CN105175333A - 5H-indeno[1,2-c]quinoline-6,11-dione compounds, and preparation method and application thereof - Google Patents
5H-indeno[1,2-c]quinoline-6,11-dione compounds, and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to the medical technical field, and specifically relates to 5H-indeno[1,2-c]quinoline-6,11-dione compounds represented by the formula (I). The compounds show good antitumor activity on human lung cancer, liver cancer, breast cancer and various tumor cells, and are expected to be used for preparation of novel antitumor medicines. Compared with camptothecin medicines, the compounds are stable in structure and good in water solubility. The invention also discloses a preparation method of the compounds represented by the formula (I), pharmaceutical compositions containing the compounds and an application of the compounds in preparation of the anti-tumor medicines and the like.
Description
Technical field
The present invention relates to medical art, be specifically related to a class 5
h-indeno [1,2-c] quinoline-6,11-cyclohexadione compounds, and its composition, preparation method.The invention still further relates to this compounds for the preparation of the purposes in antitumour drug, antifungal drug or antiviral.
Background technology
According to WHO Report, global cancer patientss in 2012 and death are all constantly increasing.In the malignant tumours such as liver cancer, esophagus cancer, cancer of the stomach and lung cancer, Chinese new cases and death toll all occupy first place in the world.Wherein, lung cancer is the most general and the most fatal cancer, about newly-increased 1,800,000 patients in 2012, and causes 1,500,000 people dead, and China accounts for more than 1/3 of this type of case.
The whole process that topoisomerase I (TopoisomeraseI, Top1) participates in DNA replication dna, transcribes, recombinates, repairs, can catalysis single stranded DNA fracture be connected again, thus relaxed DNA superhelix.In the catalysis topology de-rotation process of Top1, the phosphodiester bond of the catalytic residue Tyr723 nucleophilic attack DNA of avtive spot, forms Top1-DNA covalent complex.Inhibitor can be inserted into the ternary complex forming Top1-DNA-inhibitor in this mixture, the stable existence of this ternary complex to prevent in normal DNA de-rotation process connecting link again, thus result in DNA replication dna process and be obstructed, cause DNA damage, and then cause the apoptosis of tumour cell.
Due to Top1 at the content of kinds of tumor cells especially lung cancer, cancer of the stomach, colorectal carcinoma, ovarian cancer etc. apparently higher than normal cell, not only curative effect is high for Top1 inhibitor class, antitumor spectra wide, and also has certain selectivity to tumour cell.Camptothecine is classical Top1 specific inhibitor, is all camptothecin derivatives, has been widely used in clinical, has achieved good effect by the topotecan of FDA approval listing, irinotecan.But this compounds exists some shortcomings: poorly water-soluble, internal metabolism cell generation resistance that is unstable, that suddenly change to Top1, and there is multidrug resistance etc.
In order to overcome the deficiency of camptothecin Top1 inhibitor, non-camptothecin Top1 inhibitor has become antitumor drug study hotspot.Top1 inhibitor such as the indolocarbazole compounds of current discovery and LuotonineA, LamellarinD, but mostly there is the problems such as complex structure, poor specificity, toxic side effect are larger, approval is at present used for clinical still only having camptothecin antineoplastic agents.In non-camptothecin Top1 inhibitor, indenoisoquinoline ketone compounds has a series of advantage, is expected to the defect overcoming camptothecine: (1) this compounds is synthetic, and stable chemical nature; (2) binding site of this compounds and Top1-DNA is different from camptothecine, and this also just shows that it has different tumor cell gene target spots; (3) the Top1-DNA-medicine ternary complex that this compounds is formed compares formed with camptothecine more stable, and the camptothecine clinical effect that this also just overcomes needs the defect extending the instillation time; (4) this compounds is not the substrate of ABCG2 or MDR-1 substantially, and this also just makes it overcome multidrug resistance.Scientist now has been found that indenoisoquinoline ketone compounds NSC706744, NSC725776 and NSC724998 has clinical development prospect, and current NSC725776 and NSC724998 has entered the clinical first phase research of NCI, shows and treats potentiality preferably.
