CN101898979B - Phenyl nitrone compounds containing stilbene sections and application thereof - Google Patents
Phenyl nitrone compounds containing stilbene sections and application thereof Download PDFInfo
- Publication number
- CN101898979B CN101898979B CN201010216461.4A CN201010216461A CN101898979B CN 101898979 B CN101898979 B CN 101898979B CN 201010216461 A CN201010216461 A CN 201010216461A CN 101898979 B CN101898979 B CN 101898979B
- Authority
- CN
- China
- Prior art keywords
- toluylene
- compound
- butylnitrone
- tert
- base
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C291/00—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00
- C07C291/02—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Dermatology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses phenyl nitrone compounds containing stilbene sections and pharmaceutically acceptable salts thereof. The compounds can be used for treatment for cell hyperplasia of mammals, such as cancers, or be used as nerve protective agents. The invention also discloses a preparation method thereof, medicine composites containing the compounds and an application for preparing anti-tumour medicines.
Description
Technical field
The present invention relates to phenyl nitrone compound and pharmacy acceptable salt thereof containing toluylene fragment, this compounds is used for the treatment of mammalian cell excessively proliferative disease, and for example cancer, also can be used as neuroprotective.The invention still further relates to the preparation method of described compound, the medicinal compositions that contains these compounds and these compounds purposes in antitumor drug preparation.
Technical background
The treatment of tumour is a global difficult problem always, along with the continuous increase of people to tumour cell signal transduction pathway knowledge, for tumor-specific molecule shot design antitumor drug, more and more receives publicity.Add the development of crystalline diffraction technology, combinatorial chemistry, molecular model, High Throughput Screening Assay and computer chemistry, target medicine makes rapid progress, for the treatment of tumour provides New Policy.Medicinal design based on structure and mechanism of action has become the main way of current development antitumor drug.
Cancer resistance is one of difficult problem the most thorny in current oncotherapy.Solve this difficult problem, must start with from understanding the resistant mechanism of cancer cells, could develop targetedly like this have target optionally new drug solve the resistance problem of cancer cells.Tyrosine protein enzyme body is one of cancer target target that Recent study must be more deep.Apoptosis, help cancer cells that the major function of proteasome has pair cancer cell multiplication to play a crucial role, hinder chemotherapeutics and induces resist chemotherapeutics.Therefore, the activity of protease inhibition, a helpful solution cancer cells resistance difficult problem.Tyrosine protein enzyme body inhibitor is also one of developing direction of current cancer therapy drug.Point out a lot of other compounds, as styrene derivatives, for example, had the natural diphenylethylene compounds such as document (Drug Resist Updat 2006,9,263～273) report trans-resveratrol to there is Tyrosylprotein kinase rejection.
In cancerous tissue because blood vessel structure is abnormal and cancer cell is grown the factor such as too fast, and easily cause the state of local anoxic.Hypoxic cell is common among various cancerous tissue, and having of it helps cancer cells opposing chemotherapy and radiotherapy.Therefore, targeting is one of research topic of current cancer therapy drug in the drug research of anoxic cancer cells.Below listed global some that researching and developing at present and anoxic cancer cells has been had to the compound of targeting.
Wherein, AQ
4n is at present by Novacea Inc company and the cooperation development clinical study of KuDOS Pharmaceuticals company, and is applicable to various cancers.About the report of quinoxaline Isosorbide-5-Nitrae-di-N-oxide, with reference to the report of (Bioorg Med Chem, 2001,9,2395～2401).Tirapazamine carries out clinical study by sanofi-aventis company at present, and is applicable to various cancers.Its mechanism of action may be: by multiple reductase enzyme, activated in vivo and in hypoxic cell, produce free radical, and then the strand of inducing DNA and two strands break, base pair is impaired, finally makes necrocytosis.Hypoxic cell is ubiquity in solid tumor.Tirapazamine is only activated by hypoxic cell and plays a role, thereby this medicine has good target selectivity.
Phenyl nitrone compound is studied a kind of Green Tea Extract medicine NXY-059 that visible AstraZeneca is researched and developed recently, it has the stronger ability of catching free radical, once itself and combined with radical form a kind of stable new compound, now free radical has lost activity, can not destroy cell tissue again and participate in a series of biochemical change.
In recent years to the bioactive analysis of phenyl nitrone compound, this compounds is the micromolecular compound that a class has multiple pharmacological action, there are a lot of problems urgently to be resolved hurrily: how to make this type of medicine only act on the target spot of drafting of tumour cell, and do not act on Normocellular identical target spot; In conjoint therapy, how to carry out curative effect addition or collaborative selection etc.These have all hindered the clinical application of anti-tumor drugs targeting.Therefore the research about the mechanism of action of anti-tumor drugs targeting and the scope of application etc. has profound significance.
