liquid into 80 DEG C of oil bath and react 8 hours.Reaction falls reaction solution after terminating Enter in water (50mL), ethyl acetate extraction (50mL × 3), anhydrous magnesium sulfate is dried.Solvent is evaporated i.e. acquisition intermediate 4- nitrine Methyl toluate 310mg, yield 85%.1H-NMR(DMSO-d6, 300MHz) and δ：7.90 (d, J=8.3Hz, 2H), 7.43 (d, J=8.3Hz, 2H), 3.83 (s, 3H), 3.77 (t, J=7.0Hz, 2H), 3.20 (t, J=7.0Hz, 2H) .ESI-MS (m/ s)：206.35[M+1].
3.2 prepare intermediate 16：4- ((4- (pyridin-3-yl) -1H-1,2,3- triazol-1-yls) methyl) methyl benzoate
3- ethynyl pyridines (154mg, 1.5mmol), 4- azido-methyl benzoic acid first (287mg, 1.5mmol), Vc Na (30mg, 0.15mmol) and CuSO4.5H2O (3.8mg, 0.015mmol) is dissolved in butanol/water (1: 1,6mL) mixed solvent, N2Room temperature reaction 12 hours under protective condition.After question response terminates, reaction solution is poured into water (30mL), there is white solid to analyse Go out.Mixed liquor is filtered, filter cake is obtained.Through column chromatography, (petroleum ether: ethyl acetate=1: 2) obtains white powdery solids to filter cake 360mg, yield is 82%.1H-NMR(DMSO-d6, 300Hz) and δ：9.04 (d, J=1.7Hz, 1H), 8.79 (s, 1H), 8.53 (dd, J=1.5,4.7Hz, 1H), 8.21 (tt, J=1.8,7.9Hz, 1H), 7.97 (d, J=8.2Hz, 2H), 7.49-7.43 (m, 3H), 5.78 (s, 2H), 3.83 (s, 3H) .ESI-MS (m/s)：295.35 [M+1], 589.39 [2M+1]
3.3 prepare intermediate 17：4- ((4- (pyridin-3-yl) -1H-1,2,3- triazol-1-yls) methyl) benzoic acid
Intermediate 16 (303mg, 1.03mmol) is dissolved in THF: MeOH: H2O be 3: 2: 1 mixed solvent in (12mL). LiOH (74mg, 3.09mmol) is added, is reacted 24 hours under room temperature condition.Rear solvent evaporated is reacted, addition 15mL's is water-soluble Liquid, adjusts pH value to 3-4 with watery hydrochloric acid, has white solid to separate out, filter cake drying after filtering, as product 260mg, and yield is 90%.1H-NMR (DMSO-d6,300MHz) δ：13.05 (s, 1H), 9.06 (s, 1H), 8.80 (s, 1H), 8.55-8.53 (m, 1H), (s, the 2H) .ESI-MS of 8.23 (d, J=8.0Hz, 1H), 7.96 (d, J=8.4Hz, 2H), 7.50-7.43 (m, 3H), 5.79 (m/s)：295.35[M+1].
3.4 prepare target product C1
4- ((4- (pyridin-3-yl) -1H-1,2,3- triazol-1-yls) methyl) benzoic acid (250mg, 0.89mmol), adjacent benzene Diamines (106mg, 0.98mmol), HBTU (372mg, 0.98mmol) are dissolved in DMF (5mL), dropwise addition triethylamine (136 μ L, 0.98mmol), reaction 4 hours is stirred at room temperature.After question response is complete, reaction solution is poured into water (40mL), ethyl acetate extraction (40mL × 3), merging organic layer, anhydrous sodium sulfate drying, evaporated under reduced pressure solution, residue is through column chromatography (dichloromethane: methyl alcohol =100: 2) obtain pale yellow powder solid 88mg, yield 27%.1H-NMR(DMSO-d6, 300Hz) and δ：9.64 (s, 1H), 9.06-9.05 (d, J=1.9Hz, 1H), 8.79 (s, 1H), 8.53 (dd, J=1.4,4.7Hz, 1H), 8.21 (dt, J=1.7, 7.9Hz, 1H), 7.98 (d, J=8.1Hz, 2H), 7.49-7.45 (m, 3H), 7.14 (d, J=7.8Hz, 1H), 6.98-6.92 (m, 1H), 6.77-6.74 (m, 1H), 6.58 (t, J=7.6Hz, 1H), 5.77 (s, 2H), 4.88 (s, 2H) .ESI-MS (m/s)： 371.29[M+1].
