CN105669556B - It is a kind of with the amides compound of 3 substituted pyrazolecarboxylic 5 of antitumor activity and its application - Google Patents
It is a kind of with the amides compound of 3 substituted pyrazolecarboxylic 5 of antitumor activity and its application Download PDFInfo
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- CN105669556B CN105669556B CN201610004748.8A CN201610004748A CN105669556B CN 105669556 B CN105669556 B CN 105669556B CN 201610004748 A CN201610004748 A CN 201610004748A CN 105669556 B CN105669556 B CN 105669556B
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- 0 CCC(C=C1C(*)(CC(OC)=C)C1)=N Chemical compound CCC(C=C1C(*)(CC(OC)=C)C1)=N 0.000 description 8
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- C07—ORGANIC CHEMISTRY
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention belongs to pharmaceutical technology field; it is related to a kind of sulfenyl class compound with antitumor activity; more particularly to the amides compound of 3 substituted pyrazolecarboxylic 5 containing sulfenyl; and its pharmaceutically acceptable salt, hydrate; with the pharmaceutical composition using the compound as active component, and prepare histon deacetylase (HDAC) inhibitor and its for treat and/or pre- anti-cancer in purposes.Compound and its pharmaceutically acceptable salt, hydrate structure shown in involved formula I is as follows：Wherein, R1、R2As described in claim and specification.
Description
Technical field：
The invention belongs to pharmaceutical technology field, is related to a kind of sulfenyl class compound with antitumor activity, and in particular to
3- substituted pyrazolecarboxylic -5- amides compounds containing sulfenyl, and its pharmaceutically acceptable salt, hydrate, and with the compound
For the pharmaceutical composition of active component, and preparing histon deacetylase (HDAC) inhibitor and its for treating and/or preventing
Purposes in cancer.
Background technology：
Epigenetic research just turns into the hope that the mankind capture tumour.Epigenetic, which changes, to mostly occur in tumorigenic morning
Phase, now tumour cell material injury is not yet caused to human body, now intervened, it is more likely that strangled in cradle
In.In addition, being practically impossible to compared to genetic modification for reverse, epigenetic modification can reverse extremely, make tumour cell
Revert to normal condition.Thus, epigenetic research has more wide application prospect.
Histone modification is a kind of important way of epigenetic modification, and mankind overwhelming majority tumour cell all has group egg
White modification is abnormal, and this exception can cause tumor suppressor gene silence to cause tumour to be formed.Histon deacetylase (HDAC) (Histone
Deacetylase, HDAC) it is an enzyme family for including multiple members, 18 kinds of hypotypes are currently known, by its germline and and ferment
Female homology difference is divided into following four classes：With yeast Rpd3, HoS1, HoS2 homologous I classes, including HDAC1,2,3,8；With yeast
Hda1, HoS3 homologous IIa classes include HDAC6,10 including HDAC4,5,7,9, IIb classes；The homologous Group III with yeast Sir2,
Including SIRT1~SIRT7；There are Homoeology, but the IV classes that its germline is different with I and II classes HDAC, there is HDAC11.Wherein
I, II, IV class are classical Zn2+The HDACs of dependence, and group iii belongs to Sirtuin families, is NAD+The HDACs of dependence.Grind
Study carefully and show, I and II classes HDACs can suppress tumor cell differentiation and apoptosis, promote tumor cell proliferation etc., itself and tumour
Occur, develop one of closely related, to have been studied as antineoplastic using the inhibitor research that HDACs is target spot focus.
The present invention has designed and synthesized a series of 3- substituted pyrazolecarboxylic -5- acyls containing sulfenyl on the basis of bibliography
Aminated compounds, anti tumor activity in vitro test result show that it has good antitumor activity, and show excellent
HDAC inhibitory action.
The content of the invention：
It is an object of the invention to provide a kind of sulfenyl class compound with antitumor activity, specially contain sulfenyl
3- substituted pyrazolecarboxylic -5- amides compounds and preparation method thereof, and such compound presses down as histon deacetylase (HDAC)
Application of the preparation in preventing and/or treating tumour.
