CN107556309A - Medicinal usage of polysubstituted Tetrahydronaphthyridderivates class compound and preparation method thereof - Google Patents
Medicinal usage of polysubstituted Tetrahydronaphthyridderivates class compound and preparation method thereof Download PDFInfo
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Abstract
The present invention provides the medicinal usage and preparation method of the following polysubstituted Tetrahydronaphthyridderivates class compound of structural formula.
Description
Technical field
The invention belongs to use of a compound, it is related to medicinal usage and the preparation side of new polysubstituted Tetrahydronaphthyridderivates class compound
Method, more particularly to polysubstituted Tetrahydronaphthyridderivates class compound is in application of anti-tumor aspect and preparation method thereof.
Background technology
Malignant tumour is that current serious influences one of human health, the principal disease for threatening human life.Cancer and heart and brain
Vascular diseases and contingency together, form the three big cause of death of world today's All Countries.Therefore, World Health Organization and each
Hygiene department of government of state is all classified as a top priority cancer is captured.So the exploitation of antineoplastic have it is extremely important
Social effect and application value.
Naphthyridine type compound has extensive bioactivity and pharmacological activity.Meanwhile naphthyridine type compound still prepares it
The important intermediate of its heterocyclic compound.Therefore, studying the application in terms of polysubstituted Tetrahydronaphthyridderivates class compound antitumor has
Significance.
The content of the invention
It is an object of the invention to provide a kind of new polysubstituted Tetrahydronaphthyridderivates class compound in antineoplastic is prepared
Using the especially application in leukaemia caused by lung cancer caused by anti-cell strain A549 and cell line HL-60.It is described to take more
It is for Tetrahydronaphthyridderivates class compound formula：
Wherein, R is phenyl, 4- aminomethyl phenyls, 4- fluorophenyls or 4- chlorphenyls, it is characterised in that polysubstituted Tetrahydronaphthyridderivates
Application of the class compound in anti-lung cancer and leukaemia.
The polysubstituted Tetrahydronaphthyridderivates class compound is compound I-1, I-2, I-3 or I-4, as follows：
The application of wherein described compound I-1, I-3 and I-4 suitable for lung cancer caused by anti-cell strain A549.Compound
Applications of the I-2 suitable for leukaemia caused by anti-cell strain HL-60.
New polysubstituted Tetrahydronaphthyridderivates class compound of the present invention is with N- methyl-pi -2- ketone, R-CHO, ammonium acetate
It is raw material with malononitrile, is synthesized through one kettle way condensation reaction.Synthetic route is as follows：
New polysubstituted Tetrahydronaphthyridderivates class compound provided by the invention is respectively provided with good antitumor activity, thin to tumour
Born of the same parents' strain A549 and HL-60 are shown to be acted on compared with high inhibition, is laid a good foundation for new medicament screen and exploitation, has cheap, original
Material is easy to get, be adapted to industrialized production the advantages that, there is preferable practical value.
Embodiment
The invention will be further described by way of example below, provides the implementation detail of the present invention, but the present invention is simultaneously
It is not limited solely to the technical scheme that following examples are provided.
Method therefor is conventional method unless otherwise instructed in the following example.Material required in following examples
Material or reagent, are that market is bought unless otherwise specified.
Embodiment 1
Compound I-1 preparation：
N- methyl-pi -2- ketone 113g (1mol), benzaldehyde 212g (2mol), ammonium acetate are sequentially added in single port bottle
77g (1mol), malononitrile 66g (1mol) and trifluoromethanesulfonic acid 15g, it is warming up to 100 DEG C of reaction 5h.Reaction is finished, and is down to room temperature, according to
Secondary addition ethyl acetate 1000mL and water 500mL, organic layer is taken, add saturated sodium bicarbonate solution 500mL washings, take organic
Layer, with anhydrous sodium sulfate drying, filtering, 200mL is concentrated into, crystallization is stirred at room temperature and obtains compound I-1 303g, yield 86%.1H
NMRδ:7.40 (m, 11H), 5.23 (brs, 2H), 3.21 (s, 3H), 3.15 (t, J=7.0Hz, 2H), 2.13 (t, J=7.0Hz,
2H).
