CN106279021A - One class Antibiotic FR 901228 based on indeno quinolinone skeleton and its preparation method and application - Google Patents
One class Antibiotic FR 901228 based on indeno quinolinone skeleton and its preparation method and application Download PDFInfo
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Abstract
The invention discloses class Antibiotic FR 901228 based on indeno quinolinone skeleton and its preparation method and application, compound has the structure as shown in logical formula (I) or (II).The compound of the present invention has stronger inhibitory activity for histon deacetylase (HDAC), can prevent or treat the related mammalian disease caused because of histon deacetylase (HDAC) abnormal expression, the particularly compound of the present invention and have stronger anti-tumor activity.The invention still further relates to compositions and the 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, be specifically related to class Antibiotic FR 901228 based on indeno quinolinone skeleton and combinations thereof thing, preparation method and application.The invention still further relates to the application in the medicine of the mammal relevant disease that preparation prevents or treatment causes of this compounds, the particularly application in the treatment fields such as cancer, neurodegenerative disease, virus infection, inflammation, leukemia, malaria and diabetes because of histon deacetylase (HDAC) abnormal expression.
Background technology
According to WHO Report, global cancer patients in 2012 and death are all being constantly increasing.In the malignant tumor such as hepatocarcinoma, esophageal carcinoma, gastric cancer and pulmonary carcinoma, China's new cases and death toll all occupy first place in the world.Wherein, pulmonary carcinoma is the most universal and the most fatal cancer, within 2012, about increases 1,800,000 patients newly, and causes 1,500,000 people dead, and China accounts for more than the 1/3 of this type of case.But, existing cancer therapy drug still can not obtain satisfied therapeutic effect.Therefore, the antitumor drug developing novel mechanism of action is significant.
The acetylation of histone has important regulating and controlling effect for genetic transcription.Histone acetyltransferase (HAT) and histon deacetylase (HDAC) (HDAC) are the key enzymes regulating this process.After the terminal amino group of lysine residue specific in histone is by HATs acetylation, the declines between histidine and DNA, DNA is extended position, makes transcription factor easily and DNA binding site is specific binding, activated transcription and reproduction process, cause gene expression.When lysine residue is under HDACs effect after deacetylation; terminal amino group is protonated; positive charge density increases; histone is strengthened by effect between electrostatic interaction and electronegative DNA; make chromosome tighten thus cause gene silencing; ultimately result in transcription to be suppressed, stimulate tumor cell proliferation.
Under normal physiological conditions, the acetylation of histone and deacylation process are in the state of a kind of dynamic equilibrium.When cell occurs to convert, HDACs unconventionality expression, deacetylation effect strengthens, changes homeostasis; DNA is deflated state, stops gene expression, reduces the activity of tumor suppressor gene (such as p21; p27), cause unconfined cell proliferation, thus lead oncogenic generation.
The various aspects such as HDAC family grows at cell, differentiation, metabolism, apoptosis have important function.Have now been found that HDACs has 18 hypotypes, be largely divided into tetra-families of I, II, III, IV.Wherein I family include HDAC 1,2,3,8 four kind of hypotype, the most generally express in many tumor cell lines, thus more paid attention to.IIa family mainly have HDAC 4,5,7,9 four kind of hypotype, there are two catalysis regions in IIb family, mainly has HDAC 6,10 two kind of hypotype, and IV family only has 11 1 kinds of hypotypes of HDAC, wherein I family is positioned in nucleus, and other II, IV family all exists in nucleus and Cytoplasm.The HDAC of I, II, IV family is that Zn2+ relies on enzyme, and Group III family belongs to the protease that NAD+ relies on.
Research finds all to there is some HDAC hypotype high expressed in many tumor cells, mainly shows as I family (1,2,3,8) and the high expressed of IIb family HDAC 6 hypotype.Such as HDAC 1,2,3,8 hypotype high expressed in colon cancer, HDAC 1,2,3 hypotype high expressed in gastric cancer, HDAC 4,6 hypotype high expressed in breast carcinoma, the activity that this demonstrates HDACs is relevant with the generation of cancer, and therefore HDACs becomes an antineoplastic agent target the most promising and day by day draws attention.
Hdac inhibitor, by suppression HDAC, increases acetylation of histone degree so that they are piled up in nucleus; increase the activity of tumor suppressor gene; activate some downstream effect, including apoptosis, the minimizing breaking up and breed of tumor cell, thus reach antineoplastic purpose.
Hdac inhibitor mainly has hydroxamic acid, benzamides, cyclic peptide, short-chain fat acids.Having listed the hdac inhibitor with clinical investigation phase at present and had kind more than 30, wherein hydroxamic acid is to study widest hdac inhibitor.TSA (Trichostatin A) is the hydroxamic acid hdac inhibitor studied the earliest, though having dropped out clinical research, but TSA is still used for compound activity evaluation frequently as comparison medicine.TSA structure optimization is obtained activity preferably Vorinostat (vorinostat, Zolina, SAHA), it it is the hdac inhibitor of wide spectrum, all effective to the hypotype of I family, FDA approval listing in 2006, it is used for treating transitivity cutaneous T cell lymphoma (CTCL).The Baily promise he (Belinostat, PXD-101) of FDA approval listing in 2014 is used for the treatment of lymphoma peripheral T cell (PTCL), but there is the side effect of Q-T interval prolongation.Cyclic peptide compounds Romidepsin (FK228, Istodax) selection is in the various hypotypes of I family, and FDA approval listing in 2009, for skin and lymphoma peripheral T cell.
Hdac inhibitor has the advantages such as wide, the overriding resistance of antitumor spectra, and current this kind of medicine is with other drug share wide prospect.Romidepsin by its seldom used medicine status of FDA certification, share with Sorafenib, is used for treating primary hepatoma, significantly extend life cycle.Entinostat combines with exemestane, and FDA approved is breakthrough therapy, for treating the metastatic breast cancer of estrogen receptor positive.
But, all there is more serious cardiac toxicity in many hdac inhibitors, studies have found that the Romidepsin of listing can affect people hERG.The most all there is the side effect causing Q-T interval prolongation in Baily promise he (Belinostat, PXD-101) etc., therefore, Development of Novel, effective hdac inhibitor remain the challenging problem of antitumor drug research field.
Summary of the invention
The invention aims to provide the novel hdac inhibitor of class and a pharmaceutically acceptable salt thereof.The present invention discloses the preparation method of this compounds, medical application and compositions.
