CN103086971B - Nitogen-contained heterocycle derivant, its preparation method and the application in preparation histone deacetylase I inhibitor thereof - Google Patents

Nitogen-contained heterocycle derivant, its preparation method and the application in preparation histone deacetylase I inhibitor thereof Download PDF

Info

Publication number
CN103086971B
CN103086971B CN201310012030.XA CN201310012030A CN103086971B CN 103086971 B CN103086971 B CN 103086971B CN 201310012030 A CN201310012030 A CN 201310012030A CN 103086971 B CN103086971 B CN 103086971B
Authority
CN
China
Prior art keywords
preparation
nmr
pyrazole
nitogen
benzyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN201310012030.XA
Other languages
Chinese (zh)
Other versions
CN103086971A (en
Inventor
蒋晟
涂正超
孙巧
刘春平
姚毅武
邱亚涛
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangzhou Institute of Biomedicine and Health of CAS
Original Assignee
Guangzhou Institute of Biomedicine and Health of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guangzhou Institute of Biomedicine and Health of CAS filed Critical Guangzhou Institute of Biomedicine and Health of CAS
Priority to CN201310012030.XA priority Critical patent/CN103086971B/en
Publication of CN103086971A publication Critical patent/CN103086971A/en
Application granted granted Critical
Publication of CN103086971B publication Critical patent/CN103086971B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Abstract

The invention discloses a kind of structure such as formula the nitogen-contained heterocycle derivant shown in I or its pharmaceutical salts, its preparation method and application thereof. when R is selected from the group of nitrogen heterocyclic ring shown in formula Ia, M be selected from double bond ,-(CH2) m-or-C (O) NH (CH 2) 2-, m is selected from the positive integer of 4-8; When R is selected from the group of nitrogen heterocyclic ring shown in formula Ib, M is selected from-(CH 2) 4-;

