CN109912574A - A kind of pyrazoline class compound and its preparation method and application - Google Patents
A kind of pyrazoline class compound and its preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of pyrazoline class compounds and its preparation method and application, and wherein the general structure of pyrazoline class compound is as follows:Wherein, R1Selected from H, 4-CH3、4‑OCH3, 4-Br or 4-Cl；R2Selected from 4-Cl, 4-F, 4-OCH3Or 4-CH3.Pyrazoline analog derivative of the present invention has the melanoma cells A375 of drug resistance to vemurafenib as the bis- target spot inhibitor of BRAF/P13KRThere is good antiproliferative activity.
Description
Technical field
The present invention relates to a kind of pyrazoline class compounds and its preparation method and application.Pyrazoline class of the present invention is derivative
Object has the melanoma cells A375 of drug resistance to vemurafenib as the bis- target spot inhibitor of BRAF/P13KRHave good
Antiproliferative activity.
Background technique
Melanoma, also known as malignant mela noma are derived from a kind of malignant tumour of melanocyte, are common in skin
Skin also sees the positions such as mucous membrane, ocular choroid.Melanoma is the highest tumour of grade malignancy in skin neoplasin.In 2011 8
The vemurafenib for obtaining U.S. FDA approval listing the moon on the 17th is a kind of orally active B-RafV600EThe potent inhibition of I type of kinases
Agent.Originally, using the patient of Wei Luofeini, its state of an illness is alleviated, but the long-term efficacy of the medicine is unsatisfactory --- and it is most of to use
The final palindromia of medicine person, and develop into drug resistance and lethal melanoma.Another kind developed by GlaxoSmithKline PLC company one
Kind selectivity B-RafV600EI type inhibitor dabrafenib's of kinases, U.S. FDA approval listing is obtained on May 29th, 2013, is used
In can not perform the operation or metastatic melanoma.Studies have shown that is for many patients, the curative effect lasting time of dabrafenib
It is short, the reason is that tumour cell produces drug resistance.The resistance mechanism being elucidated at present can be divided into dependence to be believed with non-dependent MAPK
Number access two major classes.Resistance mechanism dependent on MAPK signal path mainly by NRAS mutation, the amplification of BRAF allele,
BRAF shears mutant, the overexpression of COT, MEK1/2 mutation and raising these types mechanism of CRAF level and constitutes.And independently of
The mechanism for only having 11% in the resistance mechanism of MAPK signal path is identified, is mainly activated by PI3K as compensatory signal path
With the participation of receptor tyrosine kinases (RTK).The scheme of the solution drug resistance proposed for resistance mechanism is also exploited, more targets
The discovery of point drug, which becomes, is most intended to the drug that advanced melanoma patient brings maximum existence to benefit.
Summary of the invention
The purpose of the present invention is to provide a kind of pyrazoline class compounds and its preparation method and application.Present invention synthesis
Pyrazoline class compound can be used as the bis- target spot inhibitor of BRAF/PI3K, to the melanoma cells of resistance to vemurafenib
A375RThere is good antiproliferative activity.
The melanoma cells A375RDrug resistance can be generated to vemurafenib inhibitor.
Pyrazoline class compound of the present invention has following general formula:
Wherein, R1Selected from H, 4-CH3、4-OCH3, 4-Br or 4-Cl；R2Selected from 4-Cl, 4-F, 4-OCH3Or 4-CH3。
Further, the structural formula of the pyrazoline class compound is preferably as follows:
The preparation method of pyrazoline class compound of the present invention, includes the following steps:
Step 1: taking the single-necked flask of a 50mL, benzaldehyde derivative A and acetophenone derivs B are dissolved in 20mL respectively
In ethyl alcohol, it is 10%NaOH solution that 6.5mL concentration, which is slowly added dropwise, in uniformly backward reaction solution to be mixed, and stirring at normal temperature is reacted, and
Extent of reaction is monitored with TLC, after about 3h, product is precipitated in solid form；After reaction, it stands, filters, use distilled water
It washed once, ethanol washing three times, obtains chalcone derivative C after dry；
Wherein, R1Selected from H, 4-CH3、4-OCH3, 4-Br or 4-Cl；R2Selected from 4-Cl, 4-F, 4-OCH3Or 4-CH3。
Step 2: the chalcone derivative C (3mmol) after taking drying is dissolved in 20mL normal propyl alcohol, and 0.6mL is then added
80% hydrazine hydrate is heated to 98 DEG C of reflux, and TLC constantly monitors extent of reaction, and after fully reacting, reaction solution is cooled to 5 DEG C
Hereinafter, product is precipitated automatically, stand, filter and use ethyl alcohol recrystallization, obtains 3,5- diphenyl -4,5- dihydro-1 h-pyrazole derivative
Object D；
Wherein, R1Selected from H, 4-CH3、4-OCH3, 4-Br or 4-Cl；R2Selected from 4-Cl, 4-F, 4-OCH3Or 4-CH3。
Step 3: taking the round-bottomed flask of a 50mL, quinoxaline carboxylic acid's derivative, EDCI and HOBT are dissolved in 20mL DMF
In solution, 3,5- diphenyl -4,5- dihydro-1 h-pyrazole derivatives D (1.2mmol) is added after half an hour, stirring at normal temperature is used in combination
TLC monitoring；After fully reacting, reaction solution uses water, 5%HCl, 5%Na respectively2CO3Solution is washed and is extracted with ethyl acetate, and is had
Machine mutually uses anhydrous Na2SO4It dries and is evaporated under reduced pressure, crude product is isolated and purified (PE:EA=2:1) with thin layer chromatography, is obtained
Target product.