Other C series compound C2-14 preparation methods are with reference to embodiment 3.
Embodiment 4, N- (2- aminophenyls) -8- (4- (pyridin-3-yl) -1H-1,2,3- triazol-1-yls) caprylamide (D1)
4.1 prepare intermediate 20：N- (2- aminophenyls) -8- azido caprylamides
8- azidos octanoic acid (0.43g, 2.32mmol) are dissolved in 5mL DMF with o-phenylenediamine (0.28g, 2.55mmol), HBTU (1.06g, 2.79mmol) and triethylamine 1.30mL is sequentially added, is stirred 30 minutes at room temperature, after question response is complete, will be anti- Answer liquid to be poured into water (50mL), extracted with ethyl acetate (50mL × 3), merge organic layer, dry, decompression is spin-dried for, residue warp (dichloromethane: methyl alcohol=100: 1) obtains white solid 0.07g, yield 92.1% to column chromatography.1H-NMR(DMSO-d6, 600MHz) δ：1.29-1.33 (m, 6H), 1.50-1.55 (m, 2H), 1.55-1.59 (m, 2H), 2.29 (t, J=7.78Hz, 2H), 3.31 (t, J=6.91Hz, 2H), 4.80 (s, 2H), 6.50-6.55 (m, 1H), 6.70 (dd, J=7.96Hz, 1.38Hz, 1H), 6.85-6.89 (m, 1H), 7.13 (dd, J=7.83Hz, 1.51Hz, 1H), 9.08 (s, 1H) .MS (ESI, positive) m/z： 276.17[M+H].
4.2 prepare target product D1
Compound 20 (0.2g, 0.726mmol) is dissolved in (10mL), N in the mixed solvent of the tert-butyl alcohol and water (5: 1)2Protection, It is implanted sequentially CuSO4The aqueous solution (1.45mL) and the VcNa aqueous solution (7.26mL), are stirred overnight at room temperature.After question response is complete, Reaction solution decompression is spin-dried for, remaining aqueous layer with ethyl acetate extracts (50mL × 3), merges organic layer, solution is evaporated, residue warp (dichloromethane: methyl alcohol=100: 2) obtains white solid 0.16g, yield 62% to column chromatography.1H-NMR(DMSO-d6, 600MHz) δ：1.28-1.35 (m, 6H), 1.55-1.59 (m, 2H), 1.85-1.88 (m, 2H), 2.29 (t, J=7.78Hz, 2H), 4.41 (t, J=7.08Hz, 2H), 4.78 (s, 2H), 6.49-6.53 (m, 1H), 6.69 (dd, J=7.91Hz, 1.23Hz, 1H), 6.85-6.88 (m, 1H), 7.12 (d, J=6.74Hz, 1H), 7.46 (dd, J=7.97Hz, 4.81Hz, 1H), 8.18-8.20 (m, 1H), 8.52 (dd, J=4.91Hz, 1.35Hz, 1H), 8.70 (s, 1H), 9.03 (d, J=1.44Hz, 1H), 9.06 (s, 1H) .MS (ESI, positive) m/z：379.22[M+H].
Other D series compound D2-5 preparation methods are with reference to embodiment 4.
Embodiment 5, N- (2- aminophenyls)-(4- (4- (4- ((pyridine -3- supports methyl) carbamyl) phenyl) -1H-1, 2,3- triazol-1-yls) methyl) benzamide hydrochloride salt prepared (compound C14 hydrochlorides)
By the N- (2- aminophenyls) of 0.1g-(4- (4- (4- ((pyridine -3- support methyl) carbamyl) phenyl) -1H-1, 2,3- triazol-1-yls) methyl) benzamide is dissolved in the hot ethanol of 5mL, is continually fed into dry hydrogen chloride gas.Reaction stirring 2 Hour, there is white solid to separate out, suction filtration after cooling, wash, be dried to obtain N- (2- aminophenyls)-(4- (4- (4- ((pyridine -3- Support methyl) carbamyl) phenyl) -1H-1,2,3- triazol-1-yls) methyl) benzamide hydrochloride salt 0.05g.