Description

Nitogen-contained heterocycle derivant, its preparation method and the application in preparation histone deacetylase I inhibitor thereof
Technical field:
The invention belongs to medicinal chemistry art, be specifically related to a kind of nitogen-contained heterocycle derivant and preparation method thereof and the application in preparation histone deacetylase I inhibitor, and the pharmaceutical composition containing this nitogen-contained heterocycle derivant.
Background technology:
The abnormal expression of eukaryotic gene has important effect in the pathogenesis of numerous disease, and it is expressed by genetic regulation and the dual regulation and control of epigenetic regulation.Genetic regulation comprises genetic transcription, transcribes post-treatment, the link such as translation and posttranslational modification; Epigenetic regulation refers to transcribes the structural adjustment of front gene in chromatin level, and it is the regulatory mechanism of a kind of uniqueness of eukaryote.Epigenetic regulation mainly comprises DNA methylation, RNA interferes, histone modification three aspect, can under the prerequisite not changing DNA encoding sequence, make gene that heritable silence occurs.The change of the karyomit(e) local conformation caused by histone modification, plays an important role in eukaryotic gene expression regulation.The posttranslational modification of histone, comprises the acetylize to the Methionin of histone afterbody and arginine residues, methylates, phosphorylation and ubiquitination etc., and these modifications constitute Histone Code.Histone Code, as the storage of the gene information outside a kind of DNA sequence dna and added machinery, extends the quantity of information of genes encoding greatly.Wherein, the acetylation modification of histone is comparatively general, is also the most deep Histone Code of Recent study.
Histone core containing 4 kinds of histones forms chromatinic basic repeating unit nucleosome around DNA double chain, this histone core comprises a H3-H4 tetramer and two H2A-H2B dimers, histone h1 is attached to the connection portion between nucleosome, and makes the stability in order to keep chromatin Structure by the negative charge that it is rich on the N-terminal of positive electricity core and DNA chain.The acetylation modification of histone on H3 and H4 comparatively H2A and H2B is more general, and important acetylation sites is Lys9 and Lys14 on H3 and Lys5, Lys8, Lys12, the Lys16 on H4.It is generally acknowledged, the transcriptional activity of gene is closely related with chromosomal local conformation.Acetylize/the deacetylation of histone can change chromosomal local conformation, affects the interaction between DNA and the non-nucleosome complexes of transcriptional control, and then the expression of regulation and control specific gene.The Acetylation Level of histone is is jointly regulated and controled by acetylation of histone enzyme (Histone acetylases, HATs) and histon deacetylase (HDAC) (Histone deacetylases, HDACs).Acetyl grouptransfer on HATs energy catalysis acetyl-CoA holds lysine residue to the N-of histone; in and positive charge, the interaction between DNA and histone is weakened, and karyomit(e) is the open structure of tool transcriptional activity; be conducive to transcription factor to be combined with DNA, transcriptional activation.Otherwise the deacetylation effect of HDACs causes Transcription inhibition.
In recent years research shows, suppresses HDACs to be expected to be used for the treatment of various diseases, as: leukemia, tumour, inflammation and nerve degenerative diseases.And it is the most noticeable to the useful effect of tumour.HDACs inhibitor can suppress leukemia or solid tumor cell propagation, and inducing tumor cell differentiation.Hdac inhibitor generally can make tumour cell be stagnated in the G1 phase, but sometimes also can observe G2 phase cytosis.Nearly all HDACs inhibitor all can activation cycle protein dependent kinase supressor P21CIPI/WAF1(by CHKN1A genes encoding) transcribe, P21CIPI/WAF1 can be combined with cyclin E-CDK2 and cyclin A-CDK2 mixture, makes its inactivation; In addition, a lot of HDACs inhibitor can also lower the level of cyclin A and cyclin D in cell, and stop tumor suppressor protein Retinoblastoma Protein Rb phosphorylation, cell can not enter the S phase, and the cell cycle cannot carry out.CDKN1A suppressed to play a crucial role for the G1 phase that HDACs inhibitor mediates, if Cells Depletion CDKN1A gene, firm cell enters the S phase, DNA replication dna, can detect that intracellular DNA is 4n, and cell is easy to apoptosis occurs.Hdac inhibitor does not rely on p53 for the activation of P21CIPI/WAF1, and this point is particularly important, the proliferation out of control caused because tumour cell is prevalent in P53 dysfunction.
HDACs inhibitor can also make people's normal fibroblasts and some tumour cell produce a G2 period regulation point, therefore, normal cell can exit the cell cycle in a secure manner, and this also may be that hdac inhibitor is to one of reason of the almost non-toxic side effect of normal cell or tissue.
In addition, it is that synthesis to protein is relevant that the tune that HDACs induction is all observed in a lot of research is died.If the synthesis of arrestin matter, the tune of meeting antagonism HDACs induction is died.
HDACs inhibitor impels cell to exit the cell cycle, or differentiation occurs or occurs to adjust the different pharmacological action such as to die relevant to many factors.In general, it is the prerequisite that differentiation occurs that cell exits the cell cycle, and when consumption is higher, HDACs inhibitor has cytotoxicity usually, can die by inducing cell tune, and when low dosage, just can, by cell block in the G phase, make it exit the cell cycle.In addition, this is relevant with cell type, may promote a certain cytodifferentiation, and induce another kind of natural death of cerebral cells with dose.This may cause concrete intracellular absorption is different with accretion rate due to medicine; Also may be regulate the cell cycle due to disappearance in some tumour cell or occur to adjust required gene of dying, such as, the tune that the cell of overexpression Bcl2 can not occur to be induced by HDACs inhibitor is died, but but can not affect the effect of HDACs inhibitor cell cycle.Under normal circumstances, HDACs inhibitor activates P21CIPI/WAF1, and make cells arrest in G1 phase reference mark, DNA copies as 4n further, then these cells tune occurs possibly are died.
Except promoting that cell exits the cell cycle, break up, outside inducing cell is adjusted and died, HDACs inhibitor also affects the growth of tumour cell by alternate manner.HDACs inhibitor can activate transcribing of the 1st class and the 2nd class loading compatible protein gene, costimulator CD40 can also be raised, CD89 and CD86, intercellular adhesionmolecule1 ICAM1, and 1 level of type and 2 type Interferon, rabbit, therefore can amplify identification and the activation of immunocyte.Such as, HDACs inhibitor can improve tumour cell and mixes leukocytic susceptibility to recessive allele.In addition, due to the rapid propagation of solid tumor, need new vessel to provide oxygen needed for tumour cell and nutritive substance, the expression of the Urogastron (EGFR) that HDACs inhibitor can stop histanoxia to cause, thus suppress the formation of new vessel.
Find a few class HDACs inhibitor at present: (1) short chain fatty acid, as: butyric acid and benzenebutanoic acid; (2) azanol class, as: suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA); (3) cyclic peptide, as: Apicidin, trapocin, FK228 and the largazole found in the recent period; (4) benzamide compound, as: MS-275.
Along with to the further discovery of HDACs family and relevant research, the inhibitor with class selectivity (class selectivity) and subtype-selective (isoform selectivity) has become the main flow of current HDACs inhibitor development, so that explore the effect of each hypotype in disease and the medicine that exploitation is more effective, toxic side effect is less.
Summary of the invention:
First object of the present invention is to provide a kind of nitogen-contained heterocycle derivant inhibited to histone deacetylase I or its pharmaceutical salts.
The structure inhibited to histone deacetylase I of the present invention is such as formula nitogen-contained heterocycle derivant shown in I or its pharmaceutical salts:
When wherein R is selected from the group of nitrogen heterocyclic ring shown in formula Ia, M be selected from double bond ,-(CH2) m-or-C (O) NH (CH 2) 2-, m is the positive integer of 4-8; Described double bond is carbon-carbon double bond;
When R is selected from the group of nitrogen heterocyclic ring shown in formula Ib, M is-(CH 2) 4-;
In formula Ia, Ar is selected from phenyl ring, naphthalene nucleus or containing 1 or two substituent phenyl ring, substituting group is selected from halogen, dimethylamino, nitro, alkyl, alkoxyl group, perfluoroalkyl, aryl, fragrant epoxy group(ing), aromatic ring methoxyl group, aromatic ring amino, morpholinyl or indyl; N is selected from 0 or 1; X, Y, Z are selected from carbon or nitrogen and X and Y can not be selected from nitrogen simultaneously; L is selected from hydrogen, alkyl or aryl;
In formula Ib, Y ' is selected from carbon or nitrogen;
Described nitogen-contained heterocycle derivant pharmaceutical salts is the pharmaceutical salts that nitogen-contained heterocycle derivant shown in formula I and mineral acid organic acid reaction generate.
" halogen " of the present invention, is selected from fluorine, chlorine, bromine, iodine;
" alkyl " of the present invention, is selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl etc.;
" alkoxyl group " of the present invention, is selected from methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy etc.;
" perfluoroalkyl " of the present invention, comprises trifluoromethyl, pentafluoroethyl group etc.;
" aryl " of the present invention, comprise containing substituting group or not containing substituent aromatic ring, substituting group is selected from halogen, dimethylamino, nitro, alkyl, alkoxyl group, perfluoroalkyl, aryl, fragrant epoxy group(ing), aromatic ring methoxyl group, aromatic ring amino, morpholinyl or indyl;
In formula Ia, Ar be preferably phenyl ring, biphenyl, naphthalene nucleus, benzyloxy replace phenyl ring, phenoxy group replace phenyl ring, anilino replace phenyl ring, indyl replace phenyl ring or benzo [d] [1,3] methylenedioxy.
Second object of the present invention is to provide the preparation method of nitogen-contained heterocycle derivant or its pharmaceutical salts.
The synthesis of compound of the present invention, comprises four steps:
One, the halogenide of aryl or alcohol or acid or aldehyde under the effect of salt of wormwood with 5-member heterocyclic ring containing nitrogen aldehyde room temperature reaction, obtain the aldehyde compound shown in formula B;
Two, or Ph 3p=CH (CH 2) m-2cO 2aldehyde compound shown in Et and formula B is obtained by reacting the olefin(e) acid ester shown in formula C;