The present invention relates to the compound shown in formula I and its pharmaceutically acceptable salt, hydrate：
Wherein,
R1It is independently selected from following substituent：H, C1-C4Alkyl, C3-C6Cycloalkyl, substituted or unsubstituted C6~C10Aryl or
Heteroaryl, the substituent can be C1-C4Alkoxy, C1-C4Alkyl, C6~C10Aryl, the heteroaryl contain 1-3 N, O
Or S hetero atom；
R2It is independently selected from following substituent：H, C1-C4Alkyl, C1-C4Acyl group, C1-C4Alkenyl oxygen carbonyl, benzyloxycarbonyl group, C6-
C12Artyl sulfo, oleic acid base, 3- pyridine radicals -1H- pyrazoles -5- amide groups -1,6- hexyl-sulfenyl；It is preferred that H, methyl, acetyl group,
Propiono, positive bytyry, isobutyryl, propylene oxygen carbonyl, benzyloxycarbonyl group, pyridine thio, oleic acid base, 3- pyridine radicals -1H- pyrroles
Azoles -5- amide groups -1,6- hexyls-sulfenyl；
Preferably, R1It is independently selected from following substituent：H, C1-C4Alkyl, C3-C6Cycloalkyl, substituted or unsubstituted phenyl,
Naphthyl, pyridine radicals, pyrazinyl, indyl, the substituent are C1-C4Alkoxy, phenyl；It is preferred that H, cyclohexyl, methyl, methoxy
Base phenyl, xenyl, naphthyl, pyridine radicals, pyrazinyl, indyl.
Present invention is preferably related to definition such as compounds of formula I and its pharmaceutically acceptable salt, hydrate：
R1It is independently selected from following substituent：H, cyclohexyl, methyl, methoxyphenyl, xenyl, 6~10 yuan of aryl；
R2It is independently selected from following substituent：H, C1-C4Alkyl, C1-C4Acyl group, C1-C4Alkenyl oxygen carbonyl, benzyloxycarbonyl group, C6-
C12Artyl sulfo, oleic acid base, 3- pyridine radicals -1H- pyrazoles -5- amide groups -1,6- hexyl-sulfenyl；
Present invention is preferably related to definition such as compounds of formula I and its pharmaceutically acceptable salt, hydrate：
Wherein,
R1It is independently selected from following substituent：H, cyclohexyl, methyl, phenyl, methoxyphenyl, xenyl, naphthyl, pyridine
Base, pyrazinyl, indyl；
R2It is independently selected from following substituent：H, C1-C4Alkyl, C1-C4Acyl group, C1-C4Alkenyl oxygen carbonyl, benzyloxycarbonyl group, C6-
C12Artyl sulfo, oleic acid base, 3- pyridine radicals -1H- pyrazoles -5- amide groups -1,6- hexyl-sulfenyl.
Specifically, the present invention is preferably as follows compound：
3- methyl-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
3- cyclohexyl-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
3- phenyl-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
3- (4- methoxyphenyls)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
3- (3.4- Dimethoxyphenyls)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
3- (3,4,5- trimethoxyphenyls)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
3- (4- xenyls)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
3- (1- naphthyls)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
3- (2- naphthyls)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
3- (2- pyridine radicals)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
3- (3- pyridine radicals)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
3- (4- pyridine radicals)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
3- (2- pyrazinyls)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
3- (3- indyls)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
N- (6- methyl mercaptos hexyl) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- (2- pyridyldithiols) hexyl) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- propionyl sulfydryls hexyl) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (the positive butyryl sulfydryl hexyls of 6-) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- isobutyryl sulfydryls hexyl) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- propylene oxygen carbonyl sulfydryls hexyl) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- benzyloxycarbonyl group sulfydryls hexyl) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- oleic acid base sulfydryls hexyl) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- acetyl mercaptos hexyl) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- methyl mercaptos hexyl) -3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- (2- pyridyldithiols) hexyl) -3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- propionyl sulfydryls hexyl) -3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (the positive butyryl sulfydryl hexyls of 6-) -3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- isobutyryl sulfydryls hexyl) -3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- propylene oxygen carbonyl sulfydryls hexyl) -3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- benzyloxycarbonyl group sulfydryls hexyl) -3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- oleic acid base sulfydryls hexyl) -3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- acetyl mercaptos hexyl) -3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides；
N, N '-(double 1,6- hexyls disulfide groups)-(double 3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides)；
N, N '-(double 1,6- hexyls disulfide groups)-(double 3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides).