In step 1, the ratio between amount of substance of benzaldehyde derivative A and acetophenone derivs B is 1:1.
In step 2, the ratio of chalcone derivative C and hydrazine hydrate is that 0.2mL is added in every mM of chalcone derivative
80% hydrazine hydrate.
In step 3, quinoxaline carboxylic acid's derivative, 3,5- diphenyl -4,5- dihydro-1 h-pyrazole derivatives D, EDCI with
The mass ratio of the material of HOBT is 1:1.2:1.2:1.3.Quinoxaline carboxylic acid's derivative is quinoxalin-2-carboxylic acid or quinoxaline-
6- carboxylic acid.
The purposes of pyrazoline class compound of the present invention is in the application for preparing the bis- target spot inhibitor of BRAF/P13K.Tool
Body, pyrazoline analog derivative of the present invention has the melanoma cells A375 of drug resistance to vemurafenibRHave good anti-
Proliferation activity.
Specific embodiment
By following embodiment, present invention be described in more detail, but should be noted that the scope of the present invention is not implemented by these
Any restrictions of example.
Embodiment 1:((3- (4- chlorphenyl) -5- phenyl -4,5- dihydro-1 h-pyrazole -1- base) (quinoxaline -2- base) ketone
The preparation of (compound 1)
1, the single-necked flask for taking a 50mL, by 4- chlorobenzaldehyde A (703mg, 5mmol) and acetophenone B (600mg,
It 5mmol) is dissolved in 20mL ethyl alcohol respectively, it is 10% that 6.5mL concentration, which is slowly added dropwise, in uniformly backward reaction solution to be mixed
NaOH solution.Stirring at normal temperature reaction, and extent of reaction is monitored with TLC, after about 3h, product is analysed in solid form
Out.After reaction, it stands, filters, be washed with distilled water once, ethanol washing is three times.Chalcone derivative is obtained after drying
C。
2, the chalcone derivative C (728mg, 3mmol) after taking drying is dissolved in the normal propyl alcohol of 20mL, then adds
The hydrazine hydrate of 0.6mL 80% is heated to 98 DEG C of reflux, and TLC constantly monitors extent of reaction, after fully reacting, reaction solution is cooling
It to 5 DEG C hereinafter, product is precipitated automatically, stands, filters and obtain 3,5- diphenyl -4,5- dihydro-1 h-pyrazole with ethyl alcohol recrystallization and spread out
Biological D.
3, the round-bottomed flask of a 50mL is taken, quinoxalin-2-carboxylic acid (175mg, 1mmol) and EDCI is added thereto respectively
(230mg, 1.2mmol) and HOBT (176mg, 1.3mmol) is dissolved in 20mL DMF solution, and the ratio between the amount of substance of three kinds of raw materials is
1:1.2:1.3.It is added after half an hour compound D (308mg, 1.2mmol), stirring at normal temperature is simultaneously monitored with TLC.Fully reacting
Afterwards, reaction solution uses water, 5%HCl, 5%Na respectively2CO3Solution is washed and is extracted with ethyl acetate, organic phase anhydrous Na2SO4
It dries and is evaporated under reduced pressure.Crude product is isolated and purified (PE:EA=2:1) with thin layer chromatography, obtains target compound 1.Product 1
For faint yellow solid, yield 40%, fusing point: 170-171 DEG C.1H NMR(600MHz,CDCl3)δ9.24(s,1H),8.17(dd,J
=48.5,7.8Hz, 2H), 7.79 (dd, J=32.8,8.6Hz, 2H), 7.68 (d, J=8.4Hz, 2H), 7.47 (d, J=
8.5Hz, 2H), 7.24 (d, J=7.6Hz, 2H), 7.15 (d, J=7.6Hz, 2H), 5.78 (dd, J=11.7,4.9Hz, 1H),
3.92 (dd, J=18.0,11.8Hz, 1H), 3.20 (dd, J=17.6,4.5Hz, 1H)13C NMR(151MHz,CDCl3)δ
163.38,155.38,148.36,145.29,144.84,142.42,141.68,140.67,136.89,131.14,130.46,
130.17,129.16,129.02,128.13,125.79,61.12,42.10,29.64.MS(ESI):413.8(C24H17ClN4O,
[M+H]+)
Embodiment 2:(3- (4- chlorphenyl) -5- phenyl -4,5- dihydro-1 h-pyrazole -1- base) (quinoxalin-6-yl) ketone
The preparation of (compound 2)
