CN103880841A - HDAC (histone deacetylase) inhibitor containing beta- carboline-3-acryl hydrazono as well as preparation method and application thereof - Google Patents
HDAC (histone deacetylase) inhibitor containing beta- carboline-3-acryl hydrazono as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses an HDAC (histone deacetylase) inhibitor containing beta- carboline-3-acryl hydrazono as well as a preparation method and application thereof. A product has a structure as shown in structural formula I; the HDAC inhibitor can be applied as a drug for treating and/or preventing tumors such as liver cancer, pancreatic cancer, colon cancer, lung cancer, stomach cancer, breast cancer, ovarian cancer, and the like.
Description
Technical field
The present invention relates to biomedicine field, be specifically related to novel beta-carboline alkaloid derivative and pharmacy acceptable salt thereof that a class contains hydrazono-, their preparation method, the medicinal compositions that contains these derivatives and their medicinal use, particularly in the application of preparing in antitumor drug.
Background technology
The malignant tumour serious threat mankind's health and lives safety.Though there is clinically multiple antitumor drug available, due to factors such as complicacy, the resistance of tumour and the toxic side effect of antitumor drug of tumor etiology, existing medicine still can not meet the needs for the treatment of.Therefore, exploitation drug effect new type antineoplastic medicine high, that targeting is strong, toxic side effect is little is the hot subject in drug research field always.
Biological activity widely, especially anti-tumor activity that natural product alkaloid shows, caused the extensive concern of Pharmaceutical Chemist, and the design of the original new drug of the structural modification based on natural product alkaloid skeleton is with synthetic significant for this reason.Beta-carboline alkaloid is that the plane three of the natural pyridine of a class [3,4-b] diindyl is encircled alkaloid, is distributed in widely nature.This compounds has biological activity widely, but its toxicity is very low, attract Pharmaceutical Chemist to develop the interest of research to it, nearest grind to make internal disorder or usurp show that β-carboline acts on multiple biological targets, thereby demonstrate biological activity widely, especially aspect anti-tumor activity, these unique biological characteristicses make it be expected to the important sources of the lead compound that becomes development of new clinical medicine.
Histon deacetylase (HDAC) (HDAC) inhibitor is to cause histone and DNA bonding force to strengthen by HDAC overexpression in inhibition tumor cell; hinder the deacetylation of histone; make chromosome structure lax; promote transcription factor and DNA combination; effectively inhibition tumor cell propagation; cause cell-cycle arrest, the differentiation of inducing tumor cell and apoptosis, the susceptibility of raising chemicotherapy.Therefore, HDAC becomes the novel targets of cancer therapy drug design, and it is effectively tactful that exploitation hdac inhibitor is regarded as one of oncotherapy.Meanwhile, research recently finds that HDAC6 participates in regulating Tau protein phosphorylation, glycogen synthase kinase 3 β (GSK3 β) to affect the relevant biological processes such as plastosome transport, and prompting HDAC6 may be relevant with the generation of AD, is the potential target spot for the treatment of AD.But the report that current beta-carboline alkaloid derivative is applied to NSC 630176 aspect is relatively less, has only obtained preliminary application.For this reason, the novel hdac inhibitor that exploitation contains natural β-carboline skeleton has a good application prospect.
Summary of the invention
Carrying out studies on structure-activity relationship of antitumor research by the beta-carboline alkaloid derivative to a large amount of different substituents finds: position and the character of the power of β-carboline analog derivative anti-tumor activity and β-carboline substitution in ring base are closely related; 1,3 and 9 of β-carboline ring is crucial avtive spot, conventionally carries out suitable replacement 1 and 3 of β-carboline ring and often can strengthen its anti-tumor activity, reduce toxicity (Cao R, Chen H, Peng W, et al.Eur.J.Med.Chem.2005,40,991-1001).While studying hdac inhibitor Pharmacophore Model, find: taking SAHA, panobinostat (LBH589) as example simultaneously, Zinc Ions Chelated district (ZBG), produce sequestering action with the zine ion of pocket bottom, mainly comprise (the Miller T A such as hydroximic acid, benzamide, Witter D J, Belvedere S, J.Med.Chem.2003,46 (24), 5097-5116.); Cog region, surface (CAP), interacts with enzymic activity pocket amino-acid residue around, mainly comprises that some are with substituent fragrance, cyclic peptide compounds etc.; And connect this two-part link zone (Link) that is filled in hydrophobic tubular cavity, comprise aliphatic chain or containing the aromatic group of chain etc.Enter at present the hdac inhibitor of clinical study (as entinostat (MS-275); mocetinostat (MGCD0103); panobinostat (LBH589)) in structure, in the Link that finds to be connected with ZBG, all contain to formyl radical benzylamine or to acryl benzylamine structure fragment.In addition, the hdac inhibitor that Bradner group study contains acyl hydrazono-structure fragment has remarkable HDAC1-3, and 6 suppress active (IC
50=0.018 μ M), there is good diagnosing tumor treatment prospect (Bradner JE, West N, Grachan ML, et al.Nat.Chem.Biol.20106 (3): 238-243.).Therefore, by contain the active binding fragment of the ZBG such as hydroximic acid, benzamide in 3 introducings of beta-carboline alkaloid, taking acyl hydrazono-benzyl etc. as Link, 1 and 9 of beta-carboline alkaloids are adopted to alkyl or aryl base group modification, thereby design the novel hdac inhibitor that contains β-carboline-3-acyl hydrazono-.Further investigate it to inhibiting tumour cells effect, find that this compounds can effectively stop kinds of tumor cells (comprising colorectal carcinoma, liver cancer, mammary cancer, carcinoma of the pancreas, ovarian cancer etc.) propagation, and significantly bring into play HDAC and NF-κ B dual restraining activities, inducing apoptosis of tumour cell.Further investigate mechanism of drug action and the biological characteristics of this compounds, the invention discloses the novel hdac inhibitor and the pharmacy acceptable salt thereof that contain β-carboline-3-acyl hydrazono-that a class has pharmaceutical use, have not yet to see any report to this compounds.
The object of the present invention is to provide a kind of novel hdac inhibitor and pharmacy acceptable salt, its preparation method and medicinal use thereof that contains β-carboline-3-acyl hydrazono-.New compound disclosed by the invention is the novel hdac inhibitor and the pharmacy acceptable salt thereof that contain β-carboline-3-acyl hydrazono-shown in formula I:
Formula I: R represents H, CH
3or tertbutyloxycarbonyl;
R
1represent H, CH
3, phenyl, 4-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-hydroxy phenyl, 3-hydroxy phenyl, 4-nitrophenyl, 4-fluorophenyl, 4-chloro-phenyl-, 4-bromophenyl, 4-cyano-phenyl,
or
r
2represent NHOH or
Structure optimization R, the R of above-mentioned formula I
1, R
2following combination, as shown in table 1,
Table 1 formula I part of compounds code name and corresponding structure thereof
Another object of the present invention is to provide the preparation method of compound described in formula I of the present invention.
As R in formula I
2while representing NHOH, its synthetic route is as follows:
Wherein, R represents H, CH
3or tertbutyloxycarbonyl;
R
1represent H, CH
3, phenyl, 4-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-hydroxy phenyl, 3-hydroxy phenyl, 4-nitrophenyl, 4-fluorophenyl, 4-chloro-phenyl-, 4-bromophenyl, 4-cyano-phenyl,
or
r ' represents CH
3or tertbutyloxycarbonyl;
I
abelong to generalformulaⅰcompound.
1,2,3,4-tetrahydro-beta-carboline-1-R
1-3-carboxylate methyl ester (1) obtains β-carboline-1-R through potassium permanganate oxidation
1-3-carboxylate methyl ester (2); intermediate (2) reacts and obtains 9 R ' substitution products of β-carboline (3) with halogenated alkane or two dimethyl dicarbonate butyl esters (Boc acid anhydrides); compound (2) or (3) can obtain hydrazide compound (4) with hydrazine hydrate back flow reaction in methyl alcohol; (4) obtain hydrazono-product (5) with the condensation reaction under acetic acid catalysis of p formylbenzoic acid methyl esters, (5) can obtain formula I by two kinds of methods
a.
Method one: adopt intermediate (5) directly to react and make formula I under the methanol solution of potassium hydroxide with oxammonium hydrochloride
a;
Method two: intermediate (5) is hydrolyzed and obtains hydrolysate (6) in the methanol solution of sodium hydroxide; (6) make mixed acid anhydride with Vinyl chloroformate and N-methylmorpholine under anhydrous tetrahydrofuran solution subsequently; and make with O-(tetrahydropyrans-2-yl) azanol reaction the amide product that contains tetrahydropyrans azanol, then slough tetrahydropyrans protecting group with trifluoroacetic acid immediately and make formula I
a.
As R in formula I
2representative
time, its synthetic route is as follows:
Wherein, R represents H, CH
3or tertbutyloxycarbonyl;
R
1represent H, CH
3, phenyl, 4-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-hydroxy phenyl, 3-hydroxy phenyl, 4-nitrophenyl, 4-fluorophenyl, 4-chloro-phenyl-, 4-bromophenyl, 4-cyano-phenyl,
or
i
bbelong to generalformulaⅰcompound.
Above-mentioned synthetic hydrazono-product (5) is hydrolyzed and obtains hydrolysate (6) in the methanol solution of sodium hydroxide; then react and obtain condensation product (7) in the dichloromethane solution of 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (EDCI) and DMAP (DMAP) with the O-Phenylene Diamine of single Boc protection, be used in again subsequently trifluoroacetic acid and slough Boc protecting group and obtain formula I
b.
A further object of the present invention is to provide generalformulaⅰcompound of the present invention in the application of preparing in medicine for treating tumor thing.
It is a kind of containing the generalformulaⅰcompound of the present invention of effective dose or the pharmaceutical composition of its medically acceptable salt and pharmaceutically acceptable carrier or auxiliary material that a further object of the present invention is to provide.
