CN110143964A - Tryptamines ketone derivatives and its pharmaceutical usage - Google Patents
Tryptamines ketone derivatives and its pharmaceutical usage Download PDFInfo
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Abstract
Tryptamines ketone derivatives and pharmaceutical usage, chemical formula is as described in following formula:
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to couroupitine A new derivative and its pharmaceutical usage.
Background technique
(structure is shown in formula I, entitled indoles [2,1-b] quinazoline -6, the 12- diketone (indolo [2,1-b] of chemistry to couroupitine A
Quinazolin-6,12-dione), it is present in acanthaceous indigo (Strobilanthes cusia), indigo plant (Polygonum
Tinctorum Lour) and the plants such as woaded blue (Isatis Einetorial) in and Chinese medicine indigo naturalis and folium isatidis it is main at
/ mono-.Couroupitine A and its derivative have the effects that good anticancer, anti-inflammatory and antibacterial.
Couroupitine A content in plant is seldom, main to be obtained by synthesis.The biology that this seminar has studied couroupitine A closes
It at approach, and has investigated easy synthetic method: existing using istain and derivative and isatoic anhydride and its derivative as raw material
Under triethylamine alkaline condition, the 3h that flows back in chloroform or dichloromethane solvent synthesizes couroupitine A and its derivative.Istain spreads out
Biological commercial source is easier to, and can also pass through the derivative of Sandmeyer method synthesis of indole quinone.However, isatoic anhydride derivative is not
It is easy to get to thus couroupitine A 1-4 bit derivant is more difficult to get.
Summary of the invention
To overcome above-mentioned the deficiencies in the prior art, the purpose of the present invention is to provide couroupitine A new derivative and its medicinal use
On the way, couroupitine A structure is simple, and bioactivity is extensive, and structural modification is carried out to it and transformation is possible to discovery activity more preferably, biology
Availability is high, it is possible to which therefore the new derivative of patent medicine is the ideal lead compound in medicament research and development.Although it has been reported that
Synthesis and antitumor, the antibacterial isoreactivity of a large amount of couroupitine A and its derivative, but listed so far without relevant drug,
In order to find the better couroupitine A new derivative of bioactivity, to provide basis for new drug development；The object of the invention is to
There is provided new has antitumor tryptamines ketone derivatives；The present invention has synthesized a system using the synthesis technology that this seminar develops
Column couroupitine A new derivative, synthesized couroupitine A new derivative have the preferable activity for inhibiting tumor cell line.
To achieve the above object, the technical solution adopted by the present invention is that: tryptamines ketone derivatives, chemical formula such as following formula institute
Show:
Wherein, R1, R2For substituent group independent on the position 1-4, R2For substituent group independent on the position 7-10；R1, R2
=halogen, alkyl, one or more of alkoxy.
Tryptamines ketone derivatives, chemical formula are as shown in Equation 1:
Tryptamines ketone derivatives are selected from following compound:
Tryptamines ketone derivatives are selected from following compound:
The tryptamines ketone derivatives are the pharmaceutical composition of active constituent.
The tryptamines ketone derivatives are the pharmaceutical preparation of bulk pharmaceutical chemicals.
Application of the tryptamines ketone derivatives in preparation tumor.
The pharmaceutical preparation is tablet, capsule, granule, pill, micropill preparation, oral solution, liquid drugs injection, infusion
Agent, powder-injection.
The capsule uses soft capsule.
The powder-injection is adopted as freeze drying powder injection.
The synthetic method of tryptamines ketone derivatives:
Weigh Isatine derivatives, isatoic anhydride derivative (Isatine derivatives: isatoic anhydride derivative=1:1.05, substance
Amount ratio) be added in the 100ml three-necked bottle equipped with magneton, then into three-necked bottle be added 40ml chloroform, tri- second of 1.5ml
Amine is heated to reflux 3h at 80 DEG C of oil bath, after reaction, stops heating, to be cooled, suction filtration obtains crude material yellow solid powder
End, product obtain purified product with 10ml ethanol washing 3 times, and drying, weighing calculate yield.
Tryptamines ketone derivatives 1a-1n. has been synthesized with the method
Pharmaceutical composition is formed as active constituent using obtained compound, or is prepared into pharmaceutical preparation.
The active testing of tryptamines ketone derivatives:
Human colon cancer cell strain HCT-116 (lung cancer cell types, mouse pheochromocytoma cells in logarithmic growth phase
Strain PC12, mice embryonic pre-osteoblast MC-3T3-E1) cell is seeded in 96 well culture plates by proper density, put
It is placed in 5%CO2, in 37 DEG C of constant incubators.After overnight incubation, according to 100 μM, 50 μM, 25 μM, 12.5 μM, 6.25 μM,
3.125 μM and 1.56 μM of 7 concentration, the 3 repeating hole dosings of each concentration, and blank control is set, DMSO control is added afterwards for 24 hours
The MTT (20 hole μ L/) of 5mg/mL continues to cultivate 4.0h.Culture supernatant is discarded, DMSO (200 hole μ L/) then is added, with enzyme mark
Instrument measures every hole absorbance value in 490nm, calculates to inhibition rate of tumor cell.