The preparation method is the same as that of Example 1.Quinoxalin-2-carboxylic acid is replaced with quinoxaline -6- carboxylic acid, obtains faint yellow solid, is produced
Rate 41%, fusing point: 176-177 DEG C.1H NMR(600MHz,CDCl3) δ 9.23 (s, 1H), 8.20 (dd, J=36.5,8.1Hz,
2H), 7.87-7.81 (m, 2H), 7.55 (d, J=8.4Hz, 2H), 7.39 (dd, J=8.1,5.4Hz, 4H), 7.31 (d, J=
8.3Hz, 3H), 5.89 (dd, J=11.7,4.7Hz, 1H), 3.86 (dd, J=17.7,11.7Hz, 1H), 3.28 (dd, J=
17.7,4.7Hz,1H).13CNMR(151MHz,CDCl3)δ166.20,154.43,146.06,145.58,143.93,142.14,
141.28,136.64,135.78,131.90,130.79,129.49,129.08,128.81,128.06,128.01,125.68,
61.39,41.74,29.73.MS(ESI):413.8(C24H17ClN4O,[M+H]+)
Embodiment 3:(3- (4- chlorphenyl) -5- (p-methylphenyl) -4,5- dihydro-1 h-pyrazole -1- base) (quinoxaline -2-
Base) ketone (compound 3) preparation
The preparation method is the same as that of Example 1.Acetophenone is replaced with melilotal, obtains faint yellow solid, yield 50% melts
Point: 97-98 DEG C.1H NMR(600MHz,CDCl3) δ 9.22 (s, 1H), 8.21 (dd, J=37.1,8.2Hz, 2H), 7.89-7.80
(m, 2H), 7.54 (t, J=12.9Hz, 2H), 7.31 (dd, J=15.9,8.3Hz, 4H), 7.20 (d, J=7.9Hz, 2H),
5.86 (dd, J=11.6,4.7Hz, 1H), 3.90-3.80 (m, 1H), 3.27 (dd, J=17.7,4.8Hz, 1H), 2.34 (s,
3H).13C NMR(151MHz,CDCl3)δ163.35,155.38,148.45,144.85,142.40,141.66,137.92,
137.68,136.81,131.09,130.43,130.16,129.79,129.21,129.00,128.11,125.77,60.94,
42.08,21.12.MS(ESI):427.9(C25H19ClN4O,[M+H]+)
Embodiment 4:((3- (4- chlorphenyl) -5- (p-methylphenyl) -4,5- dihydro-1 h-pyrazole -1- base) (quinoxaline -6-
Base) ketone (compound 4) preparation
The preparation method is the same as that of Example 1.Acetophenone is replaced with melilotal, quinoxaline-is replaced with quinoxaline -6- carboxylic acid
2- carboxylic acid obtains faint yellow solid, yield 49%, fusing point: 113-114 DEG C.1H NMR(600MHz,DMSO-d6))δ9.01(s,
2H), 8.56 (s, 1H), 8.19 (dd, J=32.8,8.6Hz, 2H), 7.68 (d, J=8.4Hz, 2H), 7.47 (d, J=8.5Hz,
2H), 7.24 (d, J=7.6Hz, 2H), 7.15 (d, J=7.6Hz, 2H), 5.78 (dd, J=11.7,4.9Hz, 1H), 3.92
(dd, J=18.0,11.8Hz, 1H), 3.20 (dd, J=18.1,5.0Hz, 1H), 2.25 (s, 3H)13C NMR(151MHz,
CDCl3)δ164.79,157.38,145.93,145.49,143.76,142.05,141.55,136.07,131.51,130.72,
128.98,128.80,127.75,125.53,60.71,45.89,31.89,29.66,29.33,16.14,14.12.MS
(ESI):427.9(C25H19ClN4O,[M+H]+)
Embodiment 5:((5- (4- chlorphenyl) -3- (4- bromophenyl) -4,5- dihydro-1 h-pyrazole -1- base) (quinoxaline -2-
Base) (compound 5) preparation
The preparation method is the same as that of Example 1.Acetophenone is replaced with 4- bromoacetophenone, obtains faint yellow solid, yield 39% melts
Point: 149-150 DEG C.1H NMR(600MHz,CDCl3) δ 9.22 (s, 1H), 8.20 (dd, J=33.9,8.2Hz, 2H), 7.91-
7.79 (m, 2H), 7.53 (dd, J=17.4,8.5Hz, 4H), 7.30 (dd, J=23.5,8.5Hz, 4H), 5.84 (dd, J=
11.7,4.9Hz, 1H), 3.93-3.81 (m, 1H), 3.24 (dd, J=17.8,4.9Hz, 1H)13C NMR(151MHz,CDCl3)
δ163.45,155.32,147.94,144.77,142.46,141.64,139.59,137.03,132.29,131.27,
130.56,130.17,129.14,128.94,128.15,127.70,122.11,60.67,41.91.MS(ESI):492.7
(C24H16BrClN4O,[M+H]+)
Embodiment 6:(5- (4- chlorphenyl) -3- (4- bromophenyl) -4,5- dihydro-1 h-pyrazole -1- base) (quinoxaline -6-
Base) ketone (compound 6) preparation
The preparation method is the same as that of Example 1.Acetophenone is replaced with 4- bromoacetophenone, quinoxaline -2- is replaced with quinoxaline -6- carboxylic acid
Carboxylic acid obtains faint yellow solid, yield 41%, fusing point: 123-124 DEG C.1H NMR(600MHz,CDCl3) δ 8.92 (dd, J=
6.5,1.5Hz, 2H), 8.80 (s, 1H), 8.29 (d, J=8.6Hz, 1H), 8.16 (d, J=8.7Hz, 1H), 7.62 (t, J=
7.6Hz, 2H), 7.50 (d, J=8.4Hz, 2H), 7.37 (d, J=8.5Hz, 2H), 7.25 (d, J=4.7Hz, 2H), 5.83
(dd, J=11.8,5.1Hz, 1H), 3.83 (dd, J=17.7,11.9Hz, 1H), 3.21 (dd, J=17.7,5.2Hz, 1H)13C
