CN109096272A - A kind of indoles hydroxamic acid compound with anti-tumor activity and its application - Google Patents
A kind of indoles hydroxamic acid compound with anti-tumor activity and its application Download PDFInfo
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- CN109096272A CN109096272A CN201811131149.8A CN201811131149A CN109096272A CN 109096272 A CN109096272 A CN 109096272A CN 201811131149 A CN201811131149 A CN 201811131149A CN 109096272 A CN109096272 A CN 109096272A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Abstract
The invention belongs to pharmaceutical technology fields; it is related to a kind of indoles hydroxamic acid compound with anti-tumor activity; more particularly to containing 1; 3; tri- substituted indole hydroxamic acid compound of 5-; and its pharmaceutically acceptable salt, hydrate, and using the compound as the pharmaceutical composition of active constituent, and preparing histon deacetylase (HDAC) inhibitor and its in preparation for treating and/or preventing the purposes in cancer drug.The general structure of the compound and its pharmaceutically acceptable salt, hydrate is as shown in I, wherein R is independently selected from one or more following substituent groups: H, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl；M is the integer of 4-6；Integer of the n between 0-2；
Description
Technical field:
The invention belongs to pharmaceutical technology fields, are related to a kind of indoles hydroxamic acid compound with anti-tumor activity,
More particularly to containing 1,3,5- tri- substituted indole hydroxamic acid compounds and its pharmaceutically acceptable salt, hydrate, and
Using the compound as the pharmaceutical composition of active constituent, and is preparing histon deacetylase (HDAC) inhibitor and its preparing
For treating and/or preventing the purposes in cancer drug.
Background technique:
Epigenetic research is just becoming the hope that the mankind capture tumour.Epigenetic change mostly occurs tumorigenic
In early days, tumour cell not yet causes material injury to human body at this time, is intervened at this time, it is more likely that is strangled shaking
In basket.In addition, being practically impossible to for reverse compared to genetic modification, epigenetic modification can reverse extremely, keep tumour thin
Born of the same parents revert to normal condition.Thus, epigenetic research has more extensive application prospect.
Mechanisms of Histone Acetylation Modification is a kind of important way of epigenetic modification, and mankind overwhelming majority tumour cell is all
There are histone modification exception, this exception can cause tumor suppressor gene silencing that tumour is caused to be formed.Histon deacetylase (HDAC)
(Histone deacetylase, HDAC) is the enzyme family comprising multiple members, 18 kinds of hypotypes has been currently known, by it
Germline and be divided into following four classes with yeast homologous difference: with yeast Rpd3, Hos1, Hos2 homologous I class, including HDAC1,
2,3,8；With yeast Hda1, Hos3 homologous IIa class include HDAC4,5,7,9, IIb class include HDAC6,10；With yeast Sir2
Homologous Group III, including SIRT1~SIRT7；There are Homoeology, but the IV class that its germline is different with I and II class HDAC,
There is HDAC11.Wherein I, II, IV class are classical Zn2+The HDACs of dependence, and group iii belongs to Sirtuin family, is NAD+The HDACs of dependence.Studies have shown that I and II class HDACs are able to suppress tumor cell differentiation and apoptosis, promote tumour cell
Proliferation etc., the generation, development with tumour are closely related, have become anti-tumor drug by the research of the inhibitor of target spot of HDACs
One of hot spot of research.Currently, there are many HDACs to list both at home and abroad, such as Vorinostat, west reach aniline, are mainly used for controlling
Treat non-physical knurl.
Bromine domain protein 4 (bromodomain-containing protein 4, BRD4) is BET
A member in (bromodomain and extraterminal domain) protein family, is widely present in mammal group
It knits in cell, plays important regulative in genetic transcription, cell Proliferation, apoptotic process.In BRD4 identification and bonding histone
The lysine residue of acetylation forms complex with CDK9, cyclin T1, which is P-TEFb (positive
Transcription elongation factor b) core component, and the assembling of P-TEFb is a variety of oncogene (c-
Myc, c-Jun, MCL-1) transcription key link.Targeted inhibition BRD4 can inhibit oncogene by preventing P-TEFb from assembling
Transcription and expression, these albumen promote tumor cell survival, anti-apoptotic, promote metastasis in play an important role.Mesh
Before, existing 13 enter clinical research, triazol phenodiazine by the drug of target spot of BRD4Class drug is that research is the most in-depth.
The present invention has designed and synthesized a series of containing 1,3, the 5- tri- different hydroxyl of substituted indole on the basis of bibliography
Oxime acid compounds, anti tumor activity in vitro test result show that it, with good anti-tumor activity, especially resists white blood
Sick activity, and show excellent HDAC inhibiting effect and certain BRD4 inhibiting effect.
Summary of the invention:
The purpose of the present invention is to provide a kind of indoles hydroxamic acid compounds with anti-tumor activity, specifically
For contain 1,3,5- tri- substituted indole hydroxamic acid compounds and preparation method thereof and such compound as HDAC and
BRD4 double inhibitors are preventing and/or are treating the application in tumour.
The present invention provides general formula I compound represented and its pharmaceutically acceptable salts, hydrate:
Wherein,
R is independently selected from one or more following substituent groups: H, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl；
M is the integer of 4-6；
Integer of the n between 0-2；
Preferred formula I compound represented of the present invention and its pharmaceutically acceptable salt, hydrate:
Wherein,
R is independently selected from one or more following substituent groups: H, halogen, C1-C4 alkyl, halogenated C1-C4 alkyl；
M is the integer of 4-6；
Integer of the n between 0-2；
Preferred formula I compound represented of the present invention and its pharmaceutically acceptable salt, hydrate:
Wherein,
R is independently selected from one or more following substituent groups: H, halogen, methyl, trifluoromethyl；
M is the integer of 5-6；
Integer of the n between 0-2；
Preferred formula I compound represented of the present invention and its pharmaceutically acceptable salt, hydrate:
Unless otherwise noted, term used herein " halogen " refers to fluorine, chlorine, bromine or iodine, preferably chlorine, bromine；" alkyl "
Refer to the alkyl of linear chain or branched chain.
In addition, the invention also includes the prodrugs of the compounds of this invention.According to the present invention, prodrug is compounds of formula I,
Their own may have weaker activity or even without activity, but upon administration, in physiological conditions (such as pass through
Metabolism, solvolysis or other mode) it is converted to corresponding biologically active form.
The present invention includes pharmaceutical composition, and what the composition contained formula I above contains 1,3,5- tri- substituted indole hydroxamic acid
Class compound and pharmaceutically acceptable excipients.The pharmaceutically acceptable excipients refer to that any drug that can be used for is led
Diluent, adjuvant and/or the carrier in domain.The compound of the present invention can be applied in combination with other active components, as long as they
Other unfavorable effects, such as allergic reaction are not generated.