In addition, present invention additionally comprises the prodrug of the compounds of this invention.According to the present invention, prodrug is compounds of formula I, it
Itself may have weaker activity or even without activity, but upon administration, (such as pass through generation in physiological conditions
Thank, solvolysis or other mode) it is converted to corresponding biologically active form.
The present invention includes pharmaceutical composition, and what said composition contained formula I above contains 3 (5)-substituted-phenyl -5 (3)-amide groups
The sulfenyl class compound of fragment and pharmaceutically acceptable excipients.The pharmaceutically acceptable excipients refer to any available
In the diluent, adjuvant and/or carrier of drug field.The compound of the present invention can be applied in combination with other active components,
As long as they do not produce other unfavorable effects, such as allergic reaction.
The pharmaceutical composition of the present invention can be configured to several formulation, wherein containing some excipients commonly used in drug field
Agent, for example, oral formulations (such as tablet, capsule, solution or suspension)；(solution of such as injectable is mixed for the preparation of injectable
Suspension, or the dried powder of injectable, adding water for injection before the injection can use immediately)；Topical formulations (such as ointment
Or solution).
Carrier for pharmaceutical composition of the present invention is available common type in drug field, including：Oral formulations
Adhesive, lubricant, disintegrant, cosolvent, diluent, stabilizer, suspending agent, pigment, flavouring etc.；Injectable formulation
Preservative, solubilizer, stabilizer etc.；The matrix of topical formulations, diluent, lubricant, preservative etc..Pharmaceutical preparation can
With by oral administration or parenteral (such as intravenous, subcutaneous, intraperitoneal or local) administration, if some drugses are in stomach condition
Under be unstable, enteric coated tablets can be configured to.
By press down in vitro enzyme test screen, it has been found that the compounds of this invention can inhibition of histone deacetylation enzyme activity,
Therefore, the application that the compounds of this invention can be used in the disease related to histone deacetylase activity unconventionality expression, it is such as each
Kind cancer.
Passing through external activity screening and internal pharmacodynamic study, it has been found that the compounds of this invention has antitumor activity,
Therefore the compounds of this invention can be used for preparing treatment and/or prevent the medicines of various cancers, as mammary gland, lung, colon, rectum,
Stomach, prostate, bladder, uterus, pancreas and oophoroma.
Reactive compound of the present invention can use as unique cancer therapy drug, or with one or more other antineoplastics
Thing is used in combination.Therapeutic alliance by by each therapeutic component simultaneously, order or separate administration to realize.
Examples provided hereinafter and preparation example further elucidate and illustrated the compounds of this invention and its preparation side
Method.It should be appreciated that the scope that the scope of following embodiments and preparation example is not limit the invention in any way.
Following synthetic route describes the preparation of the compound of formula I of the present invention, and all raw materials are all by these roads
Method described in line, prepared by organic chemistry filed method well-known to the ordinarily skilled artisan or it is commercially available.The present invention
Whole final compounds be all to be prepared by the method described in these routes or by similar method, these sides
Method is that organic chemistry filed is well-known to the ordinarily skilled artisan.The definition for the whole variable factor following articles applied in these routes or
Such as the definition in claim.
According to the compound of formula I of the present invention, R2For H when, according to route one method be made target compound.Each substituent
As Summary defines.
According to the compound of formula I of the present invention, R2For methyl when, according to route two method be made target compound.Respectively take
Dai Jiru Summaries are defined.
According to the compound of formula I of the present invention, R2For pyridine thio when, according to route three method be made target compound.
