CN104926726B - Hydroxamic acid histone deacetylases inhibitor and its preparation method and application - Google Patents
Hydroxamic acid histone deacetylases inhibitor and its preparation method and application Download PDFInfo
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- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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Abstract
The invention discloses a series of hydroxamic acid histone deacetylases inhibitors and its preparation method and application, compound has the structure such as logical formula (I) or (II).The compound of the present invention has histon deacetylase (HDAC) stronger inhibitory activity, the related mammalian disease caused by histon deacetylase (HDAC) abnormal expression available for prevention or treatment, particularly with preferable antitumor action.The invention further relates to composition and pharmaceutical applications with the compound of structure shown in logical formula (I) or (II).
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to a series of hydroxamic acid histone deacetylases inhibitors
And combinations thereof, preparation method and application.The invention further relates to such compound to prepare prevention or treat because histone goes second
Application in mammal relevant disease medicine caused by acylase abnormal expression, particularly in cancer, neurodegenerative disease, disease
Application in the therapy fields such as malicious infection, inflammation, leukaemia, malaria and diabetes.
Background technology
According to WHO Report, global cancer patients in 2012 and death are all being constantly increasing.Liver cancer,
In the malignant tumours such as cancer of the esophagus, stomach cancer and lung cancer, Chinese new cases and death toll occupy first place in the world.Wherein, lung cancer is
Most universal and most fatal cancer, about newly-increased 1,800,000 patients in 2012, and cause 1,500,000 people dead, China accounts for such disease
More than the 1/3 of example.However, existing cancer therapy drug cannot still obtain satisfied therapeutic effect.Therefore, new mechanism of action is developed
Antitumor drug be of great significance.
The acetylation of histone has important regulating and controlling effect for genetic transcription.Histone acetyltransferase (HAT) and
Histon deacetylase (HDAC) (HDAC) is the key enzyme for adjusting this process.When the end ammonia of specific lysine residue in histone
For base by after HATs acetylations, the declines between histidine and DNA, DNA is in extended position, make transcription factor easily and DNA
Binding site is specifically bound, and activated transcription and reproduction process, cause gene expression.When lysine residue is under HDACs effects
After deacetylation, terminal amino group is protonated, and positive charge density increase, histone passes through electrostatic interaction and negatively charged
Enhancing is acted between DNA, chromosome is tightened so as to cause gene silencing, ultimately results in transcription and be suppressed, stimulates tumour
Cell Proliferation.
The acetylation of histone and deacylation process are in a kind of state of dynamic equilibrium under normal physiological conditions.When
When cell converts, HDACs unconventionality expressions, deacetylation effect enhancing, changes homeostasis, DNA is in deflated state, resistance
Only gene expression, reduces the activity (such as p21, p27) of tumor suppressor gene, causes unconfined cell Proliferation, so as to cause to swell
The generation of knurl.
There are important function in HDAC families in various aspects such as cell growth, differentiation, metabolism, apoptosis.Have now been found that
HDACs has 18 hypotypes, is largely divided into tetra- families of I, II, III, IV.Wherein I families include HDAC 1,2,3,8 four kind of Asia
Type, is all generally expressed in many tumor cell lines, thus is more paid attention to.Mainly there are HDAC 4,5,7,9 four kind of Asia in IIa families
There are two catalysis regions in type, IIb families, mainly there is HDAC 6,10 two kind of hypotype, and IV families only have a kind of 11 hypotypes of HDAC, its
Middle I families are located in nucleus, and other II, IV families all exist in nucleus and cytoplasm.I, the HDAC of II, IV family
All it is that Zn2+ relies on enzyme, and Group III family belongs to the protease of NAD+ dependences.
Research finds in many tumour cells all to express there are some HDAC hypotypes are high, be mainly shown as I families (1,2,
3rd, 8) expressed with the high of 6 hypotypes of IIb families HDAC.1,2,3,8 hypotypes of HDAC are high such as in colon cancer expresses, HDAC in stomach cancer
1st, 2,3 hypotypes are high expresses, and the high expression of HDAC 4,6 hypotypes in breast cancer, this demonstrates the generation of the activity and cancer of HDACs
It is related, therefore HDACs becomes a very promising antineoplastic target and increasingly draws attention.
Hdac inhibitor increases acetylation of histone degree by suppressing HDAC so that they are accumulated in nucleus, are increased
Add the activity of tumor suppressor gene, activate some downstream effects, including the apoptosis of tumour cell, differentiation and the reduction of propagation, from
And achieve the purpose that antitumor.
Hdac inhibitor mainly has hydroxamic acid, benzamides, cyclic peptide, short-chain fat acids.List at present
There is kind more than 30 with the hdac inhibitor of clinical investigation phase, wherein hydroxamic acid is the widest hdac inhibitor of research.