Use the inhibiting rate (%) that compound on tumor cell growth is calculated with following equation:
Cell inhibitory rate=(experimental group OD value-DMSO control group OD value)/blank control group OD value × 100%；Then it adopts
IC50 value is calculated with SPSS 19.0.
Compound preferable for preliminary experiment inhibitory activity further adjusts concentration in 20 μm of ol/l, 10 μm of ol/l, 5 μ
Mol/l, 2.5 μm of ol/l, 1.25 μm of ol/l, 0.625 μm of ol/l gradient concentration are tested.
With anticancer drug Gefitinib (gefitinib, GFTN) and taxol (Taxol) for positive control.
The beneficial effects of the present invention are:
The present invention has designed and synthesized a series of couroupitine A new derivatives, and simple synthetic method, using mtt assay to newization
It closes object and carries out Preliminary activation experiment, new derivative has the function of preferably inhibiting tumour cell than couroupitine A, in tumour medicine
Aspect has potential development prospect.
Specific embodiment
The present invention is further explained in the light of specific embodiments.
Tryptamines ketone derivatives, have the following structure general formula:
Wherein, R1, R2For substituent group independent on the position 1-4, R2For substituent group independent on the position 7-10.R1, R2
=halogen, alkyl, one or more of alkoxy, the compound specifically protected are as follows:
Work as R1=2-Cl, R2=7-Cl, the couroupitine A new derivative are derivative 1a described in formula 1；
Work as R1=2-Cl, R2=9-Cl, the couroupitine A new derivative are derivative 1b described in formula 2:
Work as R1=2-Cl, R2=9-Br, the couroupitine A new derivative is derivative 1c described in formula 3:
Work as R1=2-Cl, R2=8-OCF3, the couroupitine A new derivative is derivative 1d described in formula 4:
Work as R1=3-Cl, R2=8-CH3, the couroupitine A new derivative is derivative 1e described in formula 5:
Work as R1=3-Cl, R2=9-Br, the couroupitine A new derivative are derivative 1f described in formula 6:
Work as R1=3-Cl, R2=8-OCH3, the couroupitine A new derivative is derivative 1g described in formula 7:
Work as R1=3-Cl, R2=7-Cl, the couroupitine A new derivative are derivative 1h described in formula 8:
Work as R1=3-Cl, R2=8-OCF3, the couroupitine A new derivative is derivative 1i described in formula 9:
Work as R1=2-Br, R2=8-OCH3, the couroupitine A new derivative is derivative 1j described in formula 10:
Work as R1=2-Br, R2=8-OCF3, the couroupitine A new derivative is derivative 1k described in formula 11:
Work as R1=2-Br, R2=7-Cl, the couroupitine A new derivative are derivative 1l described in formula 12:
Work as R1=2-Br, R2=8-Cl, the couroupitine A new derivative are derivative 1m described in formula 13:
Work as R1=2-Br, R2=9-Cl, the couroupitine A new derivative are derivative 1n described in formula 14:
The couroupitine A new derivative is the pharmaceutical preparation of bulk pharmaceutical chemicals.
Application of the couroupitine A new derivative in preparation tumor.
The pharmaceutical preparation is tablet, capsule, granule, pill, micropill preparation, oral solution, liquid drugs injection, infusion
Agent, powder-injection.
The capsule uses soft capsule.
The powder-injection is adopted as freeze drying powder injection.
Embodiment 1. synthesizes 2,7- dichloro-indole [2,1-b] quinazoline -6,12- diketone (1a):
Weigh 4- chlorisatide 1.0g (0.0055mol), 5- chloroisatoic anhydride 1.15g (0.0058mol) is added to equipped with magnetic
In the 100ml three-necked bottle of son, 40ml chloroform is then added into three-necked bottle, 1.5ml triethylamine heats back at 80 DEG C of oil bath
3h is flowed, after reaction, stops heating, to be cooled, suction filtration obtains crude material yellow solid powder, and product is washed with 10ml ethyl alcohol
It washs 3 times, obtains purified product yellow solid powder, drying, weighing 1.12g, yield 64.4%.