Point out a lot of other compounds, as styrene derivatives, there is Tyrosylprotein kinase rejection.There are partial monopoly open EP556226A1, EP602851A1, EP635507A1, EP635489A1 and EP520722A1 to disclose some quinazoline derivant and there is the anti-cancer properties being caused by Tyrosylprotein kinase inhibition activity.PCT application WO92/20642 also discloses as the monocycle of tyrosine kinase inhibitor or the aryl of dicyclo and heteroaryl compound.
Although above-mentioned anticancer compound has been made very large contribution to this area, for improving cancer therapy drug, research is still being proceeded in this area.The present invention relates to a series of phenyl nitrone analog derivatives containing toluylene fragment with new constitutional features, it is mainly manifested in the toluylene fragment of its replacement, the mode of connection of chemical constitution fragment such as aromatic ring fragment and the compound of above-mentioned patent literature of the phenyl nitrone class fragment of replacement and replacement there are differences, the inventor finds in surprise, the novel cpd obtaining by these differences has outstanding antitumor character, can be used as thus antitumor drug and develops.
Summary of the invention
The invention relates to following formula (I) phenyl nitrone compound and pharmacy acceptable salt thereof and its prodrug.
First, one aspect of the present invention, is to provide the compound of following general formula (I):
Wherein, p, q represents separately 0～4 integer, condition is p≤4 and q≤4; B represents to exist or non-existent pair of key; When two keys exist, formula (I) compound is E or Z configuration, and when two keys do not exist, the Stereocenter of formula (I) compound has R-or S-configuration;
R and R ' represent separately H; C
1-C
20straight or branched alkyl; C
2-C
20straight or branched thiazolinyl;-CO
2z ', wherein Z ' is that H, sodium, potassium or other pharmaceutically acceptable gegenions are as calcium, magnesium, ammonium, tromethane, tetramethyl-ammonium etc.;-CO
2r ' ";-NH
2;-NHR ' ";-NR
2' ";-OH; Halogen; The C replacing
1-C
20the C of straight or branched alkyl or replacement
2-C
20straight or branched thiazolinyl;-OR ' ", wherein R ' " represents C
1-C
20straight or branched alkyl, straight or branched thiazolinyl or aralkyl-(CH
2) x-Ar, wherein x is 1～6 integer;-CO
2r " ", wherein R " " represents H, the C that can replace arbitrarily
1-C
20alkyl, the C that can replace arbitrarily
1-C
20straight or branched alkyl, the C that can replace arbitrarily
2-C
20thiazolinyl or the C that can replace arbitrarily
6-C
10the circular part of aryl or expression morpholine, piperidines, piperazine etc.;
A, A ' represents monosubstituted or polysubstituted group, represents independently H, C
1-C
20amido, C
1-C
20acyloxy, C
1-C
20alkyloyl, C
1-C
20carbalkoxy, C
1-C
20alkoxyl group, C
1-C
20alkylamino, C
1-C
20alkane carboxylic amino, aroyl, aralkanoyl, carboxyl, cyano group, halogen, hydroxyl, nitro; Or
A, the straight or branched C that A ' representative can replace arbitrarily
1-C
20alkyl or C
2-C
20thiazolinyl; Or formation methylene-dioxy or ethylenedioxy group;
Further aspect of the present invention, provides the preferred compound of formula (I) compound:
The compound of following general formula (I):
Wherein, p, q represents 0～4 integer independently, condition is p≤4 and q≤4; B represents to exist or non-existent pair of key; When two keys exist, can be for E or Z configuration, when two keys do not exist, the Stereocenter of acquisition can have R-or S-configuration;
R and R ' represent H independently;-CO
2z ', wherein Z ' is that H, sodium, potassium or other pharmaceutically acceptable gegenion are as calcium, magnesium, ammonium, tromethane, tetramethyl-ammonium etc.;-CO
2r " ", wherein R " " represents separately H, the C that can replace arbitrarily
1-C
20alkyl, the C that can replace arbitrarily
1-C
20straight or branched alkyl, the C that preferably can replace arbitrarily
1-C
6alkoxyl group (for example methoxyl group, oxyethyl group or propoxy-), the C that can replace arbitrarily
2-C
20thiazolinyl or the C that can replace arbitrarily
6-C
10the circular part of aryl or expression morpholine, piperidines, piperazine etc.;
A, A ' represents monosubstituted or polysubstituted group, can be H, C
