CN103044460A - 3,5,7-triphenyl-5H-thiazolo[3,2-a]pyrimidin derivatives and application thereof - Google Patents
3,5,7-triphenyl-5H-thiazolo[3,2-a]pyrimidin derivatives and application thereof Download PDFInfo
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Abstract
The invention discloses 3,5,7-triphenyl-5H-thiazolo[3,2-a]pyrimidin derivatives of the general formula I or pharmaceutically acceptable hydrates and salts thereof, including stereisomers or tautomers thereof, wherein R1, R2 and R3 can be optionally selected by one or two independently from hydrogen, hydroxyl, nitryl, acetyl, halogen, C1-C6 alkyls, C1-C6 alkoxyls, C1-C10 arbitrarily and selectively substituted amino alkoxyls and C1-C10 arbitrarily and selectively substituted or unsubstituted amino formacyl alkoxyls. The 3,5,7-triphenyl-5H-thiazolo[3,2-a]pyrimidin derivatives according to the invention have obvious inhibition effect on cyclin dependent kinases, thus the derivatives can be applied to treatment and prevention of various diseases such as cancers of human and animals.
Description
Technical field:
The invention belongs to medical technical field, relate to 3,5,7-triphenyl-5
H-thiazole is [3,2-a] pyridine derivatives and preparation method thereof and pharmaceutical use also.This series compound can specificity suppress the cell-cycle kinases activity, can be used for treating and preventing the various diseases such as malignant tumour of humans and animals.
Background technology:
Cancer great threat human health, antitumor research are to be rich in challenge and far reaching field in the current life science.At present, antitumor drug commonly used mainly is cytotoxic drug clinically, and this kind anti-cancer drugs has the poor selectivity, the toxic side effect that are difficult to avoid and by force, easily produces the shortcomings such as resistance.In recent years, along with the progress at full speed of life science, the signal transduction in the malignant cell, Control of cellcycle, apoptoticly induce, the various primary processes such as interaction of vasculogenesis and cell and extracellular matrix are progressively illustrated.As the drug screening target spot, find that selectively acting has become the important directions of current antitumor drug research and development in efficient, the low toxicity of specific target spot, the new type anticancer medicine of high specificity with the key enzyme of some intracellular signal transduction pathway relevant with the tumour cell differentiation and proliferation.
Because the further investigation of cell cycle regulation and control has found that approximately there is the CDK increased activity in 90% tumour, in people's tumour, CDK plays central role in the cell cycle, and the startup of leading cell cycle is carried out and finished.As the development of malignant cell, inherited genetic factors and rear formation mechanism all affect the expression of cell cycle regulating protein usually, cause the overexpression of cyclin and the forfeiture that the CDK inhibitor is expressed.Its follow-up effect is out of hand to the CDK activity, and CDK has the ganglion cell's of withering selective growth effect.Another characteristics of tumour are the regulation and control of the incomplete outpost of the tax office, cause the disappearance to cellular injury response.The blocking-up of cell cycle often occurs in G
l/ S or G
2/ M has a common boundary, and when the blocking-up control sustain damage of the outpost of the tax office, will start S phase and mitotic carrying out, and causes the damage of cell and the unstable of gene, may cause the generation of malignant clone.Yet the failure of this malignant cell Cycle block can be applied to again the treatment of tumour.Therefore the CDK inhibitor is the research and development focus of present target periodic signal albumen anti-cancer agent.
Compound of the present invention has the structure type novelty as the cell cycle kinase inhibitors of brand new type, and drug action and existing medicine quite or be better than the characteristics of existing medicine have good using value and development prospect.
Summary of the invention:
The object of the present invention is to provide a kind of 3,5,7-triphenyl-5
H-thiazole is [3,2-a] pyridine derivatives also.This compound is cell cycle kinase inhibitors, the special inhibition cell-cycle kinases of energy, and apoptosis is brought out in blocking-up cell proliferation.
Another object of the present invention is to provide above-mentioned 3,5,7-triphenyl-5
H-thiazole is the preparation method of [3,2-a] pyridine derivatives also.
It is above-mentioned 3,5 that a further object of the present invention is to provide, 7-triphenyl-5
H-thiazole is the purposes of [3,2-a] pyridine derivatives also.
Below describe the present invention.
