CN108578412A - A kind of taxol and diaza * and carbazole compound drug combination compositions - Google Patents
A kind of taxol and diaza * and carbazole compound drug combination compositions Download PDFInfo
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- CN108578412A CN108578412A CN201711492796.7A CN201711492796A CN108578412A CN 108578412 A CN108578412 A CN 108578412A CN 201711492796 A CN201711492796 A CN 201711492796A CN 108578412 A CN108578412 A CN 108578412A
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- diaza
- carbazole compound
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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Abstract
A kind of taxol and diaza provided by the inventionAnd carbazole compound drug combination compositions, including active constituent and pharmaceutically acceptable auxiliary material, it is characterised in that：Active constituent diaza shown in gemcitabine and Formulas IAnd carbazole compound or its pharmaceutically acceptable salt form, gemcitabine and diaza in the active constituentAnd the mass ratio of carbazole compound or its pharmaceutically acceptable salt is (2 8)：1.The pharmaceutical composition anticancer therapeutic is good, toxic side effect is low；Due to diaza
Description
Technical field
The invention belongs to chemical medicine, a kind of taxol and diazaAnd carbazole compound combination medicine group
Close object.
Background technology
Taxol, English name Paclitaxel, alias taxol, Paclitaxe, Paclitaxe, chemical name 5 β, 20- epoxy -1,2 α,
- 13 [(2 ' R, 3 ' S)-N- of 4,7 β, 10 β, 13 α-hexahydroxy taxane -11- alkene -9- ketone -4,10- diacetate esters -2- benzoic ethers
Benzoyl -3- phenylisoserines ester], molecular weight 853.92, molecular formula C47H51NO14.It is novel breast cancer, is led to
It crosses promotion tubulin polymerization and inhibits depolymerization, tubulin is kept to stablize, inhibit cell mitogen.Experiment in vitro proves Japanese yew
Alcohol has significant radiosensitizing effect, it may be possible to so that cell is terminated in G2 the and M phase sensitive to radiotherapy, clinic is primarily adapted for use in
Oophoroma and breast cancer also have certain curative effect to lung cancer, colorectal cancer, melanoma, incidence cancer, lymthoma, brain tumor.
Another problem of generally existing is most of antitumor agent along with serious toxicity in treatment of cancer.Although
Traditional antineoplastic, such as gemcitabine and taxol have drug resistance and serious toxicity, but due to because they can subtract
Few tumour, these drugs are still very important in treatment of cancer.
Although the combination of anticancer agent has been demonstrated there is great progress in modality of cancer treatment, for difficult to treat
Or the treatment of the cancer to showing treatment resistance as the conventional anti-neoplastic agent of monotherapy, still there are some unsatisfied demands
With the space for the drug therapy for improving cancer.Although for example, there is the combined chemotherapy based on gemcitabine to control in clinical treatment
Treatment scheme, but to eventually lead to cancer of pancreas prognosis very poor for drug resistance of tumor, and median survival interval is only 3-6 months, and survival rate is less than within 5 years
5%.Therefore, novel compositions approach of the exploitation for delivering the known anticancer agents with different role mechanism is the important of this field
Progress.Although being related to that there is the scheme of the anticancer agent combination of different role mechanism can play work in the case of certain combinations
With, but identical mode may not work for other combinations of anticancer agent, and such combination may not always generate tool
There is the combination of beneficial therapeutic effect.
Invention content
Technical problem：In order to solve the defects of prior art, the present invention provides a kind of taxol and diazasAnd click
Azole compounds drug combination compositions.
Technical solution：A kind of taxol and diaza provided by the inventionAnd carbazole compound combination medicine combines
Object, including active constituent and pharmaceutically acceptable auxiliary material, it is characterised in that：The active constituent is by gemcitabine and Formulas I
Shown in diazaAnd carbazole compound or its pharmaceutically acceptable salt form, gemcitabine and two in the active constituent
AzepineAnd the mass ratio of carbazole compound or its pharmaceutically acceptable salt is 1：(2-8)；Wherein, diazaAnd carbazoles
The chemical formula of compound or its pharmaceutically acceptable salt is：
As an improvement, diazaAnd the pharmaceutically acceptable salt of carbazole compound is diaza shown in Formula IIAnd
Diaza shown in carbazole compound citrate or formula IIIAnd carbazole compound mesylate：
As an improvement, gemcitabine and diaza in the active constituentAnd carbazole compound or its is pharmaceutically acceptable
Salt mass ratio be 1：(3-6).