1-C
20amido, C
1-C
20acyloxy, C
1-C
20alkyloyl, C
1-C
20carbalkoxy, C
1-C
20alkoxyl group, C
1-C
20alkylamino, C
1-C
20alkane carboxylic amino, aroyl, aralkanoyl, carboxyl, cyano group, halogen, hydroxyl, nitro; Or
A, A ' also can represent the straight or branched C replacing arbitrarily
1-C
20alkyl or C
2-C
20thiazolinyl; Or formation methylene-dioxy or ethylenedioxy group;
Preferred compound: representative compound of the present invention comprises:
[1] (E)-3,5-dimethoxy-4 ' '-N-tert-butylnitrone base-toluylene (6);
[2] (E)-3,5-benzyloxy-4 '-N-tert-butylnitrone base-toluylene (7);
[3] (E)-3-methoxyl group-4-benzyloxy-4 '-N-tert-butylnitrone base-toluylene (8);
[4] (E)-3-methoxyl group-4 benzoic acid ester group-4 '-N-tert-butylnitrone base-toluylene (9);
[5] (E)-3-methoxyl group-4-acetate groups-4 '-N-tert-butylnitrone base-toluylene (10);
[6] (E)-3-methoxyl group-4-hydroxyl-4 '-N-tert-butylnitrone base-toluylene (11);
[7] (E) the fluoro-4 '-N-tert-butylnitrone of-4-base-toluylene (12);
[8] (E)-4-benzyloxy-4 '-N-tert-butylnitrone base-toluylene (13);
[9] (E)-4-hydroxyl-4 '-N-tert-butylnitrone base-toluylene (14);
[10] (E) the fluoro-4 '-N-tert-butylnitrone of the chloro-4-of-3-base-toluylene (15);
[11] (E)-3-itrile group-4 '-N-tert-butylnitrone base-toluylene (16);
[12] (E)-4-(the fluoro-benzyloxy of 3-)-4 '-N-tert-butylnitrone base-toluylene (17).
Secondly, the present invention further provides the preparation method of the compound of general formula (I), the representative compound 6 of the present invention of below take illustrates the preparation method of the compounds of this invention for example.
The present invention's synthetic route 1 is as follows:
According to the method for route 1, the present invention has synthesized following representational compounds:
Its two, the present invention further provides the medicinal compositions that contains general formula (I) compound, described composition comprises treats acceptable carrier on general formula (I) compound of significant quantity and physiology.
Described treatment significant quantity refers to that the amount of the contained general formula of medicinal compositions (I) compound is enough to produce the treatment effect of clinical expectation, for example, make medication person's tumor size be reduced in clinical acceptable scope.
Medicinal compositions of the present invention can pass through intravenously, intracutaneous, intramuscular, the administration such as subcutaneous, oral, the formulation of its medicinal compositions can be gi tract medication preparation as tablet, capsule, pill etc., can be also that stomach and intestine external application preparation is as injection, external preparation etc.
In addition, the present invention also provides the method for the treatment of antitumor and relative disease, and the method comprises the compound that uses the described general formula (I) for the treatment of significant quantity to suffering from the patient of cancer or related conditions.
Embodiment
Below with specific embodiment, further illustrate the present invention, but scope of the present invention is not formed to any restriction.
Universal method: measure fusing point on RT-1 melting point apparatus (Tianjin analytical instrument factory) equipment, temperature is calibrated.In Bruker AV400 (400MHz) spectrograph, record 1HNMR spectrum and it is described with 1,000,000 of TMS/portion (ppm) downfield.At Nicolet Magna 550FT-IR, pay on vertical leaf spectrophotometer and record infrared spectra.With HP1100 Esquire2000 liquid chromatography/mass spectrometry combined instrument, record mass spectrum.At Shimadzu UV2410 ultraviolet spectrophotometer, record UV spectrum.On the efficient plate of silica GF254 (Yantai City Zhifu silica gel development experiments factory), carry out TLC.On WZZ-1S polarimetry instrument (Shanghai Precision Scientific Apparatus Co., Ltd), carry out polarimetry.
Embodiment 1 is according to route 1 synthesis type (I) compound
synthesizing of 1.1 compounds (2)
Bromomethyl-benzoic acid methyl ester 1 (5g, 0.022mol) and triethyl-phosphite (5.4g, 0.033mol) are joined in 50mL toluene, be heated to 105 ℃ and reflux 24 hours, be down to room temperature, rotary evaporation is removed toluene, obtain micro-yellow liquid 2 (5.8g, 93%).