In a first aspect of the present invention, it is provided that a class leads to the compound based on indeno quinolinone skeleton shown in formula (I) or (II) or its pharmaceutically acceptable salt, solvate, prodrug 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, can be single, double or polysubstituted；Described R1、R2Substituent group is any sort in following groups: a) hydrogen；B) the straight or branched alkoxyl of substituted or unsubstituted C1-8；C) the straight or branched alkyl of substituted or unsubstituted C1-8；D) thiazolinyl of the straight or branched of substituted or unsubstituted C2-6；E) alkynyl of the straight or branched of substituted or unsubstituted C2-6；F) the straight or branched alkyl amide of substituted or unsubstituted C1-8；G) substituted or unsubstituted aryl or 5-6 unit heterocyclic aryl；H) the straight or branched alkanoyl of substituted or unsubstituted 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；
Described replacement refers to be replaced by following one or more substituent groups: C1-5 alkyl, C2-5 thiazolinyl, C2-5 alkynyl, C1-5 alkoxyl, halogen, nitro, cyano group, hydroxyl, amino, carboxyl and oxo.
In another preference, compound as above, R1The position of substitution can be located at any one in 2 and 3 or two；And/or R2The position of substitution can be located at any one in 8 and 9 or two.
In another preference, compound as above, R1、R2Substituent group is any sort in following groups: a) hydrogen；B) the straight or branched alkoxyl of C1-8；C) the straight or branched alkyl of C1-8；D) halogen.
In another preference, compound as above, A is-(CH2)m-, wherein m=2-6.
In another preference, compound as above, R1For hydrogen；R2It is positioned at 9, for any one in methyl, halogen, methoxyl group or hydrogen；A is-(CH2)6-。
In another preference, described compound is any one in following compound:
N-hydroxyl-7-(9-chloro-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) heptamide；
N-hydroxyl-7-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) heptamide；
N-hydroxyl-6-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) caproamide；
N-hydroxyl-5-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) pentanamide；
N-hydroxyl-4-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) butyramide；
N-hydroxyl-7-(9-methyl-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) heptamide；
N-(2-aminophenyl)-7-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) heptamide；
N-(2-aminophenyl)-6-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) caproamide.
In a second aspect of the present invention, it is provided that a kind of compositions, it contains the compound described in the first aspect present invention of safe and effective amount or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.In another preference, described compositions is pharmaceutical composition.
In a third aspect of the present invention, it is provided that the application in the mammal relevant disease medicine that preparation prevention or treatment cause because of histon deacetylase (HDAC) abnormal expression of the compound described in first aspect.
In another preference, described disease is any one in cancer, neurodegenerative disease, virus infection, inflammation, leukemia, malaria and diabetes.It is highly preferred that described cancer is any one in pulmonary carcinoma, colon cancer, breast carcinoma or hepatocarcinoma.
In a fourth aspect of the present invention, it is provided that the preparation method of formula (I) compound described in first aspect, comprise the following steps:
Isatin react with the phenylacetic acid of para-orientation under anhydrous sodium acetate is catalyzed and generates 3-substituted-phenyl-2-hydroxyquinoline-4-carboxylic acid, raw intramolecular dehydration condensation is issued again in polyphosphoric acids effect, generate 9-position substituted 6-hydroxyl-11H-indenes [1,2-c] quinoline-11-ketone.The ω of this intermediate and different length-bromo aliphatic carboxylic acid ethyl ester generates the upper substituted ester of 5-N, then hydrolysis obtains corresponding acid in the basic conditions.This acid is in the presence of N-methylmorpholine and isobutyl chlorocarbonate, trityl azanol reaction generate the hydroxamic acid intermediate of trityl as protecting group, is finally hydrolyzed to the target compound of hydroxamic acid under boron trifluoride is catalyzed.Synthetic route is as shown in Figure 2.
In a fourth aspect of the present invention, additionally provide the preparation method of formula (II) compound described in first aspect, comprise the following steps:
Isatin reacts generation 3-(4-methoxyphenyl)-2-hydroxyquinoline-4-carboxylic acid under anhydrous sodium acetate is catalyzed with 4-methoxyphenylacetic acid, raw molecule inner ring condensation is issued in polyphosphoric acids effect, generate 9-methoxyl group-6-hydroxyl-11H-indeno [1,2-c] quinoline-11-ketone, gained compound continues and the ω-bromo aliphatic carboxylic acid ethyl ester reaction of different length generates substituted ester on 5-N, and under LiOH effect, hydrolysis obtains corresponding acid.This acid is under condensing agent effect and o-phenylenediamine reaction generates the target compound shown in formula (II), and synthetic route is as shown in Figure 3.
The Pharmaceutical composition that the present invention relates to, the above-mentioned target compound containing safe and effective amount and pharmaceutically acceptable carrier.Can be solid form or liquid form, described pharmaceutical dosage form can be tablet, capsule, powder agent, granule, suspensoid or injection.When the compounds of this invention is for such use, can mix with one or more pharmaceutically acceptable carriers or excipient, such as solvent, diluent etc., and can be with following form oral administration: tablet, pill, capsule, dispersible powder, granule or suspension (containing such as from about 0.05-5% suspending agent), syrup (containing such as from about 10-50% sugar), with elixir (containing about 20-50% ethanol), or be administered in external mode: ointment, gel, pastille adhesive plaster etc., or carry out parenteral routes with sterile injectable solution or form of suspension (containing about 0.05-5% suspending agent in isotonic medium).Such as, these pharmaceutical preparatioies can be containing the active component of the about 0.01-99%, more preferably about 0.1%-90% (weight) mixed with carrier.
" safe and effective amount " refers to: the amount of compound be enough to improve the state of an illness, and is unlikely to produce serious side effect.Safe and effective amount determined according to age for the treatment of target, the state of an illness, course for the treatment of etc..
" pharmaceutically acceptable carrier " refers to: one or more biocompatible solid or liquid filler or gelatinous mass, and they are suitable for people and use and it is necessary to have enough purity and of a sufficiently low toxicity." compatibility " herein means generation be in compositions each component energy and the compound of the present invention and they between mutually admix, and significantly reduce the curative effect of compound.Pharmaceutically acceptable carrier part example has sugar (such as glucose, sucrose, lactose etc.), starch is (such as corn starch, potato starch etc.), cellulose and its derivates is (such as sodium carboxymethyl cellulose, ethyl cellulose sodium, cellulose ethanoate etc.), gelatin, Pulvis Talci, kollag is (such as sodium stearate, magnesium stearate), calcium sulfate, vegetable oil is (such as Oleum Glycines, Oleum sesami, Oleum Arachidis hypogaeae semen, olive oil etc.), polyhydric alcohol is (such as propylene glycol, glycerol, mannitol, sorbitol etc.), emulsifying agent (such as Tweens), wetting agent (such as dodecyl sodium sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, apirogen water etc..