TSA (Trichostatin A) is the hydroxamic acid hdac inhibitor studied earliest, though having dropped out clinical research, TSA is still
Evaluated frequently as comparison medicine for compound activity.The preferable Vorinostat of activity is obtained to TSA structure optimizations
(vorinostat, Zolina, SAHA), is the hdac inhibitor of wide spectrum, all effective to the hypotype of I families, FDA approvals in 2006
Listing, for treating metastatic skin T cell lymphoma (CTCL).The Baily promise of the approval listings of FDA in 2014 he
(Belinostat, PXD-101) is used for the treatment of lymphoma peripheral T cell (PTCL), but there are Q-T interval prolongation
Side effect.Cyclic peptide compounds Romidepsin (FK228, Istodax) selection index systems are in the various hypotypes of I families, FDA in 2009
Approval listing, for skin and lymphoma peripheral T cell.
Hdac inhibitor has the advantages such as the wide, overriding resistance of antitumor spectra, and current this kind of medicine has shared extensively with other drugs
Wealthy prospect.Romidepsin its seldom used medicine status by FDA certifications, shares with Sorafenib, thin for treating Primary Hepatic
Born of the same parents' cancer, significantly extends life cycle.Entinostat combines with Exemestane, and FDA approveds are female for treating to break through sex therapy
The metastatic breast cancer of hormone receptor positive.
However, many hdac inhibitors are all there are more serious cardiac toxic, studies have found that the Romidepsin of listing
It can influence people hERG.Also all there is the pair for causing Q-T interval prolongation in Baily promise his (Belinostat, PXD-101) etc.
Effect, therefore, Development of Novel, effective hdac inhibitor be still antitumor drug research field it is challenging and research valency
The problem of value.
The content of the invention
The invention aims to provide a kind of new hdac inhibitor and its pharmaceutically acceptable salt.The present invention is at the same time
Disclose preparation method, medical application and the composition of such compound.
In the first aspect of the present invention, there is provided the logical formula (I) of one kind or hydroxamic acid compound shown in (II) or its
Pharmaceutically acceptable salt, solvate, pro-drug or polymorph：
In formula,
R1The position of substitution can be located at 1 to 4, can be single, double or polysubstituted；R2The position of substitution can be located at 7 to 10
Position, can be single, double or polysubstituted；The R1、R2Substituent is any sort in following groups：A) hydrogen；B) substitute or do not take
The straight or branched alkoxyl of the C1-8 in generation；C) straight or branched alkyl of substituted or unsubstituted C1-8；D) substitute or do not take
The alkenyl of the straight or branched of the C2-6 in generation；E) alkynyl of the straight or branched of substituted or unsubstituted C2-6；F) substitution or not
The straight or branched alkyl amide of substituted C1-8；G) substituted or unsubstituted aryl or 5-6 circle heterocycles aryl；H) substitution or not
The straight or branched alkanoyl of substituted C1-8；I) the straight or branched alkanoyloxy of substituted or unsubstituted C1-8；J) nitro；
K) amino；L) hydroxyl；M) halogen；N) methylene-dioxy；O) ethylenedioxy；P) cyano group；
A is-(CH2)m- or-(CH2=CH2)n-, wherein m=2-8, n=1-4；
The substitution refers to be substituted by following one or more substituents：C1-5 alkyl, C2-5 alkenyls, C2-5 alkynes
Base, C1-5 alkoxies, halogen, nitro, cyano group, hydroxyl, amino, carboxyl and oxo.
In another preference, compound as described above, R1The position of substitution can be located at 2 and 3 in any one or
Two；And/or R2The position of substitution can be located at any one or two in 8 and 9.
In another preference, compound as described above, R1、R2Substituent is any sort in following groups：A) hydrogen；
B) straight or branched alkoxyl of C1-8；C) straight or branched alkyl of C1-8；D) halogen.
In another preference, compound as described above, A is-(CH2)m-, wherein m=2-6.
In another preference, compound as described above, R1For hydrogen；R2Positioned at 9, be methyl, halogen, methoxyl group or
Any of hydrogen；A is-(CH2)6-。
In another preference, the compound is any of following compounds：
N- hydroxyls -7- (chloro- 11- oximidos -6- oxygen -6,11- dihydros -5H- indenos [1,2-c] quinoline -5- bases of 9-) heptamide；
N- hydroxyls -7- (9- methoxyl group -11- oximido -6- oxygen -6,11- dihydro -5H- indenos [1,2-c] quinoline -5- bases) heptan
Acid amides；
N- hydroxyls -7- (chloro- 11- oximidos -6- oxygen -6,11- dihydros -5H- indenos [1,2-c] quinoline -5- bases of the bromo- 9- of 3-) heptan
Acid amides；
N- hydroxyls -7- (chloro- 11- oximidos -11H- indenos [1,2-c] quinoline -6- bases oxygen of 9-) heptamide；
N- hydroxyls -7- (9- methoxyl group -11- oximido -11H- indenos [1,2-c] quinoline -6- bases oxygen) heptamide；
N- hydroxyls -7- (chloro- 11- oximidos -11H- indenos [1,2-c] quinoline -6- bases oxygen of the bromo- 9- of 3-) heptamide.