Each substituent such as Summary is defined.
According to the compound of formula I of the present invention, R2For 3- pyridine radicals-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- amide groups when,
Target compound is made according to the method for route four.Each substituent such as Summary is defined.
According to the compound of formula I of the present invention, R2For other substituents when, target chemical combination is made according to the method for route four
Thing.Each substituent such as Summary is defined.
Preparation method of the present invention is simple to operate, mild condition, and gained compound is respectively provided with histon deacetylase (HDAC) suppression
Activity, antitumor action are notable.
Embodiment
Below by specific embodiment, the present invention is described in detail, but the purposes of these exemplary embodiments and
Purpose is only used for enumerating the present invention, not forms any type of any restriction to the real protection scope of the present invention, more non-to incite somebody to action
Protection scope of the present invention is confined to this.
Embodiment 1:The preparation of 3- methyl-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides
Step A：The preparation of 2,4- dioxo methyl valerates
The methanol that 20ml is dried is added dropwise at 0 DEG C into 1g sodium, stirs to sodium and all dissolves, be at room temperature added dropwise to the solution
2.1g (36mmol) acetone filters, filter cake is done with the 150ml diethyl ether solutions of 4.3g (36mmol) dimethyl oxalate, reacting 4h
It is dry.Obtain white solid, yield 99.2%..
Step B：The preparation of 3- methyl isophthalic acid H- pyrazoles -5- methyl formates
150ml acetic acid is added into 5.1g (35.7mmol) 2,4- dioxo methyl valerates, stirring and dissolving, adds 2.14ml
(43.2mmol) 98% hydrazine hydrate, back flow reaction 2h, reaction solution is poured into a large amount of cold water, separates out solid, is filtered, and filter cake is done
It is dry.Obtain white solid, yield 99.7%.
Step C：The preparation of 3- methyl isophthalic acid H- pyrazoles -5- carboxylic acids
75ml methanol is added into 10.1g (71.8mmol) 3- methyl isophthalic acid H- pyrazoles -5- methyl formates, stirring and dissolving, is added
Enter the 150ml aqueous solution of 4.4g (110mmol) sodium hydroxide, after 50 DEG C are reacted 2h, pH=2 adjusted with 2M hydrochloric acid, separates out solid,
Filter, filtration cakes torrefaction.Obtain white solid, yield 99.8%.
Step D：The preparation of N- (6- bromines hexyl) -3- methyl isophthalic acid H- pyrazoles -5- acid amides
1.2g (9.7mmol) 3- methyl isophthalic acid H- pyrazoles -5- carboxylic acids are dissolved in 50ml tetrahydrofurans, 0.5ml is added at 0 DEG C
Triethylamine, 1.6g (11.6mmol) 1- hydroxy benzo triazoles (HOBt), stirring and dissolving, add 3.0g (11.6mmol) 6- bromines oneself
Amine, 10min is stirred, add (3- dimethyl propylamines) carbodiimide (EDCI) of 2.3g (12.0mmol) 1- ethyls -3, room temperature reaction
50ml water is added after 24h, ethyl acetate extracts 2 times, merges organic layer, organic layer 0.5M salt pickling 1 time, washes 1 time, saturation
Sodium bicarbonate aqueous solution is washed 1 time, and saturated sodium-chloride water solution is washed 2 times, organic layer anhydrous sodium sulfate drying.Filtering, filtrate concentration
Obtain brown solid, yield 79.4%.
Step E：The preparation of 3- methyl-N- (6- acetyl mercaptos hexyl) -1H- pyrazoles -5- acid amides
2.9g (10mmol) N- (6- bromines hexyl) -3- methyl isophthalic acid H- pyrazoles -5- acid amides is dissolved in 100ml ethanol, added
3.42g (30mmol) thioacetic acid potassium, insoluble matter is removed by filtration after being warming up to 60 DEG C of reaction 4h, is evaporated filtrate, dichloromethane is molten
Solution, dichloromethane layer are washed 2 times, and saturated sodium-chloride water solution washes 2 times, anhydrous sodium sulfate drying.Crude product is through column chromatography after concentration
Separation (silica gel, petrol ether/ethyl acetate, 5/1), obtain brown solid, yield 71.5%.