NMR(151MHz,CDCl3)δ165.17,154.37,146.17,145.65,143.96,142.11,140.28,136.82,
135.44,132.24,131.98,130.73,129.26,129.12,128.90,128.07,127.56,121.94,60.96,
41.54.MS(ESI):492.7(C24H16BrClN4O,[M+H]+)
Embodiment 7:(3- (4- chlorphenyl) -5- (4- methoxyphenyl) -4,5- dihydro-1 h-pyrazole -1- base) (quinoxaline -
2- yl) ketone (compound 7) preparation
The preparation method is the same as that of Example 1.Acetophenone is replaced with 4- methoxyacetophenone, obtains faint yellow solid, yield 43%,
Fusing point: 102-103 DEG C.1H NMR(600MHz,CDCl3) δ 9.22 (s, 1H), 8.21 (dd, J=37.7,8.2Hz, 2H), 7.89-
7.80 (m, 3H), 7.56 (d, J=8.5Hz, 2H), 7.33 (dd, J=8.5,4.3Hz, 4H), 6.92 (d, J=8.6Hz, 2H),
5.85 (dd, J=11.6,4.6Hz, 1H), 3.87-3.81 (m, 1H), 3.80 (s, 3H), 3.31-3.22 (m, 1H)13C NMR
(151MHz,CDCl3)δ171.06,159.58,154.81,149.00,148.61,138.22,130.79,129.50,
128.45,127.02,126.90,125.47,124.13,116.38,114.20,99.26,70.80,55.43,29.60,
21.17.MS(ESI):443.9(C25H19ClN4O2,[M+H]+)
Embodiment 8:(3- (4- chlorphenyl) -5- (4- methoxyphenyl) -4,5- dihydro-1 h-pyrazole -1- base) (quinoxaline -
6- yl) ketone (compound 8) preparation
The preparation method is the same as that of Example 1.Acetophenone is replaced with 4- methoxyacetophenone, quinoline is replaced with quinoxaline -6- carboxylic acid
Quinoline -2- carboxylic acid obtains faint yellow solid, yield 46%, fusing point: 114-115 DEG C.1H NMR(600MHz,CDCl3)δ8.91(dd,
J=16.2,4.4Hz, 2H), 8.78 (s, 1H), 8.29 (d, J=8.5Hz, 1H), 8.16 (t, J=7.6Hz, 1H), 7.63 (d, J
=8.4Hz, 2H), 7.34 (dd, J=34.9,8.4Hz, 4H), 6.90 (d, J=8.4Hz, 2H), 5.84 (dd, J=11.6,
4.7Hz, 1H), 3.85-3.75 (m, 4H), 3.24 (dd, J=17.7,5.0Hz, 1H)13C NMR(151MHz,CDCl3)δ
164.87,159.17,155.71,145.94,145.49,143.87,142.20,141.02,136.12,133.75,131.89,
130.97,129.46,128.64,128.27,127.11,126.81,114.36,60.68,55.26,21.50.MS(ESI):
443.9(C25H19ClN4O2,[M+H]+)
Embodiment 9:(5- (4- methoxyphenyl) -3- (4- bromophenyl) -4,5- dihydro-1 h-pyrazole -1- base) (quinoxaline -
2- yl) ketone (compound 9) preparation
The preparation method is the same as that of Example 1.Acetophenone is replaced with 4- bromoacetophenone, 4- chlorobenzene first is replaced with 4-methoxybenzaldehyde
Aldehyde obtains faint yellow solid, yield 43%, fusing point: 122-123 DEG C.1H NMR(600MHz,CDCl3)δ9.24(s,1H),8.24
(d, J=8.0Hz, 1H), 8.16 (t, J=9.0Hz, 1H), 7.88-7.80 (m, 2H), 7.59-7.47 (m, 4H), 7.29 (d, J
=8.4Hz, 2H), 6.86 (d, J=8.8Hz, 2H), 5.81 (dd, J=11.6,4.7Hz, 1H), 3.86 (dd, J=10.4,
7.2Hz, 1H), 3.81 (s, 3H), 3.24 (dd, J=17.6,4.7Hz, 1H)13C NMR(151MHz,CDCl3)δ163.10,
161.80,156.20,148.39,144.95,142.37,141.70,139.88,132.21,131.11,130.42,130.18,
129.15,128.62,127.73,123.01,121.94,114.18,60.33,55.39,42.01.MS(ESI):488.3
(C25H19BrlN4O2,[M+H]+)
Embodiment 10:(5- (4- methoxyphenyl) -3- (4- bromophenyl) -4,5- dihydro-1 h-pyrazole -1- base) (quinoline
Quinoline -6- base) ketone (compound 10) preparation
The preparation method is the same as that of Example 1.Acetophenone is replaced with 4- bromoacetophenone, 4- chlorobenzene first is replaced with 4-methoxybenzaldehyde
Aldehyde replaces quinoxalin-2-carboxylic acid with quinoxaline -6- carboxylic acid, obtains faint yellow solid, yield 45%, fusing point: 140-141 DEG C.1H
NMR(600MHz,CDCl3) δ 8.91 (d, J=7.6Hz, 2H), 8.83 (s, 1H), 8.32 (d, J=8.5Hz, 1H), 8.16 (d, J
=8.7Hz, 1H), 7.65 (d, J=8.8Hz, 2H), 7.50 (t, J=13.8Hz, 2H), 7.26 (d, J=8.4Hz, 2H), 6.91
(d, J=8.8Hz, 2H), 5.81 (dd, J=11.7,4.8Hz, 1H), 3.86-3.79 (m, 4H), 3.20 (dd, J=17.6,
4.9Hz,1H).13C NMR(151MHz,CDCl3)δ164.84,161.66,155.31,146.04,145.56,143.89,
142.16,140.60,135.74,132.15,131.97,130.90,128.74,128.52,127.58,123.34,121.76,
114.23,60.67,55.40,41.68,29.68.MS(ESI):488.3(C25H19BrN4O2,[M+H]+)
Bis- (4- the methoxyphenyl) -4,5- dihydro-1 h-pyrazole -1- bases of embodiment 11:(3,5-) (quinoxaline -2- base) first