In the second aspect of the present invention, there is provided a kind of composition, it contains the first aspect present invention of safe and effective amount
The compound or its pharmaceutically acceptable salt and the carrier pharmaceutically received.In another preference, the combination
Thing is pharmaceutical composition.
In the third aspect of the present invention, there is provided the compound described in first aspect is preparing prevention or treating because of histone
Application in mammal relevant disease medicine caused by deacetylase abnormal expression.In another preference, the disease
Disease is any of cancer, neurodegenerative disease, viral infection, inflammation, leukaemia, malaria and diabetes.It is highly preferred that institute
The cancer stated is any of lung cancer, colon cancer, breast cancer or liver cancer.
In the fourth aspect of the present invention, there is provided the preparation method of formula (I) or (II) compound described in first aspect, bag
Include the following steps：
Using isatin or substitution isatin as raw material, the phenylacetic acid reaction generation with contraposition substitution in the presence of anhydrous sodium acetate takes
The Cinchonic Acid in generation, which heats under the conditions of polyphosphoric acids occurs intramolecular dehydration cyclization, generates the 6- hydroxyls of 9- substitutions
Base -11H- indenes [1,2-c] quinoline -11- ketone.The intermediate and 7- bromines cognac oil, Anhydrous potassium carbonate heating stirring in DMF are anti-
Should, generate ester and 6- oxygen substitution esters that 5- nitrogen substitute.Intermediate ester generates formula (I) with azanol reaction respectively again and (II) changes
Compound, synthetic route are as shown in Figure 2.
Pharmaceutical composition of the present invention, the above-mentioned target compound containing safe and effective amount and pharmaceutically acceptable
Carrier.Can be solid form or liquid form, the pharmaceutical dosage form can be tablet, capsule, powder agent, granule,
Supensoid agent or injection., can be with one or more pharmaceutically acceptable carriers when the compounds of this invention is used for such use
Or excipient mixing, such as solvent, diluent, and can be administered orally with following form：It is tablet, pill, capsule, dispersible
Powder, particle or suspension (containing such as from about 0.05-5% suspending agents), syrup (containing such as from about 10-50% sugar) and elixir (contain
Have about 20-50% ethanol), or be administered in a manner of external application：Ointment, gel, drug containing adhesive plaster etc., or with sterile injectable solution
Or form of suspension (containing about 0.05-5% suspending agents in isotonic medium) carries out parenteral routes.For example, these medicine systems
Agent contains the active ingredient of the about 0.01-99% mixed with carrier, more preferably about 0.1%-90% (weight).
" safe and effective amount " refers to：The amount of compound is enough to improve the state of an illness, and is unlikely to produce serious side effect.Peace
Full effective dose is determined according to the age for the treatment of target, the state of an illness, course for the treatment of etc..
" carrier pharmaceutically received " refers to：One or more biocompatible solids or liquid filler or gelatinous mass, it
Be adapted to people use and it is necessary to have enough purity and sufficiently low toxicity.It is each in composition that " compatibility ", which herein means generation,
Component energy and the compound of the present invention and they between mutually admix, and the effect of significantly reduce compound.Pharmaceutically may be used
The carrier part example of receiving has sugared (such as glucose, sucrose, lactose), starch (such as cornstarch, farina), fine
Dimension element and its derivative (such as sodium carboxymethylcellulose, ethyl cellulose sodium, cellulose ethanoate), gelatin, talcum powder, solid
Lubricant (such as odium stearate, magnesium stearate), calcium sulfate, vegetable oil (such as soya-bean oil, sesame oil, peanut oil, olive oil) are polynary
Alcohol (such as propane diols, glycerine, mannitol, sorbierite), emulsifying agent (such as Tweens), wetting agent (such as dodecyl sodium sulfate),
Colouring agent, flavor enhancement, stabilizer, antioxidant, preservative, apirogen water etc..
The compound of the present invention, is tested by Inhibiting enzyme activity, finds there is the activity of stronger suppression HDAC.In addition, also
Part of compounds is tested to four kinds of human tumor cells：A549 (human lung carcinoma cell), HCT116 (human colon cancer cell), MDA-
The cell in vitro inhibited proliferation of MB-231 (human breast cancer cell) and BEL7404 (human liver cancer cell), this hair of the results show
Bright target compound is provided with good broad-spectrum anti-tumor effect.In addition, the compound of the present invention can be alone, can also be with
Existing drug combination, to obtain more preferable effect.
Brief description of the drawings
The general structure of the hydroxamic acid hdac inhibitor of Fig. 1 present invention.
The formula (I) of Fig. 2 present invention and the preparation method synthetic route chart of (II) compound.
Embodiment
With reference to specific embodiment, the present invention is furture elucidated.It should be understood that it is merely to illustrate invention rather than limitation
The scope of the present invention.The implementation of actual conditions is indicated in following implementation, usually according to normal condition, or according to manufacturer
Proposed condition.Unless otherwise stated, otherwise percentage and number are percentage by weight and parts by weight.