Gemcitabine and diaza in the active constituentAnd the matter of carbazole compound or its pharmaceutically acceptable salt
Amount is than being 1：5.
The present invention also provides diazas shown in gemcitabine and Formulas IAnd carbazole compound or its is pharmaceutically acceptable
Salt composition composition prepare treatment with prevent cancer drug in application.
Wherein, the cancer include but not limited to breast cancer, colorectal cancer, oophoroma, prostate cancer, lung cancer, liver cancer,
Cancer of pancreas.
Advantageous effect：Compared with prior art, pharmaceutical composition of the present invention have the following advantages that and significantly into
Step：
(1) anticancer therapeutic is good.Present invention discover that diaza shown in Formulas IAnd carbazole compound increases gemcitabine
The bioactivity of neoplasm growth, synergistic effect of the two combination with antitumor proliferation, thirsts for exploitation into clinically anti-pancreas
The fiest-tire medication of cancer.
(2) toxic side effect is low.Due to diazaAnd carbazole compound, to the sensibility of gemcitabine, the two joint is used
Medicine produces synergistic effect, to reduce the Clinical practice dosage of capecitabine, reduces large dosage and is produced using capecitabine
Raw toxic side effect improves safety clinical treatment index, has preferable potential applicability in clinical practice.
Specific implementation mode
The present invention is further illustrated below.
1 1- of embodiment (2,3,5,10- tetrahydrochysenes-[1,2] diazasAnd [3,4,5,6-def] carbazole -6 (1H) -one -
10- yls) -3- (4- carbethoxyl groups) phenylurea
The synthesis of the bromo- 3- of step 1 2- ((3- oxocyclohex -1- alkene -1- bases) amino) methyl benzoate
3.58g 3- amino -2- methyl-bromobenzoates, 1.68g hexamethylene -1,3- diketone are weighed in reaction bulb, second is added
Sour 20ml dissolvings, 80 DEG C of reaction 8h remove solvent under reduced pressure after reaction, and column chromatography purifies to obtain title compound.LC-MS m/
z:[M+H] +=325.
The synthesis of step 2 4- oxo -2,3,4,9- tetrahydrochysene -1H- carbazole -5- carboxylate methyl esters
1.62g steps 1 gains, 0.23g acid chlorides, (o-tolyl) phosphines of 1.22g tri- and 0.63g triethylamines are weighed in close
In tube sealing, acetonitrile 15ml is added, the lower 100 DEG C of sealings reaction of nitrogen atmosphere 20 hours is after reaction, cooling, and water 15ml is added
Dilution, dichloromethane extract (50ml*3), and anhydrous sodium sulfate drying, column chromatography purifies to obtain title compound.LC-MS m/z:[M+
H] +=244.
Step 3 2,3,5,10- tetrahydrochysenes-[1,2] diazaAnd the synthesis of [3,4,5,6-def] carbazole -6 (1H) -one
0.73g steps 2 gains, 1.5ml acetic acid and 8.6ml hydrazine hydrates are weighed in reaction bulb, methanol 40ml is added, is returned
Stream reaction 8 hours, is filtered while hot, and water, ethyl acetate and dichloromethane washing obtain title compound.
LC-MS m/z:[M+H]+=226.
Step 4 10- (2- t-butoxycarbonyl aminos) ethyl -2,3,5,10- tetrahydrochysenes-[1,2] diazaAnd [3,4,5,
6-def] carbazole -6 (1H) -one
10g N- t-butoxycarbonyl aminos ethyl alcohol and 23.96g TsCl are weighed in reaction bulb, pyridine 50ml dissolvings are added,
Room temperature reaction overnight, after reaction, removes pyridine under reduced pressure, adds water 20ml, ethyl acetate to extract (50ml*3), anhydrous magnesium sulfate
Dry, column chromatography purifies (1- (tertbutyloxycarbonyl) amino) ethyl alcohol-(4- toluenesulfonic acids) ester.
0.67g steps 3 gains and 0.3g NaH are weighed in reaction bulb, 10ml DMF dissolvings, 45 DEG C of reaction 2h are added
Afterwards, (1- (tertbutyloxycarbonyl) amino) ethyl alcohol-(4- toluenesulfonic acids) ester obtained by 2.81g is added, 16h is stirred at room temperature, reaction terminates
Afterwards, water 10ml, ethyl acetate extraction, anhydrous magnesium sulfate drying is added to filter, column chromatography purifies to obtain title compound.