The compound of the present invention, tests through Inhibiting enzyme activity, finds the activity all having stronger suppression HDAC.In addition, it is also tested for part of compounds and four kinds of human tumor cells: A549 (human lung carcinoma cell), HCT116 (human colon cancer cell), MDA-MB-231 (human breast cancer cell) and the body outer cell proliferation inhibitory action of BEL7404 (human liver cancer cell), the target compound of the result display present invention are provided with good broad-spectrum anti-tumor effect.Additionally, the compound of the present invention can be alone, it is also possible to and existing drug combination, to obtain more preferable effect.
Accompanying drawing explanation
Fig. 1 contains general structure (I) and (II) of the hdac inhibitor of indeno quinolinone structure；
The synthetic route chart of Fig. 2 formula (I) compound.
The synthetic route chart of Fig. 3 formula (II) compound.
Detailed description of the invention
Below in conjunction with specific embodiment, it is further elucidated with the present invention.It should be understood that be merely to illustrate invention rather than limit the scope of the present invention.Following enforcement indicates the implementation of actual conditions, generally according to normal condition, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise percentage ratio and number are percentage by weight and parts by weight.
Nuclear magnetic resonance analyser (CDCl3Or DMSO-d6For deuterated reagent, containing 0.03%TMS) (model: Bruker Avance 300 place of production: Germany)；Mass spectrograph (model: the API-3000LC-MS place of production: the U.S.)；Infrared spectrometer (KBr tabletting) (model: the Perkin-Elmer Spectrum 1600FTIR place of production: the U.S.)；Micro-meldometer (thermometer is the most calibrated) (model: the XT4A place of production: tech electric light instrument plant of Beijing).Middle compacting is for liquid phase (model: Compact Avance 300 place of production: Li Sui Science and Technology Ltd., China), and in experiment, agents useful for same is analytical pure, is purchased from chemical reagents corporation of traditional Chinese medicines group.Column chromatography used silica gel is 300-400 mesh (place of production: Qingdao Haiyang chemical industry institute).Chromatographic sheet is GF254Silica gel plate (place of production: Yantai Jiang You silica gel development corporation, Ltd.).The structure of all target compounds is all passed through1The confirmation of H NMR, ESI-MS, IR.
Embodiment 1
The preparation (1) of 3-(4-chlorphenyl)-2-hydroxyquinoline-4-carboxylic acid
Red (the 5.51g that runs is added in 100mL three-neck flask, 0.0375mol), anhydrous sodium acetate (1.24g, after 0.0151mol) mixing with 4-Chlorophenylacetic acid (11.18g, 0.0656mol), it is heated to reflux 3h to TLC detection reaction in 200 DEG C and terminates.Adding 10% sodium hydroxide (200mL) in reactant liquor makes it dissolve, filtering, filtrate washs (3 × 80mL) with dichloromethane, separates water layer, pH 5-6 adjusted by water layer glacial acetic acid, filtering, filtrate adjusts pH 1-2 with concentrated hydrochloric acid again, filters the solid separated out, washing, drain, obtain white solid 1 (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-methoxyphenyl)-2-hydroxyquinoline-4-carboxylic acid (2)
Isatin and the reaction of 4-methoxyphenylacetic acid generate white solid 2, and synthetic method is ibid.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).
3-(4-aminomethyl phenyl)-2-hydroxyquinoline-4-carboxylic acid (3) synthetic method is ibid.
Embodiment 2
The preparation (4) of 9-chloro-6-hydroxyl-11H-indeno [1,2-c] quinoline-11-ketone
Adding polyphosphoric acids (21.95g, 0.065mol) and 3-(4-chlorphenyl)-2-hydroxyquinoline-4-carboxylic acid 1 (2.75g, 0.0097mol) in 100mL round-bottomed flask, 130 DEG C are heated to reflux to TLC monitoring reaction terminating.Reactant liquor is poured in frozen water, stirring, separate out solid after standing, filter, be washed to neutrality, obtain red brown solid 4 (2.22g, 81.9%), be directly used in the next step.ESI-MS(m/z):280.40([M-H]-, 100%).
The synthetic method of intermediate 5,6 is ibid.
Embodiment 3
The preparation of 7-(9-chloro-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) cognac oil (7)
9-chloro-6-hydroxyl-11H-indeno [1 is added in 100mL round-bottomed flask, 2-c] quinoline-11-ketone (4) (1.41g, 0.005mol), 7-bromine cognac oil (1.36g, 0.0055mol) with Anhydrous potassium carbonate (1.66g, 0.012mol) being dissolved in DMF (24mL), 60 DEG C of heated and stirred reactions terminate to TLC monitoring reaction.By reacting liquid filtering, filter cake CH2Cl2Being washed till colourless, filtrate water washs, anhydrous Na2SO4It is dried, filters, be concentrated to dryness to obtain dark red crude product.In this crude product, the standby liquid phase separation of compacting, obtains Chinese red solid 7 (0.47g).
1H NMR(300MHz,CDCl3null):δ8.71(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,J=7.6Hz,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.
The synthetic route of other intermediate 8-12 is ibid.
7-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) cognac oil (8)
Red brown solid.1H NMR(300MHz,CDCl3null):δ8.69(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.
6-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) ethyl hexanoate (9)
Red brown solid.1H NMR(300MHz,CDCl3null):δ8.69(d,J=6.8Hz,1H),7.99(d,J=8.1Hz,1H),7.55(t,J=7.3Hz,1H),7.38–7.33(m,1H),7.30(d,J=7.6Hz,1H),7.18(d,J=2.4Hz,1H),6.93(dd,J=8.1,2.4Hz,1H),4.38(t,J=6.5Hz,2H),4.13(q,J=7.1Hz,2H),3.87(s,3H),2.35(t,J=7.3Hz,2H),1.87-1.80(m,2H),1.78-1.70(m,2H),1.58-1.53(m,2H),1.26(t,J=7.1Hz,3H).
5-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) ethyl valerate (10)
Red brown solid.1H NMR(300MHz,DMSO-d6): δ 8.49 (d, J=7.7Hz, 1H), 7.75 (d, J=8.3Hz, 1H), 7.62 (dd, J=7.5,4.5Hz, 2H), 7.50 (t, J=7.2Hz, 1H), 7.16 (d, J=2.4Hz, 1H), 7.08 (dd, J=8.2,2.4Hz, 1H), 4.54 (t, J=6.1Hz, 2H), 4.05 (q, J=7.1Hz, 2H), 3.83 (s, 3H), 2.43 (t, J=7.1Hz, 2H), 1.92-1.85 (m, 2H), 1.84-1.74 (m, 2H), 1.16 (t, J=7.1Hz, 3H) .IR (KBr) cm-1:2960,2917,2851,2833,1719,1649,1580,1477,1433,1222,1206,751.