2,7- dichloro-indole [2,1-b] quinazoline -6,12- diketone (1a):
Yellow solid powder, yield 64.4%；m.p.291.2-293.4℃；1H NMR(400MHz,DMSO)δ8.47(d,
J=8.1Hz, 1H), 8.29 (dd, J=1.8,1.0Hz, 1H), 8.02 (s, 1H), 7.92-7.84 (m, 1H), 7.56 (t, J=
7.7Hz,1H),7.16(s,1H)；IR(KBr)ν:3081,3030,1733,1686,1584,1549,1460,1418,915,
796,726cm-1；EI-MS:calcd for C15H6Cl2N2O2:317.13；Found:318.3[M+1]+；Anal.Calcd.for
C15H6Cl2N2O2(%): C 56.81, H 1.91, N 8.83；Found:C 56.90,H 2.01,N 8.73.
Embodiment 2. synthesizes 2,9- dichloro-indole [2,1-b] quinazoline -6,12- diketone (1b):
Weigh 6- chlorisatide 0.3g (0.0017mol), 5- chloroisatoic anhydride 0.36g (0.0018mol) is added to equipped with magnetic
In the 100ml three-necked bottle of son, 40ml chloroform is then added into three-necked bottle, 1.5ml triethylamine heats back at 80 DEG C of oil bath
3h is flowed, after reaction, stops heating, to be cooled, suction filtration obtains crude material yellow solid powder, and product is washed with 10ml ethyl alcohol
It washs 3 times, obtains purified product yellow solid powder, drying, weighing 0.34g, yield 63.0%.
2,9- dichloro-indole [2,1-b] quinazoline -6,12- diketone (1b):
Yellow solid powder, yield 63.0%；m.p.274.5-276.4℃；1H NMR(400MHz,DMSO)δ8.02(s,
1H), 7.94 (s, 1H), 7.54 (d, J=8.1Hz, 1H), 7.13 (d, J=1.8Hz, 1H), 7.11 (d, J=1.8Hz, 1H),
6.95 (d, J=1.7Hz, 1H)；IR(KBr)ν:3117,3060,1725,1678,1591,1553,1464,1428,847,
775cm- 1；EI-MS:calcd for C15H6Cl2N2O2:317.13；Found:318.3[M+1]+；Anal.Calcd.for
C15H6Cl2N2O2(%): C 56.81, H 1.91, N 8.83；Found:C 55.78,H 1.86,N 8.94.
Embodiment 3. synthesizes chloro- 9- bromo indole [2,1-b] quinazoline -6,12- diketone (1c) of 2-:
Weigh 6- bromo-isatin 0.70g (0.0031mol), 5- chloroisatoic anhydride 0.66g (0.0033mol) is added to equipped with magnetic
In the 100ml three-necked bottle of son, 40ml chloroform is then added into three-necked bottle, 1.5ml triethylamine heats back at 80 DEG C of oil bath
3h is flowed, after reaction, stops heating, to be cooled, suction filtration obtains crude material yellow solid powder, and product is washed with 10ml ethyl alcohol
It washs 3 times, obtains purified product yellow solid powder, drying, weighing 0.63g, yield 56.3%.
Chloro- 9- bromo indole [2,1-b] quinazoline -6,12- diketone (1c) of 2-:
Yellow solid powder, yield 56.3%；m.p.283.4-285.1℃；1H NMR(400MHz,DMSO)δ8.66(d,
J=1.6Hz, 1H), 8.32 (d, J=2.1Hz, 1H), 8.05 (s, 1H), 7.90 (s, 1H), 7.88 (s, 1H), 7.78 (d, J=
1.6Hz,1H)；IR(KBr)ν:3115,3068,1725,1678,1586,1552,1463,1421,911,843,755cm- 1；
EI-MS:calcd for C15H6BrClN2O2:361.58；Found:362.3[M+1]+；Anal.Calcd.for
C15H6BrClN2O2(%): C 49.83, H 1.67, N 7.75；Found:C 50.01,H 1.72,N 7.86.
Embodiment 4. synthesizes chloro- 8- trifluoromethoxy indoles [2,1-b] quinazoline -6,12- diketone (1d) of 2-:
Weigh 5- trifluoromethoxy isatin 1.0g (0.0043mol), 5- chloroisatoic anhydride 0.9g (0.0045mol) is added to
In 100ml three-necked bottle equipped with magneton, 40ml chloroform, 1.5ml triethylamine, at 80 DEG C of oil bath are then added into three-necked bottle
It is heated to reflux 3h, after reaction, stops heating, to be cooled, suction filtration obtains crude material yellow solid powder, product 10ml
Ethanol washing 3 times, obtain purified product yellow solid powder, drying, weighing 1.12g, yield 70.9%.