Step F：The preparation of 3- methyl-N- (6- acetyl mercaptos hexyl) -1H- pyrazoles -5- acid amides
2.8g (10mmol) S- (6- (5- (4- fluorophenyls) -1H- pyrazoles -3- amide groups) hexyl) acetyl thioester is dissolved in
In 100ml ethanol, the lower LiOH aqueous solution for adding 25ml 1.2mol/L of nitrogen protection, ethanol is evaporated off after reacting at room temperature 4h, adds
100ml water, 2M hydrochloric acid adjust pH=2, and ethyl acetate extracts 2 times, and collected organic layer, organic layer washes 2 with saturated sodium-chloride water solution
It is secondary, anhydrous sodium sulfate drying.Crude product obtains white solid through column chromatography for separation (silica gel, petrol ether/ethyl acetate, 5/1) after concentration
Body, yield 65.2%.
According to the preparation method of embodiment 1, appropriate raw material is selected, the compound of embodiment 2- embodiments 15 is made.
Embodiment 2：The preparation of N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides
Embodiment 3：The preparation of 3- cyclohexyl-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides
LC-MS m/z:335.1[M+H]+.
Embodiment 4：The preparation of 3- phenyl-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides
LC-MS m/z:338.2[M+H]+.
Embodiment 5：The preparation of 3- (4- methoxyphenyls)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides
LC-MS m/z:308.4[M+H]+.
Embodiment 6：The preparation of 3- (3.4- Dimethoxyphenyls)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides
LC-MS m/z:304.2[M+H]+.
Embodiment 7：The preparation of 3- (3,4,5- trimethoxyphenyls)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides
LC-MS m/z:320.3[M+H]+.
Embodiment 8：The preparation of 3- (4- xenyls)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides
LC-MS m/z:359.3[M+H]+.
Embodiment 9：The preparation of 3- (1- naphthyls)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides
Embodiment 10：The preparation of 3- (2- naphthyls)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides
LC-MS m/z:359.5[M+H]+
Embodiment 11：The preparation of 3- (2- pyridine radicals)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides
LC-MS m/z:334.6[M+H]+
Embodiment 12：The preparation of 3- (3- pyridine radicals)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides
LC-MS m/z:358.3[M+H]+
Embodiment 13：The preparation of 3- (4- pyridine radicals)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides
LC-MS m/z:370.2[M+H]+
Embodiment 14：The preparation of 3- (2- pyrazinyls)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides
LC-MS m/z:370.6[M+H]+
Embodiment 15：The preparation of 3- (3- indyls)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides
LC-MS m/z:370.1[M+H]+
Embodiment 16：The preparation of N- (6- methyl mercaptos hexyl) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides
3.5g (10mmol) N- (6- bromines hexyl) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides is dissolved in 100ml ethanol,
1.4g (30mmol) sulfydryl methane is added, insoluble matter is removed by filtration after being warming up to 60 DEG C of reaction 4h, is evaporated filtrate, dichloromethane is molten
Solution, dichloromethane layer are washed 2 times, and saturated sodium-chloride water solution washes 2 times, anhydrous sodium sulfate drying.Crude product is through column chromatography after concentration
Separation (silica gel, petrol ether/ethyl acetate, 5/1), obtain brown solid, yield 64.1%
LC-MS m/z:366.2[M+H]+
Embodiment 17：The preparation of N- (6- (2- pyridyldithiols) hexyl) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides
1.7g (5mmol) 3- (4- pyridine radicals)-N- (6- acetyl mercaptos hexyl) -1H- pyrazoles -5- acid amides is dissolved in
In 100mlDMF, 1ml ethamine is added, 3.3g (15mmol) 2 is added dropwise, 2 '-dimercapto pyridine, reacts at room temperature 12h.Stop reaction,
Add 200ml water, ethyl acetate extracts 3 times, concentration, quickly prepares liquid phase separation, obtains white solid.Yield 37.8%.
