CN109485646A - A kind of benzothiazole quinones compound and its preparation method and application - Google Patents
A kind of benzothiazole quinones compound and its preparation method and application Download PDFInfo
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- CN109485646A CN109485646A CN201811516450.0A CN201811516450A CN109485646A CN 109485646 A CN109485646 A CN 109485646A CN 201811516450 A CN201811516450 A CN 201811516450A CN 109485646 A CN109485646 A CN 109485646A
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- compound
- pharmaceutically acceptable
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- acceptable salt
- benzothiazole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Abstract
The invention discloses benzothiazole quinones compound shown in general formula I or its pharmaceutically acceptable salt, with and preparation method thereof and prepare the application of anti-tumor drug, the compound structure is as follows:Wherein n is that 2~8, X is selected from-CH2,-NH- ,-O- orR is selected from
Description
Technical field
The invention belongs to technical field of new application of medicine, and in particular to a kind of benzothiazole quinones compound and its preparation side
Method and purposes.
Background technique
The research and development of the small molecule, anti-tumor drug of target tumor metabolism have been increasingly becoming popular research field.For swollen
The new drug development of the metabolic enzyme of tumor specificity overexpression has been achieved for important breakthrough, wherein just including NAMPT inhibitor
Research and development.Although having come into the stage of clinical research using FK866 as the NAMPT inhibitor of representative, due to biological benefit
The reasons such as expenditure difference, clinical test finally end in failure.
In the early time the study found that combination NQO1 substrate and the NAMPT inhibitor property of can choose kill tumour cell, have
Body mechanism is that experienced reduction-autoxidizable process due to NQO1 substrate to generate a large amount of reactive oxygen species (ROS) and lead
DNA of tumor cell damage is caused, NAMPT inhibitor can specificity inhibition nicotinamide adenine dinucleotide (NAD as associated with
+) remedy synthesis and NAD+ level caused in tumour cell to decline, so as to cause the enzyme of NAD+ dependence, such as: PARP-1,
The enzymes such as Sirt-1 can not play the activity of DNA repair enzyme, albumen deacetylase, so as to cause the lethal of tumor cells selectivity
Synthesis.
Currently, there are many NQO1 substrates by document report, wherein β-lapachone, Deoxynyboquinone
(DNQ) and pronqodine A is great representative compound.β-lapachone has come into clinical experimental stage,
But the test at present has terminated.DNQ is complete by University of Illinois, U.S. champagne branch school Hergenrother professor team
Obtained natural products is synthesized, but its very poor dissolubility, which limits it, further to be developed.And pronqodine A is from soil
The isolated natural products of streptomycete in earth, fully synthetic route have been reported, and structure is easy to modify, and has good
Good NQO1 substrate specificities, can be further embellished transformation.But it has not been reported at present double for NAMPT and NQO1 progress
Target drug design.
Summary of the invention
Goal of the invention: in view of the above technical problems, the present invention provides a kind of benzothiazole quinones compound and its preparations
Method and purposes.
Technical solution: in order to achieve the above object of the invention, the technical solution adopted in the present invention is as follows:
Benzothiazole quinones compound shown in general formula I or its pharmaceutically acceptable salt:
Wherein n is that 2~8, X is selected from-CH2,-NH- ,-O- or
R is selected from
It is preferred that:
The X be selected from-NH- or
The R is selected from
The n is 3-7, and R is selected fromX be selected from-NH- or
Preferred compound, as follows:
The preparation method of the compound, using organic solvent as reaction dissolvent, compound II and compound III are being urged
In the presence of agent, room temperature reaction, after, extraction, for silica gel post separation to get final product I is arrived, reaction equation is as follows:
Wherein, n, X and R are same as above.
It is preferred that the organic solvent is selected from dehydrated alcohol, the catalyst is selected from cerous chloride.
A kind of pharmaceutical composition, containing the compound or its pharmaceutically acceptable salt in the composition, and
Pharmaceutically acceptable auxiliary material.
The compound or its pharmaceutically purposes of acceptable salt in the preparation of antitumor drugs.
The present invention utilizes molecular hybridization strategy, and NQO1 substrate and the key pharmacophore of NAMPT inhibitor are integrated, obtained
To a series of double target molecules with NQO1 substrate and NAMPT inhibitory activity, to realize the consumption of NAD+ in tumour cell
And lead to the death of tumor cell specific, not only facilitate administration, but also can effectively promote anti-tumor activity, has been targeting anti-tumor
Medicament research and development provides important material base.