Pharmaceutical composition of the invention can be configured to several dosage form, wherein containing some taxes common in drug field
Type agent, for example, oral preparation (such as tablet, capsule, solution or suspension)；Injectable preparation (solution of such as injectable or
The dried powder of suspension or injectable, water for injection is added before the injection to be used immediately)；Topical formulations (such as
Ointment or solution).
Carrier for pharmaceutical composition of the present invention is available common type in drug field, comprising: oral preparation
Adhesive, lubricant, disintegrating agent, cosolvent, diluent, stabilizer, suspending agent, pigment, corrigent etc.；Injectable system
Preservative, solubilizer, stabilizer of agent etc.；Matrix, diluent, lubricant, preservative of topical formulations etc..Drug system
Agent can by oral administration or parenteral (such as in intravenous, subcutaneous, peritonaeum or part) is administered, if some drugs are in stomach
Be under the conditions of portion it is unstable, enteric coated tablets can be configured to.
By pressing down enzyme test screening in vitro, it has been found that the compounds of this invention can inhibit histone deacetylase activity,
Therefore, the application that the compounds of this invention can be used in disease relevant 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 anti-tumor activity,
Therefore the compounds of this invention can be used for preparing the drug for the treatment of and/or the various cancers of prevention, as mammary gland, lung, colon, rectum,
Liver, uterus, pancreas and oophoroma.
Reactive compound of the present invention can be used as unique anticancer drug and use, or with it is one or more other antitumor
Drug combination.Combination therapy by by each therapeutic component simultaneously, sequence or separate administration and realize.
Examples provided hereinafter and preparation example further elucidate and illustrate the present invention compound and its preparation side
Method.It should be appreciated that the range of following embodiments and preparation example does not limit the scope of the invention in any way.
Following synthetic route describes the preparation of compound of formula I of the invention, and all raw materials are all by these roads
Method described in line, by organic chemistry filed it is well-known to the ordinarily skilled artisan method preparation or it is commercially available.The present invention
Whole final compounds be all to be prepared by method described in these routes or by similar method, these
Method is that organic chemistry filed is well-known to the ordinarily skilled artisan.The whole variable factors applied in these routes are as follows to determine
Definition in justice or such as claim.
Compound of formula I according to the invention,
As n=0, target compound is made according to the method for route one.Other each substituent groups such as Summary institute
Definition.
Reagent and condition: (a) sodium nitrite, stannous chloride, concentrated hydrochloric acid, water, ice bath；(b) phenylacetaldehyde, ethyl alcohol, 80 DEG C；
(c) 3,5- dimethyl isoxazole -4- pinacol borate, potassium carbonate, [1,1'- bis- (diphenylphosphino) ferrocene] dichloride
Palladium, glycol dimethyl ether, water, 100 DEG C；(d) cesium carbonate, acetonitrile, 78 DEG C (e) hydration azanols, sodium hydroxide solution (1mol/
L), methanol, room temperature.
Work as n=1, when 2, target compound is made according to the method for route two.Other each substituent group such as summary of the invention are determined
Justice.
Reagent and condition: (a) substituted or unsubstituted acyl chlorides, alchlor, methylene chloride, room temperature；(b) Lithium Aluminium Hydride, four
Hydrogen furans, room temperature；(c) 3,5- dimethyl isoxazole -4- pinacol borate, potassium carbonate, [1,1'- bis- (diphenylphosphinos) two
Luxuriant iron] palladium chloride, glycol dimethyl ether, water, 100 DEG C；(d) cesium carbonate, acetonitrile, 78 DEG C；(e) azanol, sodium hydroxide are hydrated
Solution (1mol/L), methanol, room temperature.
Preparation method of the present invention is easy to operate, mild condition, gained compound all have histon deacetylase (HDAC) and
The inhibitory activity of BRD4 has certain antitumor action.
Specific embodiment
Below by specific embodiment, the present invention is described in detail, but the purposes of these exemplary embodiments
Only it is used to enumerate the present invention with purpose, any type of any restriction not is constituted to real protection scope of the invention, it is more non-
Protection scope of the present invention is confined to this.
Embodiment 1:6- (3- phenyl -5- (3,5- dimethyl isoxazole -4- base) -1H- indoles -1- base)-N- hydroxyl hexanoyl
The preparation of amine
The synthesis of step A:4- bromobenzene hydrazine hydrochloride
Sodium nitrite in aqueous solution (20ml, 1mol/l) is added dropwise in para-bromoaniline (3g, 17.4mmol) at 0 DEG C, after
Continuous stirring was transferred to room temperature after 30 minutes, was further continued for stirring 90 minutes.It is dense that stannous chloride (12g, 52.2 mmol) is dissolved in 10ml
It after in hydrochloric acid, is added dropwise in reaction solution at 0 DEG C, continues to stir 2h.Stop reaction, obtains white solid after suction filtration, take 5ml dense
Hydrochloric acid elutes filter cake, vacuum drying, yield 89%.
The synthesis of step B:3- phenyl -5- bromo indole
4- bromobenzene hydrazine hydrochloride (2.9g, 13.2mmol) is dissolved in 50ml ethyl alcohol, be added phenylacetaldehyde (1.5g,
12.5mmol), nitrogen protection, back flow reaction 3 hours.After reaction, ethyl acetate (50ml × 3) extracts, and merges organic
Layer, concentration, column chromatography for separation obtain white solid 3.08g, yield 86%.ESI-MS:m/z, 196.0[M+H]+。
The synthesis of step C:3,5- dimethyl -4- (3- phenyl -1H- indoles -5)-isoxazole
By 3- phenyl -5- bromo indole (0.6g, 2.2mmol), 3,5- dimethyl isoxazole -4- pinacol borates
The mixing of (0.54g, 2.4mmol), sodium bicarbonate (0.56g, 6.6mmol), addition to 100mL glycol dimethyl ether and water are molten
Agent (DME:H2O=10:1), Pd (dppf) Cl is then added2(0.1g, 0.1mmol) is transferred under the conditions of 80 DEG C of nitrogen protections
Reaction 4 hours.After reaction, ethyl acetate (50ml × 3) extracts, and merges organic layer, concentration, column chromatography for separation obtains white
Solid obtains white solid 0.38g, yield 60%. ESI-MS:m/z,289.1[M+H]+。
The synthesis of step D:6- [3- phenyl -5- (3,5- dimethyl isoxazole -4) -1H- indoles -1]-methyl caproate
It weighs 3,5- dimethyl -4- (3- phenyl -1H- indoles -5)-isoxazole (0.5g, 1.75mmol) and is dissolved in 30ml second
Nitrile is added cesium carbonate (2.5g, 5mmol), 6- bromine Methyl acetate (0.41g, 2.0 mmol) then is added dropwise thereto, 70 DEG C of item
2h is reacted under part.After reaction, ethyl acetate extraction (40ml × 3) merges organic phase, and saturated sodium chloride solution is washed once,
Anhydrous sodium sulfate is dried overnight.Decompression boils off solvent after filtering, and column chromatographic purifying obtains white solid 0.38g, yield 84%.