LC-MS m/z:376.5[M+H]+
Embodiment 18：The preparation of N- (6- propionyl sulfydryls hexyl) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides
1.5g (5mmol) 3- (4- pyridine radicals)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides is dissolved in 100ml dichloros
Methane, is added dropwise 0.46g (5mmol) propionyl chloride at 0 DEG C, and drop, which finishes, to be transferred to room temperature and continue to react 1h.Stop reaction, add 200ml
Water, dichloromethane extract 3 times, concentration, quickly prepare liquid phase separation, obtain white solid.Yield 76.3%.
LC-MS m/z:322.7[M+H]+
According to the preparation method of embodiment 18, appropriate raw material is selected, the compound of embodiment 19- embodiments 24 is made.
Embodiment 19：The preparation of N- (the positive butyryl sulfydryl hexyls of 6-) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides
LC-MS m/z:336.2[M+H]+
Embodiment 20：The preparation of N- (6- isobutyryl sulfydryls hexyl) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides
LC-MS m/z:348.4[M+H]+
Embodiment 21：The preparation of N- (6- propylene oxygen carbonyl sulfydryls hexyl) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides
LC-MS m/z:291.5[M-H]-
Embodiment 22：The preparation of N- (6- benzyloxycarbonyl group sulfydryls hexyl) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides
LC-MS m/z:294.2[M-H]-
Embodiment 23：The preparation of N- (6- oleic acid base sulfydryls hexyl) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides
LC-MS m/z:264.3[M-H]-
Embodiment 24：The preparation of N- (6- acetyl mercaptos hexyl) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides
LC-MS m/z:308.8[M+H]+
According to the preparation method of embodiment 16, appropriate raw material is selected, the compound of embodiment 25 is made.
Embodiment 25：The preparation of N- (6- methyl mercaptos hexyl) -3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides
LC-MS m/z:366.5[M+H]+
According to the preparation method of embodiment 17, appropriate raw material is selected, the compound of embodiment 26 is made.
Embodiment 26：The preparation of N- (6- (2- pyridyldithiols) hexyl) -3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides
LC-MS m/z:376.0[M+H]+
According to the preparation method of embodiment 18, appropriate raw material is selected, the compound of embodiment 27 is made.
Embodiment 27：The preparation of N- (6- propionyl sulfydryls hexyl) -3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides
LC-MS m/z:322.9[M+H]+
According to the preparation method of embodiment 27, appropriate raw material is selected, the compound of embodiment 28- embodiments 33 is made.
Embodiment 28：The preparation of N- (the positive butyryl sulfydryl hexyls of 6-) -3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides
LC-MS m/z:336.0[M+H]+
Embodiment 29：The preparation of N- (6- isobutyryl sulfydryls hexyl) -3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides
LC-MS m/z:348.1[M+H]+
Embodiment 30：The preparation of N- (6- propylene oxygen carbonyl sulfydryls hexyl) -3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides
LC-MS m/z:291.7[M-H]-
Embodiment 31：The preparation of N- (6- benzyloxycarbonyl group sulfydryls hexyl) -3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides
LC-MS m/z:294.3[M-H]-
Embodiment 32：The preparation of N- (6- oleic acid base sulfydryls hexyl) -3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides
LC-MS m/z:264.1[M-H]-
Embodiment 33：The preparation of N- (6- acetyl mercaptos hexyl) -3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides
LC-MS m/z:308.5[M+H]+
Embodiment 34：N, N '-(double 1,6- hexyls disulfide groups)-(double 3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides) system
It is standby
1.9g (5mmol) N- (6- (2- pyridyldithiols) hexyl) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides is dissolved in
100mL dichloromethane, nitrogen protection is lower to add 1.8g (5mmol) 3- (4- pyridine radicals)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5-
Acid amides, examination room temperature reaction 24h.Stop reaction, add 200mL water, 80mL dichloromethane extracts 3 times, concentration, quickly prepares liquid phase
Separation, obtains white solid.Yield 61.2%.