In early-stage Study, we are based on indenoisoquinoline ketone Top1 inhibitor, adopt skeleton transition technology and Computer-Aided Drug Design technology, design, synthesized a class indeno quinolinones Top1 inhibitor, this compounds shows good broad-spectrum anti-tumor activity.This research continues around such skeleton, carries out deep Study on Structure Optimizing, and has therefrom found the compound that activity is higher, druggability is good, for follow-up cancer therapy drug exploitation is laid a good foundation.
Summary of the invention
The present invention seeks to provide the novel indeno quinolinones compound of a class or its pharmacy acceptable salt.The present invention discloses the preparation method of this compounds, medical use and composition.
In a first aspect of the present invention, provide a kind of general formula (
i) shown in indeno quinolinones compound or its pharmacy acceptable salt, solvate, prodrug or polymorphic form:
(I)
In formula,
R
1arbitrary class in following groups: a) hydrogen; B) the straight or branched alkoxyl group of C1-8; C) halogen;
R
2arbitrary class in following groups: a) hydrogen; B) the straight or branched alkyl of C1-8; B) the straight or branched alkoxyl group of C1-8; D) halogen;
R
3for-(CH
2)
mr
4, wherein m is 2-4, R
4can be saturated or undersaturated nitrogen heterocyclic ring or-NR
5r
6, wherein R
5, R
6be the arbitrary class in following groups independently: a) hydrogen; B) straight chain of C1-8 and the alkyl of side chain.
In another preference, compound as above, R
1for any one in methoxyl group or bromine.
In another preference, compound as above, R
2for any one in methyl, halogen, methoxyl group or hydrogen.
In another preference, compound as above, R
3m be 2-3, R
4can be saturated or undersaturated 5-6 member heterocyclic ring containing nitrogen or-NR
5r
6, wherein R
5, R
6be the arbitrary class in following groups independently: a) hydrogen; B) straight chain of C1-8 and the alkyl of side chain.
In another preference, described compound is compound
1-
20.
In a second aspect of the present invention, provide a kind of composition, the carrier that it contains compound described in the first aspect present invention of safe and effective amount or its pharmacy acceptable salt and pharmaceutically accepts.
In another preference, described composition is pharmaceutical composition.
In a third aspect of the present invention, provide compound described in first aspect or its pharmacy acceptable salt is preparing the purposes in antitumour drug, antifungal drug or antiviral.
In another preference, described tumour is nonsmall-cell lung cancer, mammary cancer or liver cancer.
In a fourth aspect of the present invention, provide the preparation method of the compound described in first aspect, comprise the following steps: in inert solvent, under alkaline condition, by formula (
iI) compound and R
3x or its salt react, thus formed formula (
i) compound:
In formula, R
1, R
2, R
3definition described above, X is leavings group, and described R
3the salt of X is inorganic acid salt or organic acid salt.
Preferably, described leavings group comprises halogen or other large electronegative group, as groups such as Phenylsulfonic acid base, tosic acid base, trifluoromethanesulfonic acid bases.
In another preference, described reaction is carried out under alkaline condition (such as, under the alkali such as sodium carbonate, salt of wormwood and/or sodium hydride exist).
In another preference, the reaction times is 0.5-24 hour.
In another preference, described inert solvent comprises: DMF, DMSO or its combination.
The medicinal compositions 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 used for such use, can with one or more pharmaceutically acceptable carrier or mixed with excipients, as solvent, thinner etc., and can with following form oral administration: tablet, pill, capsule, dispersible powder, particle or suspension (containing 0.05-5% suspension agent according to appointment), syrup (containing 10-50% is sugared according to appointment), with elixir (containing 20-50% ethanol of having an appointment), or with the administration of external application mode: ointment, gel, pastille adhesive plaster etc., or carry out parenteral routes with sterile injectable solution or form of suspension (containing 0.05-5% suspension agent of having an appointment in isotonic medium).Such as, these pharmaceutical preparations containing the about 0.01-99% mixed with carrier, can more preferably be about the activeconstituents of 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 severe side effect.Safe and effective amount was determined according to the age, the state of an illness, the course for the treatment of etc. for the treatment of target.