4-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) ethyl n-butyrate. (11)
Red brown solid.1H NMR(300MHz,CDCl3): δ 8.68 (d, J=7.7Hz, 1H), 7.98 (d, J=8.1Hz, 1H), 7.67 7.53 (m, 2H), 7.36 7.28 (m, 1H), 7.17 (d, J=2.4Hz, 1H), 6.93 (dd, J=8.1,2.5Hz, 1H), 4.45 (t, J=6.5Hz, 2H), 4.20 (q, J=7.1Hz, 2H), 3.87 (s, 3H), 2.55 (t, J=6.8Hz, 2H), 2.24 1.99 (m, 2H), 1.30 (t, J=7.1Hz, 3H).
7-(9-methyl-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) cognac oil (12)
Red brown solid.1H NMR(300MHz,DMSO-d6): δ 8.53 (d, J=7.9Hz, 1H), 7.85 (d, J=7.4Hz, 1H), 7.66-7.63 (m, 2H), 7.40 7.33 (m, 3H), 4.33 (t, J=7.5Hz, 2H), 4.04 (q, J=7.1Hz, 2H), 2.35 (s, 3H), (2.29 t, J=7.3Hz, 2H), 1.72-1.60 (m, 2H), 1.57-1.50 (m, 2H), 1.41 1.32 (m, 4H), 1.17 (t, J=7.1Hz, 3H).
Embodiment 4
The preparation (13) of 7-(9-chloro-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) enanthic acid
7-(9-chloro-6 is added in 100mL round-bottomed flask, 11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) cognac oil (7) (0.219g, 0.5mmol), lithium hydroxide monohydrate (0.0882g, 2.1mmol) it is dissolved in THF (20mL) and water (8mL), reaction is stirred at room temperature to TLC monitoring reaction completely.Adjusting pH to neutral reactant liquor dilute hydrochloric acid, solvent is removed in rotation, has solid to separate out, and filters, and washing is drained, obtained red brown solid 13 (0.19g, 93.8%).1H NMR (300MHz, DMSO-d): δ 11.99 (s, 1H), (8.51 d, J=8.1Hz, 1H), (7.97 d, J=7.9Hz, 1H), (7.67 d, J=2.6Hz, 2H), 7.66-7.58 (m, 2H), 7.41-7.34 (m, 1H), 4.33 (t, J=7.5Hz, 2H), 2.20 (t, J=7.2Hz, 2H), 1.69-1.58 (m, 2H), 1.55-1.47 (m, 2H), 1.46-1.31 (m, 4H) .ESI-MS (m/z): 410.29 ([M+H]+, 100%) and .IR (KBr) cm-1:3421,2920,2852,1722,1648,1590,1577,1558,1449,1420,1290,762,738.
The synthetic route of other intermediate 14-18 is ibid.
7-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) enanthic acid (14)
1H NMR(300MHz,DMSO-d6): δ 12.01 (s, 1H), 8.47 (d, J=7.9Hz, 1H), 7.84 (d, J=8.1Hz, 1H), 7.61 (d, J=3.6Hz, 2H), 7.33 (dt, J=8.0,4.0Hz, 1H), 7.11 (d, J=2.3Hz, 1H), 7.04 (dd, J=8.1,2.4Hz, 1H), 4.29 (t, J=7.5Hz, 2H), 3.81 (s, 3H), (2.20 t, J=7.2Hz, 2H), 1.66-1.58 (m, 2H), 1.55-1.47 (m, 2H), 1.44-1.31 (m, 4H) .IR (KBr) cm-1:2924,2852,1718,1647,1577,1432,1293,1221,753.
6-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) caproic acid (15)
1H NMR(300MHz,DMSO-d6): δ 12.04 (s, 0H), 8.52 (d, J=8.0Hz, 1H), 7.89 (d, J=8.1Hz, 1H), 7.65 (d, J=3.6Hz, 2H), 7.38 (dd, J=7.9,4.0Hz, 1H), 7.17 (d, J=2.2Hz, 1H), 7.09 (dd, J=8.2,2.1Hz, 1H), 4.34 (t, J=6.5Hz, 2H), 3.85 (s, 3H), (2.24 t, J=7.1Hz, 2H), 1.71-1.63 (m, 2H), 1.62-1.55 (m, 2H), 1.49-1.42 (m, 2H) .IR (KBr) cm-1:3199,2974,2932,2862,1718,1632,1588,1558,1490,1448,1386,1283,752.
5-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) valeric acid (16)
1H NMR(300MHz,DMSO-d6): δ 12.06 (s, 1H), 8.48 (d, J=8.0Hz, 1H), 7.85 (d, J=8.1Hz, 1H), 7.62 (d, J=2.2Hz, 2H), 7.38-7.30 (m, 1H), 7.13 (d, J=2.1Hz, 1H), 7.06 (dd, J=8.1,2.3Hz, 1H), 4.33 (t, J=6.0Hz, 2H), 3.82 (s, 3H), 2.29 (t, J=6.6Hz, 2H), 1.68-1.62 (m, 4H) .IR (KBr) cm-1:2947,2855,1702,1652,1595,1579,1481,1448,1277,1238,752
4-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) butanoic acid (17)
1H NMR(300MHz,DMSO-d6): δ 12.20 (s, 1H), 8.45 (d, J=8.0Hz, 1H), 7.82 (d, J=8.1Hz, 1H), 7.71 (d, J=8.7Hz, 1H), 7.60 (t, J=7.8Hz, 1H), 7.32 (t, J=7.5Hz, 1H), 7.10 (s, 1H), 7.03 (dd, J=8.1,1.8Hz, 1H), 4.32 (t, J=6.5Hz, 2H), 3.81 (s, 3H), 2.41 (t, J=7.1Hz, 2H), 1.91-1.80 (m, 2H) .IR (KBr) cm-1:3178,2980,2935,2837,1721,1634,1574,1558,1492,1449,1286,1247,752.