LC-MS m/z:607.8[M+H]+
According to the preparation method of embodiment 34, appropriate raw material is selected, the compound of embodiment 35 is made.
Embodiment 35：N, N '-(double 1,6- hexyls disulfide groups)-(double 3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides) system
It is standby
LC-MS m/z:608.0[M+H]+
The product pharmacological research of the present invention of embodiment 36.
Experiment sets blank control group (not dosing) and positive controls (Vorinostat).At room temperature by testing compound and
Hela nuclear extracts or HDAC1 or HDAC6 preculture 15min, add fluorogenic substrate Boc-Lys (Ac)-AMC.Cultivated at 37 DEG C
After 60min, terminator (containing Trypsin and SAHA) terminating reaction is added.After 15min, exist using all-wave length multi-function microplate reader
Fluorescence intensity when being respectively 355nm and 460nm is excited with launch wavelength, calculates inhibiting rate.Target compound is to HDACs enzymes
Inhibitory activity is shown in Tab.1.
Tab.1 embodiments 1-15 is to HDACs, HDAC1, HDAC6 inhibitory activity
The external inhibitory activity experiment of suppressing cell reproduction
1. cell recovery
Cell (cryopreservation tube) rapid all thawings in 37~40 DEG C of water-baths are carefully taken out from liquid nitrogen, cell is got over rapidly
Cross 0~5 DEG C of easily impaired temperature range.Aseptically suction out cell with liquid-transfering gun to be put into centrifuge tube, in 1300r/
3min is centrifuged under min, nutrient solution is gently added after abandoning supernatant, piping and druming mixes cell, moves into blake bottle and is put into titanium dioxide
Cultivated in carbon incubator, liquid is changed after 4h once.
2. passage
Subculture 2-3 times is needed to be tested after it is stable after cell recovery, passage every time sticks training with cell
Bottom of bottle portion 90% is supported to be defined.
3. cell buried plate
Make it under the digestion of blake bottle bottom with trypsin solution (0.25%) when cell growth sticks blake bottle bottom
Come.10mL nutrient solutions are added after gently discarding trypsin solution, piping and druming mixes cell, draws 10uL cell suspensions and adds
Counted in cell counting count board, adjustment cell concentration is 3.5 × 104Individual/hole.Except A1 holes are that blank well is not added with cell in 96 orifice plates
Outside, remaining all adds 100uL cell suspensions.96 orifice plates are put into incubator and cultivate 24h.
4. cell dosing
First medicine is dissolved with 50 μ L DMSO.Appropriate nutrient solution is then added, medicine is dissolved into 2mmol/mL decoctions.So
Medicine is dissolved into 100,50,25,12.5,6.25 μm of ol/mL in 96 orifice plates afterwards.Each concentration adds 3 holes, wherein surrounding two
The row cell growing way of row two is affected by environment larger, is only used as the use of blanc cell hole.96 orifice plates are put into incubator and cultivated
24h。
MTT tests assay method
Cell is pressed 1.5~3 × 104Cell density buries 96 orifice plates, and per hole 100uL, cell attachment 24h adds various concentrations
Medicine (100uL/ holes), add MTT after medicine and cell incubation 96h, be put into incubator after 4h, discard MTT (tetrazole)
Solution, add DMSO 200uL.Vibration makes survivaling cell fully be dissolved with MTT reaction products formazan on magnetic force oscillator, puts
Enter and read OD values in ELIASA at 570nm wavelength.Inhibiting rate is calculated as follows：
Using SAHA as positive control drug, the external inhibitory activity experiment of the suppressing cell reproduction of target compound.Result of the test
See Tab.2.
Tab.2 embodiments 1-23 is to breast cancer cell MCF-7 growth in vitro inhibitory activity
Above-mentioned result of the test shows that the compound of present invention formula to be protected has good antitumor activity and HDAC
Inhibitory action.The compound of the present invention has good prospects for commercial application.