Nuclear Magnetic Resonance (CDCl3Or DMSO-d6For deuterated reagent, containing 0.03%TMS) (model:Bruker Avance
300 places of production：Germany)；Mass spectrograph (model:The API-3000LC-MS places of production:The U.S.)；Infrared spectrometer (KBr tablettings) (model：
The Perkin-Elmer Spectrum 1600FTIR places of production：The U.S.)；Micro-meldometer (thermometer is not calibrated) (model:XT4A
The place of production:Tech electric light instrument plant of Beijing).The middle standby liquid phase (model of compacting:300 places of production of Compact Avance:Sharp fringe science and technology
Co., Ltd, China), agents useful for same is that analysis is pure in experiment, is purchased from Chinese medicines group chemical reagents corporation.Silicon used in column chromatography
Glue is the 300-400 mesh (place of production：Qingdao Haiyang chemical industry institute).Chromatographic sheet is GF254Silica gel plate (the place of production：Yantai river friend's silica gel is opened
Send out Co., Ltd).The structure of all target compounds is passed through1The confirmation of H NMR, ESI-MS, IR.
Embodiment 1
The preparation (3) of 3- (4- chlorphenyls) -2- oxyquinoline -4- carboxylic acids
In 100mL three-neck flasks add run red (5.51g, 0.0375mol), anhydrous sodium acetate (1.24g,
0.0151mol) and after 4-Chlorophenylacetic acid (11.18g, 0.0656mol) mixing, 3h to TLC detection reactions are heated to reflux in 200 DEG C
Terminate.10% sodium hydroxide (200mL) is added into reaction solution makes its dissolving, filtering, filtrate washed with dichloromethane (3 ×
80mL), water layer is separated, water layer glacial acetic acid tune pH 5-6 are filtered, and filtrate with concentrated hydrochloric acid tune pH 1-2, filters consolidating for precipitation again
Body, washing, drains, obtains white solid 3 (8.87g, 79.1%).
1H NMR(300MHz,DMSO-d6):δ 12.22 (s, 1H), 7.59 (t, J=7.7Hz, 1H), 7.49 (d, J=
8.4Hz, 3H), 7.42-7.35 (m, 3H), 7.26 (t, J=8.0Hz, 1H) .3- (4- methoxyphenyls) -2- oxyquinolines -4-
Carboxylic acid (4)
Isatin and 4- methoxyphenylacetic acids reaction generation white solid 4, synthetic method is same as above.1H NMR(300MHz,
DMSO-d6):δ 12.14 (s, 1H), 7.58 (t, J=7.7Hz, 1H), 7.49 (d, J=8.0Hz, 1H), 7.40 (d, J=
8.3Hz, 1H), 7.36 (d, J=8.6Hz, 2H), 7.27 (t, J=7.6Hz, 1H), 7.00 (d, J=8.6Hz, 2H), 3.82 (s,
3H).
Bromo- 2- oxyquinolines -4- carboxylic acids (5) synthetic methods of 3- (4- chlorphenyls) -7- are same as above.
Embodiment 2
The preparation (6) of chloro- 6- hydroxyls -11H- indenos [1,2-c] quinoline -11- ketone of 9-
Polyphosphoric acids (21.95g, 0.065mol) and 3- (4- chlorphenyls) -2- hydroxyl quinolines are added in 100mL round-bottomed flasks
Quinoline -4- carboxylic acids 3 (2.75g, 0.0097mol), 130 DEG C are heated to reflux to TLC monitoring reactions terminating.Reaction solution is poured into frozen water
In, stir, solid is separated out after standing, filter, be washed to neutrality, obtain red brown solid 6 (2.22g, 81.9%), be directly used in down
Step reaction.ESI-MS(m/z):280.40([M-H]-, 100%).
The synthetic method of intermediate 7,8 is same as above.
Embodiment 3
7- (chloro- 6,11- dioxies -6,11- dihydros -5H- indenos [1,2-c] quinoline -5- bases of 9-) cognac oil (9) and 7-
The preparation of (chloro- 11- oxygen -11H- indenos [1,2-c] quinoline -6- bases oxygen of 9-) cognac oil (12)
Added in 100mL round-bottomed flasks 9- chloro- 6- hydroxyls -11H- indenos [1,2-c] quinoline -11- ketone (6) (1.41g,
0.005mol), 7- bromines cognac oil (1.36g, 0.0055mol) and Anhydrous potassium carbonate (1.66g, 0.012mol) are dissolved in DMF
In (24mL), 60 DEG C of heating stirrings, which are reacted to TLC monitoring reactions, to be terminated.By reacting liquid filtering, filter cake CH2Cl2Be washed till it is colourless,
Filtrate water washs, anhydrous Na2SO4Dry, filtering, is concentrated to dryness to obtain dark red crude product.The crude product suppresses standby liquid phase point in using
From obtaining Chinese red solid 9 (0.47g) and crocus solid 12 (0.28g).