7-(9-methyl-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) enanthic acid (18)
1H NMR(300MHz,DMSO-d6): δ 11.99 (s, 1H), 8.54 (d, J=8.2Hz, 1H), 7.86 (d, J=7.4Hz, 1H), 7.67-7.64 (m, 2H), 7.41-7.34 (m, 3H), 4.33 (t, J=6.5Hz, 2H), 2.35 (s, 3H), 2.22 (t, J=7.2Hz, 2H), 1.72-1.59 (m, 2H), 1.57-1.50 (m, 2H), 1.48-1.33 (m, 4H).
Embodiment 5
7-(9-chloro-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base)-N-(trityloxy) heptamide (19)
7-(9-chloro-6 is added in 50mL round-bottomed flask, 11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) enanthic acid (13) (0.267g, 0.4mmol), add THF (20mL), add N-methylmorpholine (0.051mL, 0.4mmol) ,-15 DEG C of stirring 5min it are cooled to.By isobutyl chlorocarbonate (0.051mL, 0.4mmol) add-15 DEG C of stirring 10min in reactant liquor, add O-trityl azanol (0.11g, 0.4mmol) and N-methylmorpholine (0.128mL, 1.0mmol)-15 DEG C stirring 10min.Reaction is stirred at room temperature to TLC monitoring reaction completely.THF is removed in reactant liquor rotation, adds CH2Cl2(100mL) and H2O (100mL), separates CH2Cl2Layer, uses H successively2O, 5%NaHCO3、H2O respectively washed once, then washs with saturated aqueous common salt, separates organic layer, anhydrous Na2SO4Being dried, filter, filtrate is concentrated to dryness, crude product CH2Cl2-MeOH recrystallization, obtains red solid 13 (0.07g, 26.5%).mp 182-183℃.1H NMR (300MHz,DMSO-d6): δ 10.17 (s, 1H), 8.49 (d, J=7.6Hz, 1H), 7.94 (d, J=7.9Hz, 1H), 7.68 (d, J=7.5Hz, 1H), 7.63 (d, J=2.1Hz, 2H), 7.60 (d, J=2.0Hz, 1H), 7.57 (d, J=1.8Hz, 1H), 7.35-7.27 (m, 15H), 4.26 (t, J=6.2Hz, 2H), 1.78 (t, J=6.8Hz, 2H), 1.58-1.49 (m, 2H), 1.29-1.15 (m, 4H), 1.06-0.97 (m, 2H) .ESI-MS (m/z): 665.22 ([M-H]-, 100%), 1355.24 ([2M+Na]+, 100%).
The synthetic route of other intermediate 20-24 is ibid.
7-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base)-N-(trityloxy) heptamide (20)
1H NMR(300MHz,DMSO-d6): δ 10.16 (s, 1H), 8.50 (d, J=8.4Hz, 1H), 7.88 (d, J=8.1Hz, 1H), 7.62 (d, J=5.5Hz, 2H), 7.39-7.25 (m, 16H), 7.15 (d, J=2.4Hz, 1H), 7.07 (dd, J=8.2,2.4Hz, 1H), 4.27 (t, J=6.5Hz, 2H), 3.83 (s, 3H), 1.78 (t, J=7.6Hz, 2H), 1.58-1.49 (m, 2H), 1.30-1.16 (m, 4H), 1.06-0.97 (m, 2H) .ESI-MS (m/z): 661.12 ([M-H]-, 100%) and .IR (KBr) cm-1:3146,2936,2861,1722,1650,1609,1578,1485,1446,1275,1224,756,702.
6-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base)-N-(trityloxy) caproamide (21)
1H NMR(300MHz,DMSO-d6): δ 10.18 (s, 1H), 8.50 (d, J=7.9Hz, 1H), 7.87 (d, J=8.1Hz, 1H), 7.63-7.56 (m, 2H), 7.37-7.29 (m, 16H), (7.14 d, J=2.3Hz, 1H), 7.07 (dd, J=8.1,2.4Hz, 1H), 4.23 (t, J=6.1Hz, 2H), 3.84 (s, 3H), (1.81 t, J=7.5Hz, 2H), 1.56-1.47 (m, 2H), 1.36-1.28 (m, 2H), 1.21-1.13 (m, 2H) .ESI-MS (m/z): 647.23 ([M-H]-, 100%), 1319.38 ([2M+Na]+, 100%).
5-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base)-N-(trityloxy) pentanamide (22)
1H NMR(300MHz,DMSO-d6): δ 10.25 (s, 1H), 8.51 (d, J=8.3Hz, 1H), 7.77 (d, J=8.6Hz, 1H), 7.63 (t, J=8.1Hz, 2H), 7.55 7.48 (m, 1H), 7.33-7.21 (m, 16H), (7.08 d, J=8.1Hz, 1H), (4.42 t, J=6.4Hz, 2H), 3.84 (s, 3H), 1.91 (t, J=5.9Hz, 2H), 1.62-1.53 (m, 2H), 1.52-1.41 (m, 2H) .ESI-MS (m/z): 633.12 ([M-H]-, 100%) and .IR (KBr) cm-1:3420,2921,2851,1722,1656,1609,1579,1477,1448,1292,1224,750,702.
4-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base)-N-(trityloxy) butyramide (23)
1H NMR(300MHz,DMSO-d6): δ 10.37 (s, 1H), 8.48 (d, J=8.0Hz, 1H), 7.83 (d, J=8.0Hz, 1H), (7.61 t, J=7.5Hz, 1H), (7.45 d, J=8.9Hz, 1H), 7.39-7.20 (m, 16H), 7.14 (d, J=1.6Hz, 1H), 7.06 (d, J=8.3Hz, 1H), 4.00 (t, J=6.1Hz, 2H), 3.82 (s, 3H), 1.98 (t, J=6.5Hz, 2H), 1.68-1.55 (m, 2H) .ESI-MS (m/z): 619.14 ([M-H]-, 100%).
7-(9-methyl-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base)-N-(trityloxy) heptamide (24)
1H NMR(300MHz,DMSO-d6): δ 10.19 (s, 1H), 8.52 (d, J=7.8Hz, 1H), 7.84 (d, J=7.4Hz, 1H), 7.64-7.59 (m, 2H), 7.41-7.37 (m, 3H), 7.35-7.25 (m, 15H), 4.27 (t, J=6.5Hz, 2H), 2.33 (s, 3H), 1.77 (t, J=6.1Hz, 2H), 1.59 1.50 (m, 2H), 1.25 1.18 (m, 4H), 1.05 0.97 (m, 2H) .ESI-MS (m/z): 669.41 ([M+Na]+, 18%), 1315.43 ([2M+Na]+, 100%).