ESI-MS:m/z,417.2[M+H]+。
The synthesis of step E:6- [3- phenyl -5- (3,5- dimethyl isoxazole -4) -1H- indoles -1]-N- hydroxyl hexanamide
Weigh 6- [3- phenyl -5- (3,5- dimethyl isoxazole -4) -1H- indoles -1]-methyl caproate (0.36g, 1
Mmol), it is dissolved in 30ml methanol, 3ml sodium hydroxide solution (1mol/L) and 3ml aqueous hydroxylamine solution (30%) is added dropwise in condition of ice bath,
It is transferred to room temperature the reaction was continued 3h.After reaction, methanol is removed under reduced pressure, aqueous hydrochloric acid solution (1mol/L) adjusts pH to 7 or so,
White solid is precipitated, filters, water washing filter cake (5ml × 3), vacuum drying obtains white solid 0.17g, yield 65%.ESI-
MS:m/z,416.2[M-H]-.1H NMR(600 MHz,DMSO-d6)δ:10.32(s,1H),8.65(s,1H),7.80(s,1H),
7.77 (d, J=0.8Hz, 1H), 7.68 (d, J=7.1Hz, 2H), 7.64 (d, J=8.4Hz, 1H), 7.43 (t, J=7.8Hz,
2H), 7.23 (t, J=7.3Hz, 1H), 7.18 (dd, J=8.5,1.3Hz, 1H), 4.23 (t, J=7.3Hz, 2H), 2.40 (s,
3H), 2.22 (s, 3H), 1.95 (t, J=7.4Hz, 2H), 1.82 (dd, J=15.0,7.5Hz, 2H), 1.56 (dd, J=
15.0,7.5Hz, 2H), 1.30 (dd, J=15.0,7.9Hz, 2H)；13C NMR(151MHz,DMSO)δ:69.40, 164.83,
158.83,136.22,135.54,129.29,127.93,126.94,125.91,123.10,121.55, 120.17,
117.42,115.49,111.17,45.94,32.51,29.87,26.27,25.10,11.67,10.95； HRMS(ESI+)m/z
calcd for C25H26N3O3[M-H]-416.2052found:416.1970。
According to the preparation method of embodiment 1, raw material appropriate is selected, embodiment 2 is made.
The conjunction of embodiment 2:7- [3- phenyl -5- (3,5- dimethyl isoxazole -4) -1H- indoles -1]-N- hydroxyl heptamide
At
Yield 62%.ESI-MS:m/z,430.1[M-H]-；1H NMR(600MHz,DMSO-d6)δ: 10.31(s,1H),
8.64 (d, J=1.6Hz, 1H), 7.80 (s, 1H), 7.78 (d, J=1.1Hz, 1H), 7.67 (d, J=7.1Hz, 2H), 7.64
(d, J=8.5Hz, 1H), 7.43 (t, J=7.7Hz, 2H), 7.23 (t, J=7.4Hz, 1H), 7.18 (dd, J=8.4,
1.5Hz, 1H), 4.24 (t, J=7.2Hz, 2H), 2.40 (s, 3H), 2.23 (s, 3H), 1.93 (t, J=7.4Hz, 2H), 1.81
(dd, J=13.6,6.7Hz, 2H), 1.51-1.44 (m, 2H), 1.33-1.27 (m, 4H)；13C NMR(101MHz,DMSO)δ:
169.44,164.82,158.82,136.24, 135.55,129.28,127.94,126.91,125.90,123.10,
121.55,120.19,117.43,115.49, 111.15,46.03,32.57,30.04,28.57,26.43,25.39,
11.67,10.95；HRMS(ESI+)m/z calcd for C26H28N3O3[M-H]-430.2209found:430.2125。
Embodiment 3:6- (3- benzyl -5- (3,5- dimethyl isoxazole -4- base) -1H- indoles -1- base)-N- hydroxyl hexanoyl
Amine
The synthesis of step A:1- (the bromo- 1H- indol-3-yl of 5-) -2- Phenyl ethyl ketone
The alchlor for weighing 1.5g (11.6mmol) is added in 250ml flask, adds the drying dichloromethane of 30ml
Alkane, is added dropwise the chlorobenzoyl chloride of 1.1ml (8.5mmol) under condition of ice bath, then weighs the drying of the 5- bromo indole 20ml of 1.5g
Methylene chloride dissolution, is added dropwise in reaction solution under condition of ice bath with dropping funel.Reaction is terminated after reaction 3 hours, is concentrated,
Column is chromatographed with methylene chloride: being eluted under conditions of methanol (v:v=98:2), is obtained pale pink solid.Yield 82%
The synthesis of the bromo- 3- benzyl -1H indoles of step B:5-
250ml flask is added in 1- (the bromo- 1H- indol-3-yl of the 5-) -2- Phenyl ethyl ketone for weighing 1.27g (4.05mmol)
In, the dry tetrahydrofuran that 50ml is added makes it dissolve, and the tetrahydro of 0.46g (12mmol) is added under conditions of being stirred at room temperature
Aluminium lithium adds the boron trifluoride ether solution of 3ml (24mmol), and the reaction was continued 1 hour.After reaction, it is transferred to cold-trap
In, aqueous hydrochloric acid solution (2mol/L) extraction is slowly added dropwise thereto and goes out, ethyl acetate extracts (30ml*3), merges organic layer, dense
Contracting, column chromatography obtain white solid with the elution of pure petroleum ether.Yield 68%
The synthesis of step C:3,5- dimethyl -4- (3- phenethyl -1H- indoles -5) isoxazole
Weigh the bromo- 3- benzyl -1H indoles of 5- of 0.6g (2.2mmol), the different evil of 3,5- dimethyl of 0.54g (2.4mmol)
The mixed solvent of glycol dimethyl ether and water is added in azoles -4- pinacol borate, the sodium bicarbonate of 0.56g (6.6mmol)