Embodiment 2
Compound I-2 preparation：
Sequentially added in single port bottle N- methyl-pi -2- ketone 113g (1mol), p-tolyl aldehyde 240g (2mol),
Ammonium acetate 77g (1mol), malononitrile 66g (1mol) and trifluoromethanesulfonic acid 15g, it is warming up to 100 DEG C of reaction 5h.Reaction is finished, and is down to
Room temperature, ethyl acetate 1000mL and water 500mL are sequentially added, take organic layer, add saturated sodium bicarbonate solution 500mL washings,
Organic layer is taken, with anhydrous sodium sulfate drying, filtering, 200mL is concentrated into, crystallization is stirred at room temperature and obtains compound I-2 274g, yield
72%.1H NMRδ:7.42 (m, 9H), 5.01 (brs, 2H), 3.21 (s, 3H), 3.15 (t, J=7.0Hz, 2H), 2.34 (s,
6H), 2.13 (t, J=7.0Hz, 2H)
Embodiment 3
Compound I-3 preparation：
N- methyl-pi -2- ketone 113g (1mol), 4-Fluorobenzaldehyde 248g (2mol), second are sequentially added in single port bottle
Sour ammonium 77g (1mol), malononitrile 66g (1mol) and trifluoromethanesulfonic acid 15g, it is warming up to 100 DEG C of reaction 5h.Reaction is finished, and is down to room
Temperature, ethyl acetate 1000mL and water 500mL are sequentially added, take organic layer, added saturated sodium bicarbonate solution 500mL washings, take
Organic layer, with anhydrous sodium sulfate drying, filtering, 200mL is concentrated into, crystallization is stirred at room temperature and obtains compound I-3 291g, yield
75%.1H NMRδ:7.47 (m, 9H), 5.16 (brs, 2H), 3.21 (s, 3H), 3.12 (t, J=7.0Hz, 2H), 2.11 (t, J
=7.0Hz, 2H)
Embodiment 4
Compound I-4 preparation：
N- methyl-pi -2- ketone 113g (1mol), 4-chloro-benzaldehyde 280g (2mol), second are sequentially added in single port bottle
Sour ammonium 77g (1mol), malononitrile 66g (1mol) and trifluoromethanesulfonic acid 15g, it is warming up to 100 DEG C of reaction 5h.Reaction is finished, and is down to room
Temperature, ethyl acetate 1000mL and water 500mL are sequentially added, take organic layer, added saturated sodium bicarbonate solution 500mL washings, take
Organic layer, with anhydrous sodium sulfate drying, filtering, 200mL is concentrated into, crystallization is stirred at room temperature and obtains compound I-4 307g, yield
73%.1H NMRδ:7.43 (m, 9H), 5.11 (brs, 2H), 3.20 (s, 3H), 3.10 (t, J=7.0Hz, 2H), 2.05 (t, J
=7.0Hz, 2H)
Embodiment 5
Anti- A549 tumour cells biological activity test
Anti tumor activity in vitro method of testing：
1st, preparation of samples：Compound I-1, I-2, I-3 and I-4 obtained by Example 1-4, it is molten with 20 μ L DMSO per 1mg
Solution, takes 2 μ L to be diluted with 1000 μ L nutrient solutions, and it is 100 μ g/mL to make concentration, then with nutrient solution serial dilution to concentration.
2nd, the culture of cell
The preparation of culture medium：Contain 800,000 units of Penicillin, 1.0g streptomysins, 10% inactivation tire ox in per 1000mL culture mediums
Serum；
The culture of cell：By A549 tumor cell inoculations in culture medium, 37 DEG C are placed in, 5%CO25 are cultivated in incubator
Its passage.
3rd, inhibitory action of the determination sample to growth of tumour cell
Cell is digested with EDTA- tryptic digestive juices, and 1 × 10 is diluted to culture medium5/ mL, it is thin to be added to 96 holes
In born of the same parents' culture plate, per the μ L of hole 100,37 DEG C are put, 5%CO2Cultivated in incubator.After being inoculated with 24h, sample that addition is diluted with culture medium
Product, per the μ L of hole 100, each concentration adds 3 holes, puts 37 DEG C, 5%CO2Cultivated in incubator.Added after 72h in cell culture well
5mg/mL MTT, per the μ L of hole 10,37 DEG C of incubation 4h are put, add DMSO, per the μ L of hole 150, shaken well, with ELIASA in 570nm
Colorimetric under wavelength, with blank control of the similarity condition without sample, the cell of the medium culture containing same concentration DMSO is made
For control, LC50 (IC of the sample to growth of tumour cell is calculated50)。
In addition, choosing medicine carboplatin as control, anti tumor activity in vitro method of testing is carried out as stated above and is surveyed
Examination.As a result it is as shown in table 1：
IC of the compound of table 1 to A549 tumour cells50(μg/mL)
| Embodiment | Compound | IC50 |
| 1 | I-1 | 7.21 |
| 2 | I-2 | >100 |
| 3 | I-3 | 9.11 |
| 4 | I-4 | 5.25 |
| Compare medicine | Carboplatin | 5.11 |
Shown according to result, compound I-1, I-3 and I-4 have significant inhibitory activity to A549 tumour cells.
Embodiment 6
Anti- HL-60 tumour cells biological activity test
Anti tumor activity in vitro method of testing：
4th, preparation of samples：Compound I-1, I-2, I-3 and I-4 obtained by Example 1-4, dissolved per 1mg with 20 μ LDMSO,
2 μ L are taken to be diluted with 1000 μ L nutrient solutions, it is 100 μ g/mL to make concentration, then with nutrient solution serial dilution to concentration.