A further object of the present invention is to provide generalformulaⅰcompound of the present invention in the application of preparing in antitumor drug and nerve protection medicine, especially Hepatoma therapy, carcinoma of the pancreas, colorectal carcinoma, lung cancer, cancer of the stomach, the application in the tumour medicines such as mammary cancer and ovarian cancer.
The compounds of this invention can be made preparation for administration separately or with one or more pharmaceutically acceptable carrier combinations.For example, solvent, thinner etc., can use oral dosage form administration, as tablet, capsule, dispersible powder, granule etc.The various formulations of pharmaceutical composition of the present invention can be prepared according to the method for knowing in pharmaceutical field.In these medicinal preparationss, can contain and for example activeconstituents of 0.05%～90% weight of carrier combinations the more common approximately activeconstituents of weight between 15%～60%.The compounds of this invention dosage can be 0.005～5000mg/kg/ days, also can exceed this dosage range according to the different using dosages of disease severity or formulation.
The compounds of this invention can with for example alkylating agent of other antitumor drugs (as endoxan or cis-platinum), antimetabolite (as 5 FU 5 fluorouracil or hydroxyurea), topoisomerase enzyme inhibitor (as camptothecine), mitotic inhibitor (as taxol or vinealeucoblastine(VLB)), DNA intercalating agent (as Zorubicin) combined utilization, in addition can also with radiotherapy combined utilization.These other antitumor drugs or radiotherapy can or give at different time with the compounds of this invention while.Thereby these combination therapys can produce synergy contributes to improve result for the treatment of.
The part pharmacological tests of the compounds of this invention is as follows:
1, adopt mtt assay to measure research to the Cytostatic to tumor cell rate of the compounds of this invention
Through a series of tumour cell tests, find that these generalformulaⅰcompounds of the present invention are stronger to most of Cytostatic to tumor cell effect, and than positive control drug SAHA is slightly strong or quite, especially in table 2, part I compound inhibiting rate under 25 μ mol/L concentration is greater than 75%;
The pharmacological results shows, the compounds of this invention has the restraining effect of stronger degree to the propagation of human tumor cells, and majority of compounds demonstrates stronger anti-tumor activity.
The inhibiting rate % (25 and 5 μ M) of table 2 the compounds of this invention to Partial tumors cell proliferation
ND: do not detect.
2, HDACs is suppressed to active testing
Experimental result is found: chemical compounds I
1-I
25all in varying degrees HDACs is suppressed to active, wherein chemical compounds I
1-I
8, I
13, I
15-I
19, I
24hDACs is suppressed to activity data in table 3, majority of compounds all demonstrates the inhibition activity slightly strong or more suitable than positive control drug SAHA, the invention compound that prompting contains β-carboline-3-acyl hydrazono-has good HDACs and suppresses active, and to demonstrate anti-tumor activity consistent with it.
Table 3 part of compounds vitro enzyme of the present invention suppresses experimental result
3, Acetylated histone H3 (Acetyl-histone H3), the test of p-NF-kB activity
Experimental result is found: chemical compounds I
1-I
25all promote in varying degrees that in tumour cell, Acetyl-histoneH3 expresses, invention compound inhibition of histone deacetylase, wherein chemical compounds I is effectively described
4-I
8, I
17-I
19, I
24under 6.125 μ M concentration, can significantly promote Acetyl-histone H3 to express; Chemical compounds I simultaneously
1-I
25can also be in varying degrees to p-NF-κ B(p65 in tumour cell) demonstrate stronger inhibition activity, point out this invention compound to there is HDAC and NF-κ B dual restraining activities, the antitumor action of collaborative performance compound.
Embodiment
In order further to illustrate the present invention, provide a series of embodiment below, these embodiment are illustrative completely, they are only used for the present invention to specifically describe, and not should be understood to limitation of the present invention.
Embodiment 1:3-(4-azanol carbonyl)-benzyl hydrazono--β-carboline (I
1) preparation
β-carboline-3-carboxylate methyl ester (2a)
1,2,3,4-tetrahydro-beta-carboline-3-carboxylate methyl ester (1a, 11.3g, 50mmol) is dissolved in 100ml DMF solvent, under-5 DEG C of mechanical stirring, adds KMnO in batches
4(11.1g, 70mmol), continues to stir after 0.5h, and reaction solution joins in 200ml cold water, separates out precipitation, filters to obtain light brown solid; Solution is used ethyl acetate (150ml × 3) extraction again, concentrated, and filters solid and merges to obtain 7.7g, yield 69.0%.
β-carboline-3-carboxylic acid hydrazides (4a)
By 2a(2.26g, 10mmol) be dissolved in 25ml methyl alcohol, add 85% hydrazine hydrate 17.3ml(300mmol), back flow reaction 3h, cooling, suction filtration obtains fallow solid 1.85g, productive rate 82%.
4-((2-(9H-pyrido [3,4-b] indoles-3-carbonyl) hydrazono-) methyl) methyl benzoate (5a)
By 4a(0.23g, 1mmol), p formyl benzoic acid methyl esters (0.49g, 3mmol) is dissolved in 10ml anhydrous methanol, add appropriate acetic acid to pH=4, heating reflux reaction 8h, adds saturated sodium carbonate solution to adjust pH=8, removes methyl alcohol under reduced pressure, ethyl acetate (20 × 3) extraction, organic phase concentrated crude product after anhydrous sodium sulfate drying, rapid column chromatography obtains yellow solid 0.32g, productive rate 86.5%.
4-((2-(9H-pyrido [3,4-b] indoles-3-carbonyl) hydrazono-) methyl) phenylformic acid (6a)
By 5a(3.72g, 10mmol), sodium hydroxide (2.00g, 50mmol), the water of 10ml joins in the methyl alcohol of 20ml, and heating reflux reaction 2h reacts complete, removes solvent under reduced pressure, adjust pH=4 with 1M HCl solution, suction filtration obtains faint yellow solid 3.35g, productive rate 93.6%.
4-((2-(9H-pyrido [3,4-b] indoles-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
1)
Method one: by the 6ml methyl alcohol suspension of oxammonium hydrochloride (6.95g, 100mmol), slowly drip KOH(5.88g under-5 DEG C of low temperature, 12ml methanol solution 105mmol), dropwises, and stirs 10min, filter, filtrate joins 5a(0.37g, 1mmol) methanol solution in, reactor is airtight, stirred overnight at room temperature, react complete, remove solvent under reduced pressure, column chromatography obtains I
1faint yellow solid 0.35g, productive rate 94.6%.
Method two: by 6a (0.36g, 1mmol), N-methylmorpholine (0.33ml, 3mmol) be dissolved in 10ml anhydrous tetrahydrofuran solution, under condition of ice bath, slowly drip Vinyl chloroformate (0.19ml, 2mmol), after 1h, react complete, in reaction solution, add triethylamine (0.42ml again, 3mmol), O-(tetrahydropyrans-2-yl) azanol (0.23g, 2mmol), after room temperature reaction 3h, react completely, after removing solvent under reduced pressure, be dissolved in 8ml methanol solution, under room temperature condition, dropwise drip 2ml trifluoroacetic acid, stir 2h reaction complete, remove solvent under reduced pressure, column chromatography obtains I
1faint yellow solid 0.31g, productive rate 81.0%, ESI-MS (m/z): 374[M+H]
+,
1h NMR (d
6-DMSO, 300MHz): δ 11.80 (br, 1H, NH), 11.21 (s, 1H, N
hoH), 9.46 (s, 1H, CONH), 9.04 (s, 1H, ArH), 8.79 (s, 1H, ArH), 8.52 (s, 1H, N=CH), 8.27 (d, J=8.7Hz, 2H, ArH), 7.67-7.76 (m, 2H, ArH), 7.56 (m, 1H, ArH), 7.38 (m, 1H, ArH), 7.18 (m, 2H, ArH).
Embodiment 2:4-((2-(9H-pyrido [3,4-b] indoles-3-carbonyl) hydrazono-) methyl)-N-(2-aminophenyl)-benzamide (I
2) preparation
By single tertbutyloxycarbonyl phenylenediamine (0.42g, 2mmol), 6a(0.36g, 1mmol), EDCI (1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride) (0.38g, 2mmol), a small amount of DMAP (DMAP) is dissolved in 10ml anhydrous methylene chloride, stirred overnight at room temperature, react complete, remove solvent under reduced pressure and obtain crude product, column chromatography obtains faint yellow solid 0.44g, and is dissolved in the methanol solution of 2ml, dropwise add trifluoroacetic acid 5ml, 3h under room temperature condition, reacts the complete solvent that removes under reduced pressure, obtains I
2faint yellow solid 0.32g, productive rate 71.4%, ESI-MS (m/z): 448[M+H]
+;
1h NMR (d
6-DMSO, 300MHz): δ 9.01 (s, 1H, ArH), 8.77 (s, 1H, ArH), 8.54 (s, 1H, N=CH), 8.23 (m, 1H, ArH), 8.20 (d, J=7.5Hz, 2H, ArH), 7.78 (d, J=8.7Hz, 2H, ArH), 7.65 (m, 1H, ArH), 7.63 (d, J=7.5Hz, 2H, ArH), 7.59 (m, 1H, ArH), 7.36 (m, 1H, ArH), 7.17 (t, 2H, J=8.7Hz, ArH), 5.00 (s, 2H, NH
2).
Embodiment 3:4-((2-(9H-pyrido [3,4-b] indoles-1-methyl-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
3) preparation
1-methyl-β-carboline-3-carboxylate methyl ester (2b)
With reference to the synthetic method of (2a) in embodiment 1, by (1a) and KMnO in 2,3,4-tetrahydro-beta-carboline-1-methyl-3-carboxylate methyl ester (1b) replacement method
4reaction, finally obtains light brown solid (2b), productive rate 71.8%.