The preparation of ketone (compound 11)
The preparation method is the same as that of Example 1.Acetophenone is replaced with 4- methoxyacetophenone, 4- chlorine is replaced with 4-methoxybenzaldehyde
Benzaldehyde obtains faint yellow solid, yield 48%, fusing point: 140-141 DEG C.1H NMR(600MHz,CDCl3) δ 9.19 (d, J=
24.4Hz, 1H), 8.22 (m, J=14.5,7.0Hz, 2H), 7.87-7.81 (m, 2H), 7.32 (d, J=8.5Hz, 1H), 7.24
(d, J=6.6Hz, 1H), 7.19 (d, J=5.6Hz, 2H), 6.94-6.85 (m, 3H), 5.77 (d, J=11.5Hz, 1H), 3.90
(q, J=12.5Hz, 4H), 3.80 (d, J=19.6Hz, 3H)13C NMR(151MHz,CDCl3)δ156.33,148.06,
145.04,136.47,131.00,130.24,130.07,129.20,128.48,127.94,127.36,123.41,121.23,
114.41,114.12,111.04,70.88,60.42,56.00,55.30,42.05.MS(ESI):439.4(C26H22N4O3,[M+
H]+)
Bis- (4- the methoxyphenyl) -4,5- dihydro-1 h-pyrazole -1- bases of embodiment 12:(3,5-) (quinoxalin-6-yl) first
The preparation of ketone (compound 12)
The preparation method is the same as that of Example 1.Acetophenone is replaced with 4- methoxyacetophenone, 4- chlorine is replaced with 4-methoxybenzaldehyde
Benzaldehyde replaces quinoxalin-2-carboxylic acid with quinoxaline -6- carboxylic acid, obtains faint yellow solid, yield 50%, fusing point: 133-134
℃。1H NMR(600MHz,CDCl3) δ 8.90 (d, J=10.0Hz, 2H), 8.81 (s, 1H), 8.31 (d, J=8.7Hz, 1H),
8.19-8.09 (m, 1H), 7.64 (d, J=8.6Hz, 2H), 7.31 (d, J=8.4Hz, 2H), 6.89 (dd, J=11.4,
8.7Hz, 4H), 5.81 (dd, J=11.5,4.5Hz, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 3.23 (dd, J=17.6,
4.7Hz,1H).13C NMR(151MHz,CDCl3)δ159.18,148.13,145.95,145.50,133.72,131.05,
128.46,127.95,127.75,127.39,127.13,121.06,118.98,114.36,114.17,111.14,70.92,
61.46,56.03,40.58.MS(ESI):439.4(C26H22N4O3,[M+H]+)
Embodiment 13:(3- (4- fluorophenyl) -5- (p-methylphenyl) -4,5- dihydro-1 h-pyrazole -1- base) (quinoxaline -2-
Base) ketone (compound 13) preparation
The preparation method is the same as that of Example 1.Acetophenone is replaced with 4- methyl acetophenone, 4- chlorobenzene first is replaced with 4- fluorobenzaldehyde
Aldehyde obtains faint yellow solid, yield 43%, fusing point: 162-163 DEG C.1H NMR(600MHz,CDCl3)δ9.23(s,1H),8.20
(dd, J=39.3,8.0Hz, 2H), 7.88-7.75 (m, 2H), 7.63 (dd, J=27.6,22.0Hz, 2H), 7.30 (d, J=
7.6Hz, 2H), 7.19 (d, J=7.6Hz, 2H), 7.03 (t, J=8.3Hz, 2H), 5.86 (dd, J=11.5,4.3Hz, 1H),
3.84 (dd, J=17.6,11.7Hz, 1H), 3.27 (dd, J=17.7,4.4Hz, 1H), 2.34 (s, 3H)13C NMR
(151MHz,CDCl3)δ165.01,163.31,155.48,148.55,144.89,142.36,141.67,137.89,
137.74,131.08,130.42,130.16,129.78,129.16,128.98,127.01,125.78,115.99,60.85,
42.23,21.12.MS(ESI):411.4(C25H19FN4O,[M+H]+)
Embodiment 14:(3- (4- fluorophenyl) -5- (p-methylphenyl) -4,5- dihydro-1 h-pyrazole -1- base) (quinoxaline -6-
Base) ketone (compound 14) preparation
The preparation method is the same as that of Example 1.Acetophenone is replaced with 4- methyl acetophenone, 4- chlorobenzene first is replaced with 4- fluorobenzaldehyde
Aldehyde replaces quinoxalin-2-carboxylic acid with quinoxaline -6- carboxylic acid, obtains faint yellow solid, yield 46%, fusing point: 100-101 DEG C.1H
NMR(600MHz,CDCl3) δ 8.92 (d, J=7.2Hz, 2H), 8.80 (s, 1H), 8.30 (d, J=8.2Hz, 1H), 8.16 (d, J
=8.6Hz, 1H), 7.76-7.64 (m, 2H), 7.27 (d, J=7.5Hz, 2H), 7.18 (d, J=7.4Hz, 2H), 7.08 (t, J
=8.4Hz, 2H), 5.85 (dd, J=11.3,4.1Hz, 1H), 3.82 (dd, J=17.6,11.8Hz, 1H), 3.24 (dd, J=
17.6,4.8Hz,1H),2.33(s,3H).13C NMR(151MHz,CDCl3)δ165.04,154.54,146.01,145.56,
143.91,142.20,138.45,137.69,135.93,131.87,130.88,129.74,128.74,127.34,125.66,
115.97,61.15,41.89,29.60,21.13.MS(ESI):411.4(C25H19FN4O,[M+H]+)
Embodiment 15:(5- (4- bromophenyl) -3- (4- fluorophenyl) -4,5- dihydro-1 h-pyrazole -1- base) (quinoxaline -2-
Base) ketone (compound 15) preparation