The invention provides 3,5 of following general formula I, 7-triphenyl-5
H-thiazole is [3,2-a] pyridine derivatives or its pharmacologically acceptable salts also.Structure is seen Fig. 1.
Wherein, R
1, R
2And R
3Can select arbitrarily independently to be selected from hydrogen, hydroxyl, nitro, ethanoyl, halogen, C by 1 or 2
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
10Select arbitrarily aminoalkoxy and the C of replacement
1-C
10Select arbitrarily to replace or non-substituted formamyl alkoxyl group.
" pharmacy acceptable salt " referred to keep biopotency and the character of formula I compound, and the conventional acid additive salt or the base addition salt that form with suitable non-toxicity organic or inorganic acid or organic or inorganic alkali.The example of acid salt comprises acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, Citrate trianion, camphorate, camsilate, cipionate, digluconate, dodecyl sulfate, esilate, fumarate, gluceptate, glycerophosphate, Hemisulphate, enanthate, hexanoate, hydrogen chlorate, hydrobromate, hydriodate, the 2-isethionate, lactic acid salt, maleate, mesylate, the 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinic acid salt, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, vitriol, tartrate, thiocyanate-, tosylate and undecylate.Alkali salt comprises ammonium salt, an alkali metal salt, for example sodium and sylvite, alkaline earth salt, for example calcium and magnesium salts, the salt of organic bases, dicyclohexyl amine salt for example, N-methyl-D-glucamine salt, and amino acid whose salt, arginine for example, Methionin etc., and, the alkalescence nitrogen-containing group can be quaternized with such reagent, and elementary alkyl halide for example is such as methyl, ethyl, the chlorine of propyl group and butyl, bromine and iodide; The sulfuric acid dialkyl, such as methyl-sulfate, diethyl ester, dibutylester and diamyl ester; Long-chain halogenide, such as decyl, lauryl, the chlorine of myristyl and stearyl-, bromine and iodide; Aralkyl halide is such as bromide of benzyl and styroyl etc.The acid that is preferred for generating acid salt comprises hydrochloric acid and acetic acid.
" pharmaceutically acceptable " such as pharmaceutically acceptable ground carrier, excipient, prodrug etc., refers to acceptable on the pharmacology and to the essentially no toxicity of the patient of administration particular compound.
The present invention also provides the preparation method of above-mentioned compound of Formula I, and the method is seen Fig. 2.
One species specificity 3,5,7-triphenyl-5
H-thiazole is the purposes of [3,2-a] pyridine derivatives also, it is characterized in that this compound is can special inhibition cell-cycle kinases active, brings out apoptosis, is used for the treatment of and prevents malignant tumour and other disease, is applicable to simultaneously humans and animals.
The tumour of indication comprises various leukemia and various solid tumor.
In use, can be single therapy, can also be combination therapy, combination therapy can be and other chemotherapy coupling, can also with the herbal medicine coupling, or with operation, radiotherapy, immunotherapy, hormonotherapy, the couplings such as gene therapy.
Described Other diseases mainly includes, but are not limited to senile dementia, cardiovascular disorder and acquired immune deficiency syndrome (AIDS) etc.
The invention still further relates to the measuring method that formula I suppresses cell-cycle kinases 1 activity.
The present invention also relates to the measuring method of formula I anti tumor activity in vitro.
Description of drawings
Fig. 1 is 3,5,7-triphenyl-5
H-thiazole is the general structure figure of [3,2-a] pyridine derivatives also;
Fig. 2 is 3,5,7-triphenyl-5
H-thiazole is the synthetic route chart of [3,2-a] pyridine derivatives also;
Fig. 3 is sample segment cell-cycle kinases 1 inhibiting active as a result figure;
Fig. 4 is the as a result figure of sample segment anti tumor activity in vitro.
Further illustrate the present invention by following examples, but should notice that scope of the present invention is not subjected to any restriction of these embodiment.