Embodiment 6
N-hydroxyl-7-(9-chloro-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) heptamide (25)
Take 7-(9-chloro-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base)-N-(trityloxy) heptamide (19) (0.053g, 0.08mmol), be dissolved in CH2Cl2In-MeOH (1:1) (14mL), add BF3-Et2O solution (0.17mL), is stirred at room temperature reaction to TLC monitoring reaction completely.Add H2O (80mL) and the CH of 10%MeOH2Cl2Solution (100mL) terminates reaction, separates water layer, uses saturated NaHCO3Regulation pH 8-9, the CH of water layer 10%MeOH2Cl2Solution extracts three times, merges organic layer, washs with saturated aqueous common salt, anhydrous Na2SO4Being dried, filter, filtrate is concentrated to dryness, and filter cake adds CH2Cl2(20mL) pulverize, filter, washing, drain to obtain red solid 25 (0.12g, 35.7%), mp 180-182 DEG C.
1H NMR(300MHz,DMSO-d6): δ 10.35 (s, 1H), 8.66 (s, 1H), 8.51 (d, J=7.8Hz, 1H), 7.97 (d, J=7.7Hz, 1H), 7.70-7.58 (m, 4H), 7.42-7.35 (m, 1H), 4.33 (t, J=7.4Hz, 2H), 1.95 (t, J=7.2Hz, 2H), 1.70-1.59 (m, 2H), 1.53-1.46 (m, 2H), 1.46-1.40 (m, 2H), 1.35-1.28 (m, 2H) .ESI-MS (m/z): 423.17 ([M-H]-, 100%), 871.07 ([2M+Na]+, 100%) and .IR (KBr) cm-1:3238,2921,2852,1719,1651,1576,1446,1421,754,739.
The synthetic route of other target compounds 26-30 is ibid.
N-hydroxyl-7-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) heptamide (26)
Red solid, mp 188-190 DEG C.1H NMR(300MHz,DMSO-d6null):δ10.36(s,1H),8.68(s,1H),8.49(d,J=7.6Hz,1H),7.86(d,J=8.0Hz,1H),7.66-7.59(m,2H),7.36(d,J=6.5Hz,1H),7.15-7.11(m,1H),7.07(d,J=7.8Hz,1H),4.31(t,J=6.5Hz,2H),3.84(s,3H),1.97(t,J=7.1Hz,2H),1.69-1.61(m,2H),1.56-1.48(m,2H),1.48-1.40(m,2H),1.38-1.31(m,2H).ESI-MS(m/z):419.44([M-H]-, 100%), 863.27 ([2M+Na]+, 100%) and .IR (KBr) cm-1:3251,2928,2854,1720,1648,1578,1479,1446,1280,1222,1041,754.
N-hydroxyl-6-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) caproamide (27)
Red solid.1H NMR(300MHz,DMSO-d6): δ 10.33 (s, 1H), 8.66 (s, 1H), 8.50 (d, J=7.9Hz, 1H), 7.87 (d, J=8.2Hz, 1H), 7.62 (d, J=3.5Hz, 2H), 7.39-7.32 (m, 1H), 7.15 (d, J=2.0Hz, 1H), 7.07 (d, J=8.1Hz, 1H), 4.31 (t, J=6.1Hz, 2H), 3.83 (s, 3H), 1.96 (t, J=7.1Hz, 2H), 1.63-1.57 (m, 4H), 1.46-1.37 (m, 2H) .ESI-MS (m/z): 407.39 ([M+H]+, 100%).
N-hydroxyl-5-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) pentanamide (28)
Red brown solid, mp 207-209 DEG C.1H NMR(300MHz,DMSO-d6): δ 10.35 (s, 1H), 8.67 (s, 1H), 8.50 (d, J=7.8Hz, 1H), 7.87 (d, J=8.2Hz, 1H), 7.63 (d, J=4.3Hz, 2H), 7.35 (t, J=7.8Hz, 1H), 7.15 (d, J=2.2Hz, 1H), 7.07 (dd, J=8.1,2.3Hz, 1H), 4.34 (t, J=6.5Hz, 2H), 3.83 (s, 3H), 2.02 (t, J=6.1Hz, 2H), 1.68-1.61 (m, 4H) .ESI-MS (m/z): 391.16 ([M-H]-,
100%)), 807.15 ([2M+Na]+, 100%) and .IR (KBr) cm-1:3270,2931,2865,1720,1646,1578,1485,1445,1281,1248,1020,757.
N-hydroxyl-4-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) butyramide (29)
Red solid.1H NMR(300MHz,DMSO-d6): δ 10.45 (s, 1H), 8.77 (s, 1H), 8.50 (d, J=7.7Hz, 1H), 7.86 (d, J=7.6Hz, 1H), 7.68 (d, J=7.9Hz, 2H), 7.42-7.32 (m, 1H), 7.14 (s, 1H), 7.07 (dd, J=8.2,1.9Hz, 1H), 4.33 (t, J=6.5Hz, 1H), 3.83 (s, 3H), 2.07 (t, J=7.1Hz, 2H), 1.95-1.79 (m, 2H) .ESI-MS (m/z): 379.33 ([M+H]+, 98%), 779.12 ([2M+Na]+, 100%).
N-hydroxyl-7-(9-methyl-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) heptamide (30)
Orange red solid, mp 177-179 DEG C.1H NMR(300MHz,DMSO-d6): δ 10.38 (s, 1H), 8.55 (d, J=8.2Hz, 1H), 7.87 (d, J=7.7Hz, 1H), 7.69 7.65 (m, 2H), 7.45 7.35 (m, 4H), 4.38 4.30 (m, 2H), 2.36 (s, 3H), 1.98 (t, J=8.3Hz, 2H), 1.71 1.63 (m, 2H), 1.57 1.50 (m, 2H), 1.48 1.41 (m, 2H), 1.38 1.31 (m, 2H) .ESI-MS (m/z): 405.45 ([M+H]+, 48%), 831.14 ([2M+Na]+, 100%).