It is prepared by embodiment 6, N- (2- aminophenyls) -4- (3- (pyridine -3- methylenes base) urea groups) benzamide succinate (compound A2 succinates)
N- (2- aminophenyls) -4- (3- (pyridine -3- methylenes base) urea groups) benzamide succinate of 0.5g is dissolved in In the hot ethanol of 10mL, the butanedioic acid ethanol solution of heat is added, room temperature reaction 3 hours has reacted rear suction filtration, washing, dry To N- (2- aminophenyls) -4- (3- (pyridine -3- methylenes base) urea groups) benzamide succinate 0.1g.
Embodiment 7, N- (2- aminophenyls)-(4- (4- (4- ((pyridine -3- supports methyl) carbamyl) phenyl) -1H-1, 2,3- triazol-1-yls) methyl) benzamide maleate prepared (compound C14 maleates)
In 50mL round-bottomed flasks, 0.3gN- (2- aminophenyls)-(4- (4- (4- ((pyridine -3- supports methyl) ammonia first is added Acyl group) phenyl) -1H-1,2,3- triazol-1-yls) methyl) benzamide, ethanol dissolving, the maleic acid ethanol solution of addition heat, Room temperature reaction 3 hours, has reacted rear suction filtration, has washed, is dried to obtain N- (2- aminophenyls)-(4- (4- (4- ((pyridine -3- support first Base) carbamyl) phenyl) -1H-1,2,3- triazol-1-yls) methyl) benzamide maleate 0.15g.
Embodiment 8, N- (2- aminophenyls) -4- (2- (4- (pyridin-3-yl)) -1H-1,2,3- triazol-1-yls) benzoyl Amine malate is prepared (compound C1 malates)
In 50mL round-bottomed flasks, addition 0.5gN- (2- aminophenyls) -4- (2- (4- (pyridin-3-yl)) -1H-1,2, 3- triazol-1-yls) benzamide, ethanol dissolving adds the malic acid ethanol solution of heat, and room temperature reaction 3 hours takes out after having reacted Filter, wash, being dried to obtain N- (2- aminophenyls) -4- (2- (4- (pyridin-3-yl)) -1H-1,2,3- triazol-1-yls) benzoyl Amine malate 0.09g.
Embodiment 9, N- (2- aminophenyls) -8- (4- (pyridin-3-yl) -1H-1,2,3- triazol-1-yls) caprylamide winestone Hydrochlorate is prepared (compound D1 tartrates)
In 50mL round-bottomed flasks, 0.5gN- (2- aminophenyls) -8- (4- (pyridin-3-yl) -1H-1,2,3- tri- are added Azoles -1- bases) caprylamide, ethanol dissolving adds the tartaric acid ethanol solution of heat, and room temperature reaction 3 hours reacted rear suction filtration, washed Wash, be dried to obtain N- (2- aminophenyls) -8- (4- (pyridin-3-yl) -1H-1,2,3- triazol-1-yls) caprylamide tartrate 0.23g。
Embodiment 10, target compound enzyme inhibition activity and anti tumor activity in vitro
(1) target compound NAMPT enzyme levels test
Following enzyme refers to Nampt, is purchased from Kang Tai bio tech ltd, also can be voluntarily Prepare.
1) preparation of enzyme：
Conversion there is into recombinant plasmid NAMPT-pET28a+BL21 (DE3) plysS cells be inoculated in 2 × YT culture mediums (37 μ g/mL chloramphenicol and 100 μ g/mL kanamycins) in, 37 DEG C of shakings are overnight, fresh with 20 times of original volumes after collects thalline Culture medium is resuspended, and 37 DEG C of cultures are induced 8 hours to OD600 about 0.6-0.8 under the conditions of 0.5mM IPTG, 28 DEG C.It is collected by centrifugation Thalline, and be resuspended in lysis buffer (20mM Tris-HCl pH 8.0,300mM NaCl), add 0.1%Triton X- 100,1%PMSF, 200W ultrasonic degradation cell, ultrasonic 1s gaps 9s, carry out 30min altogether.By lysate in 12000rpm, 4 DEG C Centrifugation 50min Aspirate supernatants.The supernatant is incubated 2 hours with Ni-NTA posts (being purchased from QIAGEN companies) in shaking on ice, then Combination buffer (5mM imidazoles, 0.5M NaCl, 20mM Tris-Hcl, pH=7.5), buffer solution (10mM/20mM/ are used successively 40mM/60mM imidazoles, 0.5M NaCl, 20mM Tris-HCl, pH=7.5) foreign protein is washed away successively, finally use elution buffer (200mM imidazoles, 0.5M NaCl, 20mM Tris-HCl, PH=7.5) elutes destination protein, and carries out SDS-PAGE detections, uses BCA methods determine protein concentration.