1HNMR(400MHz，CDCl
3)δ1.11-1.15(m，6H)，3.03-3.05(m，2H)，3.88(s，3H)，4.07-4.10(m，4H)，7.17(m，2H)，7.85(m，2H)；MS(EI)m/z 166[M]
+。
synthesizing of 1.2 compounds (3)
By sodium methylate (2.5g, 0.046mol) be dissolved in 50mL ether, compound 2 (5.8g, 0.035mol), with 3,5-dimethoxy benzaldehyde (2.5g, 0.015mol) is slowly added drop-wise in sodium methoxide solution after being dissolved in 25mL ether, within approximately 0.5 hour, add, 20 minutes metaplax layers of stirring at room are analysed (TLC) monitoring and are reacted completely, and add 70mL methylene dichloride, 100mL water, with dilute hydrochloric acid, neutralize, separatory, water is washed three times with methylene dichloride 150mL, combined dichloromethane phase, anhydrous magnesium sulfate drying, column chromatogram chromatography, obtains white solid 3 (4.2g, 96%).Mp (fusing point): 101～102 ℃.
1HNMR(400MHz，CDCl
3)δ3.83(s，6H)，3.92(s，3H)，6.42(m，1H)，6.69-6.72(m，2H)，7.07-7.17(m，2H)，7.54-7.56(d，J＝7.8Hz，2H)，8.01-8.03(d，J＝7.8Hz，2H)；MS(EI)m/z 298[M]
+。
synthesizing of 1.3 compounds (4)
By compound 3 (4g, 0.013mol) be dissolved in 100mL dry ether, under stirring, add in batches lithium aluminum hydride (0.5g, 0.013), plate layer chromatography (TLC) monitoring reacts completely, under ice bath, slowly dripping water stops reaction, dilute sulphuric acid is adjusted pH to 5～7, dichloromethane extraction, anhydrous magnesium sulfate drying, column chromatography obtains white solid 4 (3.2g, 90%).
1HNMR(400MHz，CDCl
3)δ3.84(s，6H)，4.79(s，2H)，6.40(m，1H)，6.68-6.73(m，2H)，7.06-7.15(m，2H)，7.50-7.52(d，J＝7.8Hz，2H)，8.02-8.04 (d，J＝7.8Hz，2H)；MS(EI)m/z 270[M]
+。
synthesizing of 1.4 compounds (5)
By compound 4 (1.8g, 0.007mol) be dissolved in 50mL methylene dichloride, add activated manganese dioxide (7.3g, 0.084mol), stirring at room 7 hours, plate layer chromatography (TLC) monitoring reacts completely, suction filtration, Manganse Dioxide is washed repeatedly with methylene dichloride, obtains yellow solid 1.6g after evaporate to dryness, productive rate 90%.Mp (fusing point): 94-95 ℃.
1HNMR(400MHz，CDCl
3)δ3.84(s，6H)，4.79(s，2H)，6.44-6.45(m，1H)，6.69-6.70(m，2H)，7.09-7.26(m，2H)，7.64-7.66(d，J＝7.8Hz，2H)，7.87-7.88(d，J＝7.8Hz，2H)，9.99(s，1H)；MS(EI)m/z268[M]
+。
synthesizing of 1.5 compounds (6)
In three-necked flask by compound 5 (1.0g; 0.004mol) be dissolved in 50mL methyl alcohol; add azanol methyl alcohol (0.435g, 0.005mol), under nitrogen protection, reflux is 2 hours; add again azanol methyl alcohol (0.435g; 0.05mol), continue to reflux 18～24 hours, after plate layer chromatography (TLC) monitoring reacts completely; column chromatography obtains yellow solid (0.9g, 75%).Mp (fusing point): 130-131 ℃.
1HNMR(400MHz，DMSO-d
6)δ1.59(s，9H)，3.79(s，6H)，6.44(m，1H)，6.52-6.54(m，2H)，7.07-7.17(m，2H)，7.63-7.66(d，J＝11.4Hz，2H)，7.84(m，1H)，8.34-8.36(d，J＝11.4Hz，2H)；MS(EI)m/z339[M]
+。
Embodiment 2 is by Caliper method SCREENED COMPOUND
In this embodiment, utilize Caliper method, vitro kinase EGFR, HER2, PDGFRa, PDGFRb and SRC are carried out to the screening of 12 compounds, and adopt compound staurosporine as standard control, each diluted chemical compound becomes the multiple hole of 10 concentration point to detect.Reaction conditions and result are respectively in Table 1 and table 2.