5th, the culture of cell
The preparation of culture medium：Contain 800,000 units of Penicillin, 1.0g streptomysins, 10% inactivation tire ox in per 1000mL culture mediums
Serum；
The culture of cell：By HL-60 tumor cell inoculations in culture medium, 37 DEG C are placed in, 5%CO25 are cultivated in incubator
Its passage.
6th, inhibitory action of the determination sample to growth of tumour cell
Cell is digested with EDTA- tryptic digestive juices, and 1 × 10 is diluted to culture medium5/ mL, it is thin to be added to 96 holes
In born of the same parents' culture plate, per the μ L of hole 100,37 DEG C are put, 5%CO2Cultivated in incubator.After being inoculated with 24h, sample that addition is diluted with culture medium
Product, per the μ L of hole 100, each concentration adds 3 holes, puts 37 DEG C, 5%CO2Cultivated in incubator.Added after 72h in cell culture well
5mg/mL MTT, per the μ L of hole 10,37 DEG C of incubation 4h are put, add DMSO, per the μ L of hole 150, shaken well, with ELIASA in 570nm
Colorimetric under wavelength, with blank control of the similarity condition without sample, the cell of the medium culture containing same concentration DMSO is made
For control, LC50 (IC of the sample to growth of tumour cell is calculated50)。
In addition, choosing medicine cytarabine as control, anti tumor activity in vitro method of testing is carried out as stated above and is entered
Row test.As a result it is as shown in table 2：
IC of the compound of table 2 to HL-60 tumour cells50(μg/mL)
| Embodiment | Compound | IC50 |
| 1 | I-1 | >100 |
| 2 | I-2 | 2.59 |
| 3 | I-3 | >50 |
| 4 | I-4 | >50 |
| Compare medicine | Cytarabine | 3.59 |
Shown according to result, compound I-2 has to HL-60 tumour cells significantly inhibits effect.
After the explanation of this method has been read, those skilled in the art can make various changes or modification to the present invention,
These equivalent form of values equally fall within the application appended claims and limit scope.
Claims (7)
1. application of the polysubstituted Tetrahydronaphthyridderivates class compound in antineoplastic is prepared, the polysubstituted Tetrahydronaphthyridderivates class chemical combination
Thing formula is：
Wherein, R is phenyl, 4- aminomethyl phenyls, 4- fluorophenyls or 4- chlorphenyls.
2. application according to claim 1, it is characterised in that：The polysubstituted Tetrahydronaphthyridderivates class compound is compound I-
1st, I-2, I-3 or I-4, it is as shown below：
3. the preparation method of polysubstituted Tetrahydronaphthyridderivates class compound described in claim 1, it is characterised in that：With N- methyl-pis-
2- ketone, R-CHO, ammonium acetate and malononitrile are raw material, are synthesized through one kettle way condensation reaction, and synthetic route is as follows：
Wherein, R is phenyl, 4- aminomethyl phenyls, 4- fluorophenyls or 4- chlorphenyls.
4. polysubstituted Tetrahydronaphthyridderivates class compound is preparing the application in treating leukemia tumor medicine.
5. application according to claim 4, it is characterised in that：The polysubstituted Tetrahydronaphthyridderivates class compound is compound I-
2, it is as shown below：
6. application of the polysubstituted Tetrahydronaphthyridderivates class compound in lung cancer tumor medicine is treated.
7. application according to claim 6, it is characterised in that：The polysubstituted Tetrahydronaphthyridderivates class compound is compound I-
1st, I-3 and I-4, it is as shown below：
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Citations (7)
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| WO2005021546A1 (en) * | 2003-08-22 | 2005-03-10 | Avanir Pharmaceuticals | Substituted naphthyridine derivatives as inhibitors of macrophage migration inhibitory factor and their use in the treatment of human diseases |
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| WO2009100130A1 (en) * | 2008-02-04 | 2009-08-13 | Mercury Therapeutics, Inc. | Ampk modulators |
| US20110038835A1 (en) * | 2007-12-21 | 2011-02-17 | The Scripps Research Institute | Anilides and analogs as rho kinase inhibitors |
| CN102026671A (en) * | 2008-03-14 | 2011-04-20 | Visen医药公司 | Integrin targeting agents and in-vivo and in-vitro imaging methods using the same |
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2017
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| WO2005021546A1 (en) * | 2003-08-22 | 2005-03-10 | Avanir Pharmaceuticals | Substituted naphthyridine derivatives as inhibitors of macrophage migration inhibitory factor and their use in the treatment of human diseases |
| CN101405286A (en) * | 2006-01-17 | 2009-04-08 | 先灵公司 | Hydantoin derivatives for the treatment of inflammatory disorders |
| US20110038835A1 (en) * | 2007-12-21 | 2011-02-17 | The Scripps Research Institute | Anilides and analogs as rho kinase inhibitors |
| WO2009100130A1 (en) * | 2008-02-04 | 2009-08-13 | Mercury Therapeutics, Inc. | Ampk modulators |
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