Chloro- 8- trifluoromethoxy indoles [2,1-b] quinazoline -6,12- diketone (1d) of 2-:
Yellow solid powder, yield 70.9%；m.p.266.9-269.1℃；1H NMR(400MHz,DMSO)δ8.57(d,
J=8.7Hz, 1H), 8.30 (d, J=2.0Hz, 1H), 8.03 (d, J=3.1Hz, 1H), 7.95 (d, J=7.3Hz, 1H), 7.86
(d, J=2.6Hz, 1H), 7.14 (d, J=8.7Hz, 1H)；IR(KBr)ν:3080,3029,1737,1678,1618,1591,
1551,1498,1088,1042,857,800,712cm- 1；EI-MS:calcd for C16H6ClF3N2O3:366.68；Found:
390.3[M+Na]+；Anal.Calcd.for C16H6ClF3N2O3(%): C 52.41, H 1.65, N 7,64；Found:C
52.56,H 1.78,N 7.59.
Embodiment 5. synthesizes chloro- 8- methyl indol [2,1-b] quinazoline -6,12- diketone (1e) of 3-:
Weigh 5- methylisatin 1.4g (0.0087mol), 4- chloroisatoic anhydride 1.8g (0.0091mol) is added to equipped with magnetic
In the 100ml three-necked bottle of son, 40ml chloroform is then added into three-necked bottle, 1.5ml triethylamine heats back at 80 DEG C of oil bath
3h is flowed, after reaction, stops heating, to be cooled, suction filtration obtains crude material yellow solid powder, and product is washed with 10ml ethyl alcohol
It washs 3 times, obtains purified product yellow solid powder, drying, weighing 1.51g, yield 58.5%.
Chloro- 8- methyl indol [2,1-b] quinazoline -6,12- diketone (1e) of 3-:
Yellow solid powder, yield 58.5%；m.p.296.1-297.8℃；1H NMR(400MHz,DMSO)δ8.35–
8.29 (m, 1H), 8.06 (d, J=2.0Hz, 1H), 7.79 (d, J=2.1Hz, 1H), 7.77 (d, J=2.1Hz, 1H), 7.71
(d, J=4.4Hz, 1H), 7.68 (d, J=1.2Hz, 1H), 2.42 (s, 3H)；IR(KBr)ν:3069,2910,1730,1678,
1616,1589,1485,1421,884,837,777cm- 1；EI-MS:calcd for C16H9ClN2O2:296.71；Found:
297.0[M+1]+；Anal.Calcd.for C16H9ClN2O2(%): C 64.77, H 3.06, N 9.44；Found:C 64.83,
H 3.13,N 9.42.
Embodiment 6. synthesizes the chloro- 9- of 3- bromo- indoles [2,1-b] quinazoline -6,12- diketone (1f):
Weigh 6- bromo-isatin 0.85g (0.0038mol), 4- chloroisatoic anhydride 0.79g (0.0040mol) is added to equipped with magnetic
In the 100ml three-necked bottle of son, 40ml chloroform is then added into the three-necked bottle, 1.5ml triethylamine is heated at 80 DEG C of oil bath
Flow back 3h, after reaction, stops heating, to be cooled, suction filtration obtains crude material yellow solid powder, product 10ml ethyl alcohol
Washing 3 times obtains purified product yellow solid powder, drying, weighing 0.94g, yield 68.6%.
The bromo- indoles of the chloro- 9- of 3- [2,1-b] quinazoline -6,12- diketone (1f):
Yellow solid powder, yield 68.6%；m.p.261.5-263.6℃；1H NMR(400MHz,DMSO)δ8.63(d,
J=1.6Hz, 1H), 8.33 (d, J=8.4Hz, 1H), 8.10 (d, J=2.0Hz, 1H), 7.86 (d, J=8.0Hz, 1H), 7.82
(dd, J=8.5,2.1Hz, 1H), 7.74 (dd, J=8.0,1.7Hz, 1H)；IR(KBr)ν:3080,3024,1734,1685,
1588,1464,1421,833,779cm- 1；EI-MS:calcd for C15H6BrClN2O2:361.58；Found:362.3[M+
1]+；Anal.Calcd.for C15H6BrClN2O2(%): C 49.83, H 1.67, N 7.75；Found:C 49.90,H
1.74,N 7.83.
Embodiment 7. synthesizes chloro- 8- methoxy-Indole [2,1-b] quinazoline -6,12- diketone (1g) of 3-:
Weigh 5- methoxyl group isatin 0.8g (0.0045mol), 4- chloroisatoic anhydride 0.94g (0.0048mol) is added to
In 100ml three-necked bottle equipped with magneton, 40ml chloroform, 1.5ml triethylamine, at 80 DEG C of oil bath are then added into three-necked bottle
It is heated to reflux 3h, after reaction, stops heating, to be cooled, suction filtration obtains crude material yellow solid powder, product 10ml
Ethanol washing 3 times, obtain purified product yellow solid powder, drying, weighing 0.91g, yield 64.7%.