Table 1
| Kinases | Enzyme concn (nM) | ATP concentration (μ M) | Have or not MnCl 2 | Reaction times |
| EGFR | 8 | 2.3 | Containing 10mM MnCl 2 | 1 hour |
| HER2 | 18 | 15 | Containing 10mMMnCl 2 | 1 hour |
| PDGFRa | 3.5 | 134 | 5 hours | |
| PDGFRb | 6 | 38 | 5 hours | |
| SRC | 1 | 36 | 1 hour |
Table 2
Embodiment 3 compound on cell proliferation activity influences
With mtt assay, detect the impact of above-claimed cpd 6-17 on HepG2, A549, BGC-823 and tetra-cell strain proliferation activities of HCT116.
By the compound of DMSO preparation 10mM, 1: 5 dilution proportion, each compound starts to detect from final concentration 50 μ M, pipettes 0.5 μ l and add in Tissue Culture Plate from corresponding compound plate, in 37 ℃ of incubators, hatches 72 hours.Then observation of cell form under inverted microscope, the MTT solution that every hole adds 20 μ l5mg/ml to be prepared by aseptic PBS.In 37 ℃ of incubators, hatch 5 hours, add 100 μ l tri-lysates, the dissolving of spending the night of 37 ℃ of biochemical cultivation cases.Use Flexstation3 to detect absorbance.The IC50 value of record analysis gained.Above-mentioned 12 compounds are as shown in table 3 to cell strain proliferation inhibition rate.
The proliferation inhibition rate of table 3 compound 6-17 to 4 cell strains
conclusion
According to the result that affects of compound on cell proliferation inhibiting rate and IC50, visible compound 6,15 has certain antiproliferation on HepG2 and A549 cell strain; Compound 7,11,14,16 and 17 has certain antiproliferation on HCT116 cell strain.
The tumor-inhibiting action of 6,15 pairs of A549 tumor bearing nude mices of embodiment 4 compounds
Experimental technique: the A549 cell harvesting in the vegetative period of taking the logarithm is resuspended to serum free medium, making final concentration is 5.0 * 10
7cells/ml.70 BALB/c nude mices (6～7 weeks ages of week) subcutaneous vaccination 0.2ml A549 cell suspension, inoculum density is 1.0 * 10
7cells/mouse.The monitoring of animal per sky, observes daily behavior performance.Utilize vernier callipers to measure weekly three tumour areas (long * wide), gross tumor volume is (long * wide with formula
2calculate)/2.Gross tumor volume reaches average about 150mm
3time, according to the screening rate of 60%-70%, carrying out random packet, remaining animal carries out euthanasia.48 animals are divided at random 6 groups and carry out administration: sample presentation has 3 compounds, comprising 1 positive control drug, be administered once every day, and the successive administration time is 3 weeks, compound treatment mode: be dissolved in the mother liquor that DMSO is made into 10 times of final concentrations, be diluted in physiological saline with 1: 9 before administration.
◆ Group 1:N=8; Solvent control (physiological saline)
◆ Group 2:N=8; Positive drug (middle dosage=20mg/Kg), DMSO mother liquor is 20mg/ml;
◆ Group 3:N=8; Compound 6, (high dosage=35mg/Kg), DMSO mother liquor is 35mg/ml;
◆ Group 4:N=8; Compound 6, (low dosage=5mg/Kg), DMSO mother liquor is 5mg/ml;
◆ Group 5:N=8; Compound 15, (high dosage=35mg/Kg), DMSO mother liquor is 35mg/ml;
◆ Group 6:N=8; Compound 15, (low dosage=5mg/Kg), DMSO mother liquor is 5mg/ml;
Being subject to reagent route of administration is gavage, and administration volume is 0.1ml/10g.
Before animal administration every day, measure body weight, gross tumor volume is measured weekly twice.The performance of animal per sky monitoring daily behavior.The content of Health survey comprises mortality of animals, appearance, spontaneous activity, figure and the aqueous condition of ingesting.Once find that any above-mentioned side effect will keep a record.Once remarkable weight loss (relative body weight velocity of variation is greater than 20%) appears in animal, emaciation or tumour are excessive etc. has a strong impact on the phenomenon of animal vigor (water of ingesting, ability to act), and this animal will be implemented euthanasia; As there is serious ulcer in animal, or courageous and upright tumour, also will sentence euthanasia.After experiment finishes, peel off tumour and weigh, and carry out sample collection, for carrying out follow-up detection.In whole body, research process is 28 days.
Gross tumor volume, tumor weight, inhibition rate of tumor growth and body weight relative change rate see the following form 4.
The tumor-inhibiting action of table 4 compound 6 and 15 pairs of A549 tumor bearing nude mices and oxicity analysis
* p < 0.01vs.Vehicle; * p < 0.05vs.Vehicle; After One-way ANOVA, carry out Dunnett t check.