Three, the olefin(e) acid ester shown in formula C is hydrolyzed through hydrogenating reduction again or is hydrolyzed after becoming ring or Buchwald-Hartwig reaction or Ullmann to react through hydrogenating reduction, intramolecular Heck reaction again and obtains the acid shown in corresponding formula D;
Four, the acid shown in formula D and oxalyl chloride heating reflux reaction, in the dichloromethane solution that 0 DEG C is added drop-wise to the azanol of fresh preparation, (in 50ml two neck bottle, 196mg oxammonium hydrochloride is added after product concentrates, add 9ml methylene dichloride successively, 0.93ml DIPEA, room temperature reaction 30min obtains) reaction, concentrating under reduced pressure, is separated and obtains target product.
For the bromide of aryl and 5-member heterocyclic ring containing nitrogen aldehyde as starting raw material, synthesize the synthetic route of compound of the present invention such as formula shown in II:
Formula II, wherein n '=m-3
Prove through enzymic activity experiment; nitogen-contained heterocycle derivant shown in formula I of the present invention or its pharmaceutical salts have the activity of good inhibition of histone deacetylase I; and have certain selectivity; can be used for treating a series of diseases caused because histone deacetylase I activity is abnormal, as: tumour, leukemia, inflammation and nerve degenerative diseases.
Therefore the 3rd object of the present invention is to provide the nitogen-contained heterocycle derivant shown in formula I or the application of its pharmaceutical salts in preparation histone deacetylase I inhibitor.
4th object of the present invention is to provide the nitogen-contained heterocycle derivant shown in formula I or the application of its pharmaceutical salts in the medicine preparing the disease that treatment causes because histone deacetylase I activity is abnormal.
5th object of the present invention is to provide a kind of pharmaceutical composition, its contain effective dose as active ingredient formula I shown in nitogen-contained heterocycle derivant or its pharmaceutical salts and pharmaceutical carrier.Add pharmaceutically acceptable carrier and can be made into conventional medicinal preparations, as tablet, capsule, pulvis, syrup, liquor, suspension agent, injection, the conventional medicinal adjuvants such as spices, sweeting agent, liquid or solid filler or thinner can be added.
Nitogen-contained heterocycle derivant of the present invention or its pharmaceutical salts have the activity of good inhibition of histone deacetylase I; and have certain selectivity; can be used for treating a series of diseases caused because histon deacetylase (HDAC) I activity is abnormal; as: tumour, leukemia, inflammation and nerve degenerative diseases, have broad application prospects.Its preparation method is simple and easy, effective fast, and raw material is cheap and easy to get, is adapted to suitability for industrialized production.
Embodiment:
Below further illustrate of the present invention, instead of limitation of the present invention.
The preparation of embodiment 1:5-(1-benzyl-1H-pyrazole-3-yl)-N-hydroxyvaleramide (compound 5)
The first step: the preparation of 1-benzyl-1H-pyrazoles-3-formaldehyde (compound 2)
In 50ml eggplant-shape bottle, add 300mg1H-pyrazoles-3-formaldehyde successively, 1.29g salt of wormwood, dissolve with 21ml acetonitrile, then add 0.56ml benzyl bromine (compound 1), room temperature reaction spends the night.Concentrating under reduced pressure, extraction into ethyl acetate, washing, merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, and filter, concentrating under reduced pressure, pillar layer separation obtains 248mg pale yellowish oil liquid (compound 2, productive rate 32%).
Second step: the preparation of (Z)-5-(1-benzyl-1H-pyrazole-3-yl) penta-obtusilic acid ethyl ester (compound 3)
In 50ml two-neck bottle, add 1.52g (4-oxyethyl group-4-oxygen base-butyl) three phenyl phosphonium bromides, vacuumize, fill noble gas, in triplicate, add 6ml tetrahydrofuran (THF), reaction flask is put into-78 DEG C of reactors, toward wherein dripping 1.66mlNaHMDS,-78 DEG C of reaction 30min, then add the tetrahydrofuran solution (248mg, 6ml) of 1-benzyl-1H-pyrazoles-3-formaldehyde (compound 2),-78 DEG C of reaction 2h, stop refrigeration, rise to room temperature, reaction is spent the night.Concentrating under reduced pressure, extraction into ethyl acetate, washing, merges organic phase, and saturated sodium-chloride washs, anhydrous sodium sulfate drying, and filter, concentrating under reduced pressure, pillar layer separation obtains 221mg colourless oil liquid (compound 3, productive rate 58%).
The preparation of the 3rd step: 5-(1-benzyl-1H-pyrazole-3-yl) valeric acid (compound 4)
In 25ml eggplant-shape bottle, add 221mg (Z)-5-(1-benzyl-1H-pyrazole-3-yl) penta-obtusilic acid ethyl ester (compound 3) and 22mg Pd-C, 8ml dissolve with methanol, vacuumize, fill hydrogen, in triplicate, room temperature reaction 2h.Diatomite filtration, filtrate reduced in volume, adds 4ml methyl alcohol in residue, 2ml tetrahydrofuran (THF), 2ml water and 65mg LiOH, room temperature reaction 2h.Concentrating under reduced pressure, ethyl acetate reversed phase extraction, merges organic phase, and saturated sodium-chloride washs, anhydrous sodium sulfate drying, and filter, concentrating under reduced pressure, obtains 182mg light yellow solid (compound 4, two step overall yields 91%).
The preparation of the 4th step: 5-(1-benzyl-1H-pyrazoles-3 base)-N-hydroxyvaleramide (compound 5)
In 50ml two-neck bottle, add 182mg5-(1-benzyl-1H-pyrazole-3-yl) valeric acid (compound 4), 7ml methylene dichloride dissolves, and adds two DMF, 0.30ml oxalyl chlorides successively, backflow 2h.Concentrating under reduced pressure, oil pump is drained, residue 9ml dchloromethane, in the dichloromethane solution that 0 DEG C is added drop-wise to the azanol of fresh preparation, (in 50ml two neck bottle, add 196mg oxammonium hydrochloride, add 9ml methylene dichloride successively, 0.93ml DIPEA, room temperature reaction 30min are obtained), 0 DEG C of reaction 2h, concentrating under reduced pressure, pillar layer separation obtains 157mg white solid (compound 5, productive rate 79%), is 5-(1-benzyl-1H-pyrazole-3-yl)-N-hydroxyvaleramide through Structural Identification. 1H NMR(400MHz,CD 3OD):δ7.53(d,J=2.4Hz,1H),7.33-7.24(m,3H),7.16(d,J=6.8Hz,2H),6.12(d,J=2.0Hz,1H),5.25(s,2H),2.61(t,J=7.0Hz,2H),2.10(t,J=7.0Hz,2H),1.66-1.62(m,4H)ppm. 13C NMR(125MHz,DMSO-d 6):δ169.0,151.9,138.0,130.7,128.4,127.4,127.3,103.9,54.4,32.1,28.7,27.4,24.9ppm.MS(ESI)m/z273.15(100%)(M+H) +
The preparation of embodiment 2:5-(1-([1,1'-xenyl]-3-ylmethyl)-1H-pyrroles-2-base)-N-hydroxyvaleramide
The synthesis of reference example 1 compound 5, with a phenyl benzyl bromine, 1H-pyrrole-2-aldehyde is starting raw material, 103mg white solid is obtained through four-step reaction, be 5-(1-([1,1'-xenyl]-3-ylmethyl)-1H-pyrroles-2-base)-N-hydroxyvaleramide through Structural Identification. 1H NMR(400MHz,CD 3OD):δ7.52-7.50(m,2H),7.47(d,J=7.6Hz,1H),7.41-7.33(m,3H),7.32-7.28(m,1H),7.19(s,1H),6.95(d,J=7.6Hz,1H),6.68(dd,J=2.0,2.4Hz,1H),6.04(t,J=3.2Hz,1H),5.90(s,1H),5.14(s,2H),2.48(t,J=7.2Hz,2H),2.02(t,J=7.0Hz,2H),1.62-1.53(m,4H)ppm. 13C NMR(125MHz,DMSO-d 6):δ168.9,140.4,140.0,139.8,132.3,129.1,128.9,127.5,126.6,125.4,124.7,120.9,106.7,105.7,49.2,32.0,28.0,25.2,24.8ppm.MS(ESI)m/z348.18(100%)(M+H) +
The preparation of embodiment 3:5-(1-([1,1'-xenyl]-3-ylmethyl)-1H-pyrazole-3-yl)-N-hydroxyvaleramide
The synthesis of reference example 1 compound 5, with a phenyl benzyl bromine, 1H-pyrazoles-3-formaldehyde is starting raw material, 157mg white solid is obtained through four-step reaction, be 5-(1-([1,1'-xenyl]-3-ylmethyl)-1H-pyrazole-3-yl)-N-hydroxyvaleramide through Structural Identification. 1H NMR(400MHz,CD 3OD):δ7.60(d,J=2.0Hz,1H),7.56-7.51(m,3H),7.40(q,J=7.6Hz,4H),7.31(t,J=7.2Hz,1H),7.14(d,J=7.6Hz,1H),6.14(d,J=2.0Hz,1H),5.32(s,2H),2.62(t,J=7.0Hz,2H),2.09(t,J=6.8Hz,2H),1.64(t,J=3.6Hz,4H)ppm. 13C NMR(125MHz,DMSO-d 6):δ169.0,152.0,140.3,139.9,138.7,130.8,129.1,128.9,127.5,126.6,126.4,125.8,104.0,54.4,32.0,28.7,27.4,24.8ppm.MS(ESI)m/z349.18(100%)(M+H) +
The preparation of embodiment 4:5-(1-([1,1'-xenyl]-3-ylmethyl)-1H-pyrazoles-4-base)-N-hydroxyvaleramide
The synthesis of reference example 1 compound 5, with a phenyl benzyl bromine, 1H-pyrazoles-4-formaldehyde is starting raw material, 153mg white solid is obtained through four-step reaction, be 5-(1-([1,1'-xenyl]-3-ylmethyl)-1H-pyrazoles-4-base)-N-hydroxyvaleramide through Structural Identification. 1H NMR(400MHz,CD 3OD):δ7.84(s,1H),7.69(s,1H),7.59-7.56(m,3H),7.50(s,1H),7.43(q,J=7.6Hz,3H),7.33(t,J=7.2Hz,1H),7.21(d,J=7.6Hz,1H),5.47(s,2H),2.54(t,J=6.8Hz,2H),2.41(t,J=6.8Hz,2H),1.63-1.53(m,4H)ppm. 13C NMR(125MHz,DMSO-d 6):δ169.0,140.3,139.9,138.6,138.4,129.1,128.9,128.2,127.5,126.6,126.5,125.9,125.8,120.8,54.6,30.0,29.8,24.7,23.3ppm.MS(ESI)m/z349.18(100%)(M+H) +
The preparation of embodiment 5:5-(1-([1,1'-xenyl]-3-ylmethyl)-1H-imidazoles-2-base)-N-hydroxyvaleramide
The synthesis of reference example 1 compound 5, with a phenyl benzyl bromine, 1H-imidazoles-2-formaldehyde is starting raw material, 159mg white solid is obtained through four-step reaction, be 5-(1-([1,1'-xenyl]-3-ylmethyl)-1H-imidazoles-2-base)-N-hydroxyvaleramide through Structural Identification. 1H NMR(400MHz,CD 3OD):δ7.64-7.21(m,11H),5.43(s,2H),2.95(t,J=7.2Hz,2H),2.08(t,J=6.8Hz,2H),1.68-1.62(m,4H)ppm. 13C NMR(125MHz,CD 3OD):δ172.3,149.1,143.6,141.6,136.8,130.9,130.0,128.8,128.4,128.0,127.5,127.3,123.3,121.6,51.7,32.9,27.4,25.8ppm.MS(ESI)m/z349.18(100%)(M+H) +
Embodiment 6:(E) preparation of-3-(1-([1,1'-xenyl]-3-ylmethyl)-1H-imidazoles-2-base)-N hydroxyacrylamide
(E)-3-(1-([1,1'-xenyl]-3-ylmethyl)-1H-imidazoles-2-base) preparation of-N hydroxyacrylamide, with a phenyl benzyl bromine, 1H-imidazoles-2-formaldehyde is starting raw material, first and third, four steps are with reference to first and third, four of embodiment 1 compound 5-(1-benzyl-1H-pyrazole-3-yl)-N-hydroxyvaleramide (compound 5), and second step is different.
Second step: the preparation of (E)-3-(1-([1,1'-xenyl]-3-ylmethyl)-1H-imidazoles-2-base) ethyl propenoate
1.62g ethoxycarbonyl methylene triphenyl phosphine and 1.01g1-([1,1'-xenyl]-3-ylmethyl)-1H-imidazoles-2-formaldehyde are placed in 100ml two-neck bottle, add 39ml toluene and dissolve, backflow 2h.Concentrating under reduced pressure, pillar layer separation obtains 1.21g yellow oily liquid (productive rate 94%). 1H NMR(400MHz,CD 3OD):δ7.63(d,J=15.6Hz,1H),7.56(d,J=7.6Hz,3H),7.44-7.39(m,5H),7.35-7.31(m,1H),7.17(d,J=0.4Hz,1H),7.12(d,J=8.0Hz,1H),6.67(d,J=15.6Hz,1H),5.46(s,2H),4.19(q,J=7.2Hz,2H),1.25(t,J=7.2Hz,3H)ppm.MS(ESI)m/z332.15(100%)(M+H) +
Obtaining 66mg white solid through four-step reaction, is (E)-3-(1-([1,1'-xenyl]-3-ylmethyl)-1H-imidazoles-2-base)-N hydroxyacrylamide through Structural Identification. 1H NMR(400MHz,CD 3OD):δ7.59-7.11(m,12H),6.83(d,J=15.2Hz,1H),5.44(s,2H)ppm. 13C NMR(125MHz,CD 3OD):δ165.3,144.6,143.3,141.8,138.6,130.6,130.2,129.9,128.6,128.0,127.8,126.8,126.6,125.7,124.4,121.9,50.6ppm.MS(ESI)m/z319.13(100%)(M+H) +
Embodiment 7:(E) preparation of-3-(1-([1,1'-xenyl]-3-ylmethyl)-1H-pyrroles-2-base)-N hydroxyacrylamide