Embodiment 7
The preparation (31) of N-(2-aminophenyl)-7-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) heptamide
7-(9-methoxyl group-6 is added in 100mL round-bottomed flask, 11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) enanthic acid (14) (0.081g, 0.2mmol) is dissolved in DMF (12mL), adds DIPEA (0.104mL), HATU (0.084g, 0.22mmol) with o-phenylenediamine (0.068g, 0.6mmol), reaction is stirred at room temperature to TLC monitoring reaction completely.CH is added in reactant liquor2Cl2And H2The each 100mL of O, separates organic layer, uses H successively after shaking2O, 5%NaHCO3, saturated aqueous common salt washing, organic layer anhydrous Na2SO4Being dried, filter, filtrate obtains solid 31 russet, mp 194-196 DEG C after being spin-dried for.1H NMR(300MHz,DMSO-d6null):δ9.08(s,1H),8.49(d,J=8.0Hz,1H),7.87(d,J=8.1Hz,1H),7.62(d,J=3.4Hz,2H),7.35(dd,J=10.2,5.8Hz,1H),7.18-7.11(m,2H),7.06(dd,J=8.2,2.5Hz,1H),6.87(t,J=7.0Hz,1H),6.69(d,J=6.9Hz,1H),6.52(t,J=7.5Hz,1H),4.80(s,2H),4.33(t,J=6.5Hz,2H),3.82(s,3H),2.32(t,J=7.3Hz,2H),1.71-1.56(m,4H),1.50-1.35(m,4H).ESI-MS(m/z):496.44([M+H]+, 100%) and .IR (KBr) cm-1:3418,3348,3282,2939,2853,1721,1650,1592,1578,1485,1459,751.
N-(2-aminophenyl)-6-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) caproamide (32)
Synthetic method ibid, obtains solid 32 russet, mp 191-192 DEG C.1H NMR(300MHz,DMSO-d6null):δ9.11(s,1H),8.47(d,J=8.2Hz,1H),7.85(d,J=8.1Hz,1H),7.61(d,J=4.6Hz,2H),7.33(t,J=5.6Hz,1H),7.16-7.09(m,2H),7.05(dd,J=8.2,2.4Hz,1H),6.88(t,J=7.5Hz,1H),6.70(d,J=7.9Hz,1H),6.51(t,J=7.4Hz,1H),4.95(s,2H),4.33(t,J=6.5Hz,,2H),3.82(s,3H),2.33(t,J=7.2Hz,2H),1.72-1.64(m,4H),1.51-1.45(m,2H).ESI-MS(m/z):482.44([M+H]+, 100%) and .IR (KBr) cm-1:3407,3348,3267,2919,2851,1722,1648,1592,1578,1484,1459,750.
Embodiment 8: external Inhibiting enzyme activity is studied
Investigate the target compound inhibitory action to HDAC activity, and the hydroxamic acid of different carbon chain lengths and the impact on HDAC activity of the o-phenylenediamine side chain.
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 technique
Testing compound is transferred in 384 orifice plates with 100%DMSO serial dilution compound 3-4 times, in two empty holes, separately add 100%DMSO 30 μ L, respectively as the most enzyme-added comparison with compound and the comparison that is not added with compound.Shift from source plate in the bread board in DMSO weak solution 0.25 μ L to 384 hole of cut-and-dried compound.In test buffer, prepare enzymatic solution respectively and add trypsin, the substrate solution of acetylated peptide substrate.Enzymatic solution 0.25 μ L is transferred in bread board or for low comparison, shifts 15 μ L enzymatic solution in bread board.After incubation at room temperature 15min, add 10 μ L substrate solutions in every hole to induce reaction.Incubated at room temperature 60min, launches the maximum absorbance of wavelength in 355nm excitation wavelength and 460nm.Draw matched curve, calculate suppression ratio with formula (1), calculate IC with formula (2)50。
Suppression ratio %=(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 suppression ratio, and X is the concentration of compound
3) experimental result
A. target compound the results are shown in Table 1 to the inhibitory activity of HDAC1.
SAHA, TSA are the positive control of hydroxamic acid compound, and MS275 is the positive control of o-phenylenediamine compounds.
Table 1. target compound Inhibiting enzyme activity to HDAC1
The external enzyme that presses down test result indicate that, 25,26 couples of HDAC 1 of compound show stronger inhibitory activity, its IC50It is respectively 4.5nM and 0.77nM.The two compound will be better than positive control drug SAHA to the inhibitory action of HDAC 1, is 1.9 and 11.2 times of SAHA respectively.
B. choose the preferable compound of Inhibiting enzyme activity 26, investigate its effect to HDAC hypotype.
Compound 26 the results are shown in Table 2 to the Inhibiting enzyme activity of HDAC 1,2,3,6,8,10 hypotype, and wherein SAHA and TSA is positive control.Compound 26 the results are shown in Table 3 to the Inhibiting enzyme activity of HDAC 4,5,7,9,11 hypotype, and wherein TMP-269 and CUDC-907 is positive control.
Table 2. compound 26 Inhibiting enzyme activity to HDAC 1,2,3,6,8,10
Table 3. compound 26 Inhibiting enzyme activity to HDAC 4,5,7,9,11
Can be seen that from the experimental result of table 2, compound 26 all shows preferable Inhibiting enzyme activity to HDAC 1,2,3,8,6,10, its IC50All reaching nanomolar range, its Inhibitory activity positive control drug to be significantly better than SAHA to HDAC 1,2,3,8,10, is 11 times of SAHA, 6 times, 18 times, 29 times, 2 times and 41 times respectively.Compound 26 is slightly better than positive control drug TSA to the Inhibitory activity of HDAC 8,10, is 1.7 times and 2.6 times of TSA respectively, then suitable with TSA to the Inhibitory activity of HDAC 3 and HDAC 1.
Test result indicate that of table 3, compound 26 is the most weak to the inhibitory action of HDAC 4,5,7,9,11 hypotype, it means that will not produce the side effect brought by HDAC IIa class (HDAC 4,5,7,9) and IV class (HDAC11) hypotype.Illustrating that compound 26 has higher selectivity to HDAC I family (HDAC 1,2,3,8) and IIb family (HDAC 6, HDAC 10) hypotype, Inhibitory activity is stronger.
Embodiment 9: anti tumor activity in vitro is studied
1. experimental cell strain:
The cell strain of this experiment test uses: A549 (human lung carcinoma cell), HCT116 (human colon cancer cell), MDA-MB-231 (human breast cancer cell) and BEL7404 (human liver cancer cell), and these cell strains are frozen by Shanghai Institute of Pharmaceutical Industry's pharmacological evaluation room and pass on.
2. sample configuration:
Sample is all prepared as hydrochlorate, after dissolving with DMSO (Merck), add PBS (-) be made into the solution of 1000 μ g/ml or uniform suspension, then with containing DMSO PBS (-) dilution.SAHA and DOX is positive control drug.
3. test method
The experiment of this cell in vitro anti-tumor activity uses mtt assay.It is 4-5 × 10 that the 96 every holes of orifice plate add concentration4The cell suspension 100 μ l of individual/mL, puts 37 DEG C, 5%CO2In incubator.After 24h, addition sample liquid, 10 μ L/ holes, if duplicate hole, 37 DEG C, 5%CO2Effect 72h.Every hole adds the MTT solution 20 μ L of 5mg/mL, adds lysate, 100 μ L/ holes, put in incubator after effect 4h, surveys 570nm OD value by the multi-functional microplate reader of all-wave length after dissolving.Experimental result is shown in Table 4.