Administration was defined as the 0th day the same day, namely D0.TGI%=(1-(T
i-T
0)/(T
i-T
0)) * 100%; T
ifor measuring the gross tumor volume on the same day; T
0gross tumor volume during for random packet; RCBW% (relative body weight velocity of variation)=(BW
i-BW
0)/BW
0* 100%; BW
ifor measuring the body weight on the same day; BW
0body weight during for random packet.
conclusion
Compound 6 high dose group, compound 15 high dose group and compound 6 low dose group are after administration in 28 days, compare with control group and suppressing there is statistical significance aspect A549 tumor bearing nude mice tumor growth, compound 15 low dose group are not statistically significant, does not significantly suppress tumor growth.
Embodiment 5 co-administereds
According to compound of the present invention, can be combined to provide pharmaceutical composition with physiology acceptable carrier or medium, if form is the tablet that contains various fillers and binding agent or the lyophilized powder of capsule.Similarly, compound can with other medicament co-administered, co-administered should represent at least to patient, to use two kinds of medicaments so that the beneficial effect of two kinds of medicament combinations to be provided.For example, can be within a certain period of time simultaneously or make in order with medicament.Can by those skilled in the art, select experience to determine the effective dose of compound in composition widely.In addition, according to indication and required result for the treatment of, compound of the present invention can be used separately or the medicament extra with one or more is combined with.The combination therapy of being imagined by the present invention comprises, for example, and the use in formula of medicine separately of the use in single medicine formula of the compounds of this invention and additional agent and the compounds of this invention and additional agent.
The compounds of this invention can be independent, or with pharmaceutically acceptable carrier or thinner, optionally for example in the pharmaceutical composition of establishing criteria medicinal practice, be administered to newborn animal, preferred people together with Microcrystalline Cellulose with known adjuvant.Compound Orally-administrable or parenteral administration, comprise intravenously, intramuscular, intraperitoneal, subcutaneous, rectum and local route of administration.
For the oral application of chemotherapy compound of the present invention, selected compound can for example be usingd the form of tablet or capsule or use as the aqueous solution or suspension.For oral tablet, conventionally add common carrier to comprise lactose and W-Gum, and lubricant Magnesium Stearate for example.For Orally administered with capsule form, spendable thinner comprises lactose and anhydrous W-Gum, when aqeous suspension that needs orally use, active ingredient is mixed with emulsifying agent and suspension agent.If necessary, can add some sweeting agents and/or correctives.For intramuscular, intraperitoneal, subcutaneous or intravenously application, should control solute total concn so that preparation etc. ooze.
5.1 pharmaceutical compositions that contain compound 6
Prescription 1:
Compound 6 80mg
Microcrystalline Cellulose 40mg
Lactose 50mg
Low-substituted hydroxypropyl cellulose 8mg
Magnesium Stearate 2mg
Total amount 180mg
Prescription 2:
Compound 6 60mg
Microcrystalline Cellulose 40mg
Lactose 50mg
Croscarmellose sodium 8mg
Magnesium Stearate 2mg
Total amount 160mg
Prescription 3:
Compound 6 100mg
Microcrystalline Cellulose 40mg
Lactose 50mg
Polyvinylpolypyrrolidone 8mg
Magnesium Stearate 2mg
Total amount 200mg
Prescription 4:
Compound 6 100mg
Lactose 94mg
Polyvinylpolypyrrolidone 4mg
Magnesium Stearate 2mg
Total amount 200mg
Prescription 5:
Compound 6 100mg
Microcrystalline Cellulose 40mg
Lactose 58mg
Magnesium Stearate 2mg
Total amount 200mg
Prescription 6:
Compound 6 160mg
Microcrystalline Cellulose 41mg
Lactose 50mg
Polyvinylpolypyrrolidone 6mg
Magnesium Stearate 3mg
Total amount 260mg
Prescription 7:
Compound 11 120mg
Microcrystalline Cellulose 40mg
Lactose 48mg
Polyvinylpolypyrrolidone 8mg
Magnesium Stearate 4mg
Total amount 220mg
the preparation method of 5.2 preparations
Get in proportion active compound of the present invention, disintegrating agent and weighting agent and cross 60～100 mesh sieves, mix, the ethanolic soln softwood processed of the PVP K30 with 2～20%, cross 20～50 mesh sieves and granulate, 40～90 ℃ dry, and pellet moisture is controlled in 3%, after whole grain, add appropriate lubricant, mix, compressing tablet, obtains.
Particularly, the pharmaceutical composition of above-described embodiment also can be prepared by the following method: by 50 times of recipe quantities, take compound 6, weighting agent and disintegrating agent and cross successively 60,80 mesh sieves, mix, with the 50% ethanolic soln softwood processed of 2～20% PVP K30s, 30 mesh sieves are granulated, 60 ℃ dry, pellet moisture is controlled in 3%, after the whole grain of 20 mesh sieves, adds appropriate lubricant, mixes, compressing tablet, obtains product.