1-methyl-β-carboline-3-carboxylic acid hydrazides (4b)
With reference to the synthetic method of (4a) in embodiment 1, reacted with 85% hydrazine hydrate by (2a) in (2b) replacement method, finally obtain (4b) for light brown solid, productive rate 72.7%.
4-((2-(9H-pyrido [3,4-b] indoles-1-methyl-3-carbonyl) hydrazono-) methyl) methyl benzoate (5b)
With reference to the synthetic method of (5a) in embodiment 1, reacted with p formyl benzoic acid methyl esters by (4a) in (4b) replacement method, finally obtain (5b) for yellow solid, productive rate 81.6%, ESI-MS (m/z): 387[M+H]
+.4-((2-(9H-pyrido [3,4-b] indoles-1-methyl-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
3)
With reference to embodiment I
1preparation method one, by the compound (5a) in compound (5b) alternative method, the azanol reaction of preparation, finally obtains I
3for faint yellow solid, productive rate 72.3%, ESI-MS (m/z): 388[M+H]
+,
1h NMR (d
6-DMSO, 300MHz): δ 11.81 (s, 1H, NH), 10.72 (s, 1H, OH), 8.76 (s, 1H, H-4), 8.55 (s, 1H, N=CH), 8.26 (d, J=8.0Hz, 1H, H-5), 7.74 (d, J=8.7Hz, 2H, ArH), 7.66 (d, J=7.5Hz, 1H, H-8), 7.54 (m, 1H, H-7), 7.35 (m, 1H, H-6), 7.15 (d, 2H, J=8.7Hz, ArH), 2.48 (s, 3H, CH
3).
Embodiment 4:4-((2-(9H-pyrido [3,4-b] indoles-1-(4-p-methoxy-phenyl)-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
4) preparation
1-(4-p-methoxy-phenyl)-β-carboline-3-carboxylate methyl ester (2c)
With reference to the synthetic method of (2a) in embodiment 1, by (1a) and KMnO in 2,3,4-tetrahydro-beta-carboline-1-(4-p-methoxy-phenyl)-3-carboxylate methyl ester (1c) replacement method
4reaction, finally obtains light brown solid (2c), productive rate 81.4%.
1-(4-p-methoxy-phenyl)-β-carboline-3-carboxylic acid hydrazides (4c)
With reference to the synthetic method of (4a) in embodiment 1, reacted with 85% hydrazine hydrate by (2a) in (2c) replacement method, finally obtain (4c) for light brown solid, productive rate 80.8%.
4-((2-(9H-pyrido [3,4-b] indoles-1-(4-p-methoxy-phenyl)-3-carbonyl) hydrazono-) methyl) methyl benzoate (5c)
With reference to the synthetic method of (5a) in embodiment 1, reacted with p formyl benzoic acid methyl esters by (4a) in (4c) replacement method, finally obtain (5c) for yellow solid, productive rate 72.9%, ESI-MS (m/z): 479[M+H]
+.4-((2-(9H-pyrido [3,4-b] indoles-1-(4-p-methoxy-phenyl)-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
4)
With reference to embodiment I
1preparation method one, by the compound (5a) in compound (5c) alternative method, with preparation azanol reaction, finally make I
4for faint yellow solid, productive rate 70.7%, ESI-MS (m/z): 480[M+H]
+,
1h NMR (d
6-DMSO, 300MHz): δ 11.82 (s, 1H, NH), 8.86 (s, 1H, CONH), 8.74 (s, 1H, H-4), 8.51 (s, 1H, N=CH), 8.25 (d, J=8.0Hz, 1H, H-5), 8.18 (d, J=8.0Hz, 2H, ArH), 7.77 (d, J=8.7Hz, 2H, ArH), 7.63-7.68 (m, 3H, ArH), 7.55 (m, 1H, H-7), 7.36 (m, 1H, H-6), 7.17 (d, 2H, J=8.7Hz, ArH), 3.92 (s, 3H, OCH
3).
Embodiment 5:4-((2-(9H-pyrido [3,4-b] indoles-1-(4-p-methoxy-phenyl)-3-carbonyl) hydrazono-) methyl)-N-(2-aminophenyl)-benzamide (I
5) preparation
4-((2-(9H-pyrido [3,4-b] indoles-1-(4-p-methoxy-phenyl)-3-carbonyl) hydrazono-) methyl) phenylformic acid (6c)
With reference to the synthetic method of (6a) in embodiment 1, by (5a) in (5c) replacement method and NaOH back flow reaction, finally obtain (6c) for yellow solid, productive rate 97.9%.
4-((2-(9H-pyrido [3,4-b] indoles-1-(4-p-methoxy-phenyl)-3-carbonyl) hydrazono-) methyl)-N-(2-aminophenyl)-benzamide (I
5)
With reference to embodiment I
2preparation method; by the compound (6a) in compound (6c) alternative method; react with single tertbutyloxycarbonyl phenylenediamine, EDCI (1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride), a small amount of DMAP (DMAP); obtain (6c) of single tertbutyloxycarbonyl protection through column chromatography purification (moving phase ethyl acetate: sherwood oil=1:5-5:1); (6c) of single tertbutyloxycarbonyl protection again with trifluoroacetic acid deprotection, finally make final product and finally make final product I
5for faint yellow solid, productive rate 70.7%, ESI-MS (m/z): 555[M+H]
+,
1h NMR (d
6-DMSO, 300MHz): δ 11.37 (s, 1H, NH), 8.76 (s, 1H, H-4), 8.57 (s, 1H, N=CH), 8.28 (d, J=8.0Hz, 1H, H-5), 8.26 (d, J=7.5Hz, 2H, ArH), 8.21 (d, J=8.0Hz, 2H, ArH), 7.76 (d, J=8.7Hz, 2H, ArH), 7.55-7.64 (m, 6H, ArH), 7.37 (t, 1H, J=7.5Hz, H-6), 7.14 (t, 2H, J=8.7Hz, ArH), 5.02 (s, 2H, NH2), 3.89 (s, 3H, OCH
3).
Embodiment 6:4-((2-(9H-pyrido [3,4-b] indoles-1-(3-p-methoxy-phenyl)-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
6) preparation
1-(3-p-methoxy-phenyl)-β-carboline-3-carboxylate methyl ester (2d)
With reference to the synthetic method of (2a) in embodiment 1, by (1a) and KMnO in 2,3,4-tetrahydro-beta-carboline-1-(3-p-methoxy-phenyl)-3-carboxylate methyl ester (1d) replacement method
4reaction, finally obtains light brown solid (2d), productive rate 73.7%.
1-(3-p-methoxy-phenyl)-β-carboline-3-carboxylic acid hydrazides (4d)
With reference to the synthetic method of (4a) in embodiment 1, reacted with 85% hydrazine hydrate by (2a) in (2d) replacement method, finally obtain (4d) for light brown solid, productive rate 79.8%.
4-((2-(9H-pyrido [3,4-b] indoles-1-(3-p-methoxy-phenyl)-3-carbonyl) hydrazono-) methyl) methyl benzoate (5d)
With reference to the synthetic method of (5a) in embodiment 1, reacted with p formyl benzoic acid methyl esters by (4a) in (4d) replacement method, finally obtain (5d) for yellow solid, productive rate 67.7%, ESI-MS (m/z): 479[M+H]
+.4-((2-(9H-pyrido [3,4-b] indoles-1-(3-p-methoxy-phenyl)-3-carbonyl) hydrazono-) methyl) phenylformic acid (6d)
With reference to the synthetic method of (6a) in embodiment 1, by (5a) in (5d) replacement method and NaOH back flow reaction, finally obtain (6d) for yellow solid, productive rate 92.8%.
4-((2-(9H-pyrido [3,4-b] indoles-1-(3-p-methoxy-phenyl)-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
6)
With reference to embodiment I
1preparation method two; by the compound (6a) in compound (6d) alternative method; make mixed acid anhydride with Vinyl chloroformate and N-methylmorpholine; again with pyrans azanol reaction; make the azanol of compound (6d) pyrans protection, the azanol of compound (6d) pyrans protection makes final product I under trifluoroacetic acid deprotection
6for faint yellow solid, productive rate 69.7%, ESI-MS (m/z): 480[M+H]
+,
1h NMR (d
6-DMSO, 300MHz): δ 11.51 (s, 1H, NH), 9.46 (s, 1H, CONH), 8.76 (s, 1H, H-4), 8.52 (s, 1H, N=CH), 8.27 (d, J=8.0Hz, 1H, H-5), 8.16 (d, J=8.0Hz, 2H, ArH), 7.79 (d, J=8.7Hz, 2H, ArH), 7.69 (d, J=7.5Hz, 1H, H-8), 7.57-7.61 (m, 3H, ArH), 7.35 (m, 1H, H-6), 7.16 (d, 2H, J=8.7Hz, ArH), 3.93 (s, 3H, OCH
3).
Embodiment 7:4-((2-(9H-pyrido [3,4-b] indoles-1-(3,4-methylenedioxyphenyl)-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
7) preparation
1-(3,4-methylenedioxyphenyl)-β-carboline-3-carboxylate methyl ester (2e)
With reference to the synthetic method of (2a) in embodiment 1, by (1a) and KMnO in 2,3,4-tetrahydro-beta-carboline-1-(3,4-methylenedioxyphenyl)-3-carboxylate methyl ester (1e) replacement method
4reaction, finally obtains light brown solid (2e), productive rate 81.9%.
1-(3,4-methylenedioxyphenyl)-β-carboline-3-carboxylic acid hydrazides (4e)
With reference to the synthetic method of (4a) in embodiment 1, reacted with 85% hydrazine hydrate by (2a) in (2e) replacement method, finally obtain (4e) for light brown solid, productive rate 71.7%.