" carrier pharmaceutically accepted " refers to: one or more biocompatible solid or liquid filler or gelatinous mass, and their are applicable to people and use, and must have enough purity and enough low toxicity." consistency " herein means generation be in composition each component energy and compound of the present invention and they between mutually admix, and the curative effect of not obvious reduction compound.Pharmaceutically acceptable carrier part example has sugar (as glucose, sucrose, lactose etc.), starch is (as W-Gum, yam starch etc.), cellulose and its derivates is (as Xylo-Mucine, ethyl cellulose sodium, cellulose ethanoate etc.), gelatin, talcum powder, solid lubricant is (as sodium stearate, Magnesium Stearate), calcium sulfate, vegetables oil is (as soya-bean oil, sesame oil, peanut oil, olive wet goods), polyvalent alcohol is (as propylene glycol, glycerine, N.F,USP MANNITOL, sorbyl alcohol etc.), emulsifying agent (as Tweens), wetting agent (as sodium laurylsulfonate), tinting material, seasonings, stablizer, antioxidant, sanitas, apirogen water etc.
Compound of the present invention, through Inhibiting enzyme activity test, finds to be all Top1 inhibitor.In view of bibliographical information Top1 inhibitor is except having anti-tumor activity, also there is antiviral and anti-mycotic activity.Therefore, compound of the present invention, also can have antiviral and anti-mycotic activity.
Accompanying drawing explanation
The general structure of Fig. 1 indeno quinolinones compound.
Embodiment
Below in conjunction with specific embodiment, illustrate the present invention further.Should understand only to be not used in for illustration of invention and limit the scope of the invention.The implementation method of actual conditions is indicated, usually conveniently condition in following enforcement, or according to the condition that manufacturer advises.Unless otherwise indicated, otherwise per-cent and number are weight percent and parts by weight.
embodiment 1
1. 5-(2-(dimethylin) ethyl)-9-methyl-5
h-indeno [1,2-c] quinoline-6,11-diketone (compound in table 1
15) synthesis:
(1) synthesis of 3-(4-aminomethyl phenyl)-2-oxo-1,2-dihydroquinoline-4-carboxylic acid
By isatin (12g, 81.56mmol), to methylphenyl acetic acid (21.43g, 0.14mol) with sodium-acetate (3.34g, add in the there-necked flask of 250mL after 40.78mmol) fully mixing in mortar, when question response temperature rises to 170 DEG C, reactant presents molten state, stirring reaction is about 3h at such a temperature, TLC(ethyl acetate: sherwood oil: formic acid=5:5:2d) monitoring, react completely, the saturated NaOH solution prepared in right amount is added while hot under state, by reactant transfer in beaker, after question response thing is fully dissolved in saturated NaOH solution, filter, get filtrate to wash three times with methylene dichloride and (be followed successively by 100mL, 100mL, 90mL), between rare HCl adjust pH to 5-6, filter, get filtrate, again by filtrate with rare HCl adjust pH to 1, a large amount of Off-white solid is separated out, filter, washing filter cake (is followed successively by 100mL three times, 100mL, 90mL), get filter cake, dry, obtain Off-white solid 7.53g, yield is 33.09%.
1HNMR(300MHz,DMSO)δ:8.49(d,
J=7.8Hz,1H),8.10(s,3H),7.75(d,
J=8.6Hz,1H),7.65(dd,
J=7.5,3.7Hz,2H),7.52(t,
J=7.4Hz,1H),7.15(d,
J=2.3Hz,1H),7.05(dd,
J=8.1,2.4Hz,1H),3.83(d,
J=6.6Hz,3H).