With reference to embodiment 6 (E)-3-(1-([1,1'-xenyl]-3-ylmethyl)-1H-imidazoles-2-base) synthesis of-N hydroxyacrylamide, with a phenyl benzyl bromine, 1H-pyrrole-2-aldehyde is starting raw material, 164mg white solid is obtained through four-step reaction, be (E)-3-(1-([1,1'-xenyl]-3-ylmethyl)-1H-pyrroles-2-base)-N hydroxyacrylamide through Structural Identification. 1H NMR(400MHz,DMSO-d 6):δ10.51(s,1H),8.84(s,1H),7.59-7.35(m,9H),7.15(s,1H),7.00(d,J=7.6Hz,1H),6.58(d,J=1.6Hz,1H),6.19(d,J=2.8Hz,1H),6.10(d,J=15.6Hz,1H),5.38(s,2H)ppm. 13C NMR(125MHz,DMSO-d 6):δ163.5,140.5,140.0,139.3,129.2,128.9,127.6,126.7,126.6,126.0,125.7,125.3,124.7,114.2,109.7,109.1,49.6ppm.MS(ESI)m/z318.14(100%)(M+H) +
The preparation of embodiment 8:5-(1-([1,1'-xenyl]-3-ylmethyl)-1H-pyrazoles-5-base)-N-hydroxyvaleramide
The synthesis of reference example 1 compound 5, with a phenyl benzyl bromine, 1H-pyrazoles-3-formaldehyde is starting raw material, 85mg white solid is obtained through four-step reaction, be 5-(1-([1,1'-xenyl]-3-ylmethyl)-1H-pyrazoles-5-base)-N-hydroxyvaleramide through Structural Identification. 1H NMR(400MHz,CD 3OD):δ7.54-7.28(m,9H),7.02(d,J=7.6Hz,1H),6.19(d,J=1.6Hz,1H),5.41(s,2H),2.63(t,J=6.8Hz,2H),2.04(t,J=6.6Hz,2H),1.61-1.58(m,4H)ppm. 13C NMR(125MHz,DMSO-d 6):δ168.8,142.5,140.3,139.8,138.4,137.9,128.9,128.8,127.3,126.4,125.7,125.5,125.0,104.1,51.7,31.8,27.5,24.5,24.2ppm.MS(ESI)m/z349.18(100%)(M+H) +
Embodiment 9:(E) preparation of-3-(1-(4-(dimethylamino) benzyl)-1H-imidazoles-2-base)-N-hydroxyacrylamide
With reference to embodiment 6 (E)-3-(1-([1,1'-xenyl]-3-ylmethyl)-1H-imidazoles-2-base) synthesis of-N hydroxyacrylamide, with paradimethy laminobenzaldehyde, 1H-imidazoles-2-formaldehyde is starting raw material, obtaining 222mg safran solid through four-step reaction, is (E)-3-(1-(4-(dimethylamino) benzyl)-1H-imidazoles-2-base)-N-hydroxyacrylamide through Structural Identification. 1H NMR(400MHz,DMSO-d 6):δ10.80(s,1H),9.03(s,1H),7.40-7.34(m,2H),7.01-6.87(m,3H),6.68-6.63(m,3H),5.20(s,2H),2.85(s,6H)ppm. 13C NMR(125MHz,DMSO-d 6):δ162.3,149.8,142.6,128.9,127.7,124.3,123.9,122.6,120.6,112.2,48.1ppm.MS(ESI)m/z286.14(100%)(M+H) +
Embodiment 10:(E) preparation of-3-(1-(4-(dimethylamino) benzyl)-1H-imidazoles-5-base)-N-hydroxyacrylamide
The synthesis of reference example 9 (E)-3-(1-(4-(dimethylamino) benzyl)-1H-imidazoles-2-base)-N-hydroxyacrylamide, with paradimethy laminobenzaldehyde, 1H-imidazoles-4-formaldehyde is starting raw material, obtaining 150mg white solid through four-step reaction, is (E)-3-(1-(4-(dimethylamino) benzyl)-1H-imidazoles-5-base)-N-hydroxyacrylamide through Structural Identification. 1H NMR(400MHz,DMSO-d 6):δ10.58(s,1H),8.85(s,1H),7.74(s,1H),7.39(s,1H),7.24(d,J=15.2Hz,1H),7.15(d,J=8.4Hz,2H),6.68(d,J=8.8Hz,2H),6.36(d,J=15.2Hz,1H),5.01(s,2H),2.86(s,6H)ppm. 13CNMR(125MHz,DMSO-d 6):δ163.6,150.1,138.5,137.8,131.1,128.8,124.4,121.4,115.3,112.3,49.4,40.0ppm.MS(ESI)m/z286.14(100%)(M+H) +
Embodiment 11:(E) preparation of-3-(1-(4-(dimethylamino) benzyl)-1H-imidazol-4 yl)-N-hydroxyacrylamide:
The synthesis of reference example 9 (E)-3-(1-(4-(dimethylamino) benzyl)-1H-imidazoles-2-base)-N-hydroxyacrylamide, with paradimethy laminobenzaldehyde, 1H-imidazoles-4-formaldehyde is starting raw material, obtaining 184mg white solid through four-step reaction, is (E)-3-(1-(4-(dimethylamino) benzyl)-1H-imidazol-4 yl)-N-hydroxyacrylamide through Structural Identification. 1H NMR(400MHz,DMSO-d 6):δ10.63(s,1H),8.95(s,1H),7.87(s,1H),7.35(s,1H),7.30(d,J=16Hz,1H),6.99(d,J=8.4Hz,2H),6.67(d,J=8.8Hz,2H),6.20(d,J=16Hz,1H),5.18(s,2H),2.85(s,6H)ppm. 13CNMR(125MHz,DMSO-d 6):δ162.8,149.9,140.2,129.7,128.3,127.8,124.5,124.1,117.0,112.3,47.4ppm.MS(ESI)m/z286.14(100%)(M+H) +
The preparation of embodiment 12:N-hydroxyl-5-(5H-imidazoles [5,1-a] isoindole-3-base) valeramide:
N-hydroxyl-5-(5H-imidazoles [5,1-a] isoindole-3-base) preparation of valeramide is roughly the same with the preparation of 5-(1-benzyl-1H-pyrazole-3-yl)-N-hydroxyvaleramide (compound 5), a just how step in the middle of hydrogen reducing and Ester hydrolysis: intramolecular Heck reaction Cheng Huan.
The preparation (intramolecular Heck reaction) of 5-(5H-imidazoles [5,1-a] isoindole-3-base) Valeric acid ethylester
63mg palladium is added successively in the two-neck bottle of a 25ml, 147mg triphenyl phosphorus, 1.93g salt of wormwood and 14mlDMF, vacuumize, fill noble gas, in triplicate, then add the DMF solution (1.02g of 5-(1-(2-bromobenzyl)-1H-imidazoles-2-base) Valeric acid ethylester, 14ml), 120 DEG C of reaction 6h.Diatomite filtration, filtrate reduced in volume, pillar layer separation obtains 716mg pale yellow crystals (productive rate 90%). 1H NMR(400MHz,CDCl 3):δ7.50(d,J=7.6Hz,1H),7.35(q,J=7.6Hz,2H),7.21(t,J=7.6Hz,1H),7.08(s,1H),4.85(s,2H),4.10(q,J=7.2Hz,2H),2.75(t,J=7.6Hz,2H),2.35(t,J=7.2Hz,2H),1.89-1.69(m,4H),1.23(t,J=7.2Hz,3H)ppm.MS(ESI)m/z284.15(100%)(M+H) +
With adjacent bromobenzyl bromine, 1H-imidazoles-2-formaldehyde is starting raw material, obtains 273mg white solid through four-step reaction, is N-hydroxyl-5-(5H-imidazoles [5,1-a] isoindole-3-base) valeramide through Structural Identification. 1H NMR(400MHz,DMSO-d 6):δ10.08(s,1H),8.71(s,1H),7.85(d,J=5.6Hz,2H),7.68(d,J=7.2Hz,1H),7.56-7.48(m,2H),5.43(s,2H),3.05(t,J=7.6Hz,2H),2.03(t,J=7.2Hz,2H),1.83-1.75(m,2H),1.59-1.52(m,2H)ppm. 13C NMR(125MHz,DMSO-d 6):δ168.8,143.9,140.8,137.5,128.9,128.8,127.5,124.3,121.4,108.9,50.5,31.6,24.8,24.4ppm.MS(ESI)m/z271.13(100%)(M+H) +
The preparation of embodiment 13:N-hydroxyl-5-(5H-pyrroles [2,1-a] isoindole-3-base) valeramide
With reference to embodiment 12N-hydroxyl-5-(5H-imidazoles [5,1-a] isoindole-3-base) synthesis of valeramide, with adjacent bromobenzyl bromine, 1H-pyrrole-2-aldehyde is starting raw material, 273mg white solid is obtained through four-step reaction, be N-hydroxyl-5-(5H-pyrroles [2,1-a] isoindole-3-base) valeramide through Structural Identification. 1H NMR(400MHz,DMSO-d 6):δ10.36(s,1H),8.67(s,1H),7.44(d,J=7.6Hz,2H),7.29(t,J=7.4Hz,1H),7.13(t,J=7.6Hz,1H),6.16(d,J=3.2Hz,1H),5.94(d,J=3.2Hz,1H),4.88(s,2H),2.60(t,J=6.6Hz,2H),2.00(t,J=6.4Hz,2H),1.59(s,4H)ppm. 13CNMR(125MHz,DMSO-d 6):δ169.0,140.2,135.5,133.6,130.2,127.7,124.1,123.5,117.7,109.0,97.9,48.3,32.0,27.0,25.9,24.9ppm.MS(ESI)m/z270.14(100%)(M+H) +
The preparation of embodiment 14:N-hydroxyl-5-(1-(3-phenoxy benzyl)-1H-pyrazole-3-yl) valeramide
The synthesis of reference example 1 compound 5, with m-phenoxy phenylcarbinol, 1H-pyrazoles-3-formaldehyde is starting raw material, obtains 151mg white solid through four-step reaction, is N-hydroxyl-5-(1-(3-phenoxy benzyl)-1H-pyrazole-3-yl) valeramide through Structural Identification. 1H NMR(400MHz,CD 3OD):δ7.54(d,J=2.0Hz,1H),7.34-7.27(m,3H),7.10(t,J=7.4Hz,1H),6.95-6.85(m,4H),6.73(s,1H),6.11(d,J=2.4Hz,1H),5.23(s,2H),2.59(t,J=6.8Hz,2H),2.11-2.07(m,2H),1.64-1.61(m,4H)ppm. 13C NMR(125MHz,DMSO-d 6):δ170.0,156.7,156.2,151.9,140.0,130.5,129.8,123.3,122.0,118.5,117.1,103.7,53.9,28.5,27.2,20.5,13.8ppm.MS(ESI)m/z365.17(100%)(M+H) +
The preparation of embodiment 15:5-(1-(4-(tertiary butyl) benzyl)-1H-pyrazole-3-yl)-N-hydroxyvaleramide
The synthesis of reference example 1 compound 5, with to tertiary butyl benzyl bromine, 1H-pyrazoles-3-formaldehyde is starting raw material, obtaining 201mg white solid through four-step reaction, is 5-(1-(4-(tertiary butyl) benzyl)-1H-pyrazole-3-yl)-N-hydroxyvaleramide through Structural Identification. 1H NMR(400MHz,CD 3OD):δ7.50(d,J=2.4Hz,1H),7.35(d,J=8.4Hz,2H),7.10(d,J=8.4Hz,2H),6.11(d,J=2.4Hz,1H),5.20(s,2H),2.60(t,J=6.8Hz,2H),2.11-2.08(m,2H),1.66-1.62(m,4H),1.28(s,9H)ppm. 13C NMR(125MHz,CD 3OD):δ172.8,154.3,151.9,135.5,132.2,128.2,126.6,105.5,55.8,35.3,33.5,31.7,30.2,28.5,26.3ppm.MS(ESI)m/z329.21(100%)(M+H) +
The preparation of embodiment 16:N-hydroxyl-5-(1-(4-methyl-benzyl)-1H-pyrazole-3-yl) valeramide
The synthesis of reference example 1 compound 5, with to methyl benzyl bromine, 1H-pyrazoles-3-formaldehyde is starting raw material, obtains 174mg white solid through four-step reaction, is N-hydroxyl-5-(1-(4-methyl-benzyl)-1H-pyrazole-3-yl) valeramide through Structural Identification.
1H NMR(400MHz,CD 3OD):δ7.49(d,J=2.4Hz,1H),7.13(d,J=8.0Hz,2H),7.06(d,J=8.0Hz,2H),6.11(d,J=2.0Hz,1H),5.19(s,2H),2.60(t,J=7.0Hz,2H),2.29(s,3H),2.09(t,J=6.8Hz,2H),1.65-1.62(m,4H)ppm. 13C NMR(125MHz,DMSO-d 6):δ168.9,151.6,136.4,134.6,130.1,128.7,127.2,103.6,54.1,31.9,28.5,27.2,24.7,20.4ppm.MS(ESI)m/z287.16(100%)(M+H) +
The preparation of embodiment 17:N-hydroxyl-5-(1-(3-(anilino) benzyl)-1H-pyrazole-3-yl) valeramide
The preparation of N-hydroxyl-5-(1-(3-(anilino) benzyl)-1H-pyrazole-3-yl) valeramide is roughly the same with the preparation of 5-(1-benzyl-1H-pyrazole-3-yl)-N-hydroxyvaleramide (compound 5), just in hydrogen reducing and the much middle step Buchwald-Hartwig reaction of Ester hydrolysis step.
The preparation (Buchwald-Hartwig reaction) of 5-(1-(3-(anilino) benzyl)-1H-pyrazole-3-yl) Valeric acid ethylester
15mg palladium is added successively in the two-neck bottle of a 25ml, 65mg BINAP, 592mg cesium carbonate and 6ml toluene, vacuumize, fill noble gas, in triplicate, then add the toluene solution (474mg of 5-(1-(3-bromobenzyl)-1H-pyrazole-3-yl) Valeric acid ethylester successively, 6ml), 0.14ml aniline.120 DEG C of reaction 6h, diatomite filtration, filtrate reduced in volume, pillar layer separation obtains 363mg yellow oily liquid (productive rate 74%). 1H NMR(400MHz,CDCl 3):δ7.28-7.23(m,3H),7.20(t,7.8Hz,1H),7.04(d,J=7.6Hz,2H),7.00(dd,J=1.6,8.0Hz,1H),6.93(t,J=7.4Hz,1H),6.78(s,1H),6.72(d,J=7.6Hz,1H),6.06(d,J=2.4Hz,1H),5.86(s,1H),5.20(s,2H),4.11(q,J=7.2Hz,2H),2.68-2.65(m,2H),2.34-2.30(m,2H),1.71-1.68(m,4H),1.24(t,J=7.2Hz,3H)ppm.MS(ESI)m/z377.21(100%)(M+H) +
With a bromobenzyl bromine, 1H-pyrazoles-3-formaldehyde is starting raw material, obtaining 287mg white foam solid through four-step reaction, is N-hydroxyl-5-(1-(3-(anilino) benzyl)-1H-pyrazole-3-yl) valeramide through Structural Identification. 1H NMR(400MHz,DMSO-d 6):δ10.35(s,1H),8.67(s,1H),8.18(s,1H),7.65(d,J=2.0Hz,1H),7.22-7.15(m,3H),7.03(d,J=8.0Hz,2H),6.95(dd,J=1.4,8.2Hz,1H),6.87(s,1H),6.81(t,J=7.4Hz,1H),6.65(d,J=7.6Hz,1H),6.04(d,J=2.4Hz,1H),5.17(s,2H),2.50(t,J=1.4Hz,2H),1.96(t,J=6.4Hz,2H),1.53(d,J=3.2Hz,4H)ppm. 13C NMR(125MHz,DMSO-d 6):δ169.1,151.9,143.5,143.1,140.0,130.7,129.2,129.1,119.8,118.5,116.8,115.6,115.3,103.8,54.5,32.0,28.7,27.4,24.9ppm.MS(ESI)m/z364.19(100%)(M+H) +
The preparation of embodiment 18:N-hydroxyl-5-(1-(naphthyl-2-ylmethyl)-1H-pyrazole-3-yl) valeramide
The synthesis of reference example 1 compound 5, with 2-(brooethyl) naphthalene, 1H-pyrazoles-3-formaldehyde is starting raw material, obtaining 251mg white solid through four-step reaction, is N-hydroxyl-5-(1-(naphthyl-2-ylmethyl)-1H-pyrazole-3-yl) valeramide through Structural Identification.
1H NMR(400MHz,CD 3OD):δ7.82-7.78(m,3H),7.62(s,1H),7.60(d,J=2.4Hz,1H),7.48-7.43(m,2H),7.29(dd,J=1.6,8.4Hz,1H),6.16(d,J=2.4Hz,1H),5.42(s,2H),2.65-2.61(m,2H),2.10(t,J=7.0Hz,2H),1.65(q,J=3.4Hz,4H)ppm. 13C NMR(125MHz,DMSO-d 6):δ169.0,152.0,135.5,132.8,132.3,130.7,128.1,127.7,127.5,126.3,126.1,126.0,125.6,104.0,54.6,32.0,28.7,27.4,24.9ppm.MS(ESI)m/z323.16(100%)(M+H) +
The preparation of embodiment 19:N-hydroxyl-5-(1-(4-(trifluoromethyl) benzyl)-1H-pyrazole-3-yl) valeramide