(DME:H2O=10:1 it) makes it dissolve, 0.1g (0.1mmol) de Pd (dppf) Cl is then added2, it is transferred under the conditions of 80 DEG C
Reaction 4 hours.10ml ethyl acetate, column chromatography, with petroleum ether: ethyl acetate (v:v=90:10) are added after reaction
Under the conditions of elute, obtain white solid.Yield 60%
Step D:6- methyl-(5- (3,5- dimethyl isoxazole -4- base) -3- phenethyl -1H- indyl) methyl heptanoate
Synthesis
3,5- dimethyl -4- (3- phenethyl -1H- indoles -5) isoxazole for weighing 0.5g (1.75mmol) is added to
In 100ml flask, 30ml acetonitrile is added and makes it dissolve, adds the cesium carbonate of 2.5g (5mmol), is then added dropwise thereto
0.65g (2.0mmol) 7- bromine methyl heptanoate reacts 2 hours under conditions of 70 DEG C.After reaction, it is added into reaction solution
20ml water, then (40ml*3) is extracted with ethyl acetate, merge organic layer, concentration, column chromatography, with petroleum ether: ethyl acetate (v:v
=95:5) under conditions of elute, obtain white solid.Yield 84%
Step E:6- (3- benzyl -5- (3,5- dimethyl isoxazole -4- base) -1H- indoles -1- base)-N- hydroxyl hexanamide
Synthesis
Take 6- methyl-(5- (3,5- dimethyl isoxazole -4- base) -3- phenethyl -1H- indyl) enanthic acid first of 0.2g
Ester is added in 100ml flask, and 15ml methanol, which is added, dissolves it sufficiently, and 4ml sodium hydroxide solution is added dropwise in cold-trap
(1mol/L), then the 50% hydration hydroxylamine solution of 4ml is added dropwise, room temperature reaction is transferred to after being added dropwise.It is terminated after 3 hours anti-
It answers, methanol is evaporated off, adjust pH to 5 with aqueous hydrochloric acid solution (0.5mol/L) in cold-trap, oily liquids occur, use methylene chloride
(50ml*3) extraction merges organic layer, concentration, column chromatography, with methylene chloride: eluting under conditions of methanol (v:v=97:3)
Colourless oily liquids.Yield 74%.ESI-MS: m/z,430.2[M-H]-；1H NMR(600MHz,DMSO-d6)δ:10.32
(s, 1H), 8.65 (dd, J=7.9,1.7Hz, 1H), 7.49 (d, J=8.5Hz, 1H), 7.34 (d, J=1.2Hz, 1H), 7.31
(d, J=7.1Hz, 2H), 7.27 (s, 1H), 7.25 (t, J=6.3Hz, 2H), 7.14 (t, J=7.3Hz, 1H), 7.07 (dd, J
=8.4,1.6Hz, 1H), 4.12 (t, J=7.1Hz, 2H), 4.04 (s, 2H), 2.31 (s, 3H), 2.14 (s, 3H), 1.94 (t,
J=7.3Hz, 2H), 1.74 (dt, J=14.9,7.3Hz, 2H), 1.53 (dt, J=15.1,7.5Hz, 2H), 1.29-1.24
(m,2H)；13C NMR(101MHz,DMSO)δ:169.40,164.54,158.72,141.96, 134.98,129.87,
129.55,128.88,128.59,126.77,126.05,122.41,119.90,117.35, 114.00,110.49,48.98,
36.45,32.50,30.00,28.94,26.29,25.11,11.56,10.84；HRMS (ESI+)m/z calcd for
C26H28N3O3[M-H]-430.2209found:430.2078.
According to the preparation method of embodiment 3, raw material appropriate is selected, the compound of embodiment 4- embodiment 17 is made.
Embodiment 4:7- (3- benzyl -5- (3,5- dimethyl isoxazole -4- base) -1H- indoles -1- base)-N- hydroxyl oenanthyl
Amine
Yield 49%.ESI-MS:m/z,444.0[M-H]-；1H NMR(600MHz,DMSO-d6)δ:10.32 (s,1H),
8.64 (s, 1H), 7.49 (d, J=8.4Hz, 1H), 7.34 (s, 1H), 7.31 (d, J=7.5Hz, 2H), 7.26 (s, 1H),
7.25 (d, J=7.8Hz, 2H), 7.14 (t, J=7.3Hz, 1H), 7.07 (d, J=10.0Hz, 1H), 4.12 (t, J=
7.1Hz, 2H), 4.04 (s, 2H), 2.31 (s, 3H), 2.14 (s, 3H), 1.92 (t, J=7.4 Hz, 2H), 1.74 (dd, J=
13.5,6.7Hz,2H),1.49–1.43(m,2H),1.28–1.24(m,4H)；13C NMR(101MHz,DMSO)δ:169.46,
164.59,158.84,142.43,135.57,128.79, 128.53,128.13,126.99,126.10,122.47,
119.95,119.66,117.51,114.14,110.36,45.65, 36.45,32.59,30.14,28.59,26.39,
25.39,11.67,10.95；HRMS(ESI+)m/z calcd for C27H30N3O3[M-H]-444.2365found:
444.2222。
Embodiment 5:6- [3- phenethyl -5- (3,5- dimethyl isoxazole -4) -1H- indoles -1]-N- hydroxyl hexanamide
Yield 53%.ESI-MS:m/z,444.3[M-H]-；1H NMR(600MHz,DMSO-d6)δ:10.32 (s,1H),
8.65 (s, 1H), 7.72 (t, J=7.5Hz, 1H), 7.49 (s, 1H), 7.27 (s, 2H), 7.26 (s, 2H), 7.19 (s, 1H),
7.17 (dd, J=8.6,4.4Hz, 1H), 7.08 (d, J=9.7Hz, 1H), 4.10 (t, J=7.0 Hz, 2H), 3.01-2.96
(m, 2H), 2.97-2.92 (m, 2H), 2.39 (s, 3H), 2.22 (s, 3H), 1.94 (d, J=8.6Hz, 2H), 1.72 (dt, J=
14.7,7.2Hz, 2H), 1.51 (d, J=8.6Hz, 2H), 1.39-1.31 (m, 2H)；13C NMR(101MHz,DMSO)δ:
169.37,165.04,158.62,143.29,141.61, 134.02,130.15,129.68,128.93,128.71,