(2) 9-methyl-5
hthe synthesis of-indeno [1,2-c] quinoline-6,11-diketone
Get 3-(4-aminomethyl phenyl)-2-oxo-1,2-dihydroquinoline-4-carboxylic acid (4g, 14.34mmol) with the there-necked flask of 100mL, pour PPA (31.51g again into, 93.21mmol), temperature of reaction is set to 120 DEG C, the stirring reaction time after 1h, TLC(ethyl acetate: sherwood oil: formic acid=5:5:2d) monitoring, after reacting completely, poured into by reaction solution in the frozen water prepared rapidly, fully stir frozen water, a large amount of atropurpureus solid is separated out, filter, the a small amount of saturated NaOH solution of filter cake washes three times, then washes three times, and filter cake is dried.Adopt the sherwood oil of low polarity to wash, filter, obtain atropurpureus solid 3.74g, this reaction yield is about 100%.
1HNMR(300MHz,DMSO)δ:12.36(s,1H),8.40(d,
J=8.0Hz,1H),7.83(d,
J=7.4Hz,1H),7.54(t,
J=7.8Hz,1H),7.48–7.34(m,3H),7.29(t,
J=7.3Hz,1H).
(3) 5-(2-(dimethylin) ethyl)-9-methyl-5
hthe synthesis of-indeno [1,2-c] quinoline-6,11-diketone
Learn from else's experience the DMF of Non-aqueous processing in the there-necked flask of 100mL, then puts into the intermediate 9-methyl-5 weighed up
h-indeno [1,2-c] quinoline-6,11-diketone (800mg, 3.06mmol) and K
2cO
3(1.89g, after 13.5mmol) stirring 30min under normal temperature, again by raw material N, N dimethylamine base monochloroethane hydrochloride (565.0mg, 3.285mmol) add in reaction solution, temperature is 70 DEG C of reactions 8 hours, TLC(methylene dichloride: methyl alcohol=17:1) monitoring, react completely, reaction is also poured into water, dichloromethane extraction, then organic phase is used saturated common salt water washing, anhydrous sodium sulfate drying, decompressing and extracting, press purification system to cross post in employing, obtain obtaining sterling 221mg, yield is 21.7%.
embodiment 2-20
Repeat embodiment 1, difference is: the raw material of use is different, thus obtained compound
1-14,
16-20.Specific as follows:
(1) by bromo-for 3-9-methoxyl group-5
h-indeno [1,2-c] quinoline-6,11-diketone reacts can distinguish synthetic compound with dimethylamino-chloroethane hydrochloride, dimethylin chloropropane hydrochloride, diethylin monochloroethane hydrochloride, pyrrolidyl monochloroethane hydrochloride, morpholinyl monochloroethane hydrochloride respectively
1-5.
(2) by bromo-for 3-9-chloro-5
h-indeno [1,2-c] quinoline-6,11-diketone reacts can distinguish synthetic compound with dimethylamino-chloroethane hydrochloride, dimethylin chloropropane hydrochloride, diethylin monochloroethane hydrochloride, pyrrolidyl monochloroethane hydrochloride, morpholinyl monochloroethane hydrochloride respectively
6-10.
(3) by 3,9-dimethoxy-5
h-indeno [1,2-c] quinoline-6,11-diketone reacts can distinguish synthetic compound with dimethylamino-chloroethane hydrochloride, dimethylin chloropropane hydrochloride respectively
11-12.
(4) by 3-methoxyl group-9-chloro-5
h-indeno [1,2-c] quinoline-6,11-diketone reacts can distinguish synthetic compound with dimethylamino-chloroethane hydrochloride, dimethylin chloropropane hydrochloride respectively
13-14.
(5) by 9-methyl-5
h-indeno [1,2-c] quinoline-6,11-diketone and dimethylin chloropropane hydrochloride react can distinguish synthetic compound
16.