The preparation method is the same as that of Example 1.Acetophenone is replaced with 4- bromoacetophenone, 4- chlorobenzaldehyde is replaced with 4- fluorobenzaldehyde,
Obtain faint yellow solid, yield 42%, fusing point: 143-144 DEG C.1H NMR(600MHz,CDCl3) δ 9.21 (d, J=15.0Hz,
1H), 8.19 (dd, J=35.6,7.7Hz, 2H), 7.85 (dd, J=27.7,18.7Hz, 2H), 7.61 (d, J=5.0Hz, 2H),
7.49 (t, J=11.4Hz, 2H), 7.28 (d, J=7.7Hz, 2H), 7.03 (t, J=8.2Hz, 2H), 5.83 (d, J=
10.8Hz, 1H), 3.86 (dd, J=17.1,12.0Hz, 1H), 3.24 (d, J=17.6Hz, 1H)13C NMR(151MHz,
CDCl3)δ165.15,163.48,162.91,155.59,148.33,143.93,141.94,139.55,132.30,131.78,
130.95,130.21,129.07,128.50,127.74,122.12,116.12,115.97,60.67,42.14.MS(ESI):
476.3(C24H16BrFN4O,[M+H]+)
Embodiment 16:(5- (4- bromophenyl) -3- (4- fluorophenyl) -4,5- dihydro-1 h-pyrazole -1- base) (quinoxaline -6-
Base) ketone (compound 16) preparation
The preparation method is the same as that of Example 1.Acetophenone is replaced with 4- bromoacetophenone, 4- chlorobenzaldehyde is replaced with 4- fluorobenzaldehyde,
Quinoxalin-2-carboxylic acid is replaced with quinoxaline -6- carboxylic acid, obtains faint yellow solid, yield 44%, fusing point: 101-102 DEG C.1H
NMR(600MHz,CDCl3) δ 8.89 (dd, J=38.0,36.7Hz, 3H), 8.23 (dd, J=76.9,8.6Hz, 2H), 7.72-
7.66 (m, 2H), 7.50 (d, J=8.2Hz, 2H), 7.26 (d, J=7.6Hz, 2H), 7.08 (d, J=8.4Hz, 2H), 5.83
(dd, J=11.6,4.7Hz, 1H), 3.84 (dd, J=17.6,11.8Hz, 1H), 3.21 (dd, J=17.7,5.0Hz, 1H)13C
NMR(151MHz,CDCl3)δ165.12,154.44,146.13,145.63,143.95,142.12,140.35,135.51,
132.22,131.96,130.74,128.90,127.54,127.05,121.90,116.12,60.85,41.65,29.68.MS
(ESI):476.3(C24H16BrFN4O,[M+H]+)
Embodiment 17:(5- (4- methoxyphenyl) -3- (p-methylphenyl) -4,5- dihydro-1 h-pyrazole -1- base) (quinoline
Quinoline -2- base) ketone (compound 17) preparation
The preparation method is the same as that of Example 1.Acetophenone is replaced with 4- methoxyacetophenone, 4- chlorobenzene is replaced with 4- tolyl aldehyde
Formaldehyde obtains faint yellow solid, yield 45%, fusing point: 138-139 DEG C.1H NMR(600MHz,CDCl3) δ 9.18 (d, J=
25.4Hz,1H),8.28–7.98(m,3H),7.81(s,3H),7.53(s,2H),7.42–7.26(m,4H),6.89(s,2H),
5.93-5.77 (m, 1H), 3.87-3.71 (m, 4H), 3.23 (dd, J=26.3,11.7Hz, 1H)13C NMR(151MHz,
CDCl3)δ163.32,159.39,156.50,148.47,144.70,142.18,141.69,136.81,132.76,131.15,
130.46,130.07,129.22,129.00,128.14,127.25,114.48,114.24,60.70,55.32,42.02,
29.64.MS(ESI):423.4(C26H22N4O2,[M+H]+)
Embodiment 18:(5- (4- methoxyphenyl) -3- (p-methylphenyl) -4,5- dihydro-1 h-pyrazole -1- base) (quinoline
Quinoline -6- base) ketone (compound 18) preparation
The preparation method is the same as that of Example 1.Acetophenone is replaced with 4- methoxyacetophenone, 4- chlorobenzene is replaced with 4- tolyl aldehyde
Formaldehyde replaces quinoxalin-2-carboxylic acid with quinoxaline -6- carboxylic acid, obtains faint yellow solid, yield 48%, fusing point: 150-151 DEG C
。1H NMR(600MHz,CDCl3) δ 9.04-8.69 (m, 3H), 8.38-8.08 (m, 2H), 7.60 (d, J=5.3Hz, 2H), 7.31
(s, 2H), 7.20 (d, J=5.7Hz, 2H), 6.89 (d, J=5.9Hz, 2H), 5.82 (d, J=7.0Hz, 1H), 3.88-3.70
(m, 4H), 3.25 (d, J=16.9Hz, 1H), 2.38 (s, 3H)13C NMR(151MHz,CDCl3)δ166.06,159.42,
154.42,149.04,146.10,145.56,143.71,142.14,136.68,133.45,131.91,131.76,129.57,
129.06,128.77,128.05,127.08,120.78,114.43,61.88,55.19,41.67.MS(ESI):423.4
(C26H22N4O2,[M+H]+)
Embodiment 19:(5- (4- chlorphenyl) -3- (4- methoxyphenyl) -4,5- dihydro-1 h-pyrazole -1- base) (quinoline
Quinoline -2- base) ketone (compound 19) preparation
The preparation method is the same as that of Example 1.Acetophenone is replaced with 4- chloro-acetophenone, 4- chlorobenzene first is replaced with 4-methoxybenzaldehyde
Aldehyde obtains faint yellow solid, yield 41%, fusing point: 125-126 DEG C.1H NMR(600MHz,CDCl3)δ9.25(s,1H),8.21