LC-MS m/z:[M+H]+=369.
Step 5 10- aminoethyl -2,3,5,10- tetrahydrochysenes-[1,2] diazaAnd [3,4,5,6-def] carbazole -6 (1H) -
The synthesis of ketone
1.0g step 4 gains are weighed in reaction bulb, dichloromethane 15ml dissolvings are added, lower addition 10ml is stirred at room temperature
Trifluoroacetic acid, reaction 5h removes solvent under reduced pressure after reaction, with saturated sodium bicarbonate aqueous solution to pH to 8, ethyl acetate
Extraction, anhydrous magnesium sulfate drying, filtration drying obtain title compound.
LC-MS m/z:[M+H]+=269.
The preparation of step 6 4-aminobenzoic acid ethyl ester
Measurement 10ml ethyl alcohol is in reaction bulb, addition 0.4g 3- aminobenzoic acids, after stirring and dissolving, is slowly added dropwise at 0 DEG C
Thionyl chloride, drop finish, are warmed to room temperature and are stirred to react 8h, after reaction, remove solvent under reduced pressure, saturated sodium bicarbonate solution is adjusted
PH to 7-8, ethyl acetate extraction, saturated common salt water washing, anhydrous sodium sulfate drying are concentrated to give title compound, for casting
One step.
Step 7 1- (2,3,5,10- tetrahydrochysenes-[1,2] diazasAnd [3,4,5,6-def] carbazole -6 (1H) -one -10-
Base) -3- (4- carbethoxyl groups) phenylurea synthesis
0.40g step 6 gains are weighed in reaction bulb, it is 1 to add 30ml volume ratios:1 dichloromethane/unsaturated carbonate hydrogen
The mixed solvent of sodium water solution, 0 DEG C, be added with stirring 0.22g Triphosgenes, the reaction was continued at 0 DEG C 30min, after reaction,
Liquid separation, collected organic layer after dry, after the dissolving of 10ml dichloromethane is added, is added 0.15g step 5 gains, continues at 0 DEG C
10h is stirred, after reaction, column chromatography purifies to obtain title compound.
1H NMR(400MHz,CDCl3,δppm):7.88-7.86(m,2H),7.80-7.77(m,3H),7.59-7.57(m,
1H),7.54-7.53(m,1H),7.38(m,1H),7.24-7.21(m,2H),4.69-4.67(m,2H),4.30-4.29(m,
2H),3.65-3.63(m,2H),2.78-2.76(m,2H),2.10-2.08(m,2H),1.89-1.87(m,2H),1.31-1.29
(m,3H)。LC-MS m/z:[M+H]+=460.
2 1- of embodiment (2,3,5,10- tetrahydrochysenes-[1,2] diazasAnd [3,4,5,6-def] carbazole -6 (1H) -one -
10- yls) -3- (4- carbethoxyl groups) phenylurea citrate synthesis
1 compound of 1.0g embodiments is weighed in reaction bulb, the dissolving of 20ml chloroforms is added, 0.42g citric acids, room temperature is added
3h is stirred, solvent is removed under reduced pressure, obtains title compound.
3 1- of embodiment (2,3,5,10- tetrahydrochysenes-[1,2] diazasAnd [3,4,5,6-def] carbazole -6 (1H) -one -
10- yls) -3- (4- carbethoxyl groups) phenylurea methanesulfonic acid synthesis
1 compound of 2.0g embodiments is weighed in reaction bulb, the dissolving of 50ml dichloromethane is added, 0.42g methanesulfonic acids are added,
1h is stirred at room temperature, removes solvent under reduced pressure, obtains title compound.
1 stability experiment of experimental example
4 parts of compound for weighing 0.5g embodiments 1 to 3, respectively under the conditions of illumination 4500Lx, RH70%75 DEG C of condition
Under, place under room temperature 1 month with RH70% under the conditions of RH70%60 DEG C, experimental result is shown in Table 1.
Table 1
The experimental results showed that the compound of the embodiment of the present invention 2 and 3 has very high stability.
2 solubility experiment of experimental example
Solubility test the results are shown in Table 2.