The synthesis of reference example 1 compound 5, with to trifluoromethyl benzyl bromine, 1H-pyrazoles-3-formaldehyde is starting raw material, obtaining 250mg white solid through four-step reaction, is N-hydroxyl-5-(1-(4-(trifluoromethyl) benzyl)-1H-pyrazole-3-yl) valeramide through Structural Identification. 1H NMR(400MHz,CD 3OD):δ7.63-7.61(m,3H),7.31(d,J=8.0Hz,2H),6.17(d,J=2.0Hz,1H),5.36(s,2H),2.62(t,J=7.0Hz,2H),2.10(t,J=6.8Hz,2H),1.67-1.63(m,4H)ppm. 13C NMR(125MHz,DMSO-d 6):δ169.0,152.4,142.8,131.1,127.9,125.4,125.3,104.1,53.8,32.0,28.6,27.4,24.8ppm.MS(ESI)m/z341.14(100%)(M+H) +
The preparation of embodiment 20:5-(1-(3-bromobenzyl)-1H-pyrazole-3-yl)-N-hydroxyvaleramide
The synthesis of reference example 1 compound 5, with a bromobenzyl bromine, 1H-pyrazoles-3-formaldehyde is starting raw material, obtains 220mg white solid through four-step reaction, is 5-(1-(3-bromobenzyl)-1H-pyrazole-3-yl)-N-hydroxyvaleramide through Structural Identification. 1H NMR(400MHz,CD 3OD):δ7.59(d,J=2.0Hz,1H),7.42(d,J=8.0Hz,1H),7.30(s,1H),7.24(t,J=7.8Hz,1H),7.13(d,J=7.6Hz,1H),6.15(d,J=2.4Hz,1H),5.25(s,2H),2.62(t,J=7.2Hz,2H),2.10(t,J=6.8Hz,2H),1.67-1.63(m,4H)ppm. 13C NMR(125MHz,DMSO-d 6):δ169.0,152.3,140.7,130.9,130.6,130.2,130.0,126.4,121.6,104.0,53.6,32.0,28.7,27.4,24.8ppm.MS(ESI)m/z351.06(100%)(M+H) +
The preparation of embodiment 21:5-(1-(the chloro-4-luorobenzyl of 3-)-1H-pyrazoles-3 base)-N-hydroxyvaleramide
The synthesis of reference example 1 compound 5, with the chloro-4-fluorobenzyl bromide of 3-, 1H-pyrazoles-3-formaldehyde is starting raw material, obtains 293mg white solid through four-step reaction, is 5-(1-(the chloro-4-luorobenzyl of 3-)-1H-pyrazoles-3 base)-N-hydroxyvaleramide through Structural Identification. 1H NMR(400MHz,CD 3OD):δ7.59(d,J=2.0Hz,1H),7.28(dd,J=2.0,6.8Hz,1H),7.19(t,J=8.8Hz,1H),7.15-7.11(m,1H),6.15(d,J=2.4Hz,1H),5.23(s,2H),2.61(t,J=7.0Hz,2H),2.10(t,J=7.0Hz,2H),1.65-1.62(m,4H)ppm. 13C NMR(125MHz,CD 3OD):δ163.3,150.3,148.4,145.5,126.9,126.8,123.0,121.2,119.2,112.4,112.3,108.4,108.2,96.4,45.2,24.0,20.6,19.0,16.8ppm.MS(ESI)m/z325.10(100%)(M+H) +
The preparation of embodiment 22:5-(1-([1,1'-xenyl]-4-ylmethyl)-1H-pyrazole-3-yl)-N-hydroxyvaleramide
The synthesis of reference example 1 compound 5, with to phenyl benzylalcohol, 1H-pyrazoles-3-formaldehyde is starting raw material, 200mg white solid is obtained through four-step reaction, be 5-(1-([1,1'-xenyl]-4-ylmethyl)-1H-pyrazole-3-yl)-N-hydroxyvaleramide through Structural Identification. 1H NMR(400MHz,CD 3OD):δ7.59-7.56(m,5H),7.41(t,J=7.6Hz,2H),7.31(t,J=7.2Hz,1H),7.25(d,J=8.0Hz,2H),6.14(d,J=2.0Hz,1H),5.30(s,2H),2.63(t,J=7.0Hz,2H),2.10(t,J=6.8Hz,2H),1.65(t,J=3.6Hz,4H)ppm. 13C NMR(125MHz,CD 3OD):δ168.8,150.6,138.1,137.9,133.7,128.4,125.9,124.9,124.4,124.3,124.0,101.6,51.8,29.5,26.2.24.5,22.3ppm.MS(ESI)m/z349.18(100%)(M+H) +
The preparation of embodiment 23:N-hydroxyl-5-(1-phenyl-1H-pyrazole-3-yl) valeramide
The preparation of N-hydroxyl-5-(1-phenyl-1H-pyrazole-3-yl) valeramide is roughly the same with the preparation of 5-(1-benzyl-1H-pyrazole-3-yl)-N-hydroxyvaleramide (compound 5), and just the first step have employed Ullmann reaction and realizes carbonnitrogen bond coupling.
The preparation (Ullmann reaction) of 1-phenyl-1H-pyrazoles-3-formaldehyde
79mg cuprous iodide is added successively, 134mg8-hydroxyquinoline-N-oxide compound, 2.71g cesium carbonate and 400mg1H-pyrazoles-3-formaldehyde in tube sealing; vacuumize, fill noble gas, in triplicate; then under noble gas protection, 0.70ml iodobenzene and 5mlDMSO is added successively, 90 DEG C of reaction 48h.Reaction solution thin up, extraction into ethyl acetate, merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, and filter, concentrating under reduced pressure, pillar layer separation obtains 329mg light yellow solid (productive rate 46%). 1H NMR(400MHz,CDCl 3):δ10.10(s,1H),7.98(d,J=2.0Hz,1H),7.77-7.75(m,2H),7.54-7.50(m,2H),7.40(t,J=7.4Hz,1H),7.00(d,J=2.8Hz,1H)ppm.MS(ESI)m/z172.06(100%)(M+H) +.
With iodobenzene, 1H-pyrazoles-3-formaldehyde is starting raw material, obtains 254mg yellow, waxy solid through four-step reaction, is N-hydroxyl-5-(1-phenyl-1H-pyrazole-3-yl) valeramide through Structural Identification. 1H NMR(400MHz,CD 3OD):δ8.06(d,J=2.4Hz,1H),7.68-7.66(m,2H),7.45(t,J=8.0Hz,2H),7.30-7.26(m,1H),6.34(d,J=2.4Hz,1H),2.71(t,J=7.0Hz,2H),2.14(t,J=6.8Hz,2H),1.73-1.69(m,4H)ppm. 13C NMR(125MHz,CD 3OD):δ168.8,152.2,137.5,126.5,125.7,123.4,116.2,103.6,29.5,26.1,24.6,22.4ppm.MS(ESI)m/z259.13(100%)(M+H) +
The preparation of embodiment 24:N-hydroxyl-5-(1-(4-(anilino) benzyl)-1H-pyrazole-3-yl) valeramide
With reference to the synthesis of embodiment 17N-hydroxyl-5-(1-(3-(anilino) benzyl)-1H-pyrazole-3-yl) valeramide, with to bromobenzyl bromine, 1H-pyrazoles-3-formaldehyde is starting raw material, obtaining 270mg white foam solid through four-step reaction, is N-hydroxyl-5-(1-(4-(anilino) benzyl)-1H-pyrazole-3-yl) valeramide through Structural Identification. 1H NMR(400MHz,CD 3OD):δ7.47(d,J=2.0Hz,1H),7.21-7.17(m,2H),7.08-7.00(m,6H),6.83(t,J=7.4Hz,1H),6.09(d,J=2.0Hz,1H),5.14(s,2H),2.61(t,J=6.8Hz,2H),2.10(t,J=6.8Hz,2H),1.66-1.62(m,4H)ppm. 13C NMR(125MHz,CD 3OD):δ172.8,154.2,145.2,144.8,131.9,130.1,129.7,129.4,121.5,118.7,118.0,105.4,55.9,33.5,30.2,28.5,26.3ppm.MS(ESI)m/z364.19(100%)(M+H) +
The preparation of embodiment 25:5-(1-(4-(1H-indoles-1-base) benzyl)-1H-pyrazole-3-yl)-N-hydroxyvaleramide
The preparation of 5-(1-(4-(1H-indoles-1-base) benzyl)-1H-pyrazole-3-yl)-N-hydroxyvaleramide is roughly the same with the preparation of 5-(1-benzyl-1H-pyrazole-3-yl)-N-hydroxyvaleramide (compound 5), just in hydrogen reducing and the much middle step Ullmann reaction of Ester hydrolysis step.
The preparation (Ullmann reaction) of 5-(1-(4-(1H-indoles-1-base) benzyl)-1H-pyrazole-3-yl) Valeric acid ethylester
23mg cuprous iodide is added successively in tube sealing; 167mg indoles and 528mg potassiumphosphate; vacuumize; fill noble gas; in triplicate, under noble gas protection, then add toluene solution (433mg, 1.5ml) and the 26ul N1 of 5-(1-(4-bromobenzyl)-1H-pyrazole-3-yl) Valeric acid ethylester successively; N2-dimethyl-1,2-diaminoethane.110 DEG C of reaction 24h, diatomite filtration, filtrate reduced in volume, pillar layer separation obtains 467mg yellow oily liquid (98%). 1H NMR(400MHz,CDCl 3):δ7.68(d,J=7.2Hz,1H),7.54(d,J=8.4Hz,1H),7.47(d,J=8.4Hz,2H),7.35(d,J=2.0Hz,1H),7.33-7.30(m,3H),7.24-7.19(m,1H),7.18-7.14(m,1H),6.67(d,J=3.6Hz,1H),6.12(d,J=2.4Hz,1H),5.33(s,2H),4.12(q,J=7.2Hz,2H),2.69(t,J=7.0Hz,2H),2.34(t,J=7.4Hz,2H),1.73-1.70(m,4H),1.24(t,J=7.2Hz,3H)ppm.MS(ESI)m/z401.21(100%)(M+H) +
With to bromobenzyl bromine, 1H-pyrazoles-3-formaldehyde is starting raw material, obtaining 273mg thick pale yellow liquid through four-step reaction, is 5-(1-(4-(1H-indoles-1-base) benzyl)-1H-pyrazole-3-yl)-N-hydroxyvaleramide through Structural Identification. 1H NMR(400MHz,CD 3OD):δ7.63(d,J=2.0Hz,1H),7.60(d,J=8.0Hz,1H),7.51-7.49(m,3H),7.40(d,J=3.2Hz,1H),7.36(d,J=8.4Hz,2H),7.18-7.14(m,1H),7.11-7.07(m,1H),6.63(d,J=3.6Hz,1H),6.16(d,J=2.0Hz,1H),5.35(s,2H),2.64(t,J=6.8Hz,2H),2.11(t,J=6.8Hz,2H),1.66(t,J=3.6Hz,4H)ppm. 13C NMR(125MHz,CD 3OD):δ172.8,154.7,140.8,137.1,136.8,132.5,131.0,129.8,128.9,125.3,123.4,122.0,121.3,111.2,105.7,104.7,55.5,33.5,30.2,28.5,26.3ppm.MS(ESI)m/z388.19(100%)(M+H) +
Embodiment 26:5-(the preparation of 1-(4-bromobenzyl-1H-pyrazole-3-yl)-N-hydroxyvaleramide
The synthesis of reference example 1 compound 5, with to bromobenzyl bromine, 1H-pyrazoles-3-formaldehyde is starting raw material, obtains 165mg white solid through four-step reaction, is 5-(1-(4-bromobenzyl-1H-pyrazole-3-yl)-N-hydroxyvaleramide through Structural Identification. 1H NMR(400MHz,CD 3OD):δ7.56(d,J=2.0Hz,1H),7.47(dd,J=1.8,6.6Hz,2H),7.08(d,J=8.8Hz,2H),6.14(d,J=2.0Hz,1H),5.23(s,2H),2.61(t,J=7.0Hz,2H),2.11-2.08(m,2H),1.65-1.62(m,4H)ppm. 13C NMR(125MHz,CD 3OD):δ172.8,154.8,138.0,132.8,132.5,130.2,122.6,105.8,55.3,33.5,30.2,28.5,26.3ppm.MS(ESI)m/z351.06(100%)(M+H) +
The preparation of embodiment 27:N-hydroxyl-5-(1-(4-nitrobenzyl)-1H-pyrazole-3-yl) valeramide
The synthesis of reference example 1 compound 5, with to nitrobenzyl bromine, 1H-pyrazoles-3-formaldehyde is starting raw material, obtains 95mg light yellow solid through four-step reaction, is N-hydroxyl-5-(1-(4-nitrobenzyl)-1H-pyrazole-3-yl) valeramide through Structural Identification.
1H NMR(400MHz,CD 3OD):δ8.19(d,J=8.8Hz,2H),7.64(d,J=2.0Hz,1H),7.34(d,J=8.8Hz,2H),6.18(d,J=2.4Hz,1H),5.41(s,2H),2.62(t,J=6.8Hz,2H),2.10(t,J=6.8Hz,2H),1.64(t,J=3.4Hz,4H)ppm. 13C NMR(125MHz,CD 3OD):δ172.8,155.3,148.9,146.3,133.0,129.1,124.8,106.0,55.2,33.5,30.1,28.5,26.3ppm.MS(ESI)m/z318.13(100%)(M+H) +
The preparation of embodiment 28:1-benzyl-N-(3-(azanol)-3-oxa-propyl group)-1H-pyrazoles-3-acid amides
1-benzyl-N-(3-(azanol)-3-oxa-propyl group)-1H-pyrazoles-3-acid amides can be prepared according to the methods below, and second and third step is corresponding respectively with first and third step of 5-(1-benzyl-1H-pyrazole-3-yl)-N-hydroxyvaleramide (compound 5).
The preparation of the first step: 3-(1H-pyrazoles-3-amide group) methyl propionate (compound 7)
1.00g1H-pyrazoles-3-carboxylic acid (compound 6) and 1.87g3-amino-propanoate hydrochloride is added in 100ml eggplant-shape bottle, dissolve with 36ml DMF, at 0 DEG C, add 5.16ml DIPEA, 0 DEG C of reaction 15min, then add 5.09g HATU, room temperature reaction spends the night.Decompression spins off solvent, thin up, extraction into ethyl acetate, merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, and filter, concentrating under reduced pressure, pillar layer separation obtains 1.12g pale yellowish oil liquid (compound 7, productive rate 64%). 1H NMR(400MHz,CDCl 3):δ7.83(t,J=6.0Hz,1H),7.57(d,J=2.4Hz,1H),6.80(d,J=2.4Hz,1H),3.68-3.64(m,5H),2.67(t,J=6.2Hz,2H).MS(ESI)m/z211.10(100%)(M+H) +
4th step: the preparation of 1-benzyl-N-(3-(azanol)-3-oxa-propyl group)-1H-pyrazoles-3-acid amides (compound 10)
In the two neck bottles of a 50ml, add 360mg3-(1-benzyl-1H-pyrazoles-3-amide group) propionic acid, dissolve with 13ml DMF, add 636mgTBTU and 0.37ml triethylamine successively, room temperature reaction 2h.Above-mentioned solution is added drop-wise in the hydroxylamine solution of fresh preparation and (in a 50ml two neck bottle, adds 148mg potassium hydroxide, use 1.5ml dissolve with methanol, then 184mg oxammonium hydrochloride is added, room temperature reaction 15min obtains), room temperature reaction spends the night, concentrating under reduced pressure, pillar layer separation obtains 323mg white solid (10, productive rate 85%). 1H NMR(400MHz,DMSO-d 6):δ10.43(s,1H),8.74(s,1H),8.02(s,1H),7.91(d,J=2.4Hz,1H),7.37-7.22(m,5H),6.65(d,J=2.0Hz,1H),5.39(s,2H),3.40(t,J=6.4Hz,2H),2.22(t,J=7.0Hz,2H)ppm. 13C NMR(125MHz,DMSO-d 6):δ168.0,161.7,147.1,137.5,132.7,129.1,128.3,127.9,106.6,55.6,35.7,32.8ppm.MS(ESI)m/z288.12(100%)(M+H) +
The preparation of embodiment 29:5-(1-(4-(benzyloxy) benzyl)-1H-pyrazole-3-yl)-N-hydroxyvaleramide
Example is synthesized with 5-(1-benzyl-1H-pyrazole-3-yl)-N-hydroxyvaleramide (compound 5), with to benzyloxybenzyl alcohol, 1H-pyrazoles-3-formaldehyde is starting raw material, obtaining 595mg white solid through four-step reaction, is 5-(1-(4-(benzyloxy) benzyl)-1H-pyrazole-3-yl)-N-hydroxyvaleramide through Structural Identification. 1H NMR(400MHz,CD 3OD):δ7.49(d,J=2.0Hz,1H),7.41-7.26(m,5H),7.12(d,J=8.8Hz,2H),6.94(d,J=8.4Hz,2H),6.10(d,J=2.0Hz,1H),5.17(s,2H),5.05(s,2H),2.60(t,J=6.8Hz,2H),2.09(t,J=6.8Hz,2H),1.65-1.62(m,4H)ppm. 13C NMR(125MHz,CD 3OD):δ172.8,159.9,154.4,138.6,132.1,130.8,129.9,129.5,128.9,128.5,116.1,105.5,71.0,55.6,33.5,30.2,28.5,26.3ppm.MS(ESI)m/z379.19(100%)(M+H) +