4-((2-(9H-pyrido [3,4-b] indoles-1-(3,4-methylenedioxyphenyl)-3-carbonyl) hydrazono-) methyl) methyl benzoate (5e)
With reference to the synthetic method of (5a) in embodiment 1, reacted with p formyl benzoic acid methyl esters by (4a) in (4e) replacement method, finally obtain (5e) for yellow solid, productive rate 72.8%, ESI-MS (m/z): 493[M+H]
+.4-((2-(9H-pyrido [3,4-b] indoles-1-(3,4-methylenedioxyphenyl)-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
7)
With reference to embodiment I
1preparation method one, by the compound (5a) in compound (5e) alternative method, with preparation azanol reaction, finally make final product I
7for faint yellow solid, productive rate 72.4%, ESI-MS (m/z): 494[M+H]
+,
1h NMR (d
6-DMSO, 300MHz): δ 11.63 (s, 1H, NH), 11.22 (s, 1H, N
hoH), 9.10 (s, 1H, CONH), 8.75 (s, 1H, H-4), 8.53 (s, 1H, N=CH), 8.28 (d, J=8.0Hz, 1H, H-5), 8.21 (d, J=8.0Hz, 2H, ArH), 7.78 (d, J=8.7Hz, 2H, ArH), 7.60-7.66 (m, 2H, ArH), 7.54 (m, 1H, H-7), 7.39 (d, 1H, J=7.5Hz, H-6), (7.14 m, 2H, ArH), 5.68 (s, 2H, OCH
2o).
Embodiment 8:4-((2-(9H-pyrido [3,4-b] indoles-1-(3,4-Dimethoxyphenyl)-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
8)
1-(3,4-Dimethoxyphenyl)-β-carboline-3-carboxylate methyl ester (2f)
With reference to the synthetic method of (2a) in embodiment 1, by (1a) and KMnO in 2,3,4-tetrahydro-beta-carboline-1-(3,4-Dimethoxyphenyl)-3-carboxylate methyl ester (1f) replacement method
4reaction, finally obtains light brown solid (2f), productive rate 89.8%.
1-(3,4-Dimethoxyphenyl)-β-carboline-3-carboxylic acid hydrazides (4f)
With reference to the synthetic method of (4a) in embodiment 1, reacted with 85% hydrazine hydrate by (2a) in (2f) replacement method, finally obtain (4f) for light brown solid, productive rate 70.8%.
4-((2-(9H-pyrido [3,4-b] indoles-1-(3,4-Dimethoxyphenyl)-3-carbonyl) hydrazono-) methyl) methyl benzoate (5f)
With reference to the synthetic method of (5a) in embodiment 1, reacted with p formyl benzoic acid methyl esters by (4a) in (4c) replacement method, finally obtain (5f) for yellow solid, productive rate 73.2%, ESI-MS (m/z): 509[M+H]
+.4-((2-(9H-pyrido [3,4-b] indoles-1-(3,4-Dimethoxyphenyl)-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
8)
With reference to embodiment I
1preparation method one, by the compound (5a) in compound (5f) alternative method, with preparation azanol reaction, finally make final product I
8for faint yellow solid, productive rate 76.5%, ESI-MS (m/z): 510[M+H]
+;
1h NMR (d
6-DMSO, 300MHz): δ 11.71 (s, 1H, NH), 11.25 (s, 1H, NHOH), 9.23 (s, 1H, CONH), 8.76 (s, 1H, H-4), 8.57 (s, 1H, N=CH), 8.30 (m, 1H, H-5), 8.17 (d, J=8.0Hz, 2H, ArH), 7.75 (d, J=8.7Hz, 2H, ArH), 7.68 (d, J=7.5Hz, 1H, H-8), 7.62 (m, 1H, ArH), 7.53 (m, 1H, H-7), 7.41 (t, 1H, J=7.5Hz, H-6), 7.19 (d, 2H, J=8.7Hz, ArH), 3.92 (s, 6H, 2 × OCH
3).
Embodiment 9:4-((2-(9H-pyrido [3,4-b] indoles-1-(4-nitrophenyl)-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
9) preparation
1-(4-nitrophenyl)-β-carboline-3-carboxylate methyl ester (2g)
With reference to the synthetic method of (2a) in embodiment 1, by (1a) and KMnO in 2,3,4-tetrahydro-beta-carboline-1-(4-nitrophenyl)-3-carboxylate methyl ester (1g) replacement method
4reaction, finally obtains light brown solid (2g), productive rate 71.9%
1-(4-nitrophenyl)-β-carboline-3-carboxylic acid hydrazides (4g)
With reference to the synthetic method of (4a) in embodiment 1, reacted with 85% hydrazine hydrate by (2a) in (2g) replacement method, finally obtain (4g) for light brown solid, productive rate 66.3%.
4-((2-(9H-pyrido [3,4-b] indoles-1-(4-nitrophenyl)-3-carbonyl) hydrazono-) methyl) methyl benzoate (5g)
With reference to the synthetic method of (5a) in embodiment 1, reacted with p formyl benzoic acid methyl esters by (4a) in (4g) replacement method, finally obtain (5g) for yellow solid, productive rate 77.7%, ESI-MS (m/z): 494[M+H]
+.4-((2-(9H-pyrido [3,4-b] indoles-1-(4-nitrophenyl)-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
9)
With reference to embodiment I
1preparation method one, by the compound (5a) in compound (5g) alternative method, and prepare azanol reaction, finally make final product I
9for faint yellow solid, productive rate 74.7%, ESI-MS (m/z): 495[M+H]
+.
Embodiment 10:4-((2-(9H-pyrido [3,4-b] indoles-1-(4-fluorophenyl)-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
10) preparation
1-(4-fluorophenyl)-β-carboline-3-carboxylate methyl ester (2h)
With reference to the synthetic method of (2a) in embodiment 1, by (1a) and KMnO in 2,3,4-tetrahydro-beta-carboline-1-(4-fluorophenyl)-3-carboxylate methyl ester (1h) replacement method
4reaction, finally obtains light brown solid (2h), productive rate 71.2%.
1-(4-fluorophenyl)-β-carboline-3-carboxylic acid hydrazides (4h)
With reference to the synthetic method of (4a) in embodiment 1, reacted with 85% hydrazine hydrate by (2a) in (2h) replacement method, finally obtain (4h) for light brown solid, productive rate 64.8%.
4-((2-(9H-pyrido [3,4-b] indoles-1-(4-fluorophenyl)-3-carbonyl) hydrazono-) methyl) methyl benzoate (5h)
With reference to the synthetic method of (5a) in embodiment 1, reacted with p formyl benzoic acid methyl esters by (4a) in (4h) replacement method, finally obtain (5h) for yellow solid, productive rate 76.7%, ESI-MS (m/z): 467[M+H]
+.4-((2-(9H-pyrido [3,4-b] indoles-1-(4-fluorophenyl)-3-carbonyl) hydrazono-) methyl) phenylformic acid (6h)
With reference to the synthetic method of (6a) in embodiment 1, by (5a) in (5h) replacement method and NaOH back flow reaction, finally obtain (6h) for yellow solid, productive rate 94.3%.
4-((2-(9H-pyrido [3,4-b] indoles-1-(4-fluorophenyl)-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
10)
With reference to embodiment I
1preparation method two; by the compound (6a) in compound (6h) alternative method; make mixed acid anhydride with Vinyl chloroformate and N-methylmorpholine; again with pyrans azanol reaction; make the azanol of compound (6h) pyrans protection, the azanol of compound (6h) pyrans protection makes final product I under trifluoroacetic acid deprotection
10for faint yellow solid, productive rate 76.5%, ESI-MS (m/z): 468[M+H]
+,
1h NMR (d
6-DMSO, 300MHz): δ 11.64 (s, 1H, NH), 11.23 (s, 1H, N
hoH), 8.78 (s, 1H, H-4), 8.56 (s, 1H, N=CH), 8.27 (d, J=8.0Hz, 1H, H-5), 8.15 (d, J=8.0Hz, 2H, ArH), 7.77 (d, J=8.7Hz, 2H, ArH), 7.69 (d, J=7.5Hz, 1H, H-8), 7.58-7.63 (m, 3H, ArH), 7.44 (t, 1H, J=7.5Hz, H-6), 7.22 (d, 2H, J=8.7Hz, ArH).
Embodiment 11:4-((2-(9H-pyrido [3,4-b] indoles-1-(4-chloro-phenyl-)-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
11) preparation
1-(4-chloro-phenyl-)-β-carboline-3-carboxylate methyl ester (2i)
With reference to the synthetic method of (2a) in embodiment 1, by (1a) and KMnO in 2,3,4-tetrahydro-beta-carboline-1-(4-chloro-phenyl-)-3-carboxylate methyl ester (1i) replacement method
4reaction, finally obtains light brown solid (2i), productive rate 81.6%.
1-(4-chloro-phenyl-)-β-carboline-3-carboxylic acid hydrazides (4i)
With reference to the synthetic method of (4a) in embodiment 1, reacted with 85% hydrazine hydrate by (2a) in (2i) replacement method, finally obtain (4i) for light brown solid, productive rate 73.8%.
4-((2-(9H-pyrido [3,4-b] indoles-1-(4-chloro-phenyl-)-3-carbonyl) hydrazono-) methyl) methyl benzoate (5i)
With reference to the synthetic method of (5a) in embodiment 1, reacted with p formyl benzoic acid methyl esters by (4a) in (4i) replacement method, finally obtain (5i) for yellow solid, productive rate 77.9%, ESI-MS (m/z): 483[M+H]
+.4-((2-(9H-pyrido [3,4-b] indoles-1-(4-chloro-phenyl-)-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
11)
With reference to embodiment I
1preparation method one, by the compound (5a) in compound (5i) alternative method, with preparation azanol reaction, finally make final product I
11for faint yellow solid, productive rate 78.5%, ESI-MS (m/z): 484[M+H]
+.