128.65,126.29,124.95,123.68,116.39, 109.08,60.96,44.68,32.60,31.71,26.28,
25.15,11.69,10.85；HRMS(ESI+)m/z calcd for C27H30N3O3[M-H]-444.2365found:
444.2279。
Embodiment 6:7- [3- phenethyl -5- (3,5- dimethyl isoxazole -4) -1H- indoles -1]-N- hydroxyl heptamide
Yield 51%.ESI-MS:m/z,458.1[M-H]-；1H NMR(600MHz,DMSO-d6)δ:10.32 (s,1H),
8.65 (s, 1H), 7.50 (d, J=1.4Hz, 1H), 7.48 (d, J=8.5Hz, 1H), 7.26 (s, 2H), 7.25 (s, 2H),
7.18 (s, 1H), 7.17-7.15 (m, 1H), 7.08 (dd, J=8.4,1.6Hz, 1H), 4.10 (t, J=7.0Hz, 2H),
3.01-2.97 (m, 2H), 2.97-2.93 (m, 2H), 2.39 (s, 3H), 2.22 (s, 3H), 1.92 (t, J=7.4Hz, 2H),
1.74–1.68(m,2H),1.49–1.43(m,2H),1.27–1.21(m, 4H)；13C NMR(101MHz,DMSO)δ:169.48,
164.54,158.72,141.97,134.98,129.87, 129.64,129.55,129.16,128.95,128.87,
128.80,128.58,127.92,117.34,114.00, 110.48,48.98,32.57,30.38,28.61,26.41,
25.37,11.57,10.83；HRMS(ESI+)m/z calcd for C28H32N3O3[M-H]-458.2522found:
458.2187。
Embodiment 7:6- [3- (4- luorobenzyl) -5- (3,5- dimethyl isoxazole -4) -1H- indoles -1]-N- hydroxyl hexanoyl
Amine
Yield 55%.ESI-MS:m/z,448.0[M-H]-；1H NMR(600MHz,DMSO-d6)δ:10.32 (s,1H),
8.66 (s, 1H), 7.49 (d, J=8.4Hz, 1H), 7.34 (t, J=2.3Hz, 2H), 7.32 (t, J=2.8 Hz, 1H), 7.27
(s, 1H), 7.08 (dd, J=6.7,2.0Hz, 2H), 7.06 (d, J=1.7Hz, 1H), 4.14-4.10 (m, 2H), 4.03 (s,
2H), 2.32 (s, 3H), 2.15 (s, 3H), 1.93 (t, J=7.3Hz, 2H), 1.77-1.70 (m, 2H), 1.53 (p, J=
7.5Hz,2H),1.28–1.20(m,3H)；13C NMR(101MHz, DMSO)δ:169.35,164.55,158.71,135.74,
130.58,130.53,127.83,127.59,122.47, 120.06,119.84,117.34,115.29,115.15,
113.91,110.53,45.65,32.53,30.40,29.99, 26.30,25.11,11.55,10.83；HRMS(ESI+)m/z
calcd for C26H27FN3O3[M-H]- 448.2115found:448.2089。
Embodiment 8:7- [3- (4- luorobenzyl) -5- (3,5- dimethyl isoxazole -4) -1H- indoles -1]-N- hydroxyl oenanthyl
Amine
Yield 53%.ESI-MS:m/z,462.2[M-H]-；1H NMR(600MHz,DMSO-d6)δ:10.32 (s,1H),
8.65 (s, 1H), 7.49 (d, J=8.4Hz, 1H), 7.34 (d, J=5.9Hz, 2H), 7.32 (d, J=5.7Hz, 1H), 7.26
(s, 1H), 7.09-7.08 (m, 1H), 7.07 (d, J=2.4Hz, 1H), 7.07-7.05 (m, 1H), 4.14-4.10 (m, 2H),
4.03 (s, 2H), 2.32 (s, 3H), 2.15 (s, 3H), 1.92 (t, J=7.4 Hz, 2H), 1.73 (dt, J=13.0,6.3Hz,
2H),1.50–1.43(m,2H),1.30–1.24(m,4H)；13C NMR(101MHz,DMSO)δ:169.46,164.55,
158.71,135.75,130.57,130.52,127.82, 127.59,122.46,120.05,119.84,117.34,
115.28,115.14,113.92,110.52,45.70,32.56, 30.39,30.12,28.54,26.41,25.41,11.56,
10.83；HRMS(ESI+)m/z calcd for C27H29FN3O3[M-H]-462.2271found:462.2182。
Embodiment 9:6- [3- (4- fluorobenzene ethyl) -5- (3,5- dimethyl isoxazole -4) -1H- indoles -1]-N- hydroxyl oneself
The synthesis of amide
Yield 50%.ESI-MS:m/z,462.2[M-H]-；1H NMR(600MHz,DMSO-d6)δ:10.32 (s,1H),
8.66 (s, 1H), 7.49 (d, J=2.1Hz, 1H), 7.48 (d, J=4.3Hz, 1H), 7.28 (dd, J=10.3,3.9Hz,
2H), 7.17 (s, 1H), 7.08 (d, J=1.6Hz, 1H), 7.06 (d, J=8.9Hz, 2H), 4.10 (t, J=7.0Hz, 2H),
2.99-2.95 (m, 2H), 2.95-2.91 (m, 2H), 2.39 (s, 3H), 2.22 (s, 3H), 1.93 (t, J=7.4Hz, 2H),
1.75–1.69(m,2H),1.55–1.49(m,2H),1.24–1.20 (m,2H)；13C NMR(101MHz,DMSO)δ:169.35,
164.59,158.84,135.57,130.54, 130.49,128.12,127.01,122.49,119.97,119.67,
117.51,115.21,115.08,113.99, 110.38,45.58,35.60,32.52,30.00,27.16,26.26,
25.12,11.65,10.93；HRMS(ESI+) m/z calcd for C27H29FN3O3[M-H]-462.2271found:
462.2193。
Embodiment 10:7- [3- (4- fluorobenzene ethyl) -5- (3,5- dimethyl isoxazole -4) -1H- indoles -1]-N- hydroxyl heptan
The synthesis of amide
Yield 47%.ESI-MS:m/z,476.2[M-H]-；1H NMR(600MHz,DMSO-d6)δ:10.32 (s,1H),
8.64 (s, 1H), 7.48 (s, 1H), 7.48 (d, J=5.2Hz, 1H), 7.27 (dd, J=8.6,5.7Hz, 2H), 7.17 (s,
1H), 7.08 (d, J=2.3Hz, 1H), 7.06 (dd, J=9.2,2.3Hz, 2H), 4.10 (t, J=7.0Hz, 2H), 2.99-
2.95 (m, 2H), 2.95-2.92 (m, 2H), 2.39 (s, 3H), 2.22 (s, 3H), 1.92 (t, J=7.4Hz, 2H), 1.74-
1.68 (m, 2H), 1.49-1.43 (m, 2H), 1.23 (dd, J=17.4,10.3 Hz, 4H)；13C NMR(101MHz,DMSO)δ:
169.45,164.59,158.84,135.57,130.53, 130.48,128.12,127.04,122.48,119.96,
119.67,117.51,115.20,115.06,113.95, 110.36,45.64,35.59,32.57,30.13,28.57,
27.12,26.38,25.37,11.65,10.93；HRMS (ESI+)m/z calcd for C28H32FN3O3[M-H]-
476.2428found:476.2341。
Embodiment 11:6- [3- (2- methylbenzyl) -5- (3,5- dimethyl isoxazole -4) -1H- indoles -1]-N- hydroxyl oneself
The synthesis of amide