The preparation of embodiment 30:N-hydroxyl-5-(1-(4-phenoxy benzyl)-1H-pyrazole-3-yl) valeramide
The synthesis of reference example 1 compound 5, with to phenoxy benzoic acid, 1H-pyrazoles-3-formaldehyde is starting raw material, obtains 280mg white solid through four-step reaction, is N-hydroxyl-5-(1-(4-phenoxy benzyl)-1H-pyrazole-3-yl) valeramide through Structural Identification. 1H NMR(400MHz,CD 3OD):δ7.54(d,J=2.0Hz,1H),7.35-7.31(m,2H),7.18(d,J=8.8Hz,2H),7.09(t,J=7.4Hz,1H),6.97-6.92(m,4H),6.12(d,J=2.0Hz,1H),5.23(s,2H),2.61(t,J=7.0Hz,2H),2.10(t,J=6.8Hz,2H),1.66-1.62(m,4H)ppm. 13C NMR(125MHz,CD 3OD):δ163.3,149.0,145.1,123.9,122.7,121.4,120.6,115.1,110.5,110.3,96.1,46.0,24.0,20.7,19.0,16.8ppm.MS(ESI)m/z365.17(100%)(M+H) +
The preparation of embodiment 31:N-hydroxyl-5-(1-(3-methoxy-benzyl)-1H-pyrazole-3-yl) valeramide
The synthesis of reference example 1 compound 5, with meta-methoxy benzyl bromine, 1H-pyrazoles-3-formaldehyde is starting raw material, obtains 258mg white solid through four-step reaction, is N-hydroxyl-5-(1-(3-methoxy-benzyl)-1H-pyrazole-3-yl) valeramide through Structural Identification. 1H NMR(400MHz,CD 3OD):δ7.53(d,J=2.4Hz,1H),7.22(t,J=7.8Hz,1H),6.82(dd,J=2.2,8.2Hz,1H),6.74-6.70(m,2H),6.13(d,J=2.4Hz,1H),5.22(s,2H),3.74(s,3H),2.62(t,J=7.0Hz,2H),2.11-2.08(m,2H),1.66-1.62(m,4H)ppm. 13C NMR(125MHz,CD 3OD):δ168.8,157.5,150.5,136.2,128.4,126.7,116.5,110.3,110.0,101.6,52.0,51.7,29.5,26.2,24.5,22.3ppm.MS(ESI)m/z303.16(100%)(M+H) +
The preparation of embodiment 32:5-(1-(benzo [d] [1,3] methylenedioxy-5-methyl)-1H-pyrazole-3-yl)-N-hydroxyvaleramide
The synthesis of reference example 1 compound 5, with benzo [d] [1,3] methylenedioxy benzylalcohol, 1H-pyrazoles-3-formaldehyde is starting raw material, 206mg white solid is obtained through four-step reaction, be 5-(1-(benzo [d] [1,3] methylenedioxy-5-methyl)-1H-pyrazole-3-yl)-N-hydroxyvaleramide through Structural Identification. 1H NMR(400MHz,CD 3OD):δ7.50(d,J=2.4Hz,1H),6.77-6.67(m,3H),6.11(d,J=2.0Hz,1H),5.91(s,2H),5.14(s,2H),2.61(t,J=7.0Hz,2H),2.10(t,J=6.8Hz,2H),1.66-1.62(m,4H)ppm. 13C NMR(125MHz,CD 3OD):δ168.8,150.5,145.4,144.8,128.3,128.1,118.1,105.2,104.9,101.6,98.5,51.9,29.5,26.2,24.5,22.3ppm.MS(ESI)m/z317.14(100%)(M+H) +
The preparation of embodiment 33:5-(1-(2,4-difluorobenzyl)-1H-pyrazole-3-yl)-N-hydroxyvaleramide
The synthesis of reference example 1 compound 5, with 2,4-bis-fluorobenzyl bromide, 1H-pyrazoles-3-formaldehyde is starting raw material, obtaining 231mg white solid through four-step reaction, is 5-(1-(2,4-difluorobenzyl)-1H-pyrazole-3-yl)-N-hydroxyvaleramide through Structural Identification.
1H NMR(400MHz,CD 3OD):δ7.55(d,J=2.4Hz,1H),7.16-7.10(m,1H),7.00-6.90(m,2H),6.13(d,J=2.4Hz,1H),5.28(s,2H),2.60(t,J=7.0Hz,2H),2.09(t,J=7.0Hz,2H),1.65-1.61(m,4H)ppm. 13C NMR(125MHz,CD 3OD):δ168.8,161.3,161.2,159.3,159.2,159.0,157.0,150.9,128.5,128.3,128.2,117.9,117.8,108.6,108.5,108.4,101.7,100.9,100.7,100.5,29.5,26.2,24.5,22.3ppm.MS(ESI)m/z309.13(100%)(M+H) +
The preparation of embodiment 34:5-(1-(4-luorobenzyl)-1H-pyrazole-3-yl)-N-hydroxyvaleramide
The synthesis of reference example 1 compound 5, with to fluorobenzyl bromide, 1H-pyrazoles-3-formaldehyde is starting raw material, obtains 214mg white solid through four-step reaction, is 5-(1-(4-luorobenzyl)-1H-pyrazole-3-yl)-N-hydroxyvaleramide through Structural Identification. 1H NMR(400MHz,CD 3OD):δ7.54(d,J=2.0Hz,1H),7.22-7.18(m,2H),7.06-7.02(m,2H),6.12(d,J=2.4Hz,1H),5.23(s,2H),2.61(t,J=7.0Hz,2H),2.11-2.08(m,2H),1.65-1.62(m,4H)ppm. 13CNMR(125MHz,CD 3OD):δ168.8,160.8,158.8,150.7,130.7,128.3,126.4,112.5,112.3,101.7,51.3,29.5,26.2,24.5,22.3ppm.MS(ESI)m/z291.14(100%)(M+H) +
The preparation of embodiment 35:5-(1-benzyl-4-methyl isophthalic acid H-pyrazole-3-yl)-N-hydroxyvaleramide
The synthesis of reference example 1 compound 5, with benzyl bromine, 4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid, ethyl ester is starting raw material, obtains 72mg white solid through four-step reaction, is 5-(1-benzyl-4-methyl isophthalic acid H-pyrazole-3-yl)-N-hydroxyvaleramide through Structural Identification.
1H NMR(400MHz,CD 3OD):δ7.32-7.23(m,4H),7.14(d,J=7.2Hz,2H),5.18(s,2H),2.57(t,J=7.0Hz,2H),2.10(t,J=6.8Hz,2H),2.00(s,3H),1.63-1.59(m,4H)ppm. 13C NMR(125MHz,CD 3OD):δ168.8,148.4,134.9,127.2,125.7,124.7,124.3,111.3,51.9,29.5,25.8,22.7,22.4,4.4ppm.MS(ESI)m/z287.16(100%)(M+H) +
The preparation of embodiment 36:N-hydroxyl-5-(1-(4-morpholinyl benzyl)-1H-pyrazole-3-yl) valeramide
The synthesis of reference example 17N-hydroxyl-5-(1-(3-(anilino) benzyl)-1H-pyrazole-3-yl) valeramide, with to bromobenzyl bromine, 1H-pyrazoles-3-formaldehyde is starting raw material, obtaining 286mg white foam solid through four-step reaction, is N-hydroxyl-5-(1-(4-morpholinyl benzyl)-1H-pyrazole-3-yl) valeramide through Structural Identification. 1H NMR(400MHz,CD 3OD):δ7.46(d,J=2.0Hz,1H),7.11(d,J=8.8Hz,2H),6.91(d,J=8.8Hz,2H),6.09(d,J=2.0Hz,1H),5.15(s,2H),3.80(t,J=4.8Hz,4H),3.10(t,J=4.8Hz,4H),2.60(t,J=6.8Hz,2H),2.09(s,2H),1.65-1.62(m,4H)ppm. 13C NMR(125MHz,CD 3OD):δ168.8,150.3,148.6,128.0,125.7,125.6,113.0,101.4,63.9,51.7,46.6,29.5,26.2,24.5,22.3ppm.MS(ESI)m/z358.20(100%)(M+H) +
The preparation of embodiment 37:6-(1-([1,1'-xenyl]-4-ylmethyl)-1H-pyrazole-3-yl)-N-hydroxyl hexanamide
The synthesis of reference example 1 compound 5, with to phenyl benzylalcohol, 1H-pyrazoles-3-formaldehyde is starting raw material, 217mg white solid is obtained through four-step reaction, be 6-(1-([1,1'-xenyl]-4-ylmethyl)-1H-pyrazole-3-yl)-N-hydroxyl amide through Structural Identification. 1H NMR(400MHz,CD 3OD):δ7.59-7.57(m,5H),7.41(t,J=7.8Hz,2H),7.31(t,J=7.2Hz,1H),7.25(d,J=8.0Hz,2H),6.14(d,J=2.0Hz,1H),5.30(s,2H),2.61(t,J=7.6Hz,2H),2.07(t,J=7.4Hz,2H),1.69-1.59(m,4H),1.40-1.33(m,2H)ppm. 13C NMR(125MHz,CD 3OD):δ170.9,154.9,142.1,141.9,137.7,132.4,129.9,128.9,128.4,128.3,127.9,105.6,55.8,33.7,30.5,30.1,29.7,28.8ppm.MS(ESI)m/z363.19(100%)(M+H) +
The preparation of embodiment 38:7-(1-([1,1'-xenyl]-4-ylmethyl)-1H-pyrazole-3-yl)-N-hydroxyl heptamide
The synthesis of reference example 1 compound 5, with to phenyl benzylalcohol, 1H-pyrazoles-3-formaldehyde is starting raw material, 193mg white solid is obtained through four-step reaction, be 7-(1-([1,1'-xenyl]-4-ylmethyl)-1H-pyrazole-3-yl)-N-hydroxyl heptamide through Structural Identification. 1H NMR(400MHz,CD 3OD):δ7.57(d,J=6.0Hz,5H),7.41(t,J=7.6Hz,2H),7.31(t,J=7.4Hz,1H),7.25(d,J=8.0Hz,2H),6.13(d,J=1.6Hz,1H),5.30(s,2H),2.60(t,J=7.4Hz,2H),2.05(t,J=7.4Hz,2H),1.64-1.57(m,4H),1.35(s,4H)ppm. 13C NMR(125MHz,CD 3OD):δ173.0,155.0,142.1,141.9,137.7,132.4,129.9,128.9,128.4,128.3,127.9,105.6,55.8,33.7,30.7,29.9,29.8,28.8,26.7ppm.MS(ESI)m/z377.21(100%)(M+H) +
The preparation of embodiment 39:8-(1-([1,1'-xenyl]-4-ylmethyl)-1H-pyrazole-3-yl)-N-hydroxy capryloyl amine
The synthesis of reference example 1 compound 5, with to phenyl benzylalcohol, 1H-pyrazoles-3-formaldehyde is starting raw material, 398mg white solid is obtained through four-step reaction, be 8-(1-([1,1'-xenyl]-4-ylmethyl)-1H-pyrazole-3-yl)-N-hydroxy capryloyl amine through Structural Identification. 1H NMR(400MHz,CD 3OD):δ7.59-7.56(m,5H),7.41(t,J=7.6Hz,2H),7.31(t,J=7.4Hz,1H),7.25(d,J=8.0Hz,2H),6.13(d,J=2.4Hz,1H),5.30(s,2H),2.60(t,J=7.6Hz,2H),2.05(t,J=7.4Hz,2H),1.65-1.57(m,4H),1.33(s,6H)ppm. 13C NMR(125MHz,DMSO-d 6):δ169.7,152.6,140.0,139.6,137.3,131.0,129.2,128.3,127.7,127.0,126.8,104.3,54.3,32.5,29.3,28.8,28.7,27.8,25.3ppm.MS(ESI)m/z391.23(100%)(M+H) +
The preparation of embodiment 40:9-(1-([1,1'-xenyl]-4-ylmethyl)-1H-pyrazole-3-yl)-N-hydroxyl pelargonamide
The synthesis of reference example 1 compound 5, with to phenyl benzylalcohol, 1H-pyrazoles-3-formaldehyde is starting raw material, 204mg white solid is obtained through four-step reaction, be 9-(1-([1,1'-xenyl]-4-ylmethyl)-1H-pyrazole-3-yl)-N-hydroxyl pelargonamide through Structural Identification. 1H NMR(400MHz,CD 3OD):δ7.58-7.56(m,5H),7.41(t,J=7.6Hz,2H),7.31(t,J=7.2Hz,1H),7.25(d,J=8.0Hz,2H),6.13(d,J=2.0Hz,1H),5.30(s,2H),2.60(t,J=7.6Hz,2H),2.05(t,J=7.4Hz,2H),1.65-1.58(m,4H),1.31(s,8H)ppm. 13C NMR(125MHz,DMSO-d 6):δ169.3,152.3,139.8,139.4,137.2,130.8,129.0,128.1,127.5,126.8,126.7,104.0,54.2,32.3,29.2,28.8,28.7,28.6,27.7,25.1ppm.MS(ESI)m/z405.24(100%)(M+H) +
Embodiment 41: enzymic activity is tested
It is test with HDAC fluorescent reagent testing cassete (catalog#:50033, BPS Bioscience SanDiego, CA, USA) that compound biochemical activity measures.Mainly the deacetylation effect degree of HDAC enzyme is suppressed to determine its activity according to compound.Its test philosophy is: after the people HDAC enzyme effect with fluorescently-labeled acetylizad deacetylase lysine side-chain substrate and restructuring, this fluorogenic substrate is by deacetylation.Fluorescent mark substrate after deacetylation, by after Trypsin cleaves, discharges fluorescent substance, and this fluorescent substance produces the utilizing emitted light of 460nm under the exciting of 360nm light.The activity change of enzyme is calculated according to the intensity of exciting light.
Concrete steps:
1. with the reaction buffer in BPS HDAC fluorescent reagent testing cassete, the BPS HDAC fluorogenic substrate (catalog#:50032BPS Bioscience, San Diego, CA, USA) of 5mM is diluted 25 times and become 200uM.
2. the reaction buffer in use BPS HDAC fluorescent reagent testing cassete is by recombinant human HDAC1 enzyme (catalog#:50051, BPSBioscience, San Diego, CA, USA) to be diluted to proper concn be that (reaction final concentration is 50ng/ul: 5ng/ul).3. following reaction mixture is added in black 384 orifice plate of a low absorption, hatches 30 minutes for 37 DEG C:
Reaction buffering in 6ul BPS HDAC fluorescent reagent testing cassete
1ul1mg/ml bSA
The recombinant human HDAC1 enzyme of 1ul50ng/ul
1ul compound
The substrate of 1ul200uM
4. termination reaction
There are liquid (2 × HDAC assaydeveloper) room temperature reaction 15 minutes in the interior reaction of BPS HDAC fluorescent reagent testing cassete adding 10ul double strength.
5. use exciting light 350-380nm, utilizing emitted light 440-460 detects fluorescent value.
6. use Prim Data Analysis Computer software to data analysis.The active testing result of compound is as shown in table 1.
Table 1: active testing result
N.S. represent there is no obvious restraining effect (Not Significant)
From above-mentioned activity experiment; nitogen-contained heterocycle derivant of the present invention or its pharmaceutical salts are to HDAC1(histon deacetylase (HDAC) I type) there is good inhibit activities; especially when introducing naphthalene nucleus or containing the phenyl ring of aromatic substituent as phenyl, anilino, indyl, benzyloxy, phenoxy group, the IC of embodiment 18,2,7,22,24,25, the 29 and 30 couples of HDAC1 obtained 50value can reach 42.6 respectively, 63.9,35.1,33.2,35.3,75.2,67.3,86.6nM, this shows suitably in this type of compound molecule, to introduce the stronger group of aromaticity, effectively can improve the anti-tumor activity of this compounds.Nitogen-contained heterocycle derivant of the present invention or the activity of its pharmaceutical salts to inhibition of histone deacetylase have certain selectivity; can be used for treating a series of diseases caused because histon deacetylase (HDAC) I activity is abnormal, as tumour, leukemia, inflammation and nerve degenerative diseases.