2) enzyme reaction system is 25 μ L, wherein various components is final concentration of：50mM Tris-HCl(pH 7.5)、 0.02%BSA, 12mM MgCl2, 2mM ATP, 0.4mM PRPP, 2mM DTT, 2 μ g/mL NAMPT, 0.2 μM of NAM, DMSO and The compound of the invention of doubling dilution.The various concentrations solution of 0.5 μ L compounds of the invention is first added on 96 orifice plates, then is added Enter 20 μ L enzyme reactions mixed solutions (the enzyme reaction component in addition to substrate), in after incubation at room temperature 5 minutes, add 4.5 μ L substrates NAM solution after 37 DEG C are reacted 15 minutes, enzyme reaction is terminated in 1 minute in 95 DEG C of heating to start reaction.
3) by reaction solution after cooled on ice, the acetophenones of 10 μ L 20% and 2M KOH are sequentially added, is mixed on vortex mixed instrument It is even to be acted on 2 minutes after 0 DEG C, the formic acid of 45 μ L 88% is added, 37 DEG C are incubated 10 minutes.
4) fluorescent value at excitation wavelength 382nm, launch wavelength 445nm is determined using ELIASA.
5) according to formula：E=R/ (1+ (C/IC50)s) (wherein E is enzymatic activity to+B, and C is compound concentration, R, IC50、S、B It is parameter to be fitted), enzymatic activity is fitted to the curve of compound concentration in origin softwares, obtain compound IC50。
(2) target compound HDAC1 enzyme levels test
1) experiment material：
HDAC1 enzymes, buffer solution (137mM sodium chloride, 2.7mM potassium chloride, 1mM magnesium chlorides, 0.1mg/mL BSA, PH=8's Tris-HCl 25mM), HDAC substrates 3, trypsase, 96 hole black plates.
2) experimental technique：
A () 96 hole black plate is balanced to room temperature.
B () dilutes testing compound with the buffer solution containing 10% DMSO, the concentration of compound is followed successively by 100 μM, 30 μ M, 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003 μM.
C be added to the HDAC1 of 11 μ L in the buffer solution of 400 μ L by (), shake up；
The d buffer solution containing HDAC1 enzymes that () has just prepared to 2-11 holes 35 μ L of addition on 96 orifice plates, and sequentially add The compound of the various concentrations that 5 μ L have diluted in corresponding reacting hole, for negative control (first hole) and blank Hole (the 11st hole), is separately added into 40 μ L and 5 μ L buffer solutions.
(e) to HDAC substrates 35 the μ L and 0.5mg/mL that 100 μM are added in all reacting holes trypsase 5 μ L, 37 degree Reading after hatching 30min.
F () calculates inhibiting rate according to formula：Inhibiting rate=(100% active hole-sample well)/100% activity hole * 100, Enzymatic activity is fitted to the curve of compound concentration in orgin softwares, obtains the IC of compound50Value.
(3) target compound anti tumor activity in vitro test
1) sample preparation：After being dissolved into DMSO (Merck), the solution or uniform mixed that PBS (-) is made into 1000 μM is added Suspension, then with PBS (-) dilution containing DMSO.100,10,1,0.1,0.01,0.001 μM of sample final concentration.
2) cell line
HCT116 (people's colon-cancer cell), MDA-MB-231 (human breast cancer cell), HepG2 (human liver cancer cell), by this Laboratory freezes and passes on.