Table 2
The vitro kinase activity of 3 the compounds of this invention of experimental example is evaluated
Establish IDO1/2 inhibition of enzyme activity molecule screening models, detection positive control drug Epacadostat
(INCB024360) inhibition IC on this model50Value, the results showed that ICs of the Epacadostat to IDO150Value is 90nM left
The right side, to the IC of IDO250Value is 3.0uM or so, close with document report, illustrates that screening model is built successfully.Under room temperature environment,
The L-Trp of the IDO enzymes of 40nM and 900uM are mixed, and reaction buffer (20mM ascorbate, 3.5uM is added
methylene blue and 0.2mg/mL catalase in 50mM potassium phosphate buffer pH
6.5), in room temperature reaction 3 hours, ultraviolet determination, Detection wavelength 321nm are then carried out in microplate reader.Enzymatic activity percentage
It (%)=(OD value dosing holes-OD is worth background)/(OD value control wells-OD is worth background) × 100%, then uses
PrismGraphPad sofeware software the Fitting Calculations IC50Value, the results are shown in Table 1.
Table 1
Can be seen that the compound of the present invention from the above experimental result there is preferable inhibition to live IDO1 and IDO2 kinases
Property, especially 7 compound of 5 compound of embodiment and embodiment.
The cell in vitro activity rating of 4 the compounds of this invention of experimental example
Using Sulforhodamine B (SRB) colorimetric method, the HT29 human colon cancer cells of exponential phase are blown and beaten at unicellular
Suspension is inoculated in 96 well culture plates (5x103 cells/wells), 200 μ L of culture medium is added per hole, in 37 DEG C, 5%CO2In incubator
Overnight incubation；After cell is adherent, it is further cultured in the incubator after the test-compound and positive control drug of debita spissitudo is added
72 hours.1 hour is fixed at 4 DEG C after 10% trichloroacetic acid is added.It is washed 5 times with distilled water, after dry, it is micro- that 70 is added per hole
SRB solution (4mg/mL) is risen, room temperature dyes 20 minutes, and 1% acetic acid washs 5 times, dry.100 μ L10mM Tris- are added per hole
Base solution makes SRB dissolve.Microplate reader detects each hole OD values, records as a result, inhibiting rate is calculated according to the following formula：Inhibiting rate (%)
=(OD controls-OD administrations)/OD controls × 100%, and calculate IC50.It the results are shown in Table 2.
Table 2
| Compound | HT29 cells IC50Value |
| Epacadostat | 50.1 |
| 1 compound of embodiment | 20.5 |
| 2 compound of embodiment | 15.4 |
| 3 compound of embodiment | 10.2 |
Can be seen that the compound of the present invention from the above experimental result has higher inhibitory activity to colon cancer cell.
Experimental example 5
Human pancreatic carcinoma PANC-1 cell line after taking out cryopreservation tube, puts into 37 DEG C of water-baths, shakes defrosting 2min, and alcohol disappears
It after on the outside of malicious tube wall, is transferred in super-clean bench, pipe inner cell is transferred in centrifuge tube, 5ml37 DEG C of preheating of addition contains
The DMEM culture mediums of 10% fetal calf serum, and it is primary to clean cryopreservation tube, and centrifuge tube is centrifuged (1000rpm, 5min), is discarded supernatant
Liquid adds the DMEM culture mediums containing 10% fetal calf serum of 37 DEG C of 2ml preheating, is transferred in culture bottle, be positioned over 37 DEG C,
50mL/L CO2It is cultivated in the incubator of saturated humidity, and with 0.5% trypsin digestion and routine passage.
SPF grades of BALB/c-nu nude mouses, 6 week old, male, 18~20g of weight.Take the human pancreas in exponential phase
Cancer cell PANC-1 is inoculated in the right oxter of nude mice, and every mouse about injects 2 × 106 cells, after 3 generation of continuous passage, when the 4th generation
When growth of transplanted human was to 3 weeks, tumor bearing nude mice is put to death, fresh tumor tissue is taken, is cut into volume about 8mm3Tumor mass is inoculated in experiment nude mice
Right side oxter, the above operation all carry out under aseptic condition in super-clean bench.
