CN108047232A - The methanesulfonic acid and its application of diaza * and carbazole compound - Google Patents
The methanesulfonic acid and its application of diaza * and carbazole compound Download PDFInfo
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- CN108047232A CN108047232A CN201711492770.2A CN201711492770A CN108047232A CN 108047232 A CN108047232 A CN 108047232A CN 201711492770 A CN201711492770 A CN 201711492770A CN 108047232 A CN108047232 A CN 108047232A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/06—Peri-condensed systems
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Abstract
The invention belongs to chemical medicines, and in particular to a kind of diaza with IDO kinase inhibiting activitiesAnd carbazole compound, and the pharmaceutical composition containing the compound and application of the compound or composition in medicine preparation, more particularly to mesylate or its solvate of compound, crystallization or prodrug shown in formula (I), the compound has good dissolubility and stability, better choice is provided for dosage form research
Description
Technical field
The invention belongs to chemical medicines, and in particular to a kind of diaza with IDO kinase inhibiting activitiesAnd click
Azole compounds and the pharmaceutical composition containing the compound and application of the compound or composition in medicine preparation.
Background technology
Indole amine 2,3-dioxygenase (IDO) is the limit that unique catalysis tryptophan is metabolized along kynurenine pathway beyond liver
Fast enzyme has been found and a variety of close phases of mankind's major disease such as tumour, alzheimer disease, depression and cataract of old people
It closes, and IDO must be expressed or the exception of activity increases, and be a key factor for causing above-mentioned disease, therefore, screening is efficient
IDO inhibitor can provide effective medicine for these diseases.
In recent years, research confirms IDO in a variety of solid tumors in such as lung cancer, liver cancer, breast cancer, colon cancer tumor tissues
Expression is remarkably reinforced, and closely related with prognosis.Therefore, using IDO inhibitor be likely to become it is a kind of treat tumour have efficacious prescriptions
Method.
Therefore, developing IDO inhibitor has wide potential applicability in clinical practice.
The content of the invention
It is an object of the present invention to provide the methanesulfonic acids of compound shown in the formula (I) with IDO kinase inhibiting activities
Salt or its solvate, crystallization or prodrug, the compound have good dissolubility and stability, are provided for dosage form research
Better choice,
It is another object of the present invention to provide containing the mesylate of compound shown in formula (I) or its solvate,
Crystallization or the pharmaceutical composition of prodrug and pharmaceutically acceptable carrier.
It is yet a further object of the present invention to provide the mesylate of compound shown in formula (I) or its solvate, crystallizations
Or the purposes of prodrug or its pharmaceutical composition in preparing for the drug for the treatment of and/or pre- preventing tumor.
For above-mentioned purpose, the present invention provides following technical scheme：
In a first aspect, mesylate or its solvate, the crystallization or prodrug of compound shown in offer formula (I) of the present invention,
Second aspect, the present invention provide pharmaceutical composition, it includes the methanesulfonic acid of compound shown in formula (I) of the present invention or its
Solvate, crystallization or prodrug and pharmaceutically acceptable carrier.
It can be by the mesylate of compound, solvate, crystallization or prodrug shown in formula (I) of the present invention with can pharmaceutically connect
Carrier, diluent or the excipient received are prepared by mixing into pharmaceutical preparation, to be suitable for oral or parenteral.Medication bag
It includes, but is not limited to that intracutaneous, intramuscular, peritonaeum is interior, intravenous, subcutaneous, intranasal and peroral route.The preparation can pass through any way
Footpath is applied, such as by being transfused or injecting, passes through transepithelial or the way of mucocutaneous (such as oral mucosa or rectum etc.) absorption
It applies in footpath.Administration can be whole body or local.The example of oral administration preparation includes solid or liquid dosage form, it is specific and
Speech, including tablet, pill, granula, pulvis, capsule, syrup, emulsion, suspension etc..The preparation can be by known in the art
Method prepare, and include the conventional use of carrier of field of pharmaceutical preparations, diluent or excipient.
The third aspect, the present invention provide the mesylate of compound, solvate, crystallization or preceding shown in formula (I) of the present invention
Application of the pharmaceutical composition of medicine or the present invention in prevention and/or tumor is prepared, including easily sending out crowd to tumour
Or tumor patient is applied the compound of the present invention, solvate, crystallization or prodrug or is closed comprising the compound of the present invention, solvent
The pharmaceutical composition of object, crystallization or prodrug, effectively to reduce Tumor incidence, extend tumor patient life.
Specific embodiment
Representative embodiment is the protection model and is not intended to limit the present invention in order to which the present invention is better described below
It encloses.
1 1- of embodiment (2,3,5,10- tetrahydrochysenes-[1,2] diazaAnd [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, adds in second
Sour 20ml dissolvings, 80 DEG C of reaction 8h, after reaction, remove solvent under reduced pressure, 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 in, when the lower 100 DEG C of sealings reaction 20 of nitrogen atmosphere is small, after reaction, cooling adds in water 15ml
Dilution, dichloromethane extraction (50ml*3), anhydrous sodium sulfate drying, column chromatography purify 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, adds in methanol 40ml, is returned
It when stream reaction 8 is small, filters while hot, 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, adds in pyridine 50ml dissolvings,
Room temperature reaction overnight, after reaction, removes pyridine under reduced pressure, adds water 20ml, ethyl acetate extraction (50ml*3), anhydrous magnesium sulfate
Dry, column chromatography purifies (1- (tertbutyloxycarbonyl) amino) ethyl alcohol-(4- toluenesulfonic acids) ester.