3) nutrient solution
DMEM+10%FBS+ is dual anti-
4) test method
Mtt assay.It is 4-5 × 10 that 96 orifice plates add concentration per hole4The μ l of cell suspension 100 of individual/mL, put 37 DEG C, 5%CO2Training Support in case.After 24 hours, addition sample liquid, 10 μ L/ holes, if three wells, 37 DEG C, 5%CO2Effect 72 hours.Added per hole The μ L of MTT solution 20 of 5mg/mL, effect adds lysate after 4 hours, and 100 μ L/ holes are put in incubator, and all-wave length is used after dissolving Multi-function microplate reader surveys 570nm OD values
(4) target compound enzyme inhibition activity and anti tumor activity in vitro test result (table 2)
The target compound enzyme inhibition activity of table 2. and external activity result (μM)
Pharmacological evaluation shows the compound or its salt that the present invention is told, pair associated histones deacetylation close with tumour The hypotype of enzyme 1 (HDAC1) with strong inhibitory activity.
Pharmacological evaluation shows the compound or its salt that the present invention is told, pair niacinamide ribose phosphate related to tumour is shifted Enzyme (NAMPT) has strong inhibitory activity.
Pharmacological evaluation shows the compound or its salt that the part present invention is told, there is preferably suppression to HDAC1 and NAMPT Activity.Especially compound C14 is 55nM to the inhibitory activity of HDAC1, and the inhibitory activity to NAMPT is 31nM, to double target spots Inhibitory activity reach preferably balance；Compound D1 is 15nM to the inhibitory activity of HDAC1, and the inhibitory activity to NAMPT is 18nM, shows preferable external activity.The external inhibitory activity to HDAC1 and NAMPT of compound D2 distinguishes 31nM and 36nM, External activity is preferable.The external inhibitory activity to HDACl and NAMPT of compound D3 distinguishes 40nM and 41nM, and external activity is preferable.
Anti tumor activity in vitro test uses mtt assay, and majority of compounds is to intestinal cancer (HCT116), breast cancer (MDA-MB- 231) stronger GIA is shown with liver cancer (HepG2) tumor line.A2、A4、A5、A8、A13-18、A20、B1- 3rd, B5, B7, C1-5, C7-10, C14, D3 are better than positive drug CI-994 to intestinal cancer activity.A1-3、A5、A8、A12-18、A20、 B1-5, B7, C1-10, C12-14, D1-3, D5 are better than positive drug CI-994 to liver cancer activity.
Embodiment 11, target compound HDAC selectivity tests
The pharmacological results (table 3) show that compound C14 has selective inhibitory to HDAC1 and HDAC2.
The compound C14 of table 3. is to each hypotype histamine results of HDAC
Antitumous effect in embodiment 12, target compound body
According to anticancer experiment in vitro result and the design feature of compound, we select human colon carcinoma HCT116 as naked Mouse Transplanted tumor model, using compound C14 as research object, SAHA and FK866 are used as positive control drug.
The dosage of designing animal experiment is 25mg/kg, twice a day, continuous intraperitoneal injection 21 days.Result shows naked Mouse survival condition is good, and obvious Mouse Weight significant change is not observed.Compound on tumor growth inhibiting rate is 68.88% (Fig. 1, table 4), is significantly higher than positive drug SAHA (33.05%) and FK866 (39.35%).As can be seen here, the double targets of HDAC/NAMPT The point more single target spot inhibitor of inhibitor has obvious advantage, shows the advantage of high-efficiency low-toxicity, is worth further research.
Curative effect of the target compound of table 4 to human body intestinal cancer HCT116 transplanted tumor in nude mice
Compare with Control：* P ＜ 0.05, * * P ＜ 0.01.
Specific embodiment of the invention is described above.It is to be appreciated that the invention is not limited in above-mentioned Particular implementation, those skilled in the art can within the scope of the claims make various deformations or amendments, this not shadow Sound substance of the invention.