Chloro- 8- methoxy-Indole [2,1-b] quinazoline -6,12- diketone (1g) of 3-:
Brick-red solid powder, yield 64.7%；m.p.268.5-270.4℃；1H NMR(400MHz,DMSO)δ8.39–
8.35 (m, 1H), 8.30 (d, J=8.5Hz, 1H), 8.06 (d, J=1.9Hz, 1H), 7.78 (dd, J=8.5,2.1Hz, 1H),
7.45 (d, J=2.7Hz, 1H), 7.43 (s, 1H), 3.88 (s, 3H)；IR(KBr)ν:3060,2937,1727,1676,1615,
1598,1492,1457,1042,1020,898,855,778cm- 1；EI-MS:calcd for C16H9ClN2O3:312.71；
Found:318.3[M+1]+；Anal.Calcd.for C16H9ClN2O3(%): C 61.46, H 2.90, N 8.96；Found:C
61.45,H 3.01,N 9.05.
Embodiment 8. synthesizes 3,7- dichloro-indole [2,1-b] quinazoline -6,12- diketone (1h):
Weigh 4- chlorisatide 1.0g (0.0055mol), 4- chloroisatoic anhydride 1.15g (0.0058mol) is added to and is being equipped with
In the 100ml three-necked bottle of magneton, 40ml chloroform is then added into three-necked bottle, 1.5ml triethylamine is heated at 80 DEG C of oil bath
Flow back 3h, after reaction, stops heating, to be cooled, suction filtration obtains crude material yellow solid powder, product 10ml ethyl alcohol
Washing 3 times obtains purified product yellow solid powder, drying, weighing 1.12g, yield 63.2%.
3,7- dichloro-indole [2,1-b] quinazoline -6,12- diketone (1h):
Yellow solid powder, yield 63.2%；m.p.285.6-287.4℃；1H NMR(400MHz,DMSO)δ8.46(d,
J=7.6Hz, 1H), 8.32 (d, J=8.5Hz, 1H), 8.10 (d, J=2.0Hz, 1H), 7.86 (t, J=8.1Hz, 1H), 7.80
(dd, J=8.5,2.1Hz, 1H), 7.54 (d, J=8.1Hz, 1H)；IR(KBr)ν:3091,1730,1683,1584,1462,
1419,939,898,795cm- 1；EI-MS:calcd for C15H6Cl2N2O2:317.13；Found:318.2[M+1]+；
Anal.Calcd.for C15H6Cl2N2O2(%): C 56.81, H 1.91, N 8.83；Found:C 56.84,H 1.95,N
8.73.
Embodiment 9. synthesizes chloro- 8- trifluoromethoxy indoles [2,1-b] quinazoline -6,12- diketone (1i) of 3-:
Weigh 5- trifluoromethoxy isatin 0.95g (0.0041mol), 4- chloroisatoic anhydride 0.85g (0.0043mol) addition
Into the 100ml three-necked bottle equipped with magneton, 40ml chloroform, 1.5ml triethylamine, in oil bath 80 are then added into three-necked bottle
DEG C it is heated to reflux 3h, after reaction, stops heating, to be cooled, suction filtration obtains crude material yellow solid powder, and product is used
10ml ethanol washing 3 times, obtain purified product yellow solid powder, drying, weighing 0.92g, yield 60.1%.
Chloro- 8- trifluoromethoxy indoles [2,1-b] quinazoline -6,12- diketone (1i) of 3-:
Brick-red solid powder, yield 60.1%；m.p.273.4-275.1℃；1H NMR(400MHz,DMSO)δ8.56
(d, J=8.7Hz, 1H), 8.33 (d, J=8.5Hz, 1H), 8.10 (d, J=2.0Hz, 1H), 7.95 (s, 1H), 7.92 (d, J=
8.7Hz, 1H), 7.81 (dd, J=8.5,2.1Hz, 1H)；IR(KBr)ν:3085,3026,1737,1690,1591,1481,
1418,1073,1045,906,849,781cm- 1；EI-MS:calcd for C16H6ClF3N2O3:366.68；Found:367.0
[M+1]+；Anal.Calcd.For C16H6ClF3N2O3(%): C 52.41, H 1.65, N 7.64；Found:C 52.46,H
1.69,N 7.58.