Technical effect: compared with the existing technology, the present invention is based on the mother nucleus structures of natural products pronqodine A, utilize
Principle of hybridization carries out splicing with the key pharmacophore of NAMPT inhibitor to be integrated into a molecule.These compounds are dividing
Son, cellular level have good anti-tumor activity, specificity can generate a large amount of live in the tumour cell of height expression NQO1
Property oxygen species and effectively inhibit nicotinamide phosphoribosyl transferase (NAMPT) activity, can be used for preparing anti-tumor drug.
Specific embodiment
All embodiments prepare generalformulaⅰcompound according to following reaction equation:
Wherein compound ii can be according to document Angew Chem Int Ed.2015；54 (30): 8740-5 is made.
Compound I prepares logical method:
Compound II (1.0eq), different aminated compounds (compound III) (1.1eq), cerous chloride (0.1eq) are molten
In dehydrated alcohol, react at room temperature 2 hours.After reaction, methylene chloride and water (1:1) is added, is extracted with dichloromethane 3
It is secondary, merge organic phase, washed twice with saturated salt solution, organic phase is dry with anhydrous sodium sulfate, and revolving removes solvent, silicagel column
It separates (methylene chloride/isopropanol), obtains final product I, color is orange red to aubergine, solid.
Embodiment 1
The preparation of compound P2:
According to logical method, wherein aminated compounds isIt is purplish red for obtaining product
Color solid, yield 28%.
ESI-MS,m/z,[M+H+]calcd 451.2,found 451.2；1H NMR(300MHz,DMSO-d6)δ(ppm):
8.96 (s, 1H), 8.73 (s, 1H), 8.53 (d, J=4.5Hz, 1H), 8.12 (s, 2H), 7.95 (d, J=7.7Hz, 1H), 7.45
~7.40 (m, 2H), 6.71 (d, J=15.9Hz, 1H), 5.88 (s, 1H), 4.08 (d, J=12.6Hz, 2H), 3.18~3.02
(m, 4H), 1.76 (d, J=12.0Hz, 2H), 1.57~1.43 (m, 4H), 1.32~1.22 (m, 6H)
Embodiment 2
The preparation of compound P3:
According to logical method, wherein aminated compounds isIt is orange red solid for obtaining product
Body, yield 31%.
ESI-MS,m/z,[M+H+]calcd 369.1,found 369.1；1H NMR(300MHz,DMSO-d6)δ(ppm):
9.02 (s, 1H), 8.75 (s, 1H), 8.54 (d, J=3.8Hz, 1H), 8.23 (m, 1H), 8.02~7.96 (m, 2H), 7.48~
7.41 (m, 2H), 6.71 (d, J=15.9Hz, 1H), 5.62 (s, 1H), 3.33~3.24 (m, 4H), 1.81~1.76 (m, 2H)
Embodiment 3
The preparation of compound P4:
According to logical method, wherein aminated compounds isObtaining product is aubergine
Solid, yield 29%.
ESI-MS,m/z,[M+H+]calcd 382.1,found 382.2；1H NMR(300MHz,DMSO-d6)δ(ppm):
9.01 (s, 1H), 8.72 (s, 1H), 8.52 (d, J=4.0Hz, 1H), 8.15 (m, 1H), 8.03 (s, 1H), 7.93 (d, J=
7.7Hz, 1H), 7.44~7.39 (m, 2H), 6.69 (d, J=15.9Hz, 1H), 5.60 (s, 1H), 3.29~3.19 (m, 4H),
1.60~1.50 (m, 4H)
Embodiment 4
The preparation of compound P5:
According to logical method, wherein aminated compounds isIt is purplish red for obtaining product
Color solid, yield 35%.
ESI-MS,m/z,[M+H+]calcd 396.2,found 396.2；1H NMR(300MHz,DMSO-d6)δ(ppm):
9.02 (s, 1H), 8.73 (s, 1H), 8.54 (d, J=3.8Hz, 1H), 8.13 (m, 1H), 8.02 (m, 1H), 7.95 (d, J=
7.9Hz, 1H), 7.45~7.37 (m, 2H), 6.71 (d, J=15.9Hz, 1H), 5.59 (s, 1H), 3.22~3.17 (m, 4H),
1.63~1.59 (m, 2H), 1.50~1.47 (m, 2H), 1.34~1.30 (m, 2H)
Embodiment 5
The preparation of compound P6:
According to logical method, wherein aminated compounds isProduct is obtained as purple
Red solid, yield 37%.