Specific embodiment
Embodiment 1
4,6-phenylbenzene-3, the preparation of 4-dihydro-pyrimidin-2 (1H)-thioketones
Add phenyl aldehyde 0.1 mol, thiocarbamide 0.1 mol, methyl phenyl ketone 0.11 mol, trimethylchlorosilane 0.1mol in the round-bottomed flask of 250 ml, acetonitrile 30 mL stir back flow reaction 10 h.Cooling, suction filtration, filter cake dehydrated alcohol recrystallization obtains yellow crystals 21.5 grams, yield 81%.MS?m/z?(M)?266。
Embodiment 2
4-(4-hydroxy phenyl)-6-phenyl-3, the preparation of 4-dihydro-pyrimidin-2 (1H)-thioketones
Add p-Hydroxybenzaldehyde 0.1 mol, thiocarbamide 0.1 mol, methyl phenyl ketone 0.11 mol, trimethylchlorosilane 0.1mol in the round-bottomed flask of 250 ml, acetonitrile 30 mL stir back flow reaction 10 h.Cooling, suction filtration, filter cake dehydrated alcohol recrystallization obtains yellow crystals 23.5 grams, yield 83.3%.MS?m/z?(M)?282。
Embodiment 3
4-(4-chloro-phenyl-)-6-phenyl-3, the preparation of 4-dihydro-pyrimidin-2 (1H)-thioketones
Add 4-chloro-benzaldehyde 0.1 mol, thiocarbamide 0.1 mol, methyl phenyl ketone 0.11 mol, trimethylchlorosilane 0.1mol in the round-bottomed flask of 250 ml, acetonitrile 30 mL stir back flow reaction 10 h.Cooling, suction filtration, filter cake dehydrated alcohol recrystallization obtains yellow crystals 25.4 grams, yield 84.7%.MS?m/z?(M)?300。
Embodiment 4
3,5,7-triphenyl-5
H-thiazole also [3,2-a] pyrimidine (
L1) preparation
With 4,6-phenylbenzene-3,4-dihydro-pyrimidin-2 (1H)-thioketones 2.66 g (10 mmol), chloroacetophenone 1.54 g (10 mmol), sodium-acetate/Glacial acetic acid (2 g/20 mL), heating reflux reaction 8-24 hour, TLC monitoring reaction.After the cooling, suction filtration, the dehydrated alcohol recrystallization gets 2.56 g white powders, yield 69.9 %.MS：?366；
1H-NMR(300MHz，DMSO)δ(ppm)：?4.71(1H,?d)，6.74(H,?s)，6.94(H,?s)，7.26-7.68(15H，m)。
Embodiment 5
3,7-phenylbenzene-5-(4-hydroxy phenyl)-5
H-thiazole also [3,2-a] pyrimidine (
L2) preparation
With 4-(4-hydroxy phenyl)-6-phenyl-3,4-dihydro-pyrimidin-2 (1H)-thioketones 2.82 g (10 mmol), chloroacetophenone 1.54 g (10 mmol), sodium-acetate/Glacial acetic acid (2 g/20 mL), heating reflux reaction 8-24 hour, the TLC monitoring reaction.After the cooling, suction filtration, the dehydrated alcohol recrystallization gets 2.45 g white powders, yield 64.1 %.MS：382；
1H-NMR(300MHz，DMSO)δ(ppm)：4.71(1H，d)，6.73(H，s)，6.91(H，s)，6.73(2H,?d,?
J=8.7)，7.15(2H,?d,?
J=8.7)，7.31-7.84(10H，m)，9.?01?(H，s)。
Embodiment 6
3,7-phenylbenzene-5-(4-chloro-phenyl-)-5
H-thiazole also [3,2-a] pyrimidine (
L3) preparation
With 4-(4-chloro phenyl)-6-phenyl-3,4-dihydro-pyrimidin-2 (1H)-thioketones 3.00 g (10 mmol), chloroacetophenone 1.54 g (10 mmol), sodium-acetate/Glacial acetic acid (2 g/20 mL), heating reflux reaction 8-24 hour, the TLC monitoring reaction.After the cooling, suction filtration, the dehydrated alcohol recrystallization gets 2.95 g white powders, yield 73.7 %.MS：400；
1H-NMR(300MHz，DMSO)δ(ppm)：4.71(1H，?d)，6.71(H，s)，6.96(H，s)，7.31-7.55(10H，m)，7.56(2H,?d,?
J=8.4)，7.75(2H,?d,?