7- (chloro- 6,11- dioxies -6,11- dihydros -5H- indenos [1,2-c] quinoline -5- bases of 9-) cognac oil (9)
1H NMR(300MHz,CDCl3):δ 8.71 (dd, J=8.0,1.5Hz, 1H), 8.07 (d, J=7.9Hz, 1H),
7.62 (ddd, J=8.7,7.2,1.6Hz, 1H), 7.56 (d, J=1.8Hz, 1H), 7.48 (dd, J=7.9,2.0Hz, 1H),
7.40 (d, J=8.6Hz, 1H), 7.34 (t, J7.6Hz, 1H), 4.38 (t, J=7.5Hz, 2H), 4.14 (q, J=7.1Hz,
2H), 2.33 (t, J=7.4Hz, 2H), 1.88-1.75 (m, 2H), 1.74-1.65 (m, 2H), 1.59-1.51 (m, 2H), 1.46
(m, 2H), 1.27 (t, J=7.1Hz, 3H) .IR (KBr) cm-1:2926,2851,1725,1649,1590,1557,1446,
1282,1168,761,739.
7- (chloro- 11- oxygen -11H- indenos [1,2-c] quinoline -6- bases oxygen of 9-) cognac oil (12)
1H NMR(300MHz,CDCl3):δ 8.68 (dd, J=8.3,0.9Hz, 1H), 7.83 (d, J=8.0Hz, 1H),
7.74 (d, J=7.9Hz, 1H), 7.66-7.62 (m, 1H), 7.60 (d, J=1.7Hz, 1H), 7.51-7.45 (m, 2H), 4.65
(t, J=6.6Hz, 2H), 4.15 (q, J=7.1Hz, 2H), 2.36 (t, J=7.4Hz, 2H), 2.03-1.92 (m, 2H), 1.67-
1.75 (m, 2H), 1.64-1.56 (m, 2H), 1.46-1.55 (m, 2H), 1.28 (t, J=7.1Hz, 3H) .IR (KBr) cm-1:
2934,2859,1746,1721,1601,1577,1515,1459,1227,1211,1172,758,608.
The synthetic route of other intermediates 10,13,11,14 is same as above.
7- (9- methoxyl group -6,11- dioxy -6,11- dihydro -5H- indenos [1,2-c] quinoline -5- bases) cognac oil (10)
1H NMR(300MHz,CDCl3):δ 8.69 (d, J=7.8Hz, 1H), 8.00 (d, J=8.2Hz, 1H), 7.56 (t, J
=7.4Hz, 1H), 7.31-7.39 (m, 2H), 7.18 (d, J=2.1Hz, 1H), 6.94 (dd, J=8.2,2.2Hz, 1H), 4.37
(t, J=7.5Hz, 2H), 4.14 (q, J=7.1Hz, 2H), 3.88 (s, 3H), 2.33 (t, J=7.3Hz, 2H), 1.82-1.76
(m, 2H), 1.72-1.66 (m, 2H), 1.57-1.42 (m, 4H), 1.27 (t, J=7.1Hz, 3H) .IR (KBr) cm-1:2927,
2858,1716,1650,1604,1579,1482,1446,1277,1241,751.
7- (9- methoxyl group -11- oxygen -11H- indenos [1,2-c] quinoline -6- bases oxygen) cognac oil (13)
1H NMR(300MHz,CDCl3):δ 8.63 (d, J=8.4Hz, 1H), 7.77 (d, J=8.4Hz, 1H), 7.59
(dd, J=8.4,1.5Hz, 1H), 7.52 (t, J=6.9Hz, 1H), 7.42 (t, J=7.8Hz, 1H), 7.17 (d, J=
2.4Hz, 1H), 6.92 (dd, J=8.1,2.4Hz, 1H), 4.59 (t, J=6.6Hz, 2H), 4.13 (q, J=6.9Hz, 2H),
3.86 (s, 3H), 2.34 (t, J=7.5Hz, 2H), 1.94-1.89 (m, 2H), 1.74-1.66 (m, 2H), 1.61-1.42 (m,
4H), 1.26 (t, J=6.9Hz, 3H)
7- (chloro- 6,11- dioxies -6,11- dihydros -5H- indenos [1,2-c] quinoline -5- bases of the bromo- 9- of 3-) cognac oil (11)
1H NMR(300MHz,CDCl3):δ 8.55 (d, J=8.7Hz, 1H), 8.05 (d, J=7.8Hz, 1H), 7.55
(dd, J=7.2,5.4Hz, 2H), 7.44-7.50 (m, 2H), 4.33 (t, J=8.1Hz, 2H), 4.14 (q, J=7.2Hz,
2H), 2.34 (t, J=7.2Hz, 2H), 1.85-1.76 (m, 2H), 1.72-1.61 (m, 2H), 1.59-1.40 (m, 4H), 1.27
(t, J=7.2Hz, 3H)