Can carry out various improvement as mentioned above and in the present invention of following claim definition.
Claims (5)
1. the compound that following general formula (I) represents:
Wherein, described compound is selected from:
(E)-3,5-dimethoxy-4 ' '-N-tert-butylnitrone base-toluylene (6);
(E)-3,5-benzyloxy-4 '-N-tert-butylnitrone base-toluylene (7);
(E)-3-methoxyl group-4-benzyloxy-4 '-N-tert-butylnitrone base-toluylene (8);
(E)-3-methoxyl group-4 benzoic acid ester group-4 '-N-tert-butylnitrone base-toluylene (9);
(E)-3-methoxyl group-4-acetate groups-4 '-N-tert-butylnitrone base-toluylene (10);
(E)-3-methoxyl group-4-hydroxyl-4 '-N-tert-butylnitrone base-toluylene (11);
(E) the fluoro-4 '-N-tert-butylnitrone of-4-base-toluylene (12);
(E)-4-benzyloxy-4 '-N-tert-butylnitrone base-toluylene (13);
(E)-4-hydroxyl-4 '-N-tert-butylnitrone base-toluylene (14);
(E) the fluoro-4 '-N-tert-butylnitrone of the chloro-4-of-3-base-toluylene (15);
(E)-3-itrile group-4 '-N-tert-butylnitrone base-toluylene (16);
(E)-4-(the fluoro-benzyloxy of 3-)-4 '-N-tert-butylnitrone base-toluylene (17).
2. the application of compound as claimed in claim 1 in preparing antitumor drug.
3. a pharmaceutical composition, comprises and treats acceptable carrier on the compound claimed in claim 1 of significant quantity and physiology.
4. pharmaceutical composition as claimed in claim 3, it is characterized in that, described medicinal compositions is by intravenously, intracutaneous, intramuscular, subcutaneous, oral administration, and the formulation of described pharmaceutical composition is the stomach and intestine external application preparation that is selected from the gi tract medication preparation of tablet, capsule and pill or is selected from injection, external preparation.
5. using compound claimed in claim 1 as the tablet of activeconstituents, it is characterized in that, comprise that weight ratio is 30～80% activeconstituents, 2～20% disintegrating agent, 0.2～2% lubricant, all the other are weighting agent.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010216461.4A CN101898979B (en) | 2010-07-01 | 2010-07-01 | Phenyl nitrone compounds containing stilbene sections and application thereof |
| PCT/CN2011/001031 WO2012000306A1 (en) | 2010-07-01 | 2011-06-21 | Phenyl nitrone compounds containing stilbene segment and use thereof |
| AU2011274194A AU2011274194B2 (en) | 2010-07-01 | 2011-06-21 | Phenyl nitrone compounds containing stilbene segment and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010216461.4A CN101898979B (en) | 2010-07-01 | 2010-07-01 | Phenyl nitrone compounds containing stilbene sections and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101898979A CN101898979A (en) | 2010-12-01 |
| CN101898979B true CN101898979B (en) | 2014-03-05 |
Family
ID=43224950
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010216461.4A Active CN101898979B (en) | 2010-07-01 | 2010-07-01 | Phenyl nitrone compounds containing stilbene sections and application thereof |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN101898979B (en) |
| AU (1) | AU2011274194B2 (en) |
| WO (1) | WO2012000306A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101898979B (en) * | 2010-07-01 | 2014-03-05 | 深圳海王药业有限公司 | Phenyl nitrone compounds containing stilbene sections and application thereof |
| CN105175288B (en) * | 2014-06-09 | 2017-07-07 | 深圳海王医药科技研究院有限公司 | A kind of preparation method of the phenyinitrone class compound containing talan fragment |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101638395A (en) * | 2009-06-30 | 2010-02-03 | 深圳海王药业有限公司 | Heterocyclic analog of diphenylethlene compound and application thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100503539C (en) * | 2007-06-14 | 2009-06-24 | 复旦大学 | Diphenylethene compound with anti-tumor activity and preparing method |
| CN101684114B (en) * | 2008-09-27 | 2012-10-17 | 江苏正大天晴药业股份有限公司 | Novel toluylene compound and preparation method thereof |
| CN101898979B (en) * | 2010-07-01 | 2014-03-05 | 深圳海王药业有限公司 | Phenyl nitrone compounds containing stilbene sections and application thereof |
-
2010
- 2010-07-01 CN CN201010216461.4A patent/CN101898979B/en active Active
-
2011
- 2011-06-21 WO PCT/CN2011/001031 patent/WO2012000306A1/en active Application Filing