(dd, J=42.9,8.0Hz, 2H), 7.88-7.80 (m, 2H), 7.57 (d, J=8.6Hz, 2H), 7.35 (s, 4H), 6.87 (d, J
=8.6Hz, 2H), 5.83 (dd, J=11.4,4.3Hz, 1H), 3.89-3.80 (m, 4H), 3.25 (dd, J=17.6,4.3Hz,
1H).13CNMR(151MHz,CDCl3)δ163.04,161.77,156.14,148.38,144.96,141.60,139.18,
133.63,131.10,130.43,130.19,129.21,128.62,127.43,122.80,114.18,60.29,55.41,
42.10,29.67.MS(ESI):443.9(C25H19ClN4O2,[M+H]+)
Embodiment 20:(5- (4- chlorphenyl) -3- (4- methoxyphenyl) -4,5- dihydro-1 h-pyrazole -1- base) (quinoline
Quinoline -6- base) ketone (compound 2) preparation
The preparation method is the same as that of Example 1.Acetophenone is replaced with 4- chloro-acetophenone, 4- chlorobenzene first is replaced with 4-methoxybenzaldehyde
Aldehyde replaces quinoxalin-2-carboxylic acid with quinoxaline -6- carboxylic acid, obtains faint yellow solid, yield 46%, fusing point: 147-148 DEG C.1H
NMR(600MHz,CDCl3) δ 8.92 (d, J=7.7Hz, 2H), 8.83 (s, 1H), 8.32 (d, J=8.6Hz, 1H), 8.16 (d, J
=8.7Hz, 1H), 7.65 (d, J=8.7Hz, 2H), 7.37-7.29 (m, 4H), 6.91 (d, J=8.7Hz, 2H), 5.83 (dd, J
=11.7,4.8Hz, 1H), 3.87-3.79 (m, 4H), 3.21 (dd, J=17.6,4.9Hz, 1H)13C NMR(151MHz,
CDCl3)δ164.91,161.36,155.33,146.03,145.58,143.86,142.06,139.92,135.62,133.55,
132.00,130.89,129.21,128.74,128.54,127.26,123.32,114.23,60.61,55.29,41.77.MS
(ESI):443.9(C25H19ClN4O2,[M+H]+)
Embodiment 21:(5- (4- chlorphenyl) -3- (4- fluorophenyl) -4,5- dihydro-1 h-pyrazole -1- base) (quinoxaline -2-
Base) ketone (compound 21) preparation
The preparation method is the same as that of Example 1.Acetophenone is replaced with 4- chloro-acetophenone, 4- chlorobenzaldehyde is replaced with 4- fluorobenzaldehyde,
Obtain faint yellow solid, yield 44%, fusing point: 141-142 DEG C.1H NMR(600MHz,CDCl3)δ9.23(s,1H),8.20
(dd, J=32.5,8.1Hz, 2H), 7.92-7.79 (m, 2H), 7.54 (t, J=9.4Hz, 2H), 7.45-7.30 (m, 6H),
5.89-5.83 (m, 1H), 3.86 (dd, J=17.5,11.9Hz, 1H), 3.30-3.21 (m, 1H)13C NMR(151MHz,
CDCl3)δ163.40,155.34,148.09,144.71,142.41,141.64,139.05,137.03,134.00,131.34,
130.57,130.14,129.33,129.15,129.07,128.14,127.36,60.59,41.93,29.67.MS(ESI):
431.8(C24H16ClFN4O,[M+H]+)
Embodiment 22:(5- (4- chlorphenyl) -3- (4- fluorophenyl) -4,5- dihydro-1 h-pyrazole -1- base) (quinoxaline -6-
Base) ketone (compound 22) preparation
The preparation method is the same as that of Example 1.Acetophenone is replaced with 4- chloro-acetophenone, 4- chlorobenzaldehyde is replaced with 4- fluorobenzaldehyde,
Quinoxalin-2-carboxylic acid is replaced with quinoxaline -6- carboxylic acid, obtains faint yellow solid, yield 47%, fusing point: 135-136 DEG C.1H
NMR(600MHz,CDCl3) δ 8.91 (d, J=4.9Hz, 2H), 8.79 (s, 1H), 8.22 (dd, J=73.3,8.6Hz, 2H),
7.62 (d, J=8.4Hz, 2H), 7.38-7.29 (m, 6H), 5.84 (dd, J=11.5,4.4Hz, 1H), 3.83 (dd, J=
17.5,12.0Hz, 1H), 3.20 (dd, J=17.7,4.8Hz, 1H)13C NMR(151MHz,CDCl3)δ164.66,154.70,
145.24,144.83,142.98,141.33,139.65,136.93,136.22,133.89,131.62,131.31,129.30,
129.15,128.28,128.15,127.24,60.94,41.59.MS(ESI):431.8(C24H16ClFN4O,[M+H]+)
Embodiment 23:(5- (4- chlorphenyl) -3- (p-methylphenyl) -4,5- dihydro-1 h-pyrazole -1- base) (quinoxaline -2-
Base) ketone (compound 23) preparation
The preparation method is the same as that of Example 1.Acetophenone is replaced with 4- chloro-acetophenone, 4- chlorobenzene first is replaced with p-tolyl aldehyde
Aldehyde obtains faint yellow solid, yield 49%, fusing point: 99-100 DEG C.1H NMR(600MHz,CDCl3)δ9.12(s,1H),8.17
(dd, J=48.5,7.8Hz, 2H), 7.80 (dd, J=12.2,5.5Hz, 2H), 7.79 (dd, J=30.8,7.8Hz, 2H),
7.34 (m, J=14.3,7.1Hz, 5H), 5.71 (dd, J=11.4,4.4Hz, 1H), 3.48 (dd, J=18.1,11.7Hz,
1H), 2.82 (dd, J=18.3,4.1Hz, 1H), 2.02 (s, 3H)13C NMR(151MHz,CDCl3)δ156.59,148.37,
144.91,142.44,141.72,141.47,139.32,133.90,131.08,130.41,130.20,129.47,129.26,