Embodiment 12:4-((2-(9H-pyrido [3,4-b] indoles-1-(4-bromophenyl)-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
12) preparation
1-(4-bromophenyl)-β-carboline-3-carboxylate methyl ester (2j)
With reference to the synthetic method of (2a) in embodiment 1, by (1a) and KMnO in 2,3,4-tetrahydro-beta-carboline-1-(4-bromophenyl)-3-carboxylate methyl ester (1j) replacement method
4reaction, finally obtains light brown solid (2j), productive rate 84.5%.
1-(4-bromophenyl)-β-carboline-3-carboxylic acid hydrazides (4j)
With reference to the synthetic method of (4a) in embodiment 1, reacted with 85% hydrazine hydrate by (2a) in (2j) replacement method, finally obtain (4j) for light brown solid, productive rate 73.9%.
4-((2-(9H-pyrido [3,4-b] indoles-1-(4-bromophenyl)-3-carbonyl) hydrazono-) methyl) methyl benzoate (5j)
With reference to the synthetic method of (5a) in embodiment 1, reacted with p formyl benzoic acid methyl esters by (4a) in (4j) replacement method, finally obtain (5j) for yellow solid, productive rate 72.9%, ESI-MS (m/z): 527[M+H]
+.
4-((2-(9H-pyrido [3,4-b] indoles-1-(4-bromophenyl)-3-carbonyl) hydrazono-) methyl) phenylformic acid (6j)
With reference to the synthetic method of (6a) in embodiment 1, by (5a) in (5j) replacement method and NaOH back flow reaction, finally obtain (6j) for yellow solid, productive rate 93.8%.
4-((2-(9H-pyrido [3,4-b] indoles-1-(4-bromophenyl)-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
12)
With reference to embodiment I
1preparation method two; by the compound (6a) in compound (6j) alternative method; make mixed acid anhydride with Vinyl chloroformate and N-methylmorpholine; again with pyrans azanol reaction; make the azanol of compound (6j) pyrans protection, the azanol of compound (6j) pyrans protection makes final product I under trifluoroacetic acid deprotection
12for faint yellow solid, productive rate 77.7%, ESI-MS (m/z): 528[M+H]
+.
Embodiment 13:4-((2-(9H-pyrido [3,4-b] indoles-1-(4-cyano-phenyl)-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
13) preparation
1-(4-cyano-phenyl)-β-carboline-3-carboxylate methyl ester (2k)
With reference to the synthetic method of (2a) in embodiment 1, by (1a) and KMnO in 2,3,4-tetrahydro-beta-carboline-1-(4-cyano-phenyl)-3-carboxylate methyl ester (1k) replacement method
4reaction, finally obtains light brown solid (2k), productive rate 81.8%.
1-(4-cyano-phenyl)-β-carboline-3-carboxylic acid hydrazides (4k)
With reference to the synthetic method of (4a) in embodiment 1, reacted with 85% hydrazine hydrate by (2a) in (2k) replacement method, finally obtain (4k) for light brown solid, productive rate 75.5%.
4-((2-(9H-pyrido [3,4-b] indoles-1-(4-cyano-phenyl)-3-carbonyl) hydrazono-) methyl) methyl benzoate (5k)
With reference to the synthetic method of (5a) in embodiment 1, reacted with p formyl benzoic acid methyl esters by (4a) in (4k) replacement method, finally obtain (5k) for yellow solid, productive rate 77.5%, ESI-MS (m/z): 474[M+H]
+.4-((2-(9H-pyrido [3,4-b] indoles-1-(4-cyano-phenyl)-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
13)
With reference to embodiment I
1preparation method one, by the compound (5a) in compound (5k) alternative method, with preparation azanol reaction, finally make final product I
13for faint yellow solid, productive rate 71.7%, ESI-MS (m/z): 475[M+H]
+.
Embodiment 14:4-((2-(9H-pyrido [3,4-b] indoles-1-phenyl-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
14) preparation
1-phenyl-β-carboline-3-carboxylate methyl ester (2l)
With reference to the synthetic method of (2a) in embodiment 1, by (1a) and KMnO in 2,3,4-tetrahydro-beta-carboline-1-phenyl-3-carboxylate methyl ester (1l) replacement method
4reaction, finally obtains light brown solid (2l), productive rate 81.8%.
1-phenyl-β-carboline-3-carboxylic acid hydrazides (4l)
With reference to the synthetic method of (4a) in embodiment 1, reacted with 85% hydrazine hydrate by (2a) in (2l) replacement method, finally obtain (4l) for light brown solid, productive rate 79.2%.
4-((2-(9H-pyrido [3,4-b] indoles-1-phenyl-3-carbonyl) hydrazono-) methyl) methyl benzoate (5l)
With reference to the synthetic method of (5a) in embodiment 1, reacted with p formyl benzoic acid methyl esters by (4a) in (4l) replacement method, finally obtain (5l) for yellow solid, productive rate 72.7%, ESI-MS (m/z): 449[M+H]
+.
4-((2-(9H-pyrido [3,4-b] indoles-1-phenyl-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
14)
With reference to embodiment I
1preparation method one, by the compound (5a) in compound (5l) alternative method, with preparation azanol reaction, finally make final product I
14for faint yellow solid, productive rate 73.3%, ESI-MS (m/z): 450[M+H]
+,
1h NMR (d
6-DMSO, 300MHz): δ 11.58 (s, 1H, NH), 8.89 (s, 1H, H-4), 8.63 (s, 1H, N=CH), 8.33 (d, J=8.0Hz, 1H, H-5), 8.17 (d, J=8.0Hz, 2H, ArH), 7.79 (d, J=8.7Hz, 2H, ArH), 7.58-7.67 (m, 5H, ArH), 7.39 (m, 1H, H-6), 7.18 (t, 2H, J=8.7Hz, ArH).
Embodiment 15:4-((2-(9H-pyrido [3,4-b] indoles-1-[4-(N, N-dimethyl) phenyl]-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
15) preparation
1-[4-(N, N-dimethyl) phenyl]-β-carboline-3-carboxylate methyl ester (2m)
With reference to the synthetic method of (2a) in embodiment 1, by 2,3,4-tetrahydro-beta-carboline-1-[4-(N, N-dimethyl) phenyl] (1a) and KMnO in-3-carboxylate methyl ester (1m) replacement method
4reaction, finally obtains light brown solid (2m), productive rate 71.1%.
1-[4-(N, N-dimethyl) phenyl]-β-carboline-3-carboxylic acid hydrazides (4m)
With reference to the synthetic method of (4a) in embodiment 1, reacted with 85% hydrazine hydrate by (2a) in (2m) replacement method, finally obtain (4m) for light brown solid, productive rate 61.9%.
4-((2-(9H-pyrido [3,4-b] indoles-1-[4-(N, N-dimethyl) phenyl]-3-carbonyl) hydrazono-) methyl) methyl benzoate (5m)
With reference to the synthetic method of (5a) in embodiment 1, reacted with p formyl benzoic acid methyl esters by (4a) in (4m) replacement method, finally obtain (5m) for yellow solid, productive rate 66.6%, ESI-MS (m/z): 492[M+H]
+.
4-((2-(9H-pyrido [3,4-b] indoles-1-[4-(N, N-dimethyl) phenyl]-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
15)
With reference to embodiment I
1preparation method one, by the compound (5a) in compound (5m) alternative method, with preparation azanol reaction, finally make final product I
15for faint yellow solid, productive rate 72.9%, ESI-MS (m/z): 493[M+H]
+.
Embodiment 16:4-((2-(9H-pyrido [3,4-b] indoles-9-methyl-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
16) preparation
9-methyl-β-carboline-3-carboxylate methyl ester (3a
1)
By 2a(2.26g, 10mmol) be dissolved in 15ml DMF, add NaH (0.36g, 15mmol) to activate after 1h under condition of ice bath, dropwise add CH
3after I (1.86ml, 30mmol) reaction 3h, in reaction solution, add frozen water to separate out a large amount of solids, suction filtration obtains 3a
1fallow solid 1.80g, productive rate 75.0%.
9-methyl-β-carboline-3-carboxylic acid hydrazides (4a
1)
With reference to the synthetic method of 4a, obtain faint yellow solid 4a
1, productive rate 69.6%.
4-((2-(9H-pyrido [3,4-b] indoles-9-methyl-3-carbonyl) hydrazono-) methyl) methyl benzoate (5a
1)
With reference to the synthetic method of 5a, obtain faint yellow solid 5a
1, productive rate 64.8%.
4-((2-(9H-pyrido [3,4-b] indoles-9-methyl-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
16)
With reference to embodiment I
1preparation method one, by compound (5a
1) compound (5a) in alternative method, with the azanol reaction of preparation, finally making final product is faint yellow solid, productive rate 74.6%.ESI-MS(m/z):388[M+H]
+,
1H?NMR(d
6-DMSO,300MHz):δ11.28(s,1H,N
HOH),9.01(s,1H,H-1),8.78(s,1H,H-4),8.53(s,1H,N=CH),8.26(d,J=8.0Hz,1H,H-5),7.78(d,J=8.7Hz,2H,ArH),7.69(d,J=7.5Hz,1H,H-8),7.58(m,1H,H-7),7.46(d,1H,J=7.5Hz,H-6),7.25(d,2H,J=8.7Hz,ArH),3.84(s,3H,NCH
3).
Embodiment 17:4-((2-(9H-pyrido [3,4-b] indoles-1-(4-p-methoxy-phenyl)-9-methyl-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
17) preparation
1-(4-p-methoxy-phenyl)-9-methyl-β-carboline-3-carboxylate methyl ester (3b
1)
With reference to (3a in embodiment 16
1) synthetic method, by (2a) in (2c) replacement method and NaH and CH
3i reaction, finally obtains light brown solid (3b
1), productive rate 77.8%.