J=8.4)。
Embodiment 7
3-(4-hydroxy phenyl)-5-(4-hydroxy phenyl)-7-phenyl-5
H-thiazole also [3,2-a] pyrimidine (
L4) preparation
With 4-(4-hydroxy phenyl)-6-phenyl-3,4-dihydro-pyrimidin-2 (1H)-thioketones 2.82 g (10 mmol), 4-hydroxyl chloroacetophenone 1.70 g (10 mmol), sodium-acetate/Glacial acetic acid (2 g/20 mL), heating reflux reaction 8-24 hour, the TLC monitoring reaction.After the cooling, suction filtration, the dehydrated alcohol recrystallization gets 3.13 g white powders, yield 78.6 %.MS：398；
1H-NMR(300MHz，DMSO)δ(ppm)：?4.71(1H，d)，6.74(H，s)，6.84(H，s)，6.93(2H，d，
J=8.4Hz)，7.14(2H，d，
J=8.4Hz)，7.28(2H，d，
J=8.4Hz)，7.33(2H，d，
J=8.4Hz)，7.34-7.57(5H，m)。
Embodiment 8
3-(4-hydroxy phenyl)-5-(4-chloro phenyl)-7-phenyl-5
H-thiazole also [3,2-a] pyrimidine (
L5) preparation
With 4-(4-chloro-phenyl-)-6-phenyl-3,4-dihydro-pyrimidin-2 (1H)-thioketones 3.00 g (10 mmol), 4-hydroxyl chloroacetophenone 1.70 g (10 mmol), sodium-acetate/Glacial acetic acid (2 g/20 mL), heating reflux reaction 8-24 hour, the TLC monitoring reaction.After the cooling, suction filtration, the dehydrated alcohol recrystallization gets 2.98 g white powders, yield 71.6 %.MS：416；
1H-NMR(300MHz，DMSO)δ(ppm)：?4.70(1H，d)，6.67(2H，d，
J=8.4Hz)，6.73(H，s)，6.93(2H，d，
J=8.4Hz)，6.94(H，s)，7.14(2H，d，
J=8.4Hz)，7.24-7.47(5H，m)，7.53(2H，d，
J=8.4Hz)。
Embodiment 9
3-(4-hydroxy phenyl)-5-(4-chloro phenyl)-7-phenyl-5
H-thiazole also [3,2-a] pyrimidine (
L6) preparation
With 4-(4-chloro-phenyl-)-6-phenyl-3,4-dihydro-pyrimidin-2 (1H)-thioketones 3.00 g (10 mmol), 4-chlorine chloroacetophenone 1.87 g (10 mmol), sodium-acetate/Glacial acetic acid (2 g/20 mL), heating reflux reaction 8-24 hour, the TLC monitoring reaction.After the cooling, suction filtration, the dehydrated alcohol recrystallization gets 3.12 g white powders, yield 71.7 %.MS：434；
1H-NMR(300MHz，DMSO)δ(ppm)：?4.68(1H，d)，?6.73(H，s)，?6.93(H，s)，7.24(2H，d，
J=8.4Hz)，7.33(2H，d，
J=8.4Hz)，?7.34-7.47(5H，m)，?7.51(2H，d，
J=8.4Hz)，7.65(2H，d，
J=8.4Hz)。
Embodiment 10
The active determination test of cell-cycle kinases enzyme inhibitors
Method: CDK1/cyclin B suppresses activity and adopts CycLex CDK1/cyclinB kinases assay kit institute calibration method to measure: each sample ligand is made three kinds of different concns (3 * 10
-6, 3 * 10
-7With 3 * 10
-8Mol/L), add respectively in 96 orifice plates, 10 μ L/ holes are hatched 30 min, are washed with damping fluid for 30 ℃; Every hole adds the Cdc7 T376 monoclonal antibody TK-3H7 of the anti-phosphorylation of 100 μ L, and incubated at room 30 min wash with damping fluid; Every hole adds the anti-mouse IgG of the HRP combination of 100 μ L again, incubated at room 30min, and wash with damping fluid: every hole adds 100 substrate reagents, incubated at room 5-15min, every hole adds 100 again and ends liquid, then surveys absorption value in 450 nm wavelength, compare with the optical density value of blank, calculate IC
50Value.
The result: compound L 1, L4, L5 and L6 all have preferably restraining effect to CDK1, and its activity data is seen Fig. 3.