7- (chloro- 11- oxygen -11H- indenos [1,2-c] quinoline -6- bases oxygen of the bromo- 9- of 3-) cognac oil (14)
1H NMR(300MHz,CDCl3):δ 8.49 (d, J=8.7Hz, 1H), 8.01 (d, J=1.5Hz, 1H), 7.70 (d, J
=7.8Hz, 1H), 7.57 (dd, J=7.5,1.8Hz, 1H), 7.53 (t, J=6.9Hz, 1H), 7.48 (t, J=5.7Hz,
1H), 4.61 (t, J=6.6Hz, 2H), 4.15 (q, J=7.2Hz, 2H), 2.36 (t, J=7.5Hz, 2H), 1.98-1.94 (m,
2H), 1.75-1.70 (m, 2H), 1.62-1.49 (m, 4H), 1.28 (t, J=6.9Hz, 3H)
Embodiment 4
N- hydroxyls -7- (chloro- 11- oximidos -6- oxygen -6,11- dihydros -5H- indenos [1,2-c] quinoline -5- bases of 9-) heptamide
(15) and N- hydroxyls -7- (chloro- 11- oximidos -11H- indenos [1,2-c] quinoline -6- bases oxygen of 9-) heptamide (18) preparation
Hydroxylamine hydrochloride (1.17g, 0.0168mmol) is weighed to be dissolved in MeOH (6.0mL), at 0 DEG C by KOH (1.40g,
Methanol solution (3.5mL) 0.0249mol) is added in the methanol solution of above-mentioned hydroxylamine hydrochloride, and stirring reaction 30min, filters off analysis
The precipitation gone out, filtrate are stored in spare in refrigerator.
Intermediate 9 (0.05g, 0.114mmol) is taken to add the azanol methanol solution of above-mentioned Fresh at 0 DEG C
(3.0mL), is stirred at room temperature reaction, the reaction was complete for TLC monitorings.Methanol is removed in rotation after reaction, and water is added into reaction solution, uses vinegar
Acid adjusts pH weakly acidic pHs, there is solid precipitation, filters, and washing, drains, obtain Chinese red solid 15 (0.025g, 50%).mp 240℃
(dec.).1H NMR(300MHz,DMSO-d6):δ 10.35 (s, 1H), 8.68 (d, J=7.8Hz, 2H), 8.23 (s, 1H), 8.12
(d, J=8.1Hz, 1H), 7.60 (t, J=7.0Hz, 2H), 7.51 (d, J=8.1Hz, 1H), 7.30 (t, J=6.9Hz, 1H),
4.29 (t, J=6.1Hz, 2H), 1.94 (t, J=7.2Hz, 2H), 1.61-1.68 (m, 2H), 1.53-1.46 (m, 2H), 1.37-
1.45(m,2H),1.27-1.32(m,2H).ESI-MS(m/z):440.21([M+H]+, 50%), 900.99 ([2M+Na]+,
100%)
Intermediate 12 (0.05g, 0.114mmol) is taken to add the azanol methanol solution of above-mentioned Fresh at 0 DEG C
(3.0mL), experimental procedure is same as above, and obtains yellow solid 18 (0.015g, 30%).mp 210℃(dec.).1H NMR(300MHz,
DMSO-d6):δ 13.77 (s, 1H), 10.34 (s, 1H), 8.68 (d, J=11.2Hz, 2H), 8.33 (s, 1H), 7.88 (d, J=
8.1Hz, 1H), 7.79 (d, J=8.1Hz, 1H), 7.68-7.54 (m, 2H), 7.49 (d, J=7.4Hz, 1H), 4.54 (t, J=
6.2Hz, 2H), 1.97 (t, J=7.0Hz, 2H), 1.84-1.90 (m, 2H), 1.50-1.58 (m, 4H), 1.36-1.38 (m,
2H).ESI-MS(m/z):440.31([M+H]+),438.06([M-H]-, 100%) and
The synthetic route of other target compounds 16,17,19,20 is same as above.