0.67g steps 3 gains and 0.3gNaH are weighed in reaction bulb, adds in 10ml DMF dissolvings, 45 DEG C of reaction 2h
Afterwards, 2.81g gained (1- (tertbutyloxycarbonyl) amino) ethyl alcohol-(4- toluenesulfonic acids) esters are added in, 16h are stirred at room temperature, reaction terminates
Afterwards, water 10ml, ethyl acetate extraction are added, anhydrous magnesium sulfate drying is filtered, and 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 is added in, lower addition 10ml is stirred at room temperature
Trifluoroacetic acid reacts 5h, after reaction, solvent is removed under reduced pressure, 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] diazaAnd [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 adding in the dissolving of 10ml dichloromethane, add in 0.15g step 5 gains, continue 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] diazaAnd [3,4,5,6-def] carbazole -6 (1H) -one -
10- yls) -3- (4- carbethoxyl groups) phenylurea Chinese holly methanesulfonic acid synthesis
1 compound of 2.0g embodiments is weighed in reaction bulb, the dissolving of 50ml dichloromethane is added in, adds in 0.42g methanesulfonic acids,
1h is stirred at room temperature, removes solvent under reduced pressure, obtains title compound.
1 stability experiment of experimental example
Weigh 3 parts of 2 compound of 0.5g embodiments, respectively under the conditions of illumination 4500Lx, under the conditions of RH70%60 DEG C and
RH70% is placed 6 months under room temperature, and HPLC detection active constituent contents are shown in Table 1.
Table 1
The experimental results showed that 2 compound of the embodiment of the present invention has very high stability.
2 solubility experiment of experimental example
Solubility test the results are shown in Table 2.
Table 2
3 vitro enzyme activity rating of experimental example
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 Epacadostat is to the IC of IDO150It is worth for a 90nM left sides
The right side, to the IC of IDO250It is worth for 3.0uM or so, it is close with document report, illustrate that screening model is built successfully.Under room temperature environment,
The L-Trp of the IDO enzymes of 40nM and 900uM are mixed, and add in reaction buffer (20mM ascorbate, 3.5uM
methylene blue and0.2mg/mL catalase in 50mM potassium phosphate buffer pH
6.5), when room temperature reaction 3 is small, ultraviolet determination, Detection wavelength 321nm are then carried out in microplate reader.Enzymatic activity percentage
(%)=(OD value dosing holes-OD is worth background)/(OD value control wells-OD is worth background) × 100%, Ran Houyong
PrismGraphPad sofeware software the Fitting Calculations IC50Value, the results are shown in Table 1.
Table 1
| Compound | IDO1(nM) | IDO2(uM) |
| Epacadostat | 90 | 3.0 |
| 1 compound of embodiment | 86 | 0.8 |
| 2 compound of embodiment | 98 | 0.5 |
Can be seen that the compound of the present invention from more than experimental result there is preferable inhibition to live IDO1 and IDO2 kinases
Property.
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 into unicellular
Suspension is inoculated in 96 well culture plates (5x103 cells/wells), 200 μ L of culture medium is added in per hole, in 37 DEG C, 5%CO2In incubator
Overnight incubation；After cell attachment, it is further cultured in the incubator after adding in the test-compound and positive control drug of debita spissitudo
72 it is small when.Add in 10% trichloroacetic acid after fixed at 4 DEG C 1 it is small when.It is washed 5 times with distilled water, after dry, it is micro- that 70 is added in 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 in per hole
Base solution dissolves SRB.Microplate reader detects each hole OD values, and record by following equation as a result, calculate inhibiting rate：Inhibiting rate (%)
=(OD controls-OD administrations)/OD controls × 100%, and calculate IC50.It the results are shown in Table 2.
Table 2
Can be seen that the compound of the present invention from more than experimental result has higher inhibitory activity to colon cancer cell.
Although being described in detail above to the present invention, however it is understood by skilled practitioners that without departing from this hair
The present invention can be carry out various modifications and changed on the premise of bright spirit and scope.The interest field of the present invention is not limited to
The detailed description made above, and claims should be belonged to.
Claims (6)
1. the mesylate of compound shown in Formulas I or its solvate, crystallization or prodrug,
2. a kind of pharmaceutical preparation, it includes the mesylate of compound described in claim 1 or its solvate, crystallizations or preceding
Medicine and one or more pharmaceutically acceptable carriers.
3. pharmaceutical preparation according to claim 2 is configured to be suitable for oral or parenteral.
4. pharmaceutical preparation according to claim 3 is tablet, pill, granule, capsule or injection.
5. the hydrobromate of compound described in claim 1 or its solvate, crystallization or prodrug or claim 2-4 it is any
Application of the pharmaceutical preparation in preparing for the drug for the treatment of and/or pre- preventing tumor described in.
6. application according to claim 5, wherein the tumour is colon cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711492770.2A CN108047232A (en) | 2017-12-30 | 2017-12-30 | The methanesulfonic acid and its application of diaza * and carbazole compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711492770.2A CN108047232A (en) | 2017-12-30 | 2017-12-30 | The methanesulfonic acid and its application of diaza * and carbazole compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108047232A true CN108047232A (en) | 2018-05-18 |
Family
ID=62129377
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711492770.2A Withdrawn CN108047232A (en) | 2017-12-30 | 2017-12-30 | The methanesulfonic acid and its application of diaza * and carbazole compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108047232A (en) |
-
2017
- 2017-12-30 CN CN201711492770.2A patent/CN108047232A/en not_active Withdrawn
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Application publication date: 20180518 |