1-(4-p-methoxy-phenyl)-9-methyl-β-carboline-3-carboxylic acid hydrazides (4b
1)
With reference to the synthetic method of (4a) in embodiment 1, by (3b
1) (2a) in replacement method react with 85% hydrazine hydrate, finally obtains (4b
1) be light brown solid, productive rate 69.2%.
4-((2-(9H-pyrido [3,4-b] indoles-1-(4-p-methoxy-phenyl)-9-methyl-3-carbonyl) hydrazono-) methyl) methyl benzoate (5b
1)
With reference to the synthetic method of (5a) in embodiment 1, by (4b
1) (4a) in replacement method react with p formyl benzoic acid methyl esters, finally obtains (5b
1) be yellow solid, productive rate 77.2%, ESI-MS (m/z): 493[M+H]
+.4-((2-(9H-pyrido [3,4-b] indoles-1-(4-p-methoxy-phenyl)-9-methyl-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
17)
With reference to embodiment I
1preparation method one, by compound (5b
1) compound (5a) in alternative method, the azanol reaction with preparation, finally makes final product I
17for faint yellow solid, productive rate 76.7%, ESI-MS (m/z): 494[M+H]
+,
1h NMR (d
6-DMSO, 300MHz): δ 11.27 (s, 1H, N
hoH), 8.92 (s, 1H, H-4), 8.60 (s, 1H, N=CH), 8.36 (d, J=8.0Hz, 1H, H-5), 8.24 (d, J=8.0Hz, 2H, ArH), 7.82 (d, J=8.7Hz, 2H, ArH), 7.62-7.66 (m, 3H, ArH), 7.53 (m, 1H, H-7), 7.32 (t, 1H, J=7.5Hz, H-6), 7.20 (d, 2H, J=8.7Hz, ArH), 3.88 (s, 3H, OCH
3), 3.79 (s, 3H, NCH
3).
Embodiment 18:4-((2-(9H-pyrido [3,4-b] indoles-1-(4-p-methoxy-phenyl)-9-methyl-3-carbonyl) hydrazono-) methyl)-N-(2-aminophenyl)-benzamide (I
18) preparation
4-((2-(9H-pyrido [3,4-b] indoles-1-(4-p-methoxy-phenyl)-9-methyl-3-carbonyl) hydrazono-) methyl) phenylformic acid (6b
1)
With reference to the synthetic method of (6a) in embodiment 1, by (5b
1) (5a) and NaOH back flow reaction in replacement method, finally obtain (6b
1) be yellow solid, productive rate 93.6%.
4-((2-(9H-pyrido [3,4-b] indoles-1-(4-p-methoxy-phenyl)-9-methyl-3-carbonyl) hydrazono-) methyl)-N-(2-aminophenyl)-benzamide (I
18)
With reference to embodiment I
2preparation method, by compound (6b
1) compound (6a) in alternative method; react with single tertbutyloxycarbonyl phenylenediamine, EDCI (1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride), a small amount of DMAP (DMAP), obtain (the 6b of single tertbutyloxycarbonyl protection through column chromatography purification (moving phase ethyl acetate: sherwood oil=1:5-5:1)
1), (6b of single tertbutyloxycarbonyl protection
1) again with trifluoroacetic acid deprotection, finally make final product and finally make final product I
18for faint yellow solid, productive rate 74.9%, ESI-MS (m/z): 569[M+H]
+.
Embodiment 19:4-((2-(9H-pyrido [3,4-b] indoles-1-(3,4-methylenedioxyphenyl)-9-methyl-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
19) preparation
1-(3,4-methylenedioxyphenyl)-9-methyl-β-carboline-3-carboxylate methyl ester (3c
1)
With reference to (3a in embodiment 16
1) synthetic method, by (2a) in (2e) replacement method and NaH and CH
3i reaction, finally obtains light brown solid (3c
1), productive rate 72.8%.
1-(3,4-methylenedioxyphenyl)-9-methyl-β-carboline-3-carboxylic acid hydrazides (4c
1)
With reference to the synthetic method of (4a) in embodiment 1, by (3c
1) (2a) in replacement method react with 85% hydrazine hydrate, finally obtains (4c
1) be light brown solid, productive rate 69.7%.
4-((2-(9H-pyrido [3,4-b] indoles-1-(3,4-methylenedioxyphenyl)-9-methyl-3-carbonyl) hydrazono-) methyl) methyl benzoate (5c
1)
With reference to the synthetic method of (5a) in embodiment 1, by (4c
1) (4a) in replacement method react with p formyl benzoic acid methyl esters, finally obtains (5c
1) be yellow solid, productive rate 72.8%, ESI-MS (m/z): 507[M+H]
+.
4-((2-(9H-pyrido [3,4-b] indoles-1-(3,4-methylenedioxyphenyl)-9-methyl-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
19)
With reference to embodiment I
1preparation method, by compound (5c
1) compound (5a) in alternative method, and prepare azanol reaction, finally make final product I
19for faint yellow solid, productive rate 73.6%, ESI-MS (m/z): 508[M+H]
+;
1h NMR (d
6-DMSO, 300MHz): δ 11.21 (s, 1H, N
hoH), 8.77 (s, 1H, H-4), 8.49 (s, 1H, N=CH), 8.29 (m, 1H, H-5), 8.15 (d, J=8.0Hz, 2H, ArH), 7.78 (d, J=8.7Hz, 2H, ArH), 7.62-7.67 (m, 2H, ArH), 7.46 (m, 1H, H-7), 7.37 (t, 1H, J=7.5Hz, H-6), 7.11 (d, 2H, J=8.7Hz, ArH), 5.63 (s, 2H, OCH
2o), 3.85 (s, 3H, NCH
3).
Embodiment 20:4-((2-(9H-pyrido [3,4-b] indoles-1-(4-fluorophenyl)-9-methyl-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
20) preparation
1-(4-fluorophenyl)-9-methyl-β-carboline-3-carboxylate methyl ester (3d
1)
With reference to (3a in embodiment 16
1) synthetic method, by (2a) in (2h) replacement method and NaH and CH
3i reaction, finally obtains light brown solid (3d
1), productive rate 82.1%.
1-(4-fluorophenyl)-9-methyl-β-carboline-3-carboxylic acid hydrazides (4d
1)
With reference to the synthetic method of (4a) in embodiment 1, by (3d
1) (2a) in replacement method react with 85% hydrazine hydrate, finally obtains (4d
1) be light brown solid, productive rate 73.6%.
4-((2-(9H-pyrido [3,4-b] indoles-1-(4-fluorophenyl)-9-methyl-3-carbonyl) hydrazono-) methyl) methyl benzoate (5d
1)
With reference to the synthetic method of (5a) in embodiment 1, by (4d
1) (4a) in replacement method react with p formyl benzoic acid methyl esters, finally obtains (5d
1) be yellow solid, productive rate 81.6%, ESI-MS (m/z): 481[M+H]
+.
4-((2-(9H-pyrido [3,4-b] indoles-1-(4-fluorophenyl)-9-methyl-3-carbonyl) hydrazono-) methyl) phenylformic acid (6d
1)
With reference to the synthetic method of (6a) in embodiment 1, by (5d
1) (5a) and NaOH back flow reaction in replacement method, finally obtain (6d
1) be yellow solid, productive rate 96.8%.
4-((2-(9H-pyrido [3,4-b] indoles-1-(4-fluorophenyl)-9-methyl-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
20)
With reference to embodiment I
1preparation method two, by compound (6d
1) compound (6a) in alternative method, make mixed acid anhydride with Vinyl chloroformate and N-methylmorpholine, then with pyrans azanol reaction, make compound (6d
1) azanol of pyrans protection, compound (6d
1) azanol of pyrans protection makes final product and finally make final product I under trifluoroacetic acid deprotection
20for faint yellow solid, productive rate 68.5%, ESI-MS (m/z): 482[M+H]
+.
Embodiment 21:4-((2-(9H-pyrido [3,4-b] indoles-1-(4-bromophenyl)-9-methyl-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
21) preparation
1-(4-bromophenyl)-9-methyl-β-carboline-3-carboxylate methyl ester (3e
1)
With reference to (3a in embodiment 16
1) synthetic method, by (2a) in (2j) replacement method and NaH and CH
3i reaction, finally obtains light brown solid (3e
1), productive rate 83.7%.
1-(4-bromophenyl)-9-methyl-β-carboline-3-carboxylic acid hydrazides (4e
1)
With reference to the synthetic method of (4a) in embodiment 1, by (3e
1) (2a) in replacement method react with 85% hydrazine hydrate, finally obtains (4e
1) be light brown solid, productive rate 74.2%.
4-((2-(9H-pyrido [3,4-b] indoles-1-(4-bromophenyl)-9-methyl-3-carbonyl) hydrazono-) methyl) methyl benzoate (5e
1)
With reference to the synthetic method of (5a) in embodiment 1, by (4e
1) (4a) in replacement method react with p formyl benzoic acid methyl esters, finally obtains (5e
1) be yellow solid, productive rate 74.4%, ESI-MS (m/z): 541[M+H]
+.
4-((2-(9H-pyrido [3,4-b] indoles-1-(4-bromophenyl)-9-methyl-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
21)
With reference to embodiment I
1preparation method one, by compound (5e
1) compound (5a) in alternative method, the azanol reaction with preparation, finally makes final product I
21for faint yellow solid, productive rate 64.7%, ESI-MS (m/z): 542[M+H]
+.
Embodiment 22:4-((2-(9H-pyrido [3,4-b] indoles-1-(4-(N, N-3,5-dimethylphenyl))-9-methyl-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
22) preparation
1-(4-(N, N-3,5-dimethylphenyl))-9-methyl-β-carboline-3-carboxylate methyl ester (3f
1)
With reference to (3a in embodiment 16
1) synthetic method, by (2a) in (2m) replacement method and NaH and CH
3i reaction, finally obtains light brown solid (3f
1), productive rate 83.8%.