N- hydroxyls -7- (9- methoxyl group -11- oximido -6- oxygen -6,11- dihydro -5H- indenos [1,2-c] quinoline -5- bases) heptan
Acid amides (16)
Yellow orange solid, mp 204-206 DEG C1H NMR(300MHz,DMSO-d6):δ13.64(s,1H),10.34(s,
1H), 8.74 (d, J=8.0Hz, 1H), 8.65 (s, 1H), 8.09 (d, J=8.3Hz, 1H), 7.91 (d, J=2.4Hz, 1H),
7.61 (d, J=4.7Hz, 2H), 7.31 (t, J=6.8Hz, 1H), 7.05 (dd, J=8.4,2.5Hz, 1H), 4.34 (t, J=
6.1Hz, 2H), 3.82 (s, 3H), 1.94 (t, J=7.2Hz, 2H), 1.61-1.68 (m, 2H), 1.56-1.45 (m, 2H),
1.38-1.46(m,2H),1.29-1.37(m,2H).ESI-MS(m/z):436.26([M+H]+, 100%) and
N- hydroxyls -7- (9- methoxyl group -11- oximido -11H- indenos [1,2-c] quinoline -6- bases oxygen) heptamide (19)
Orange red solid, mp 181-183 DEG C1H NMR(300MHz,DMSO-d6):δ13.41(s,1H),10.35(s,
1H), 8.70 (d, J=8.2Hz, 2H), 7.96 (d, J=2.4Hz, 1H), 7.83 (d, J=8.4Hz, 1H), 7.78 (d, J=
8.2Hz, 1H), 7.59 (t, J=7.1Hz, 1H), 7.45 (t, J=7.5Hz, 1H), 7.10 (dd, J=8.4,2.4Hz, 1H),
4.54 (t, J=6.3Hz, 2H), 3.83 (s, 3H), 1.97 (t, J=7.3Hz, 2H), 1.91-1.85 (m, 2H), 1.56-1.50
(m,4H),1.40-1.34(m,2H).ESI-MS(m/z):436.37([M+H]+, 100%) and
N- hydroxyls -7- (chloro- 11- oximidos -6- oxygen -6,11- dihydros -5H- indenos [1,2-c] quinoline -5- bases of the bromo- 9- of 3-) heptan
Acid amides (17)
Orange red solid, 217 DEG C of (dec.) of mp1H NMR(300MHz,DMSO-d6):δ10.33(s,1H),8.60(d,J
=8.7Hz, 1H), 8.24 (s, 1H), 8.11 (d, J=8.1Hz, 1H), 7.77 (s, 1H), 7.50 (d, J=8.8Hz, 2H),
4.29 (t, J=7.1Hz, 2H), 1.95 (t, J=7.2Hz, 2H), 1.65-1.57 (m, 2H), 1.54-1.47 (m, 2H), 1.43-
1.38(m,2H),1.36-1.30(m,2H).ESI-MS(m/z):516.24([M-H]-, 100%) and
N- hydroxyls -7- (chloro- 11- oximidos -11H- indenos [1,2-c] quinoline -6- bases oxygen of the bromo- 9- of 3-) heptamide (20)
Yellow orange solid, 206 DEG C of (dec.) of mp1H NMR(300MHz,DMSO-d6):δ10.36(s,1H),8.67(d,J
=8.9Hz, 1H), 8.38 (d, J=1.6Hz, 1H), 7.90 (s, 1H), 7.84 (d, J=8.1Hz, 1H), 7.57 (d, J=
8.8Hz, 1H), 7.50 (d, J=8.1Hz, 1H), 4.50 (t, J=5.9Hz, 2H), 1.97 (t, J=7.3Hz, 2H), 1.88-
1.82(m,2H),1.56-1.50(m,4H),1.40-1.34(m,2H).ESI-MS(m/z):516.23([M-H]-),518.34
([M+H]+).
Embodiment 5：External Inhibiting enzyme activity research
Investigate inhibitory action of the target compound to HDAC1 activity.
1) experiment material
384 orifice plates (are purchased from Perkin Elmer, Cat.No.6007279)；HDAC 1,2,3,4,5,6,7,8,9,10,11
(being purchased from BPS Bioscience, USA, Cat.No.50051,50004,50006,50008,50060,50011)；SAHA
(Sigma,Cat.No.SML0061)；CUDC-907(TRC,Cat.No.C834510)；TSA(Sigma,Cat.No.T8552-
5MG)；TMP269(XCESSBIO,Cat.No.M60119-2s).
2) experimental method
Testing compound is transferred in 384 orifice plates and uses 3-4 times of 100%DMSO serial dilutions compound, separately in two skies
Hole in add 30 μ L of 100%DMSO, respectively as the not enzyme and control of compound and be not added with the control of compound.From source
In the breadboard of DMSO weak solutions 0.25 μ L to 384 holes that cut-and-dried compound is shifted in plate.Divide in buffer solution is tested
Enzyme solutions are not prepared and add trypsase, the substrate solution of acetylated peptide substrate.0.25 μ L of enzyme solutions are transferred to breadboard
In or for low control, 15 μ L enzyme solutions of transfer are into breadboard.After incubation at room temperature 15min, add 10 μ L substrate solutions to often
Reacted in hole with inducing.Incubated at room temperature 60min, in the maximum absorbance of 355nm excitation wavelengths and 460nm launch wavelengths.Draw
Matched curve, calculates inhibiting rate with formula (1), IC is calculated with formula (2)50。
Inhibiting rate %=(peak signal-background)/(maximum-minimum) * 100 (1)
Equation(1):Inh%=(Max-Signal)/(Max-Min) * 100
Y%=Bottom+ (Top-Bottom)/(1+10^ ((LogIC50-X) * Hill Slope))
(2)
Y is inhibiting rate, and X is the concentration of compound
3) experimental result
A. target compound the results are shown in Table 8 to the inhibitory activity of HDAC1.
SAHA, TSA are the positive control of hydroxamic acid compound.