Claims (10)

1. a kind of amide derivatives and its pharmaceutically acceptable salt, the amide derivatives general structure such as formula (I) institute Show：
Wherein, A groups are selected from any one in (1)~(4)：
(1) phenyl, substituted-phenyl,
(2) pyridine radicals, substituted pyridinyl,
(3) quinary heterocyclic radical, substituted five-membered heterocyclic radical,
(4) five yuan or the parallel base and bicyclic heterocycles base of hexatomic ring composition,
The substitution base on substitution base, substituted pyridinyl on the substituted-phenyl phenyl ring, the substitution base on substituted five-membered heterocycle are equal For monosubstituted or polysubstituted, and be respectively selected from it is following any one or a few：Halogen atom, the straight chained alkyl of 1-6 carbon atom, 3-6 the branched alkyl of carbon atom, hydroxyl, cyano group, cyano methyl, amino, nitro, trifluoromethyl, trifluoromethoxy, methoxy Base, ethyoxyl, propoxyl group, isopropoxy, butoxy, acetyl group；
E groups are selected from the one kind in following group：
X group is selected from the one kind in following group：
Wherein, R1 is selected from following any One or more：Hydrogen atom, halogen atom, the straight chained alkyl of 1-6 carbon atom, the branched alkyl of 3-6 carbon atom, hydroxyl, Cyano group, cyano methyl, amino, nitro, trifluoromethyl, trifluoromethoxy, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, fourth Epoxide, acetyl group；
Y group is carbon atom or nitrogen-atoms；
Z group is selected from hydrogen atom, halogen atom, phenyl, hexa-member heterocycle base or quinary heterocyclic radical.
2. amide derivatives according to claim 1 and its pharmaceutically acceptable salt, it is characterised in that described five yuan Or the parallel base and bicyclic heterocycles base of hexatomic ring composition, comprising：
3. amide derivatives according to claim 1 and its pharmaceutically acceptable salt, it is characterised in that described medicine Acceptable salt is hydrochloride, hydrobromate, sulfate, acetate, lactate, tartrate, tannate, citric acid on Salt, trifluoroacetate, malate, maleate, succinate, tosilate or mesylate.
4. amide derivatives according to claim 1 and its pharmaceutically acceptable salt, it is characterised in that described medicine Acceptable salt on, without the crystallization water, or the crystallization water containing one or more molecules.
5. amide derivatives according to claim 1 and its pharmaceutically acceptable salt, it is characterised in that described medicine The crystallization water of the acceptable salt containing 0.5-3.0 molecules on.
6. amide derivatives according to claim 1 and its pharmaceutically acceptable salt, it is characterised in that the acid amides Analog derivative is：
N- (2- aminophenyls) -4- (3- (6- fluorine pyridin-3-yl) methyl) ghiourea group) benzamide,
N- (2- aminophenyls) -4- (3- (pyridin-3-yl methyl) urea groups) benzamide,
N- (2- aminophenyls) -4- (3- (pyridin-3-yl) acrylamido) benzamide,
N- (2- aminophenyls) -4- (3- (6- chloropyridine -3- bases) methyl) ghiourea group) benzamide,
N- (2- aminophenyls) -4- (3- (6- chloropyridine -3- bases) methyl) urea groups) benzamide,
N- (2- aminophenyls) -4- (3- (6- fluorine pyridin-3-yl) methyl) urea groups) benzamide,
N- (2- aminophenyls) -4- (3- (6- aminopyridine -3- bases) methyl) ghiourea group) benzamide,
N- (2- aminophenyls) -4- (3- (6- aminopyridine -3- bases) methyl) urea groups) benzamide,