(6) by bromo-for 3-9-methyl-5
h-indeno [1,2-c] quinoline-6,11-diketone reacts can distinguish synthetic compound with dimethylamino-chloroethane hydrochloride, dimethylin chloropropane hydrochloride respectively
17-18.
(7) by 3-methoxyl group-9-methyl-5
h-indeno [1,2-c] quinoline-6,11-diketone reacts can distinguish synthetic compound with dimethylamino-chloroethane hydrochloride, dimethylin chloropropane hydrochloride respectively
19-20.
The present invention synthesis general formula (
i) in the chemical structure of target product in table 1.Nucleus magnetic hydrogen spectrum, carbon spectrum, mass spectrum and the fusing point characterized systematically chemical structure of target product, its concrete data are shown in
table 1,2,3.
the mass spectrum of table 1 compound, melting point data
Compound
1-
20be respectively the compound prepared in embodiment 1-20.
the hydrogen modal data of table 2 compound
the carbon modal data of table 3 part of compounds
embodiment 21: anti tumor activity in vitro testing experiment
1. experimental cell strain:
The cell strain of this experiment test adopts: A549 (Non-small cell lung carcinoma), MDA-MB-231 (human breast carcinoma), SK-Hep-1 (people's liver cancer), and these cell strains are frozen and go down to posterity by Shanghai Institute of Pharmaceutical Industry's pharmacological evaluation room.
2. sample configuration:
Sample is all prepared into hydrochloride, after dissolving, adds PBS (-) and is made into the solution of 1000 μ g/ml or uniform suspension, then dilute with the PBS (-) containing DMSO with DMSO (Merck).Positive control drug is
sF-27, Zorubicin (DOX).
3. test method
The experiment of this cell in vitro anti-tumor activity adopts mtt assay.It is 4-5 × 10 that the 96 every holes of orifice plate add concentration
4the cell suspension 100 μ l of individual/mL, puts 37 DEG C, 5%CO
2in incubator.After 24h, add sample liquid, 10 μ L/ holes, if duplicate hole, 37 DEG C, 5%CO
2effect 72h.Every hole adds the MTT solution 20 μ L of 5mg/mL, and add lysate after effect 4h, 100 μ L/ holes, put in incubator, surveys 570nmOD value after dissolving by the long multi-functional microplate reader of all-wave.(anti tumor activity in vitro is in table 3)
table 3. compound is to the in-vitro multiplication restraining effect (μM) of human body tumour cell
DOX: Zorubicin
SF-27：
As known from Table 3, indeno quinolinones compound of the present invention shows good spectrum anti-tumor activity to people's lung cancer, liver cancer and mammary cancer, particularly part of compounds shows better cytotoxic activity to human liver cancer cell, and wherein part of compounds is better than positive reference compound
sF-27, as compound
18active suitable with positive control drug Zorubicin in the test of human lung carcinoma cell.
embodiment 33: anti-tumor in vivo activity test
(1) test method:
1. the preparation of sample:
The configuration of injection solvent: 20mMHCl:10mM citric acid: 5% glucose=1:1:6 (V/V/V), containing the tween of 5% in injection solvent, takes
18the compound of mg
18be dissolved in the 18mL injection solvent configured, injection liquid concentration is 1mg/mL.
2. get well-grown A549 solid tumor, under aseptic condition, cut into the even fritter of about 3mm size, with the right armpit subcutaneous vaccination of trochar every mouse one piece, be divided into 2 groups at random, be respectively:
1) Control (physiological saline)
2) compound
18, 10mg/kg, iv × 14
Inoculate latter 13 days again to divide into groups according to tumor size, eliminate the animal that tumour is excessive and too small, often organize tumor average volume basically identical, start by above administration, administration volume is 0.2ml/20g body weight.Major diameter (a), the minor axis (b) of knurl block is surveyed 2 times weekly with digimatic calipers, gross tumor volume (tumorvolume, TV) calculation formula is: TV=1/2 × a × b2, relative tumour volume (relativetumorvolume, RTV) calculation formula is: RTV=Vt/Vo, Vo measures gained gross tumor volume for (d1) during point cage, and Vt is gross tumor volume when measuring each time.The evaluation index of anti-tumor activity is Relative tumor proliferation rate T/C (%), T/C (%)=TRTV/CRTV × 100%, or Relative tumor proliferation inhibition rate (%): (1-T/C) × 100%.And carry out T inspection.Inoculate latter 34 days and put to death animal, solution takes knurl block, claims knurl weight.