Inhibiting enzyme activity of 8. target compound of table to HDAC1
External suppression enzyme test result indicates that, compound 15,16,17,18,19,20 couples of HDAC 1 show stronger suppression
System activity, the wherein IC of compound 15,16,1750Respectively 4.7nM, 2.5nM, 4.5nM, are significantly better than that marketed drug SAHA.
Embodiment 6：Anti tumor activity in vitro is studied
1. experimental cell strain：
The cell line of this experiment test uses：A549 (human lung carcinoma cell), HCT116 (human colon cancer cell), MDA-MB-
231 (human breast cancer cells) and BEL7404 (human liver cancer cell), these cell lines are real by Shanghai Institute of Pharmaceutical Industry's pharmacology
Room is tested to freeze and pass on.
2. sample configures：
Sample is prepared into hydrochloride, after being dissolved with DMSO (Merck), adds the solution that PBS (-) is made into 1000 μ g/ml
Or uniform suspension, then with PBS (-) dilution containing DMSO.SAHA and DOX is positive control drug,.
3. test method
The experiment of this cell in vitro antitumor activity uses mtt assay.It is 4-5 × 10 that 96 orifice plates add concentration per hole4A/mL
100 μ l of cell suspension, put 37 DEG C, 5%CO2In incubator.After 24h, addition sample liquid, 10 μ L/ holes, if duplicate hole, 37 DEG C,
5%CO2Act on 72h.The 20 μ L of MTT solution of 5mg/mL are added per hole, add lysate after acting on 4h, 100 μ L/ holes, put culture
In case, 570nm OD values are surveyed with all-wave length multi-function microplate reader after dissolving.The experimental result of cell in vitro inhibited proliferation is shown in
Table 1.
In-vitro multiplication inhibitory action of 1. target compound of table to tumour cell
Cyto toxic experiment showed shows that 15,18 pairs of four kinds of tumour cells of compound all show certain cytotoxic activity,
Wherein compound 15 is better than the positive to the cytotoxic activity of colon carcinoma cell line HCT116 and breast cancer cell MDA-MB-231
Comparison medicine SAHA, is 3.1 times and 2.8 times of SAHA respectively.In addition, compound 15 is to lung cancer cell line A549 and liver cancer cell lines
BEL7404 also has preferable cytotoxic activity, and therefore, compound 15 has preferable broad-spectrum anti-tumor activity.
The compounds of this invention has broad-spectrum anti-tumor activity activity, and particularly part of compounds is to lung cancer, colon cancer, mammary gland
Cancer, liver cancer have stronger antitumor activity, have good Development volue.The compound of the present invention represents a kind of brand-new knot
The histon deacetylase (HDAC) inhibitor of structure, this lays a good foundation to develop new antitumor drug.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To be made various changes or modifications to the present invention, such equivalent forms equally fall within the model that the application the appended claims are limited
Enclose.
Claims (7)
1. hydroxamic acid compound or its pharmaceutically acceptable salt shown in the logical formula (I) of one kind：
In formula,
R1The position of substitution can be located at any one or two in 2 and 3；R2The position of substitution can be located at 8 and 9 in any
It is a or two；R1、R2For any sort in following groups：A) hydrogen；B) straight or branched alkoxyl of C1-8；C) halogen；
A is-(CH2)m-, wherein m=2-6.
2. compound as claimed in claim 1, it is characterised in that R1For hydrogen；R2It is in halogen, methoxyl group or hydrogen positioned at 9
It is any；A is-(CH2)6-。
3. compound as claimed in claim 1, it is characterised in that the compound is any one in following compounds：
N- hydroxyls -7- (chloro- 11- oximidos -6- oxygen -6,11- dihydros -5H- indenos [1,2-c] quinoline -5- bases of 9-) heptamide；
N- hydroxyls -7- (9- methoxyl group -11- oximido -6- oxygen -6,11- dihydro -5H- indenos [1,2-c] quinoline -5- bases) heptamide；
N- hydroxyls -7- (chloro- 11- oximidos -6- oxygen -6,11- dihydros -5H- indenos [1,2-c] quinoline -5- bases of the bromo- 9- of 3-) oenanthyl
Amine；
N- hydroxyls -7- (9- methoxyl group -11- oximido -11H- indenos [1,2-c] quinoline -6- bases oxygen) heptamide.
4. a kind of composition, compound and pharmaceutically acceptable carrier described in the claim 1 containing safe and effective amount.
5. a kind of compound as claimed in claim 1 is preparing prevention or is treating because histon deacetylase (HDAC) abnormal expression is led
Application in the mammal relevant disease medicine of cause.
6. application as claimed in claim 5, it is characterised in that the disease is cancer, neurodegenerative disease, virus are felt
Any of dye, inflammation, leukaemia, malaria and diabetes.
7. application as claimed in claim 6, it is characterised in that the cancer is lung cancer, in liver cancer, colon cancer, breast cancer
It is any.
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