Embodiment 11
Mtt assay (tetramethyl-azo azoles blue laws) is measured the anti tumor activity in vitro of part of compounds
Method: compound is dissolved with dimethyl sulfoxide (DMSO) (DMSO), dilution, tumour cell HL60, SMMC-7721, HCT-l16, A549 plant 4000/200 μ L/holes at 96 orifice plates, and every hole adds compound 2 μ L, and final concentration is 12.0,6.0,3.0,1.5 μ molL
-1, jointly in 37 ℃, 5%CO
2Hatch 72 h in the cell culture incubator, be blank .72 h with DMSO (1%, volume fraction) after, adding people's final concentration is 0.25 mgmL
-1MTT, place 37 ℃, 5%CO
24 h in the cell culture incubator blot solvent afterwards, and every hole adds 100 μ L DMSO, measure absorbancy (OD value) in the 570nm place with the enzyme linked immunological instrument, and the data obtained is used for calculating IC
50
The result:
Compound L 1, L2, L3, L4 and L5 see Fig. 4 to the anti tumor activity in vitro experimental result of HL60, SMMC-7721, these 4 kinds of cell strains of HCT-116, A549. experimental result shows, compound L 1, L2, L3, L4 all has stronger restraining effect with L5 to 4 kinds of different tumor cell lines, and wherein the restraining effect of 5 pairs of HL60 cell strains of compound L is the strongest, IC
50Value reaches 0.15 μ mol/L, illustrates that it has stronger restraining effect to tumour cell.
Claims (8)
1. has 3,5 of general formula I, 7-triphenyl-5
H-thiazole is [3,2-a] pyridine derivatives or the acceptable hydrate of its pharmacy, salt also, comprises its steric isomer or tautomer, it is characterized in that it has the general formula of I,
Wherein, R
1, R
2And R
3Can select arbitrarily independently to be selected from hydrogen, hydroxyl, nitro, ethanoyl, halogen, C by 1 or 2
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
10Select arbitrarily aminoalkoxy and the C of replacement
1-C
10Select arbitrarily to replace or non-substituted formamyl alkoxyl group.
2. a pharmaceutical composition comprises as any one compound in the claim 1 of activeconstituents and medicine acceptable carrier or excipient.
3. described this analog derivative according to claim 1 is characterized in that: R
1Preferred hydroxyl.
4. described this analog derivative according to claim 1 is characterized in that: R
2Preferred chlorine.
5. described this analog derivative according to claim 1 is characterized in that: R wherein
3Preferred 4-[2-(1-piperidines) oxyethyl group].
6. a species specificity 3,5,7-triphenyl-5
H-thiazole is the purposes of [3,2-a] pyridine derivatives also, it is characterized in that this compound is can special inhibition cell-cycle kinases active, brings out apoptosis, is used for the treatment of and prevents malignant tumour and other disease, is applicable to simultaneously humans and animals.
7. purposes according to claim 6 is characterized in that the tumour of indication comprises various leukemia and various solid tumor; Other diseases mainly comprises senile dementia, cardiovascular disorder and acquired immune deficiency syndrome (AIDS).
8. purposes according to claim 6 is characterized in that in use, can be single therapy, can also be combination therapy, combination therapy can be and other chemotherapy coupling, can also with the herbal medicine coupling, or with operation, radiotherapy, immunotherapy, hormonotherapy, the couplings such as gene therapy.
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| CN104844628A (en) * | 2015-04-16 | 2015-08-19 | 石家庄学院 | 2H,6H-pyrimido[2,1-b][1,3]thiazine derivative and application thereof |
| CN107235994A (en) * | 2017-08-16 | 2017-10-10 | 石家庄学院 | The simultaneously acetamide derivative of [3,2 a] pyrimidine 3 and the application of 5,7 diphenyl 5H thiazoles |
| CN107501299A (en) * | 2017-09-06 | 2017-12-22 | 石家庄学院 | The simultaneously carboxamides derivatives of [3,2 a] pyrimidine 2 and the application of 5,7 diphenyl 5H thiazoles |
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| CN107235994A (en) * | 2017-08-16 | 2017-10-10 | 石家庄学院 | The simultaneously acetamide derivative of [3,2 a] pyrimidine 3 and the application of 5,7 diphenyl 5H thiazoles |
| CN107501299A (en) * | 2017-09-06 | 2017-12-22 | 石家庄学院 | The simultaneously carboxamides derivatives of [3,2 a] pyrimidine 2 and the application of 5,7 diphenyl 5H thiazoles |
| CN107501299B (en) * | 2017-09-06 | 2019-07-16 | 石家庄学院 | Simultaneously [3,2-a] pyrimidine -2- carboxamides derivatives and the application of 5,7- diphenyl -5H- thiazole |
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