Table 4. target compound in-vitro multiplication inhibitory action to tumor cell
Experimental result shows, the cytotoxic activity of 25,26 couples of breast cancer cell MDA-MB-231 of compound is all better than positive control drug SAHA, is 2.5 times and 5.1 times of SAHA respectively.Compound 26 is suitable with positive control drug DOX to the cytotoxic activity of breast cancer cell MDA-MB-231 and human liver cancer cell BEL7404, and the especially effect to BEL7404 is stronger, IC50It it is 0.53 μM.
Experimental result is it is also shown that compound 26 also has preferable cytotoxic activity to HCT116, MDA-MB-231 and BEL7404, and therefore, compound 26 has the anti-tumor activity of wide spectrum.
The compounds of this invention has broad-spectrum anti-tumor activity activity, and particularly part of compounds has stronger anti-tumor activity to hepatocarcinoma, pulmonary carcinoma, breast carcinoma, has good Development volue.The indeno quinolinones compound of the present invention represents the compound with anti-tumor activity of a class brand new, and this is to further investigate and develop new antitumor drug to open approach and direction.
The all documents mentioned in the present invention are incorporated as reference the most in this application, are individually recited as with reference to like that just as each document.In addition, it is to be understood that after the above-mentioned teachings having read the present invention, the present invention can be made various changes or modifications by those skilled in the art, these equivalent form of values fall within the application appended claims limited range equally.
Claims (10)
1. a class leads to the compound based on indeno quinolinone skeleton shown in formula (I) or (II) or it pharmaceutically may be used
Salt, solvate, prodrug or the polymorph accepted:
In formula,
R1The position of substitution can be located at 1 to 4, can be single, double or polysubstituted；R2The position of substitution can position
In 7 to 10, can be single, double or polysubstituted；Described R1、R2Substituent group is appointing in following groups
One class: a) hydrogen；B) the straight or branched alkoxyl of substituted or unsubstituted C1-8；C) replace or do not take
The straight or branched alkyl of the C1-8 in generation；D) thiazolinyl of the straight or branched of substituted or unsubstituted C2-6；
E) alkynyl of the straight or branched of substituted or unsubstituted C2-6；F) substituted or unsubstituted C1-8's is straight
Chain or branched alkane amide groups；G) substituted or unsubstituted aryl or 5-6 unit heterocyclic aryl；H) replace or not
The straight or branched alkanoyl of substituted C1-8；I) the straight or branched alkane acyl of substituted or unsubstituted C1-8
Epoxide；J) nitro；K) amino；L) hydroxyl；M) halogen；N) methylene-dioxy；O) sub-second dioxy
Base；P) cyano group；
A is-(CH2)m-or-(CH2=CH2)n-, wherein m=2-8, n=1-4；
Described replacement refers to be replaced by following one or more substituent groups: C1-5 alkyl, C2-5 thiazolinyl,
C2-5 alkynyl, C1-5 alkoxyl, halogen, nitro, cyano group, hydroxyl, amino, carboxyl and oxo.
2. compound as claimed in claim 1, it is characterised in that R1The position of substitution can be located at 2 and 3
Any one in Wei or two；And/or R2The position of substitution can be located at any one in 8 and 9 or two.
3. compound as claimed in claim 1, it is characterised in that R1、R2Substituent group is in following groups
Any sort: a) hydrogen；B) the straight or branched alkoxyl of C1-8；C) the straight or branched alkyl of C1-8；
D) halogen.
4. compound as claimed in claim 1, it is characterised in that A is-(CH2)m-, m=2-6.
5. compound as claimed in claim 1, it is characterised in that R1For hydrogen；R2It is positioned at 9, for first
Any one in base, halogen, methoxyl group or hydrogen；A is-(CH2)6-。
6. compound as claimed in claim 1, it is characterised in that described compound is in following compounds
Any one:
N-hydroxyl-7-(9-chloro-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) oenanthyl
Amine；
N-hydroxyl-7-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base)
Heptamide；
N-hydroxyl-6-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base)
Caproamide；
N-hydroxyl-5-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base)
Pentanamide；
N-hydroxyl-4-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base)
Butyramide；
N-hydroxyl-7-(9-methyl-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline-5-base) heptan
Amide；
N-(2-aminophenyl)-7-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline
Quinoline-5-base) heptamide；
N-(2-aminophenyl)-6-(9-methoxyl group-6,11-dioxy-6,11-dihydro-5H-indeno [1,2-c] quinoline
Quinoline-5-base) caproamide.
7. a compositions, compound described in the claim 1 containing safe and effective amount and pharmaceutically can connecing
The carrier being subject to.
8. a compound as claimed in claim 1 in preparation prevention or is treated because of histon deacetylase (HDAC)
Application in the mammal relevant disease medicine that abnormal expression causes.
Apply the most as claimed in claim 8, it is characterised in that described disease is cancer, neural degeneration
Any one in disease, virus infection, inflammation, leukemia, malaria and diabetes.
Apply the most as claimed in claim 9, it is characterised in that described cancer be pulmonary carcinoma, hepatocarcinoma,
Any one in colon cancer, breast carcinoma.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090111987A1 (en) * | 2007-10-31 | 2009-04-30 | Kaohsiung Medical University | Imino-Indeno[1,2-c] quinoline derivatives, their preparation processes, and pharmaceutical compositions comprising the same |
| WO2011144020A1 (en) * | 2010-05-17 | 2011-11-24 | 中国人民解放军第二军医大学 | Indenoquinolone compound, preparation method and use thereof |
-
2015
- 2015-05-19 CN CN201510255972.XA patent/CN106279021A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090111987A1 (en) * | 2007-10-31 | 2009-04-30 | Kaohsiung Medical University | Imino-Indeno[1,2-c] quinoline derivatives, their preparation processes, and pharmaceutical compositions comprising the same |
| WO2011144020A1 (en) * | 2010-05-17 | 2011-11-24 | 中国人民解放军第二军医大学 | Indenoquinolone compound, preparation method and use thereof |
Non-Patent Citations (2)
| Title |
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| TSENG, CHIH-HUA等: "Discovery of Indeno[1,2-c]quinoline Derivatives as Inhibitors of Osteoclastogenesis Induced by Receptor Activator of NF-.kappa.B Ligand (RANKL)", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
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