Claims (5)

1. structure is such as formula the nitogen-contained heterocycle derivant shown in I or its pharmaceutical salts,
When R is selected from the group of nitrogen heterocyclic ring shown in formula Ia, M is selected from-(CH2) m-or-C (O) NH (CH 2) 2-, m is the positive integer of 4-8;
When R is selected from the group of nitrogen heterocyclic ring shown in formula Ib, M is-(CH 2) 4-;
In formula Ia, Ar is selected from phenyl ring, naphthalene nucleus or benzo [d] [1,3] methylenedioxy or containing 1 or two substituent phenyl ring, described substituting group is selected from halogen, nitro, C1-C4 alkyl, C1-C4 alkoxyl group, trifluoromethyl, pentafluoroethyl group, phenyl, phenoxy group, benzyloxy, phenylamino, morpholinyl or indyl; N is 1; X, Y, Z are selected from carbon or nitrogen and X and Y can not be selected from nitrogen simultaneously; L is selected from hydrogen;
In formula Ib, Y ' is selected from carbon or nitrogen.
2. a preparation method for nitogen-contained heterocycle derivant according to claim 1 or its pharmaceutical salts, is characterized in that; Reaction equation is selected from one of following equation:
Wherein Ar is selected from phenyl ring, naphthalene nucleus or benzo [d] [1,3] methylenedioxy or containing 1 or two substituent phenyl ring, described substituting group is selected from halogen, nitro, C1-C4 alkyl, C1-C4 alkoxyl group, trifluoromethyl, pentafluoroethyl group, phenyl, phenoxy group, benzyloxy, phenylamino, morpholinyl or indyl; N is 1; X, Y, Z are selected from carbon or nitrogen and X and Y can not be selected from nitrogen simultaneously; L is selected from hydrogen; Y ' is selected from carbon or nitrogen; M is selected from-(CH2) m-, m is the positive integer of 4-8; N '=m-3.
3. nitogen-contained heterocycle derivant according to claim 1 or the application of its pharmaceutical salts in preparation histone deacetylase I inhibitor.
4. nitogen-contained heterocycle derivant according to claim 1 or its pharmaceutical salts treat the application in the medicine of the disease caused because histone deacetylase I activity is abnormal in preparation.
5. a pharmaceutical composition, it contains the nitogen-contained heterocycle derivant according to claim 1 as active ingredient of effective dose or its pharmaceutical salts and pharmaceutical carrier.
CN201310012030.XA 2013-01-11 2013-01-11 Nitogen-contained heterocycle derivant, its preparation method and the application in preparation histone deacetylase I inhibitor thereof Expired - Fee Related CN103086971B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201310012030.XA CN103086971B (en) 2013-01-11 2013-01-11 Nitogen-contained heterocycle derivant, its preparation method and the application in preparation histone deacetylase I inhibitor thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201310012030.XA CN103086971B (en) 2013-01-11 2013-01-11 Nitogen-contained heterocycle derivant, its preparation method and the application in preparation histone deacetylase I inhibitor thereof