1-(4-(N, N-3,5-dimethylphenyl))-9-methyl-β-carboline-3-carboxylic acid hydrazides (4f
1)
With reference to the synthetic method of (4a) in embodiment 1, by (3f
1) (2a) in replacement method react with 85% hydrazine hydrate, finally obtains (4f
1) be light brown solid, productive rate 77.2%.
4-((2-(9H-pyrido [3,4-b] indoles-1-(4-(N, N-3,5-dimethylphenyl))-9-methyl-3-carbonyl) hydrazono-) methyl) methyl benzoate (5f
1)
With reference to the synthetic method of (5a) in embodiment 1, by (4f
1) (4a) in replacement method react with p formyl benzoic acid methyl esters, finally obtains (5f
1) be yellow solid, productive rate 84.3%, ESI-MS (m/z): 507[M+H]
+.
Embodiment 23:4-((2-(9H-pyrido [3,4-b] indoles-9-tertbutyloxycarbonyl-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
23) preparation
9-Boc-β-carboline-3-carboxylate methyl ester (3a
2)
By 4a(0.90g, 4mmol) be dissolved in 10mL CH
2cl
2with the mixed solvent of 10mL acetone, add the DMAP of catalytic amount, drip Boc acid anhydrides (2.6mL, 12mmol), stirring at room temperature, until TLC detection reaction is complete.Solvent evaporated, adds 20mL water, and ethyl acetate extraction (20mL × 3) merges organic layer, saturated common salt water washing, and anhydrous sodium sulfate drying, concentrating under reduced pressure obtains brown color solid 1.19g, yield 87.5%.
9-Boc-β-carboline-3-carboxylic acid hydrazides (4a
2)
With reference to the synthetic method of (4a) in embodiment 1, by (3a
2) (2a) in replacement method react with 85% hydrazine hydrate, finally obtains (4a
2) be light brown solid, productive rate 73.2%.
4-((2-(9H-pyrido [3,4-b] indoles-9-tertbutyloxycarbonyl-3-carbonyl) hydrazono-) methyl) methyl benzoate (5a
2)
With reference to the synthetic method of (5a) in embodiment 1, by (4a
2) (4a) in replacement method react with p formyl benzoic acid methyl esters, finally obtains (5a
2) be yellow solid, productive rate 81.3%, ESI-MS (m/z): 473[M+H]
+.
4-((2-(9H-pyrido [3,4-b] indoles-9-tertbutyloxycarbonyl-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
23)
With reference to embodiment I
1preparation method one, by compound (5a
2) compound (5a) in alternative method, and prepare azanol reaction, finally make final product I
23for faint yellow solid, productive rate 68.7%, ESI-MS (m/z): 474[M+H]
+;
1h NMR (d
6-DMSO, 300MHz): δ 11.16 (s, 1H, N
hoH), 8.98 (s, 1H, H-1), 8.81 (s, 1H, H-4), 8.57 (s, 1H, N=CH), 8.26 (m, 1H, H-5), 7.78 (d, J=8.7Hz, 2H, ArH), 7.57-7.65 (m, 2H, H-7), 7.39 (t, 1H, J=7.5Hz, H-6), 7.19 (d, 2H, J=8.7Hz, ArH), 1.25 (s, 9H, C (CH
3)
3).
Embodiment 24:4-((2-(9H-pyrido [3,4-b] indoles-1-(4-p-methoxy-phenyl)-9-tertbutyloxycarbonyl-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
24) preparation
1-(4-p-methoxy-phenyl)-9-Boc-β-carboline-3-carboxylate methyl ester (3b
2)
With reference to (3a in embodiment 23
2) synthetic method, by (2a) in (2c) replacement method and DMAP and Boc anhydride reaction, finally obtain light brown solid (3b
2), productive rate 81.3%.
1-(4-p-methoxy-phenyl)-9-Boc-β-carboline-3-carboxylic acid hydrazides (4b
2)
With reference to the synthetic method of (4a) in embodiment 1, by (3b
2) (2a) in replacement method react with 85% hydrazine hydrate, finally obtains (4b
2) be light brown solid, productive rate 72.4%.
4-((2-(9H-pyrido [3,4-b] indoles-1-(4-p-methoxy-phenyl)-9-tertbutyloxycarbonyl-3-carbonyl) hydrazono-) methyl) methyl benzoate (5b
2)
With reference to the synthetic method of (5a) in embodiment 1, by (4b
2) (4a) in replacement method react with p formyl benzoic acid methyl esters, finally obtains (5b
2) be yellow solid, productive rate 81.3%, ESI-MS (m/z): 580[M+H]
+,
1h NMR (d
6-DMSO, 300MHz): δ 11.27 (s, 1H, N
hoH), 8.85 (s, 1H, H-4), 8.61 (s, 1H, N=CH), 8.19-8.27 (m, 3H, ArH), 7.79 (d, J=8.7Hz, 2H, ArH), 7.58-7.67 (m, 4H, ArH), 7.38 (t, 1H, J=7.5Hz, H-6), 7.22 (d, 2H, J=8.7Hz, ArH), 3.98 (s, 3H, OCH
3), 1.29 (s, 9H, O (CH
3)
3).
Embodiment 25:4-((2-(9H-pyrido [3,4-b] indoles-1-(4-(N, N-3,5-dimethylphenyl))-9-tertbutyloxycarbonyl-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
25) preparation
1-(4-(N, N-3,5-dimethylphenyl))-9-Boc-β-carboline-3-carboxylate methyl ester (3c
2)
With reference to (3a in embodiment 23
2) synthetic method, by (2a) in (2m) replacement method and DMAP and Boc anhydride reaction, finally obtain light brown solid (3c
2), productive rate 80.6%.
1-(4-(N, N-3,5-dimethylphenyl))-9-Boc-β-carboline-3-carboxylic acid hydrazides (4c
2)
With reference to the synthetic method of (4a) in embodiment 1, by (3c
2(2a) in replacement method reacts with 85% hydrazine hydrate, finally obtains (4c
2) be light brown solid, productive rate 72.3%.
4-((2-(9H-pyrido [3,4-b] indoles-1-(4-(N, N-3,5-dimethylphenyl))-9-tertbutyloxycarbonyl-3-carbonyl) hydrazono-) methyl) methyl benzoate (5c
2)
With reference to the synthetic method of (5a) in embodiment 1, by (4c
2) (4a) in replacement method react with p formyl benzoic acid methyl esters, finally obtains (5c
2) be yellow solid, productive rate 83.7%, ESI-MS (m/z): 607[M+H]
+.
4-((2-(9H-pyrido [3,4-b] indoles-1-(4-(N, N-3,5-dimethylphenyl))-9-tertbutyloxycarbonyl-3-carbonyl) hydrazono-) methyl)-N-hydroxyl-benzamide (I
25)
With reference to embodiment I
1preparation method one, by compound (5c
2) compound (5a) in alternative method, and prepare azanol reaction, finally make final product I
25for faint yellow solid, productive rate 68.9%, ESI-MS (m/z): 608[M+H]
+.
Embodiment 26: blue colorimetry (MTT) antitumor activity in vitro of tetramethyl-nitrogen azoles
Adopt routinely MTT to evaluate the antiproliferative activity of the compounds of this invention to 7 kinds of human cancer cell strains.Mtt assay has been widely used in the responsive mensuration of large-scale screening anti-tumor medicine, cell toxicity test and tumour radiotherapy etc.Select SAHA as positive control drug.
Human cancer cell strain: liver cancer cell Hep G2, pancreatic cancer cell Panc-1, colon cancer cell HCT116, lung cell A549, stomach cancer cell SGC7901, breast cancer cell Mcf-7, Proliferation of Human Ovarian Cell SKOV-3.Experimental technique is as follows: get in one bottle, cell in good condition exponential phase of growth, add 0.25% tryptic digestion, attached cell is come off, make every milliliter containing 2 × 10
4～4 × 10
4the suspension of individual cell.Obtained cell suspension is inoculated on 96 orifice plates, and every hole 180 μ L, put constant temperature CO
2in incubator, cultivate 24 hours.Change liquid, add test-compound I
1-I
25(compound is with diluting with PBS after DMSO dissolving, and test-compound concentration is respectively 5 × 10
-6, 2.5 × 10
-5mol/L), every hole 20 μ L, cultivate 48 hours.MTT is added in 96 orifice plates, and every hole 20 μ L, react in incubator 4 hours.Suck supernatant liquor, add DMSO, every hole 150 μ L, jolting 5 minutes on dull and stereotyped shaking table.Be the optical density in the every hole of mensuration, 570nm place with enzyme-linked immunosorbent assay instrument at wavelength, calculate cell inhibitory rate.Experimental result is as shown in table 2.
Cell inhibitory rate=(negative control group OD Zhi – tested material group OD value)/negative control group OD value × 100%.
Embodiment 27: HDACs is suppressed to active testing
Adopt the ELISA enzyme linked immunological test compounds inhibition activity to HDAC in vitro.EpiQuik
tMhADC Activity/Inhibition Assay Kit is purchased from Epigentek company, test-compound is configured to respectively to the solution of 10nM, 100nM and tri-concentration of 1 μ M, after getting respectively HDACs damping fluid and Hela nucleus extraction thing and jointly hatching at 37 DEG C, add HDAC fluorogenic substrate, at 37 DEG C, hatch 45min, then in reacting hole, add HDAC Assay developer termination reaction, and hatch 20min at 37 DEG C, use microplate reader to go out to survey absorbancy at 405nm.Compound under each concentration of each compound is tested in triplicate.