Yield 54%.ESI-MS:m/z,444.3[M-H]-；1H NMR(600MHz,DMSO-d6)δ:10.31 (s,1H),
8.65 (s, 1H), 7.49 (d, J=8.4Hz, 1H), 7.34 (d, J=1.2Hz, 1H), 7.25-7.22 (m, 1H), 7.15-7.12
(m, 1H), 7.11-7.09 (m, 2H), 7.09-7.06 (m, 2H), 4.11 (t, J=7.0Hz, 2H), 4.03 (s, 2H), 2.33
(s, 3H), 2.29 (s, 3H), 2.16 (s, 3H), 1.92 (t, J=7.4Hz, 2H), 1.75-1.69 (m, 2H), 1.54-1.48
(m, 2H), 1.23 (d, J=3.3Hz, 2H)；13C NMR(101 MHz,DMSO)δ:169.34,164.53,158.71,139.57,
136.35,135.68,130.40,129.59, 128.09,127.82,126.35,126.11,122.39,119.97,
119.91,117.37,112.76,110.50,45.63, 32.52,30.01,29.22,26.28,25.11,19.55,11.60,
10.88；HRMS(ESI+)m/z calcd for C27H30N3O3[M-H]-444.2365found:444.2221。
Embodiment 12:7- [3- (2- methylbenzyl) -5- (3,5- dimethyl isoxazole -4) -1H- indoles -1]-N- hydroxyl heptan
The synthesis of amide
Yield 50%.ESI-MS:m/z,458.3[M-H]-；1H NMR(600MHz,DMSO-d6)δ:10.31 (s,1H),
8.64 (s, 1H), 7.49 (d, J=8.4Hz, 1H), 7.35 (d, J=1.2Hz, 1H), 7.25-7.21 (m, 1H), 7.15-7.12
(m, 1H), 7.11-7.09 (m, 2H), 7.09-7.06 (m, 2H), 4.11 (t, J=7.0Hz, 2H), 4.03 (s, 2H), 2.33
(s, 3H), 2.28 (s, 3H), 2.16 (s, 3H), 1.91 (t, J=7.4Hz, 2H), 1.74-1.68 (m, 2H), 1.48-1.40
(m,2H),1.23(s,4H)；13C NMR(101MHz,DMSO) δ:169.44,164.53,158.71,139.58,136.34,
135.68,130.41,129.59,128.09,127.85, 126.36,126.11,122.39,119.97,119.92,
117.38,112.76,110.49,45.67,32.57,30.12, 29.22,28.55,26.40,25.42,19.54,11.61,
10.88；HRMS(ESI+)m/z calcd for C28H32N3O3[M-H]-458.2522found:458.2438。
Embodiment 13:6- [3- (3- methylbenzyl) -5- (3,5- dimethyl isoxazole -4) -1H- indoles -1]-N- hydroxyl oneself
The synthesis of amide
Yield 57%.ESI-MS:m/z,444.2[M-H]-；1H NMR(600MHz,DMSO-d6)δ:10.32 (s,1H),
8.65 (s, 1H), 7.48 (d, J=8.4Hz, 1H), 7.36 (s, 1H), 7.26 (s, 1H), 7.13 (d, J=7.2Hz, 2H),
7.10 (d, J=7.8Hz, 1H), 7.07 (dd, J=8.4,1.5Hz, 1H), 6.96 (d, J=7.5 Hz, 1H), 4.12 (t, J=
7.1Hz, 2H), 3.99 (s, 2H), 2.32 (s, 3H), 2.24 (s, 3H), 2.15 (s, 3H), 1.93 (t, J=7.4Hz, 2H),
1.74 (dt, J=14.7,7.3Hz, 2H), 1.52 (dd, J=14.8,7.4Hz, 2H), 1.28-1.24 (m, 2H)；13C NMR
(101MHz,DMSO)δ:169.35,164.52,158.70, 141.88,137.54,135.70,129.52,128.48,
127.95,127.47,127.28,126.69,126.01, 122.37,119.94,117.35,114.08,110.48,45.64,
32.53,31.28,30.00,26.30,25.12, 21.38,11.56,10.84；HRMS(ESI+)m/z calcd for
C27H30N3O3[M-H]-445.2365found: 444.2287。
Embodiment 14:7- [3- (3- methylbenzyl) -5- (3,5- dimethyl isoxazole -4) -1H- indoles -1]-N- hydroxyl heptan
The synthesis of amide
Yield 51%.ESI-MS:m/z,458.4[M-H]-；1H NMR(600MHz,DMSO-d6)δ: 10.32(s,1H),
8.64 (s, 1H), 7.48 (d, J=8.4Hz, 1H), 7.37 (s, 1H), 7.26 (s, 1H), 7.14 (t, J=7.4Hz, 2H),
7.10 (d, J=7.6Hz, 1H), 7.07 (dd, J=8.4,1.1Hz, 1H), 6.96 (d, J=7.3Hz, 1H), 4.12 (t, J=
6.9Hz, 2H), 3.99 (s, 2H), 2.33 (s, 3H), 2.23 (s, 3H), 2.16 (s, 3H), 1.92 (t, J=7.4Hz, 2H),
1.74 (dd, J=13.0,6.7Hz, 2H), 1.46 (dd, J=13.9,6.8 Hz, 2H), 1.26 (d, J=2.6Hz, 4H)；13C
NMR(101MHz,DMSO)δ:169.44,164.52, 158.71,141.90,137.54,135.69,129.51,128.47,
127.95,127.50,127.28,126.69, 126.00,122.37,119.94,117.35,114.08,110.47,45.68,
32.57,31.26,30.13,28.57, 26.43,25.42,21.38,11.56,10.85；HRMS(ESI+)m/z calcd
for C28H32N3O3[M-H]- 459.2522found:458.2470。
Embodiment 15:6- [3- (4- methylbenzyl) -5- (3,5- dimethyl isoxazole -4) -1H- indoles -1]-N- hydroxyl oneself
The synthesis of amide
Yield 45%.ESI-MS:m/z,444.3[M-H]-；1H NMR(600MHz,DMSO-d6)δ:10.32 (s,1H),
8.66 (s, 1H), 7.48 (d, J=8.4Hz, 1H), 7.32 (s, 1H), 7.23 (s, 1H), 7.18 (d, J=7.6Hz, 2H),
7.06 (d, J=7.8Hz, 3H), 4.11 (s, 3H), 3.99 (s, 2H), 2.32 (s, 3H), 2.23 (s, 3H), 2.15 (s, 3H),
1.93(s,2H),1.73(s,2H),1.52(s,2H),1.25(s,3H)；13C NMR(101 MHz,DMSO)δ:169.35,
164.52,158.71,145.64,138.83,135.72,134.93,130.11, 129.98,129.14,128.79,
122.38,119.92,117.36,114.25,110.46,45.63,32.53,30.92, 30.01,26.30,25.11,
20.95,11.55,10.83；HRMS(ESI+)m/z calcd for C27H30N3O3 [M-H]-444.2365found:
444.2281。
Embodiment 16:7- [3- (4- methylbenzyl) -5- (3,5- dimethyl isoxazole -4) -1H- indoles -1]-N- hydroxyl heptan
The synthesis of amide
Yield 42%.ESI-MS:m/z,458.0[M-H]-；1H NMR(600MHz,DMSO-d6)δ:10.32 (s,1H),
8.64 (d, J=1.1Hz, 1H), 7.48 (d, J=8.4Hz, 1H), 7.32 (d, J=1.0Hz, 1H), 7.23 (s, 1H), 7.18
(d, J=7.9Hz, 2H), 7.06 (d, J=7.6Hz, 3H), 4.11 (t, J=7.2Hz, 2H), 3.99 (s, 2H), 2.32 (s,