Embodiment 10. synthesizes bromo- 8- methoxy-Indole [2,1-b] quinazoline -6,12- diketone (1j) of 2-:
Weigh 5- methoxyl group isatin 0.35g (0.0020mol), 5-bromoisatin acid anhydrides 0.51g (0.0021mol) is added to dress
Have in the 100ml three-necked bottle of magneton, 40ml chloroform is then added into three-necked bottle, 1.5ml triethylamine adds at 80 DEG C of oil bath
Heat reflux 3h stops heating after reaction, and to be cooled, suction filtration obtains crude material yellow solid powder, product 10ml second
Alcohol washs 3 times, obtains purified product yellow solid powder, drying, weighing 0.51g, yield 70.4%.
Bromo- 8- methoxy-Indole [2,1-b] quinazoline -6,12- diketone (1j) of 2-
Brick-red solid powder, yield 70.4%；m.p.>300℃；1H NMR(400MHz,DMSO)δ8.40–8.38(m,
1H), 8.36 (s, 1H), 8.12 (d, J=2.3Hz, 1H), 8.10 (d, J=2.4Hz, 1H), 7.90 (d, J=8.6Hz, 1H),
7.43(s,1H),3.88(s,3H)；IR(KBr)ν:3066,1732,1672,1617,1589,1545,1488,1459,1041,
1017,829,789,706cm- 1；EI-MS:calcd for C16H9BrN2O3:357.16；Found:358.3[M+1]+；
Anal.Calcd.For C16H9BrN2O3(%): C 53.81, H 2.54, N 7.84；Found:C 53.90,H 2.56,N
7.87.
Embodiment 11. synthesizes bromo- 8- trifluoromethoxy indoles [2,1-b] quinazoline -6,12- diketone (1k) of 2-:
Weigh 5- trifluoromethoxy isatin 0.35g (0.0015mol), 5-bromoisatin acid anhydrides 0.39g (0.0016mol) addition
Into the 100ml three-necked bottle equipped with magneton, 40ml chloroform, 1.5ml triethylamine, in oil bath 80 are then added into three-necked bottle
DEG C it is heated to reflux 3h, after reaction, stops heating, to be cooled, suction filtration obtains crude material yellow solid powder, and product is used
10ml ethanol washing 3 times, obtain purified product yellow solid powder, drying, weighing 0.45g, yield 72.6%.
Bromo- 8- trifluoromethoxy indoles [2,1-b] quinazoline -6,12- diketone (1k) of 2-:
Yellow solid powder, yield 72.6%；m.p.274.5-276.3℃；1H NMR(400MHz,DMSO)δ8.58(d,
J=8.1Hz, 1H), 8.44 (s, 1H), 8.17 (s, 1H), 8.15 (s, 1H), 7.96 (s, 1H), 7.93 (s, 1H)；IR(KBr)ν:
3088,3064,1739,1681,1617,1589,1545,1478,1086,1041,863,839,782cm- 1；EI-MS:calcd
for C16H6BrF3N2O3:411.13；Found:412.9[M+1]+；Anal.Calcd.For C16H6BrF3N2O3(%): C
46.74,H 1.47,N 6.81；Found:C 46.93,H 1.56,N 6.78.
Embodiment 12: synthesis bromo- 7- chloro-indole [2,1-b] quinazoline -6,12- diketone (1l) of 2-:
Weigh 4- chlorisatide 0.80g (0.0044mol), 5-bromoisatin acid anhydrides 1.11g (0.0046mol) is added to equipped with magnetic
In the 100ml three-necked bottle of son, 40ml chloroform is then added into three-necked bottle, 1.5ml triethylamine heats back at 80 DEG C of oil bath
3h is flowed, after reaction, stops heating, to be cooled, suction filtration obtains crude material yellow solid powder, and product is washed with 10ml ethyl alcohol
It washs 3 times, obtains purified product yellow solid powder, drying, weighing 0.91g, yield 57.2%.
Bromo- 7- chloro-indole [2,1-b] quinazoline -6,12- diketone (1l) of 2-:
Yellow solid powder, yield 57.2%；m.p.>300℃；1H NMR (400MHz, DMSO) δ 8.45 (d, J=
7.9Hz, 1H), 8.40 (d, J=2.2Hz, 1H), 8.22 (s, 1H), 8.12 (d, J=10.8Hz, 1H), 7.91 (d, J=
8.6Hz, 1H), 7.52 (d, J=7.7Hz, 1H)；IR(KBr)ν:3057,3024,1730,1684,1582,1547,1456,
1411,912,857,797cm- 1；EI-MS:calcd for C15H6BrClN2O2:361.58；Found:362.3[M+1]+；
Anal.Calcd.for C15H6BrClN2O2(%): C 49.83, H 1.67, N 7.75；Found:C 50.02,H 1.78,N
7.74.