Claims (8)
1. compound and its pharmaceutically acceptable salt as shown in formula I：
Wherein,
R1It is independently selected from following substituent：H, C1-C4Alkyl, C3-C6Cycloalkyl, substituted or unsubstituted naphthyl, pyridine radicals, pyrazine
Base, indyl, the substituent are C1-C4Alkoxy, phenyl；
R2It is independently selected from following substituent：H, C1-C4Alkyl, C1-C4Acyl group, C1-C4Alkenyl oxygen carbonyl, benzyloxycarbonyl group, C6-C12Virtue
Base sulfenyl, oleic acid base, 3- pyridine radicals -1H- pyrazoles -5- amide groups -1,6- hexyl-sulfenyl.
2. compound and its pharmaceutically acceptable salt described in claim 1：
Wherein,
R1It is independently selected from following substituent：H, cyclohexyl, methyl, naphthyl, pyridine radicals, pyrazinyl, indyl.
3. compound and its pharmaceutically acceptable salt any one of claim 1-2：
Wherein,
R2It is independently selected from following substituent：H, methyl, acetyl group, propiono, positive bytyry, isobutyryl, propylene oxygen carbonyl, benzyl
Oxygen carbonyl, pyridine thio, oleic acid base, 3- pyridine radicals -1H- pyrazoles -5- amide groups -1,6- hexyl-sulfenyl.
4. following compound and its pharmaceutically acceptable salt, are selected from：
3- methyl-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
3- cyclohexyl-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
3- phenyl-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
3- (4- methoxyphenyls)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
3- (3.4- Dimethoxyphenyls)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
3- (3,4,5- trimethoxyphenyls)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
3- (4- xenyls)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
3- (1- naphthyls)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
3- (2- naphthyls)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
3- (2- pyridine radicals)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
3- (3- pyridine radicals)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
3- (4- pyridine radicals)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
3- (2- pyrazinyls)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
3- (3- indyls)-N- (6- sulfydryls hexyl) -1H- pyrazoles -5- acid amides；
N- (6- (2- pyridyldithiols) hexyl) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- methyl mercaptos hexyl) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- acetyl mercaptos hexyl) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- propionyl sulfydryls hexyl) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (the positive butyryl sulfydryl hexyls of 6-) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- isobutyryl sulfydryls hexyl) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- propylene oxygen carbonyl sulfydryls hexyl) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- benzyloxycarbonyl group sulfydryls hexyl) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- oleic acid base sulfydryls hexyl) -3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides；
N, N '-(double 1,6- hexyls disulfide groups)-(double 3- (4- pyridine radicals) -1H- pyrazoles -5- acid amides)；
N- (6- (2- pyridyldithiols) hexyl) -3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- methyl mercaptos hexyl) -3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- acetyl mercaptos hexyl) -3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- propionyl sulfydryls hexyl) -3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (the positive butyryl sulfydryl hexyls of 6-) -3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- isobutyryl sulfydryls hexyl) -3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- propylene oxygen carbonyl sulfydryls hexyl) -3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- benzyloxycarbonyl group sulfydryls hexyl) -3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides；
N- (6- oleic acid base sulfydryls hexyl) -3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides；
N, N '-(double 1,6- hexyls disulfide groups)-(double 3- (3- pyridine radicals) -1H- pyrazoles -5- acid amides).
A kind of 5. pharmaceutical composition, it is characterised in that：Compound comprising any one in claim 1-4 and its pharmaceutically may be used
The salt of receiving, and pharmaceutically acceptable excipient.
6. medicine group described in the compound and its pharmaceutically acceptable salt or claim 5 of any one in claim 1-4
Application of the compound in the disease medicament related to histone deacetylase activity unconventionality expression is prepared.
7. medicine group described in the compound and its pharmaceutically acceptable salt or claim 5 of any one in claim 1-4
Application of the compound in antineoplastic is prepared.
8. application as claimed in claim 7, it is characterised in that described tumour is prostate cancer, breast cancer, cervical carcinoma or white
Blood disease.
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