ESI-MS,m/z,[M+H+]calcd 410.2,found 410.2；1H NMR(300MHz,DMSO-d6)δ(ppm):
9.01 (s, 1H), 8.72 (s, 1H), 8.52 (d, J=4.0Hz, 1H), 8.16 (m, 1H), 8.01 (m, 1H), 7.94 (d, J=
7.9Hz, 1H), 7.44~7.38 (m, 2H), 6.69 (d, J=15.9Hz, 1H), 5.56 (s, 1H), 3.20~3.15 (m, 4H),
1.57(m,2H),1.45(m,2H),1.32(m,4H).
Embodiment 6
The preparation of compound P7:
According to logical method, wherein aminated compounds isObtaining product is
Aubergine solid, yield 33%.
ESI-MS,m/z,[M+H+]calcd 424.2,found 424.2；1H NMR(300MHz,DMSO-d6)δ(ppm):
9.02 (s, 1H), 8.73 (s, 1H), 8.53 (d, J=3.9Hz, 1H), 8.13 (m, 1H), 8.02 (m, 1H), 7.95 (d, J=
7.9Hz, 1H), 7.45~7.40 (m, 2H), 6.71 (d, J=15.9Hz, 1H), 5.57 (s, 1H), 3.19~3.16 (m, 4H),
1.58 (m, 2H), 1.46 (m, 2H), 1.31~1.23 (m, 6H)
Embodiment 7
The preparation of compound P8:
According to logical method, wherein aminated compounds isObtain product
For aubergine solid, yield 27%.
ESI-MS,m/z,[M+Na+]calcd 461.2,found 461.2；1H NMR(300MHz,DMSO-d6)δ
(ppm): 9.03 (s, 1H), 8.74 (s, 1H), 8.54 (d, J=3.7Hz, 1H), 8.12 (m, 1H), 8.01~7.95 (m, 2H),
7.46~7.41 (m, 2H), 6.71 (d, J=15.9Hz, 1H), 5.57 (s, 1H), 3.18~3.13 (m, 4H), 1.58 (m, 2H),
1.45(m,2H),1.29(m,8H).。
The Pharmacological Testing Results of the compounds of this invention:
Experimental method: Sulforhodamine B (SRB) method measures IC50Value.Every hole is inoculated with 8000, MCF-7 cell in 96 orifice plates.
Administration time is 24 hours.Srb assay concrete operations are referring to Nature Protocols, 2006:1 (3)；1112-1116., as a result
It see the table below 1:
Inhibitory activity of 1 compound of table to MCF-7 breast cancer cell
| Compound numbers | IC50(μM) |
| P2 | 16.80 |
| P3 | 1.25 |
| P4 | 4.55 |
| P5 | 3.88 |
| P6 | 9.67 |
| P7 | 1.94 |
| P8 | 11.43 |
Claims (8)
1. benzothiazole quinones compound shown in general formula I or its pharmaceutically acceptable salt:
Wherein n is that 2~8, X is selected from-CH2,-NH- ,-O- or
R is selected from
2. compound according to claim 1 or its pharmaceutically acceptable salt, which is characterized in that the X is selected from-
NH- or
3. compound according to claim 1 or its pharmaceutically acceptable salt, which is characterized in that the R is selected from
4. compound according to claim 1 or its pharmaceutically acceptable salt, which is characterized in that the n is 3-7, R
It is selected fromX be selected from-NH- or
5. the preparation method of the described in any item compounds of claim 1-4, which is characterized in that organic solvent is molten as reaction
Agent, compound II and compound III, in the presence of a catalyst, room temperature reaction, after, extraction, silica gel post separation is to get arriving
Final product I, reaction equation are as follows:
Wherein, n, X and R are the same as described in claim 1.
6. the preparation method of compound according to claim 5, which is characterized in that the organic solvent is selected from anhydrous second
Alcohol；The catalyst is selected from cerous chloride.
7. a kind of pharmaceutical composition, which is characterized in that in the composition containing the described in any item compounds of claim 1-4 or
Its pharmaceutically acceptable salt and pharmaceutically acceptable auxiliary material.
8. claim 1-4 described in any item compounds or its pharmaceutically acceptable salt is in the preparation of antitumor drugs
Purposes.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113248490A (en) * | 2021-05-25 | 2021-08-13 | 泰州葛林美克医药科技有限公司 | Benzothiazole quinone compounds, preparation method and medical application thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113248490A (en) * | 2021-05-25 | 2021-08-13 | 泰州葛林美克医药科技有限公司 | Benzothiazole quinone compounds, preparation method and medical application thereof |
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