3H), 2.23 (s, 3H), 2.15 (s, 3H), 1.92 (t, J=7.3Hz, 2H), 1.73 (dd, J=13.5,6.7Hz, 2H),
1.49–1.42(m,2H),1.29–1.24(m,4H)；13C NMR (101MHz,DMSO)δ:169.46,164.52,158.71,
145.64,138.84,135.72,134.93,130.11, 129.97,129.13,128.78,122.37,119.92,
117.36,114.26,110.45,45.68,32.57,30.91, 30.13,28.55,26.41,25.41,20.95,11.55,
10.83；HRMS(ESI+)m/z calcd for C28H32N3O3[M-H]-458.2522found:458.2446。
Embodiment 17:7- [3- (3- trifluoromethyl benzyl) -5- (3,5- dimethyl isoxazole -4) -1H- indoles -1]-N- hydroxyl
The synthesis of base heptamide
Yield 47%.ESI-MS:m/z,512.1[M-H]-；1H NMR(600MHz,DMSO-d6)δ:10.32 (s,1H),
8.65 (s, 1H), 7.68 (s, 1H), 7.63 (d, J=6.9Hz, 1H), 7.51 (s, 2H), 7.49 (s, 1H), 7.39 (s, 1H),
7.35 (s, 1H), 7.08 (dd, J=8.4,1.5Hz, 1H), 4.15 (s, 2H), 4.13 (t, J=7.1 Hz, 2H), 2.31 (s,
3H), 2.13 (s, 3H), 1.91 (d, J=7.7Hz, 2H), 1.76-1.71 (m, 2H), 1.51-1.47 (m, 2H), 1.25 (d, J
=7.0Hz, 4H)；13C NMR(101MHz,DMSO)δ:169.41, 164.54,158.69,143.68,135.67,133.07,
129.62,127.83,127.76,125.18,122.86, 122.54,120.18,119.77,117.31,113.20,
110.60,45.72,35.49,32.79,30.09,28.88, 28.04,27.61,25.31,19.03,11.49,10.77；
HRMS(ESI+)m/z calcd for C28H29F3N3O3 [M-H]-512.2239found:512.2143。
The product pharmacological research of the present invention of embodiment 18.
Experiment sets blank control group (not dosing) and positive controls (Vorinostat).At room temperature by untested compound and
Fluorogenic substrate Boc-Lys (Ac)-AMC or Boc-Lys (TFA)-AMC is added in Hela nuclear extract (50ng) preculture 15min.
After cultivating 60min at 37 DEG C, 25 μ L terminators (containing Trypsin and SAHA) are added and terminate reaction.After 15min, using all-wave length
Multi-function microplate reader fluorescence intensity when excitation and launch wavelength are respectively 355nm and 460nm, calculates inhibiting rate.Target
Compound is shown in Table 1 to HDACS enzyme inhibition activity.
The 1. total enzyme of target compound HDAC of table and part hypotype enzymatic activity are tested①.
①Buffer salt solution (pH=8.0) includes 25mmolL-1Hydrochloric acid three (methylol) aminomethane, 137 mmolL-1Sodium chloride, 2.7mmolL-1Potassium chloride, 1mmolL-1Magnesium chloride, 0.1mgmL-1All tests of bovine serum albumin(BSA) are all
It is carried out in 96 orifice plates.
②Vorinostat is positive control drug.
Embodiment 19BRD4 enzymatic activity testing experiment.
Destination protein GST-BRD4 20nM；Test buffer (Cisbio Bioassays, USA)；Substrate peptide fragment, [Lys
(5,8,12,16)Ac]H4(1-21)biotinylated peptide 20nM；HTRF detection reagent, GST antibody-Tb2+Coordination
Compound (donor) 2nM, Streptavidin-XL665 compound (receptor) 2nM.In reaction system: 4 μ L of albumen, experiment buffering
Liquid 2 μ L, substrate Peptide 4 μ L, 5 μ L of receptor, 5 μ L of donor, 2 μ L of small molecule compound.By above-mentioned volume by small molecule chemical combination
Object and each component are added in 384 hole white board of Greiner, and room temperature, which is protected from light, is incubated for 3h.Multi-function microplate reader detect 665nm and
Fluorescence intensity under 620nm wavelength.Target compound is shown in Table 2 to BRD4 inhibiting rate.
The BRD4 enzymatic activity of 2. target compound of table and (+)-JQ1 test
The external inhibitory activity of 20 suppressing cell reproduction of embodiment is tested
1. cell recovery
From cell (cryopreservation tube) all thawings rapidly in 37~40 DEG C of water-baths are carefully taken out in liquid nitrogen, keep cell rapid
Cross 0~5 DEG C of easily impaired temperature range.Cell aseptically is sucked out with liquid-transfering gun to be put into centrifuge tube,
It is centrifuged 3min under 1300r/min, culture solution is added after gently discarding supernatant liquid, piping and druming mixes cell, moves into culture bottle and is put into
It cultivates in carbon dioxide incubator, is changed the liquid once after 4h.
2. cell passes on
It needs to be tested after it is stablized for subculture 2-3 times after cell recovery, passage sticks training with cell every time
It supports subject to bottom of bottle portion 90%.