- 2011-06-21 AU AU2011274194A patent/AU2011274194B2/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101638395A (en) * | 2009-06-30 | 2010-02-03 | 深圳海王药业有限公司 | Heterocyclic analog of diphenylethlene compound and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| Stefan Hauck，et al.p-Nitrostilbene-tert-Butyl-Nitrone: a Novel Fluorescent Spin Trap for the Detection of ROS with Subcellular Resolution..《Appl Magn Reson》.2009,第36卷第139页图2. * |
| 刘颖 等.白藜芦醇结构修饰的研究进展.《中草药》.2007,第38卷第308页图2. |
| 白藜芦醇结构修饰的研究进展;刘颖 等;《中草药》;20071231;第38卷;第308页图2 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2012000306A1 (en) | 2012-01-05 |
| CN101898979A (en) | 2010-12-01 |
| AU2011274194B2 (en) | 2015-12-17 |
| AU2011274194A1 (en) | 2013-02-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5719770B2 (en) | Icotinib hydrochloride, compound, crystallographic form, concomitant drug and its use | |
| CN106905322B (en) | Pyrrolopyrimidine penta azacyclo derivative and its application | |
| BR112020003865A2 (en) | pharmaceutical compositions comprising sepiapterin and their uses | |
| CN110343090B (en) | Quinazoline derivative salt crystal form, preparation method and application | |
| JP2019528318A (en) | Substituted quinazoline compounds with ability to cross the blood-brain barrier | |
| EP3658147A1 (en) | Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylic acid and its use for the treatment of cancer | |
| TR201815685T4 (en) | Combinations of act and mec inhibitory compounds for the treatment of cancer. | |
| EP2269994A1 (en) | The polymorphs of 4-anilinoquinazoline derivatives, the preparation methods and uses thereof | |
| CN102234254A (en) | Benzisoselenazol compounds, and preparation method and application thereof | |
| CN101735276A (en) | Water-soluble phosphate monoester derivatives and application thereof | |
| Patel et al. | Multi-targeted HDAC inhibitors as anticancer agents: Current status and future prospective | |
| CN101898979B (en) | Phenyl nitrone compounds containing stilbene sections and application thereof | |
| CN104557909B (en) | 3- acyloxy replaces dextrorotation deoxidation tylophorinine derivative, its preparation method and pharmaceutical composition and purposes | |
| CN107141284B (en) | Coptisine analog derivative, preparation method, pharmaceutical composition and anticancer usage | |
| RU2627692C1 (en) | N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2h-pyrido[4,3-d]pyrimidine-1-il]-phenyl}-cyclopropanecarboxamide dimethylsulfoxide solvate as mek1/2 inhibitor | |
| CN101863901A (en) | 2-(substituted phenyl)-2-(4,5,6,7-thiophane[3,2-c] pyridine-5(4H)-group)-N-substitute-acetamide as well as preparation method and application thereof | |
| CN113149960A (en) | Crystal of salt of quinazoline derivative | |
| CN107501283B (en) | Preparation of substituted arylmethyl hetero-substituted anilino ethylene glycol ether cycloquinazoline and application of tumor treatment drug | |
| Zhang et al. | Synthesis and biological evaluation of 1-phenyl-tetrahydro-β-carboline-based first dual PRMT5/EGFR inhibitors as potential anticancer agents | |
| CN112279863A (en) | Conjugate of Hsp90 inhibitor and camptothecin derivative as well as preparation method and application thereof | |
| CN109721557A (en) | Letrozole crystalline substance II type solid matter and preparation method and its pharmaceutical composition and purposes | |
| EP3596054B1 (en) | 5-carboxamide-2-thiobarbituric acids and use thereof as medicaments | |
| CN103172578A (en) | 4-ring end substituted 2-1,2,3-triazole phenylamines compound, preparation and purpose | |
| CN109553558A (en) | A kind of selenium-containing compound and its anticancer usage | |
| WO2024015793A2 (en) | Enantiomer of azopodophyllotoxin derivative su056 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20170418 Address after: Two road 518000 Guangdong city of Shenzhen province Nanshan District science and Technology Park, Xili Street North Long Road No. 16 Building 1 Neptune research Patentee after: Shenzhen Neptune medical science and Technology Research Institute Co., Ltd. Address before: 518057 Guangdong city of Shenzhen province Nanshan District high-tech road two North Long Hill Haiwang industrial city Patentee before: Haiwang Pharmaceutical Industry Co., Ltd., Shenzhen |
|
| TR01 | Transfer of patent right |