The tert-butyl group (5- ((3- (4- ((2- aminophenyls) carbamyl) phenyl) urea groups) methyl) pyridine -2- bases) carbamic acid Ester,
N- (2- aminophenyls) -4- (3- (5- fluorine pyridin-3-yl) methyl) urea groups) benzamide,
N- (2- aminophenyls) -4- (3- (6- picoline -3- bases) methyl) urea groups) benzamide,
N- (2- aminophenyls) -4- (3- (4- luorobenzyls) ghiourea group) benzamide,
N- (2- aminophenyls) -4- (3- (3- luorobenzyls) ghiourea group) benzamide,
N- (2- aminophenyls) -4- (3- (2- luorobenzyls) ghiourea group) benzamide,
N- (2- aminophenyls) -4- (3- (3- chlorobenzyls) ghiourea group) benzamide,
N- (2- aminophenyls) -4- (3- (3- bromobenzyls) ghiourea group) benzamide,
N- (2- aminophenyls) -4- (3- (benzo [d] [1,3] dioxole -5- ylmethyls) ghiourea group) benzamide,
N- (2- aminophenyls) -4- (3- (3- aminobenzyls) ghiourea group) benzamide,
4- (3- ((1H- benzos [d] imidazoles -2- bases) methyl) ghiourea group)-N- (2- aminophenyls) benzamide,
N- (2- aminophenyls) -4- (2,3- bis- chloro- 3- (pyridin-3-yl) acrylamido) benzamide,
N- (4- ((2- aminophenyls) carbamoyl) benzyl) thieno [3,2-c] pyridine-2-carboxamide,
N- (4- ((2- aminophenyls) carbamyl) benzyl) -1H- pyrroles [2,3-c] pyridine-2-carboxamide,
N- (4- ((2- aminophenyls) carbamyl) benzyl) -1H- pyrrolo-es [3,2-c] pyridine-2-carboxamide,
N- (4- ((2- aminophenyls) carbamyl) benzyl) -1H- pyrrolo-es [2,3-b] pyridine-2-carboxamide,
N- (4- ((2- aminophenyls) carbamoyl) benzyl) imidazo [1,5-a] pyridine -6- formamides,
N- (4- ((2- aminophenyls) carbamoyl) benzyl) -1H- pyrazolos [4,3-b] pyridine -6- formamides,
N- (4- ((2- aminophenyls) carbamoyl) benzyl) imidazoles [1,2-a] pyridine -7- formamides,
N- (2- aminophenyls) -4- ((4- (pyridin-3-yl) -1H-1,2,3- triazol-1-yls) methyl) benzamide,
N- (2- aminophenyls) -4- (2- (4- (pyridin-3-yl) -1H-1,2,3- triazol-1-yls) methyl) benzamide,
N- (2- aminophenyls) -4- ((4- (pyridin-4-yl) -1H-1,2,3- triazol-1-yls) methyl) benzamide,
N- (2- aminophenyls) -4- ((4- (6- chloropyridine -3- bases) -1H-1,2,3- triazol-1-yls) methyl) benzamide,
N- (2- aminophenyls) -4- ((4- (3- aminophenyls) -1H-1,2,3- triazol-1-yls) methyl) benzamide,
N- (2- aminophenyls) -4- ((4- (tolyl) -1H-1,2,3- triazol-1-yls) methyl) benzamide,
4- ((4- (4- acetylphenyls) -1H-1,2,3- triazol-1-yls) methyl)-N- (2- aminophenyls) benzamide,
N- (2- aminophenyls) -4- ((4- (thiophene -2- bases) -1H-1,2,3- triazol-1-yls) methyl) benzamide,
N- (4- ammonia-[1,1 '-biphenyl] -3- bases) -4- ((5- (pyridin-3-yl) -1H-1,2,3- triazol-1-yls) methyl) benzene first Acid amides,
N- (4- amino-[1,1 '-biphenyl] -3- bases) -4- ((5- (3- aminophenyls) -1H-1,2,3- triazol-1-yls) methyl) benzene Formamide,
N- (4- amino-[1,1 '-biphenyl] -3- bases) -4- ((5- (3- hydroxy phenyls) -1H-1,2,3- triazol-1-yls) methyl) benzene Formamide,
4- ((5- (4- acetylphenyls) -1H-1,2,3- triazol-1-yls) methyl)-N- (4- amino-[1,1 '-biphenyl] -3- bases) Benzamide,
N- (2- aminophenyls) -4- ((4- (4- (3- (pyridin-3-yl methyl) -1H-1,2,3- triazol-1-yls) methyl) benzoyls Amine,
N- (2- aminophenyls) -4- ((4- (4- ((pyridin-3-yl methyl) carbamyl) phenyl) -1H-1,2,3- triazole -1- Base) methyl) benzamide,
N- (2- aminophenyls) -8- (4- (pyridin-3-yl) -1H-1,2,3- triazol-1-yls) caprylamide,
N- (2- aminophenyls) -8- (4- (3- aminophenyls) -1H-1,2,3- triazol-1-yls) caprylamide,
N- (4- amino-[1,1 '-biphenyl] -3- bases) -8- (4- (pyridin-3-yl) -1H-1,2,3- triazol-1-yls) caprylamide,
N- (4- amino-[1,1 '-biphenyl] -3- bases) -8- (4- (3- aminophenyls) -1H-1,2,3- triazol-1-yls) caprylamide,
N- (4- amino-[1,1 '-biphenyl] -3- bases) -8- (4- (3- hydroxy phenyls) -1H-1,2,3- triazol-1-yls) caprylamide.