Publications (2)

Publication Number Publication Date
CN103086971A CN103086971A (en) 2013-05-08
CN103086971B true CN103086971B (en) 2015-08-26

Family

ID=48200156

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201310012030.XA Expired - Fee Related CN103086971B (en) 2013-01-11 2013-01-11 Nitogen-contained heterocycle derivant, its preparation method and the application in preparation histone deacetylase I inhibitor thereof

Country Status (1)

Country Link
CN (1) CN103086971B (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103664734B (en) * 2013-12-10 2015-09-23 广州康缔安生物科技有限公司 Heterocycle hydroximic acid compound and medicinal compositions thereof and application
CN104447608B (en) * 2014-11-10 2017-01-11 华东师范大学 Hydroxamic acid micromolecule organic compound with thaizolidinone structure as well as derivatives, application and preparation method of hydroxamic acid micromolecule organic compounds
CN107226790A (en) * 2016-03-25 2017-10-03 苏州朗科生物技术有限公司 A kind of preparation method and midbody compound of high-purity tafluprost and its similar compound

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009055917A1 (en) * 2007-11-02 2009-05-07 Methylgene Inc. Inhibitors of histone deacetylase
WO2009129335A2 (en) * 2008-04-15 2009-10-22 Pharmacyclics, Inc. Selective inhibitors of histone deacetylase
CN102153549A (en) * 2010-12-14 2011-08-17 华东理工大学 Gamma carboline compound as well as preparation method and application thereof
CN102477001A (en) * 2010-11-29 2012-05-30 江苏先声药物研究有限公司 Benzamide histone deacetylase inhibitor

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009055917A1 (en) * 2007-11-02 2009-05-07 Methylgene Inc. Inhibitors of histone deacetylase
WO2009129335A2 (en) * 2008-04-15 2009-10-22 Pharmacyclics, Inc. Selective inhibitors of histone deacetylase
CN102477001A (en) * 2010-11-29 2012-05-30 江苏先声药物研究有限公司 Benzamide histone deacetylase inhibitor
CN102153549A (en) * 2010-12-14 2011-08-17 华东理工大学 Gamma carboline compound as well as preparation method and application thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Yujia Dai,等.Indole Amide Hydroxamic Acids as Potent Inhibitors of Histone Deacetylases.《Bioorganic & Medicinal Chemistry Letters》.2003,第13卷第1897–1901页. *
组蛋白去乙酰化酶抑制剂的QSAR 研究;林克江,等;《中国药科大学学报》;20041231;第35卷(第2期);第107页表格化合物32-34 *

Also Published As

Publication number Publication date
CN103086971A (en) 2013-05-08

Similar Documents

Publication Publication Date Title
US9562013B2 (en) Selective HDAC3 inhibitors
CA2797011C (en) Tranylcypromine derivatives as inhibitors of histone demethylase lsd1 and/or lsd2
JP2012524715A (en) Dihydroorotate dehydrogenase inhibitor
EP0773937A1 (en) Novel aryl piperazine-derived piperazide derivatives, methods for their preparation, their use as drugs and pharmaceutical compositions comprising same
JP2010513326A (en) Inhibitors of histone deacetylase and prodrugs thereof
EP2443092A1 (en) Bicyclic and tricyclic compounds as kat ii inhibitors
WO2010043953A2 (en) Novel bridged cyclic compounds as histone deacetylase inhibitors
CN103086971B (en) Nitogen-contained heterocycle derivant, its preparation method and the application in preparation histone deacetylase I inhibitor thereof
EP3705476A1 (en) 2-(1h-pyrazol-3-yl) phenol compound and use thereof
Ugwu et al. Synthesis and biological applications of hydroxamates
CA3144075A1 (en) Pharmaceutically active pyrazolo-pyridone modulators of dcn1/2-mediated cullin neddylation
ES2280799T3 (en) HETEROARENCARBOXAMIDAS FOR USE AS DOPAMINE-D3 LINKS FOR THE TREATMENT OF CNS DISEASES (CENTRAL NERVOUS SYSTEM).
KR102044904B1 (en) Tripeptide epoxyketone compound constructed by heterocycle and preparation method and use thereof
CN102260210B (en) Preparation method of naphthoyl amine derivatives of protein kinase inhibitor and histone deacetylase inhibitor
CN102746213B (en) Cinnamamide histone deacetylase inhibitor, preparation method thereof, and application thereof
US5486518A (en) 4-indolylpiperazinyl derivatives
KR20020065916A (en) Substituted piperazine derivatives as MTP inhibitors
MX2011002574A (en) Ortho-aminoanilides for the treatment of cancer.
Li et al. Development of 3-hydroxycinnamamide-based HDAC inhibitors with potent in vitro and in vivo anti-tumor activity
Zhang et al. Design, synthesis and activity evaluation of indole-based double–Branched HDAC1 inhibitors
CN102311398A (en) Triazole compounds, preparation method thereof, and application thereof in preparing histone deacetylase I inhibitor
WO2023077049A1 (en) Methods of preparing 6-membered aza-heterocyclic containing delta-opioid receptor modulating compounds
CN102477001B (en) Benzamide histone deacetylase inhibitor
EP2994122A1 (en) Novel transcription factor modulators
KR102114389B1 (en) Novel sodium channel inhibitor compound, preparation method thereof, and pharmaceutical composition for prevention or treatment of sodium channel related diseases containing the same as an active ingredient

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20150826

Termination date: 20200111