The 8th day tumour is in locally surviving and growing to diameter about 0.5cm after plant, by the successful Transplanted tumor model mouse of modeling
Stochastic averagina is divided into four groups, and every group 8, each group carries out treatment 3 weeks by the tested material of following dosage respectively：
Blank control group：Every 1% sodium cellulose glycolate solution 0.1ml/10g of nude mice gavage, one time a day；
Taxol group：Every nude mice presses the taxol of weight gavage 30mg/kg, with 1% sodium cellulose glycolate solution
Gavage after suspension, one time a day；
Compound group one：Every nude mice presses the compound of the embodiment 1 of weight gavage 100mg/kg, with 1% methylol
Gavage after sodium cellulosate solution is suspended, one time a day；
Compound group two：Every nude mice presses the compound of the embodiment 2 of weight gavage 100mg/kg, with 1% methylol
Gavage after sodium cellulosate solution is suspended, one time a day；
Compound group three：Every nude mice presses the compound of the embodiment 3 of weight gavage 100mg/kg, with 1% methylol
Gavage after sodium cellulosate solution is suspended, one time a day；
Joint group one：Every nude mice is by the compound of the embodiment 1 of weight gavage 75mg/kg and the purple of 15mg/kg
China fir alcohol, gavage after being suspended with 1% sodium cellulose glycolate solution, one time a day.
Joint group two：Every nude mice is by the compound of the embodiment 2 of weight gavage 75mg/kg and the purple of 15mg/kg
China fir alcohol, gavage after being suspended with 1% sodium cellulose glycolate solution, one time a day.
Joint group three：Every nude mice is by the compound of the embodiment 3 of weight gavage 75mg/kg and the purple of 15mg/kg
China fir alcohol, gavage after being suspended with 1% sodium cellulose glycolate solution, one time a day.
The 2nd day after administration, each group animal is put to death, detaches transplantable tumor, claims knurl weight, tumour inhibiting rate=(control group knurl weight-it controls
Treatment group knurl weight)/control group knurl weight × 100%.Each group average knurl weight and tumour inhibiting rate refer to table 5.
Table 5
Claims (6)
1. a kind of taxol and diazaAnd carbazole compound drug combination compositions, including active constituent and pharmaceutically
Acceptable auxiliary material, it is characterised in that：Active constituent diaza shown in gemcitabine and Formulas IAnd carbazoles
It closes object or its pharmaceutically acceptable salt forms, gemcitabine and diaza in the active constituentAnd carbazole compound or its
The mass ratio of pharmaceutically acceptable salt is 1：(2-8)；Wherein, diazaAnd carbazole compound or its pharmaceutically acceptable salt
Chemical formula be：
2. a kind of taxol according to claim 1 and diazaAnd carbazole compound drug combination compositions,
It is characterized in that：DiazaAnd the pharmaceutically acceptable salt of carbazole compound is diaza shown in Formula IIAnd carbazoles
Close diaza shown in object citrate or formula IIIAnd carbazole compound mesylate：
3. a kind of taxol according to claim 1 and diazaAnd carbazole compound drug combination compositions,
It is characterized in that：Gemcitabine and diaza in the active constituentAnd the matter of carbazole compound or its pharmaceutically acceptable salt
Amount is than being 1：(3-6).
4. a kind of taxol according to claim 1 and diazaAnd carbazole compound drug combination compositions,
It is characterized in that：Gemcitabine and diaza in the active constituentAnd the matter of carbazole compound or its pharmaceutically acceptable salt
Amount is than being 1：5.
5. diaza shown in gemcitabine and Formulas IAnd the composition of carbazole compound or its pharmaceutically acceptable salt composition
Application in preparing treatment and preventing cancer drug.
6. application as claimed in claim 5, it is characterised in that：The cancer include but not limited to breast cancer, colorectal cancer,
Oophoroma, prostate cancer, lung cancer, liver cancer, cancer of pancreas.
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| CN109481443A (en) * | 2018-10-31 | 2019-03-19 | 南京先进生物材料与过程装备研究院有限公司 | A kind of taxol and adjacent benzene fluorine phthalazines ketone BTK inhibitor drug combination compositions and its application |
| CN109481444A (en) * | 2018-10-31 | 2019-03-19 | 南京先进生物材料与过程装备研究院有限公司 | A kind of taxol and phthalazines class BTK inhibitor drug combination compositions and its application |
| CN109481442A (en) * | 2018-10-31 | 2019-03-19 | 南京先进生物材料与过程装备研究院有限公司 | A kind of taxol and adjacent phenyl phthalazines ketone BTK inhibitor drug combination compositions and its application |
| CN109481441A (en) * | 2018-10-31 | 2019-03-19 | 南京先进生物材料与过程装备研究院有限公司 | A kind of taxol and novel methoxyl group phthalazines ketone BTK inhibitor drug combination compositions and its application |
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