Embodiment 13. synthesizes bromo- 8- chloro-indole [2,1-b] quinazoline -6,12- diketone (1m) of 2-:
Weigh 5- chlorisatide 0.50g (0.0028mol), 5-bromoisatin acid anhydrides 0.70g (0.0029mol) is added to equipped with magnetic
In the 100ml three-necked bottle of son, 40ml chloroform is then added into three-necked bottle, 1.5ml triethylamine heats back at 80 DEG C of oil bath
3h is flowed, after reaction, stops heating, to be cooled, suction filtration obtains crude material yellow solid powder, and product is washed with 10ml ethyl alcohol
It washs 3 times, obtains purified product yellow solid powder, drying, weighing 0.62g, yield 61.4%.
Bromo- 8- chloro-indole [2,1-b] quinazoline -6,12- diketone (1m) of 2-:
Yellow solid powder, yield 61.4%；m.p.276.4-279.2℃；1H NMR(400MHz,DMSO)δ8.47(d,
J=8.6Hz, 1H), 8.42 (d, J=2.3Hz, 1H), 8.15 (dd, J=8.6,2.3Hz, 1H), 8.00 (d, J=2.2Hz,
1H), 7.95 (dd, J=8.5,2.3Hz, 1H), 7.92 (s, 1H)；IR(KBr)ν:3130,3074,1735,1678,1586,
1549,1463,898,848,755cm- 1；EI-MS:calcd for C15H6BrClN2O2:361.58；Found:362.3[M
+1]+；Anal.Calcd.For C15H6BrClN2O2(%): C 49.83, H 1.67, N 7.75；Found:C 50.01,H
1.71,N 7.69.
Embodiment 14. synthesizes bromo- 9- chloro-indole [2,1-b] quinazoline -6,12- diketone (1n) of 2-:
Weigh 6- chlorisatide 0.35g (0.0019mol), 5-bromoisatin acid anhydrides 0.48g (0.0020mol) is added to equipped with magnetic
In the 100ml three-necked bottle of son, 40ml chloroform is then added into three-necked bottle, 1.5ml triethylamine heats back at 80 DEG C of oil bath
3h is flowed, after reaction, stops heating, to be cooled, suction filtration obtains crude material yellow solid powder, and product is washed with 10ml ethyl alcohol
It washs 3 times, obtains purified product yellow solid powder, drying, weighing 0.45g, yield 66.2%.
Bromo- 9- chloro-indole [2,1-b] quinazoline -6,12- diketone (1n) of 2-:
Yellow solid powder, yield 66.2%；m.p.>300℃；1H NMR (400MHz, DMSO) δ 8.47 (d, J=
1.7Hz, 1H), 8.43 (d, J=2.2Hz, 1H), 8.16 (dd, J=8.6,2.4Hz, 1H), 7.94 (dd, J=8.4,6.9Hz,
1H), 7.54 (d, J=8.1Hz, 1H), 7.12 (dd, J=8.0,1.8Hz, 1H)；IR(KBr)ν:3118,3078,1726,
1683,1588,1550,1461,1426,909,847,769cm- 1；EI-MS:calcd for C15H6BrClN2O2:361.58；
Found:362.3[M+1]+；Anal.Calcd.for C15H6BrClN2O2(%): C 49.83, H 1.67, N 7.75；Found:
C 49.98,H 1.72,N 7.72.
Embodiment 15.
The active testing of tryptamines ketone derivatives:
Human colon cancer cell strain HCT-116 (lung cancer cell types, mouse pheochromocytoma cells in logarithmic growth phase
Strain PC12, mice embryonic pre-osteoblast MC-3T3-E1) cell is seeded in 96 well culture plates by proper density, put
It is placed in 5%CO2, in 37 DEG C of constant incubators.After overnight incubation, according to 100 μM, 50 μM, 25 μM, 12.5 μM, 6.25 μM,
3.125 μM and 1.56 μM of 7 concentration, the 3 repeating hole dosings of each concentration, and blank control is set, DMSO control is added afterwards for 24 hours
The MTT (20 hole μ L/) of 5mg/mL continues to cultivate 4.0h.Culture supernatant is discarded, DMSO (200 hole μ L/) then is added, with enzyme mark
Instrument measures every hole absorbance value in 490nm, calculates to inhibition rate of tumor cell.
Use the inhibiting rate (%) that compound on tumor cell growth is calculated with following equation:
Cell inhibitory rate=(experimental group OD value-DMSO control group OD value)/blank control group OD value × 100%；Then it adopts
IC50 value is calculated with SPSS 19.0.
Compound preferable for preliminary experiment inhibitory activity further adjusts concentration in 20 μm of ol/l, 10 μm of ol/l, 5 μ
Mol/l, 2.5 μm of ol/l, 1.25 μm of ol/l, 0.625 μm of ol/l gradient concentration are tested.