7. the preparation method of a kind of amide derivatives according to claim 1 and its pharmaceutically acceptable salt, it is special Levy and be：
When general structure isAnd X2For O or S, R are-NH-CH2- A ,-CH=CH-A orA For phenyl, amino substituted-phenyl, halogen substituted phenyl, pyridine radicals, the straight chained alkyl substituted pyridinyl of 1-6 carbon atom, 3-6 The branched alkyl substituted pyridinyl of carbon atom, halogen substituted pyridinyl, amino substituted pyridinyl, When, methods described comprises the following steps：
A1, cyano compound 1It is catalyzed through Raney Ni, hydrogen reducing obtains amino chemical combination in ammoniacal liquor methanol solution Thing 2aX1For N or CH, R2 are hydrogen, halogen, amino or t-butoxycarbonyl amino；
A2, p-aminobenzoic acid and CDI or TCDI react obtain intermediate 4 at room temperature
A3, compound 2a or compound 2cRoom temperature reaction obtains intermediate 5 in tetrahydrofuran with intermediate 4
Or, compound 2bIntermediate 5 is condensed to yield in dichloromethane with p-aminobenzoic acid；R3For H or C1；
A4, intermediate 5 in DMF with o-phenylenediamine room temperature reaction, obtain target compound through column chromatography
When general structure isAnd A is When, methods described includes following step Suddenly：
B1,4- amine methyl toluate and carboxylic acid obtain midbody compound 8 through EDC/DMAP catalyzing and condensings
B2, in tetrahydrofuran/methanol/water mixed solvent system, the midbody compound 8 through LiOH hydrolysis obtain Carboxylation Compound 9
B3, the carboxylic acid compound 9 react at ambient temperature in DMF with o-phenylenediamine, obtain final product target compound
When general structure isAnd n=1 or 2, A are pyridine radicals, halogen substituted pyridines Base, amino substituted pyridinyl, 1-6 carbon atom straight chain alkyl-substituted phenyl, acetyl group substituted-phenyl, thienyl,When Z is hydrogen atom or phenyl, methods described comprises the following steps：
C1, compound 11Compound 12 is reacted to obtain with trimethyl silicane ethyl-acetyleneIn the basic conditions The de- trimethyl silicon substrate of room temperature is obtained compound 13The R4 is chlorine or hydrogen；
C2, bromide 14Intermediate 15 is obtained through sodium azide substitution
Intermediate product 16 obtained and click reactions with compound 13 or other alkynyl compounds in C3, intermediate 15 there is
C4, the intermediate product 16 are hydrolyzed in the basic conditions, with o-phenylenediamine or the final acquisition of 4- phenyl o-phenylenediamine condensation Targeted and thing
When formula isAnd R ' is amino, hydroxyl or hydrogen atom, X3It is N Or CH, Z be hydrogen atom or phenyl when, methods described comprises the following steps：
D1, compound 19It is catalyzed in HBTU and triethylamine with o-phenylenediamine or 4- phenyl o-phenylenediamine Lower generation condensation reaction obtains intermediate 20
Target compound obtained and Click reactions in the aryl ethane of D2, intermediate 20 containing different substituents there is
8. a kind of amide derivatives according to claim 1 and its pharmaceutically acceptable salt are preparing niacinamide phosphoric acid Purposes in the double target spot inhibitor of phosphoribosynltransferase inhibitor, histon deacetylase (HDAC) inhibitor or HDAC/NAMPT.
9. a kind of amide derivatives according to claim 1 and its pharmaceutically acceptable salt are preparing antineoplastic In purposes.
10. purposes according to claim 9, it is characterised in that the tumour is liver cancer, lung cancer, intestinal cancer, oophoroma, preceding Row gland cancer, stomach cancer or lymph cancer.
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