3. test-results
Continuous tail vein injection 14 times, compound
18dosage 10mg/kg, during off-test in d22 days, 50.06% is respectively to the tumour inhibiting rate of Human lung cancer A549.The weight of animals, without obvious decline, has no overt toxicity reaction.
embodiment 34: pharmaceutical composition
Prescription:
Compound in embodiment
1820.0g
Starch 80.0g
Lactose 60.0g
Microcrystalline Cellulose 35.0g
10% polyvinylpyrrolidone ethanolic soln is appropriate
Magnesium Stearate 0.5g
Make 1000 altogether
Compound 7 and various auxiliary material are crossed 80 mesh sieves, measures by prescription, with 10% polyvinylpyrrolidone ethanolic soln for tackiness agent, make suitable particle with 16 mesh sieves, 65 DEG C of dryings, the whole grain of 14 mesh sieve, adds Magnesium Stearate and mixes, and surveys granule content, calculate loading amount, incapsulate, to obtain final product.
The compounds of this invention has broad-spectrum anti-tumor activity activity, particularly part of compounds and has stronger anti-tumor activity to liver cancer, lung cancer, mammary cancer, has good Development volue.Indeno quinolinones compound of the present invention represents the compound with anti-tumor activity of a class brand new, and this is further investigate and develop new antitumor drug to open new approach and direction.
The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (8)
1. a class general formula (
i) shown in indeno quinolinones compound or its pharmacy acceptable salt, solvate, prodrug or polymorphic form:
(I)
In formula,
R
1arbitrary class in following groups: a) hydrogen; B) the straight or branched alkoxyl group of C1-8; C) halogen;
R
2arbitrary class in following groups: a) hydrogen; B) the straight or branched alkyl of C1-8; B) the straight or branched alkoxyl group of C1-8; D) halogen;
R
3for-(CH
2)
mr
4, wherein m is 2-4, R
4can be saturated or undersaturated nitrogen heterocyclic ring or-NR
5r
6, wherein R
5, R
6be the arbitrary class in following groups independently: a) hydrogen; B) straight chain of C1-8 and the alkyl of side chain.
2. compound as claimed in claim 1, is characterized in that, R
1for any one in methoxyl group or bromine.
3. compound as claimed in claim 1, is characterized in that, R
2for any one in methyl, halogen, methoxyl group or hydrogen.
4., as the compound as described in arbitrary in claims 1 to 3, it is characterized in that, R
3m be 2-3, R
4can be saturated or undersaturated 5-6 member heterocyclic ring containing nitrogen or-NR
5r
6, wherein R
5, R
6be the arbitrary class in following groups independently: a) hydrogen; B) straight chain of C1-8 and the alkyl of side chain.
5. compound as claimed in claim 1, it is characterized in that, described compound is compound
1-
20.
6. a composition, the compound according to claim 1 containing safe and effective amount or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
7. a compound as claimed in claim 1 or its pharmacy acceptable salt are preparing the purposes in antitumour drug, antifungal drug or antiviral.
8. a preparation method for compound as claimed in claim 1, is characterized in that, comprises the following steps: in inert solvent, under alkaline condition, by formula (
iI) compound and R
3x or its salt react, thus formed formula (
i) compound:
In formula, R
1, R
2, R
3definition as shown in claim 1, X is leavings group, and described R
3the salt of X can be inorganic acid salt or organic acid salt.
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2014
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