Hela nucleus extraction thing working method: get Hela cell strain, the lower cell of piping and druming, it is centrifugal that to leave cell precipitation for subsequent use.Every 20 μ L cell precipitations (approximately 2 × 10
6cell) add 200 μ L interpolation phenylmethylsulfonyl fluoride (PMSF) cell protein extract reagent, high speed vortex disperse, ice bath 5-10min, adds suppressor proteins extraction agent 10 μ L, centrifugal 5min after high speed vortex.Absorb supernatant, then add 50uL interpolation PMSF Nuclear extract extract reagent, after repeated removal supernatant, can extract the Hela Nuclear extract obtaining.
Data analysing method: a. calculates the average signal value of each sample; B. the signal value of each concentration of specimens deducts average background signal value; C. calculate the inhibiting rate of each sample.100% active hole count value is deducted respectively after each testing compound different concns corresponding aperture numerical value, divided by 100% active hole count value, be multiplied by 100 inhibiting rates that obtain respectively each test-compound different concns.Inhibiting rate=(100% active hole count value-testing compound corresponding aperture numerical value)/100% active hole count value × 100.The IC of test-compound
50in Excel, with concentration and corresponding inhibiting rate, obtain through nonlinear regression and fitting.
Embodiment 28:Acetyl-histone H3, the test of p-NF-kB activity
Adopt Western blotting to detect test-compound I
1-I
25acetyl-histone H3 to tumour cell HCT116, the test of p-NF-kB activity.Get in exponential phase of growth cell in good condition make every milliliter containing 1.5 × 10
5the suspension of individual cell, is inoculated on 96 orifice plates, puts constant temperature CO
2in incubator, cultivate 24h.Change liquid, add 6.125 μ M test-compounds, negative control adds equivalent PBS, continues to cultivate 8h.Trysinization, PBS cleans twice.Sample is resuspended in PBS, abandons supernatant, and cell is placed in 2mL EP pipe and adds protein cleavage liquid, 200 μ L/ pipes, repeatedly after piping and druming, react 30min in ice bath, in centrifuging and taking supernatant liquor 2mL EP pipe, adopting SDS-PAGE(gum concentration is 12%) separate and transfer on nitrocellulose membrane.Film is put in 5% the skim-milk confining liquid of now joining, sealing finishes with a small amount of Blot wash clean remaining milk powder rinsing, and primary antibodie is diluted to working concentration with TBST, 500 μ L/ bars, and room temperature shaking table reacts 1h, can put thereafter 4 DEG C and spend the night.After reaction finishes, cut off valve bag, discarded antibody, is placed in ware TBST by each film and cleans 4 times.Dilute two of peroxidase mark with TBST and resist to working fluid concentration, 500 μ L/ bars.By front method envelope and shaking table reaction, after reaction finishes, abandon two and resist, with TBST cleaning 4 times.PIERCE luminescent solution A liquid+B liquid equal-volume mixes and pours in the valve bag making, and after reaction 5min, film is transferred to exposure image in BIO-RAD gel imaging instrument magazine.
Claims (7)
1. the hdac inhibitor and the pharmacy acceptable salt thereof that contain β-carboline-3-acyl hydrazono-, is characterized in that: the structure with following formula I:
Formula I: R represents H, CH
3or tertbutyloxycarbonyl;
R
1represent H, CH
3, phenyl, 4-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-hydroxy phenyl, 3-hydroxy phenyl, 4-nitrophenyl, 4-fluorophenyl, 4-chloro-phenyl-, 4-bromophenyl, 4-cyano-phenyl,
or
r
2represent NHOH or
2. hdac inhibitor and the pharmacy acceptable salt thereof that contains β-carboline-3-acyl hydrazono-according to claim 1, is characterized in that: R, R in the structure of described formula I
1, R
2be selected from following combination:
R=H，R
1=H，R
2=NHOH；
Or R=H, R
1=H,
Or R=H, R
1=CH
3, R
2=NHOH;
Or R=H, R
1=4-p-methoxy-phenyl, R
2=NHOH;
Or R=H, R
1=4-p-methoxy-phenyl,
Or R=H, R
1=3-p-methoxy-phenyl, R
2=NHOH;
Or R=H,
r
2=NHOH;
Or R=H, R
1=3,4-Dimethoxyphenyl, R
2=NHOH;
Or R=H, R
1=4-nitrophenyl, R
2=NHOH;
Or R=H, R
1=4-fluorophenyl, R
2=NHOH;
Or R=H, R
1=4-chloro-phenyl-, R
2=NHOH;
Or R=H, R
1=4-bromophenyl, R
2=NHOH;
Or R=H, R
1=4-cyano-phenyl, R
2=NHOH;
Or R=H, R
1=phenyl, R
2=NHOH;
Or R=H,
r
2=NHOH;
Or R=CH
3, R
1=H, R
2=NHOH;
Or R=CH
3, R
1=4-p-methoxy-phenyl, R
2=NHOH;
Or R=CH
3, R
1=4-p-methoxy-phenyl,
Or R=CH
3,
r
2=NHOH;
Or R=CH
3, R
1=4-fluorophenyl, R
2=NHOH;
Or R=CH
3, R
1=4-bromophenyl, R
2=NHOH;
Or R=CH
3,
r
2=NHOH;
Or R=tertbutyloxycarbonyl,
r
2=NHOH;
Or R=tertbutyloxycarbonyl, R
1=4-p-methoxy-phenyl, R
2=NHOH;
Or R=tertbutyloxycarbonyl, R
1=H, R
2=NHOH.
3. the hdac inhibitor that contains β-carboline-3-acyl hydrazono-claimed in claim 1 and a preparation method for pharmacy acceptable salt thereof, is characterized in that: comprise the following steps: 1,2,3,4-tetrahydro-beta-carboline-1-R
1-3-carboxylate methyl ester (1) obtains β-carboline-1-R through potassium permanganate oxidation
1-3-carboxylate methyl ester (2), intermediate β-carboline-1-R
1-3-carboxylate methyl ester (2) reacts and obtains 9 R ' substitution products of β-carboline (3) with halogenated alkane or two dimethyl dicarbonate butyl esters (Boc acid anhydrides); above-claimed cpd (2) or (3) obtain hydrazide compound (4) with hydrazine hydrate back flow reaction in methyl alcohol; hydrazide compound (4) obtains hydrazono-product (5) with the condensation reaction under acetic acid catalysis of p formylbenzoic acid methyl esters, and hydrazono-product (5) can be prepared formula I by one of following two kinds of methods
a:
Method one: adopt hydrazono-product (5) directly to react and make formula I under the methanol solution of potassium hydroxide with oxammonium hydrochloride
a;
Method two: hydrazono-product (5) is hydrolyzed and obtains hydrolysate (6) in the methanol solution of sodium hydroxide; hydrolysate (6) makes mixed acid anhydride with Vinyl chloroformate and N-methylmorpholine under anhydrous tetrahydrofuran solution subsequently; and make with O-(tetrahydropyrans-2-yl) azanol reaction the amide product that contains tetrahydropyrans azanol, then slough tetrahydropyrans protecting group with trifluoroacetic acid immediately and make formula I
a;
Synthetic route is as follows:
Wherein, R represents H, CH
3or tertbutyloxycarbonyl;
R
1represent H, CH
3, phenyl, 4-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-hydroxy phenyl, 3-hydroxy phenyl, 4-nitrophenyl, 4-fluorophenyl, 4-chloro-phenyl-, 4-bromophenyl, 4-cyano-phenyl,
or
r ' represents CH
3or tertbutyloxycarbonyl;
I
abelong to generalformulaⅰcompound.
4. the hdac inhibitor that contains β-carboline-3-acyl hydrazono-claimed in claim 1 or a preparation method for its pharmacy acceptable salt, is characterized in that: 1,2,3,4-tetrahydro-beta-carboline-1-R
1-3-carboxylate methyl ester (1) obtains β-carboline-1-R through potassium permanganate oxidation
1-3-carboxylate methyl ester (2), intermediate β-carboline-1-R
1-3-carboxylate methyl ester (2) reacts and obtains 9 R ' substitution products of β-carboline (3) with halogenated alkane or two dimethyl dicarbonate butyl esters (Boc acid anhydrides), above-claimed cpd (2) or (3) obtain hydrazide compound (4) with hydrazine hydrate back flow reaction in methyl alcohol, and hydrazide compound (4) obtains hydrazono-product (5) with the condensation reaction under acetic acid catalysis of p formylbenzoic acid methyl esters; Hydrazono-product (5) is hydrolyzed and obtains hydrolysate (6) in the methanol solution of sodium hydroxide; then react and obtain condensation product (7) in the dichloromethane solution of 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride and DMAP with the O-Phenylene Diamine of single Boc protection, be used in again subsequently trifluoroacetic acid and slough Boc protecting group and obtain formula I
b;
Obtain synthetic route after hydrazono-product as follows:
Wherein, R represents H, CH
3or tertbutyloxycarbonyl;
R
1represent H, CH
3, phenyl, 4-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-hydroxy phenyl, 3-hydroxy phenyl, 4-nitrophenyl, 4-fluorophenyl, 4-chloro-phenyl-, 4-bromophenyl, 4-cyano-phenyl,
or
i
bbelong to generalformulaⅰcompound.
5. a pharmaceutical composition, contains the hdac inhibitor that contains β-carboline-3-acyl hydrazono-claimed in claim 1 or its pharmacy acceptable salt and pharmaceutically acceptable auxiliary material.
6. hdac inhibitor or its pharmacy acceptable salt that contains β-carboline-3-acyl hydrazono-claimed in claim 1 treats and/or prevents the application in tumour medicine in preparation.
7. hdac inhibitor or its pharmacy acceptable salt that contains β-carboline-3-acyl hydrazono-claimed in claim 6 treats and/or prevents the application in tumour medicine in preparation, it is characterized in that: described in treat and/or prevent tumour medicine for treating and/or preventing liver cancer, carcinoma of the pancreas, colorectal carcinoma, lung cancer, cancer of the stomach, the medicine of the tumours such as mammary cancer and ovarian cancer.
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