With anticancer drug Gefitinib (gefitinib, GFTN) and taxol (Taxol) for positive control.
1 compound 1a-1n experimental result of table
3-Cl, 9-Br couroupitine A have good inhibiting effect (IC to mouse pheochromocytoma cells strain PC1250=8.61 μ
mol.L-1), it is better than parent couroupitine A and positive control, there is potential therapeutic effect to nerve-cell tumor.Designed by the present invention
Novel tryptamines ketone derivatives have the function of inhibit tumour cell, can treatment tumour drug in use.
Claims (10)
1. tryptamines ketone derivatives, which is characterized in that its chemical formula is shown below:
Wherein, R1, R2For substituent group independent on the position 1-4, R2For substituent group independent on the position 7-10；R1, R2=halogen
Element, alkyl, one or more of alkoxy.
2. tryptamines ketone derivatives, which is characterized in that its chemical formula is as shown in Equation 1:
。
3. tryptamines ketone derivatives, which is characterized in that be selected from following compound:
。
4. tryptamines ketone derivatives, which is characterized in that be selected from following compound:
。
5. tryptamines ketone derivatives are the pharmaceutical composition of active constituent according to claim 1.
6. tryptamines ketone derivatives are the pharmaceutical preparation of bulk pharmaceutical chemicals according to claim 1.
7. application of the tryptamines ketone derivatives according to claim 1 in preparation tumor.
8. pharmaceutical preparation according to claim 5 is tablet, capsule, granule, pill, micropill preparation, oral solution, water
Injection, infusion solution, powder-injection.
9. pharmaceutical preparation according to claim 8, the capsule uses soft capsule.
10. pharmaceutical preparation according to claim 8, the powder-injection is adopted as freeze drying powder injection.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115124531A (en) * | 2022-08-09 | 2022-09-30 | 贵州大学 | 4-azatryptanthrin aromatic thioether derivatives, and preparation method and application thereof |
| CN115197227A (en) * | 2022-08-09 | 2022-10-18 | 贵州大学 | Tryptanthrin 1-position or 3-position substituted aromatic thioether derivative, and preparation method and application thereof |
| CN117298119A (en) * | 2023-11-28 | 2023-12-29 | 云南中医药大学 | Application of tryptanthrin derivative in preparation of drug-resistant candida albicans drug |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104844607A (en) * | 2015-03-26 | 2015-08-19 | 玉林师范学院 | Tryptanthrin bromo derivative with antineoplastic activity and synthetic method therefor |
| CN105330666A (en) * | 2015-11-27 | 2016-02-17 | 西北大学 | Novel tryptanthrin derivative, synthetic method and medicinal application thereof |
-
2019
- 2019-06-17 CN CN201910522207.8A patent/CN110143964A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104844607A (en) * | 2015-03-26 | 2015-08-19 | 玉林师范学院 | Tryptanthrin bromo derivative with antineoplastic activity and synthetic method therefor |
| CN105330666A (en) * | 2015-11-27 | 2016-02-17 | 西北大学 | Novel tryptanthrin derivative, synthetic method and medicinal application thereof |
Non-Patent Citations (5)
| Title |
|---|
| RAMA KRISHNAM RAJU ADDADA，等: "Novel and Efficient One-Pot Tandem Synthesis of Tryptanthrin Derivatives for Biological Activity", 《INTERNATIONAL JOURNAL OF PHARMA RESEARCH AND HEALTH SCIENCES》 * |
| 侯宝龙，等: "色胺酮衍生物设计、合成及抗肿瘤活性构效关系研究", 《有机化学》 * |
| 王翠玲，等: "天然产物色胺酮及其衍生物的仿生合成", 《高等学校化学学报》 * |
| 王翠玲: "色胺酮、吴茱萸次碱等天然产物的生物合成及仿生合成研究", 《西北大学博士学位论文》 * |
| 陈焕，等: "色胺酮及其衍生物的合成工艺及抑制肿瘤细胞增殖的研究", 《西北大学学报( 自然科学版)》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115124531A (en) * | 2022-08-09 | 2022-09-30 | 贵州大学 | 4-azatryptanthrin aromatic thioether derivatives, and preparation method and application thereof |
| CN115197227A (en) * | 2022-08-09 | 2022-10-18 | 贵州大学 | Tryptanthrin 1-position or 3-position substituted aromatic thioether derivative, and preparation method and application thereof |
| CN117298119A (en) * | 2023-11-28 | 2023-12-29 | 云南中医药大学 | Application of tryptanthrin derivative in preparation of drug-resistant candida albicans drug |
| CN117298119B (en) * | 2023-11-28 | 2024-01-23 | 云南中医药大学 | Application of tryptanthrin derivative in preparation of drug-resistant candida albicans drug |
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