3. cell buried plate
Make it under the digestion of culture bottle bottom with trypsin solution (0.25%) when culture bottle bottom is sticked in cell growth
Come.10mL culture solution is added after gently discarding trypsin solution, piping and druming mixes cell, draws 10uL cell suspension and adds
Enter in cell counting board and count, adjustment cell concentration is 3.5 × 104A/hole.Except the hole A1 is blank well not refinement in 96 orifice plates
Extracellular, 100uL cell suspension is all added in remaining.96 orifice plates are put into incubator and are cultivated for 24 hours.
4. cell dosing
First drug is dissolved with 50 μ L DMSO.Appropriate culture solution is then added, drug is made to be dissolved into 2 mmol/mL medical fluids.So
Drug is dissolved into 100,50,25,12.5,6.25 μm of ol/mL in 96 orifice plates afterwards.3 holes are added in each concentration, wherein around
Two rows, two column cell growing way is affected by environment larger, is only used as the use of blanc cell hole.96 orifice plates are put into incubator and are cultivated
24h。
MTT tests measuring method
Cell is pressed 1.5~3 × 104Cell density buries 96 orifice plates, every hole 100uL, cell is adherent be added for 24 hours it is different dense
MTT is added after the drug (hole 100uL/) of degree, drug and cell incubation 96h, is put into incubator after 4h, discards MTT (four nitrogen
Azoles) solution, DMSO 200uL is added.Oscillation keeps survivaling cell and MTT reaction product formazan sufficiently molten on magnetic force oscillator
Solution is put into microplate reader the reading OD value at 570nm wavelength.Inhibiting rate is calculated as follows:
Using SAHA and (+)-JQ1 as positive control drug, the external inhibitory activity of the suppressing cell reproduction of target compound is tried
It tests.Test result is shown in Table 3.
3. target compound of table tests the antiproliferative activity of two cell strains of THP-1 and MDA-MB-231.
Vorinostat and (+)-JQ1 are positive control drug.
Above-mentioned test result show the compound of present invention general formula to be protected have good anti-tumor activity and
HDAC inhibiting effect.The compound of the present invention has good prospects for commercial application.
Claims (10)
1. such as general formula I compound represented and its pharmaceutically acceptable salt, hydrate:
Wherein,
R is independently selected from one or more following substituent groups: H, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl；
M is the integer of 4-6；
Integer of the n between 0-2.
2. the general formula I compound represented and its pharmaceutically acceptable salt of claim 1, hydrate:
Wherein,
R is independently selected from one or more following substituent groups: H, halogen, C1-C4 alkyl, halogenated C1-C4 alkyl.
3. the general formula I compound represented and its pharmaceutically acceptable salt of claims 1 or 2, hydrate:
Wherein,
R is independently selected from one or more following substituent groups: H, halogen, methyl, trifluoromethyl.
4. the general formula I compound represented and its pharmaceutically acceptable salt of any one of claim 1-3, hydrate:
The integer that m is 5 or 6.
5. the general formula I compound represented and its pharmaceutically acceptable salt of claim 1, hydrate:
6- (5- (3,5- dimethyl isoxazole -4- base) -3- phenyl -1H- indoles -1- base)-N- hydroxyl hexanamide
7- (5- (3,5- dimethyl isoxazole -4- base) -3- phenyl -1H- indoles -1- base)-N- hydroxyl heptamide
6- (3- benzyl -5- (3,5- dimethyl isoxazole -4- base) -1H- indoles -1- base)-N- hydroxyl hexanamide
7- (3- benzyl -5- (3,5- dimethyl isoxazole -4- base) -1H- indoles -1- base)-N- hydroxyl heptamide
6- (3- phenethyl -5- (3,5- dimethyl isoxazole -4- base) -1H- indoles -1- base)-N- hydroxyl hexanamide
7- (3- phenethyl -5- (3,5- dimethyl isoxazole -4- base) -1H- indoles -1- base)-N- hydroxyl heptamide
6- (3- (4- luorobenzyl) -5- (3,5- dimethyl isoxazole -4- base) -1H- indoles -1- base)-N- hydroxyl hexanamide
7- (3- (4- luorobenzyl) -5- (3,5- dimethyl isoxazole -4- base) -1H- indoles -1- base)-N- hydroxyl heptamide
6- (3- (4- fluorobenzene ethyl) -5- (3,5- dimethyl isoxazole -4- base) -1H- indoles -1- base)-N- hydroxyl hexanamide
7- (3- (4- fluorobenzene ethyl) -5- (3,5- dimethyl isoxazole -4- base) -1H- indoles -1- base)-N- hydroxyl heptamide
6- (3- (2- methylbenzyl) -5- (3,5- dimethyl isoxazole -4- base) -1H- indoles -1- base)-N- hydroxyl hexanamide
7- (3- (2- methylbenzyl) -5- (3,5- dimethyl isoxazole -4- base) -1H- indoles -1- base)-N- hydroxyl heptamide
6- (3- (3- methylbenzyl) -5- (3,5- dimethyl isoxazole -4- base) -1H- indoles -1- base)-N- hydroxyl hexanamide
7- (3- (3- methylbenzyl) -5- (3,5- dimethyl isoxazole -4- base) -1H- indoles -1- base)-N- hydroxyl heptamide
6- (3- (4- methylbenzyl) -5- (3,5- dimethyl isoxazole -4- base) -1H- indoles -1- base)-N- hydroxyl hexanamide
7- (3- (4- methylbenzyl) -5- (3,5- dimethyl isoxazole -4- base) -1H- indoles -1- base)-N- hydroxyl heptamide
7- (3- (3- (trifluoromethyl) benzyl) -5- (3,5- dimethyl isoxazole -4- base) -1H- indoles -1- base)-N- hydroxyl heptan
Amide.
6. a kind of pharmaceutical composition, it is characterised in that: the compound comprising any one of claim 1-5 and its pharmaceutically may be used
Salt, hydrate and the pharmaceutically acceptable excipient of receiving.
7. described in the compound and its pharmaceutically acceptable salt of any one of claim 1-5, hydrate or claim 6
Pharmaceutical composition preparing the application in relevant to histone deacetylase activity unconventionality expression disease medicament.
8. described in the compound and its pharmaceutically acceptable salt of any one of claim 1-5, hydrate or claim 6
Pharmaceutical composition application in preparation of anti-tumor drugs.
9. described in the compound and its pharmaceutically acceptable salt of any one of claim 1-5, hydrate or claim 6
Application of the pharmaceutical composition in preparation treatment and/or prevention prostate cancer, breast cancer, cervical carcinoma or leukemia medicament.
10. application as claimed in claim 8 or 9, which is characterized in that the compound and its pharmaceutically acceptable salt,
Hydrate or pharmaceutical composition are used alone, or are used in combination with other anti-tumor drugs.
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| CN109096272B (en) | 2021-04-02 |
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