129.16,127.70,127.41,126.90,60.32,42.05,29.66,21.50.MS(ESI):427.1(C25H19ClN4O,
[M+H]+)
Embodiment 24:(5- (4- chlorphenyl) -3- (p-methylphenyl) -4,5- dihydro-1 h-pyrazole -1- base) (quinoxaline -6-
Base) ketone (compound 24) preparation
The preparation method is the same as that of Example 1.Acetophenone is replaced with 4- chloro-acetophenone, 4- chlorobenzene first is replaced with p-tolyl aldehyde
Aldehyde replaces quinoxalin-2-carboxylic acid with quinoxaline -6- carboxylic acid, obtains faint yellow solid, yield 50%, fusing point: 143-144 DEG C.1H
NMR(600MHz,CDCl3) δ 8.87 (dd, J=66.7,13.8Hz, 3H), 8.32 (d, J=8.6Hz, 1H), 8.16 (d, J=
8.7Hz, 1H), 7.60 (d, J=8.0Hz, 2H), 7.38-7.28 (m, 4H), 7.21 (d, J=7.9Hz, 2H), 5.83 (dd, J=
11.7,4.8Hz, 1H), 3.84 (dd, J=17.6,11.8Hz, 1H), 3.22 (dd, J=17.7,4.9Hz, 1H), 2.38 (s,
3H).13C NMR(151MHz,CDCl3)δ164.99,155.65,146.05,145.57,142.15,141.25,140.04,
135.70,133.69,131.99,130.89,129.52,129.22,128.75,127.99,127.25,126.84,60.62,
42.02,29.80,21.53.MS(ESI):427.1(C25H19ClN4O,[M+H]+)
Embodiment 25: there is the melanoma cells A375 of drug resistance to vemurafenibRCulture
We choose BRAFV600EThe melanoma cells A375 of mutation makees drug resistance culture.By A375 in culture medium culture
To logarithmic growth phase.It being seeded in T25 culture bottle after the cell dilution of logarithmic growth phase, cell number is 3000000 selected,
Continuation is cultivated for 24 hours in cell incubator.In mdr cell culture, first vemurafenib inhibitor is added in culture medium,
Inhibitor concentration is 5 μm of ol/L, and then the culture medium containing inhibitor is added in culture bottle.It places and is cultivated in incubator
After 48h, the culture medium culture for being free of inhibitor is added after PBS cleaning in microscopically observation, initial stage visible cell mortality,
Continue dosing culture to cell Proliferation to initial density.After 10 wheel dosings, unobvious death obtains mdr cell to cell
A375R。
Embodiment 26: pyrazoline analog derivative (compound 1-24) is to A375 and A375RThe work of two plants of tumor cell lines
Use activity rating
We determine pyrazoline analog derivative (compound 1-24) to A375 and A375 using CCK-8 methodRTwo kinds swollen
The growth inhibition ability of tumor cell strain.By tested tumor cell line in culture medium culture to logarithmic growth phase.Logarithmic growth phase
Cell dilution after be seeded in 96 orifice plates, continuation cultivated for 24 hours in cell incubator.In primary dcreening operation, by sample
It is added in 96 orifice plates, and each compound is respectively provided with 3 as parallel test.Placing will be each after cultivating 48h in incubator
CCK-8 solution is added in a hole, continues to cultivate 3h.It is placed on shaking table after shaking, is detected using microplate reader in the case where wavelength is 450nm
Absorbance (OD value) calculates sample to be tested to the survival rate of tumor cell line.The compound 1-24 and reference substance measured
Inhibiting rate when vemurafenib concentration is 10 μm of ol/L is shown in Table 1.
1. compound of table is to A375 and A375RThe inhibiting rate (100%) of tumor cell line
Note: inhibiting rate indicates the average value of three parallel laboratory tests when compound concentration is 10 μm of ol/L, A375RIt is pair
Vemurafenib has the cell of drug resistance.
It can be seen that vemurafenib to A375 from the data in table 1RThere is no inhibiting effect, is successfully established drug resistance black
Plain oncocyte system, 14,15,23 couples of A375 of compoundRInhibiting effect comparison A375 is strong, is expected to become solution clinically melanoma
The lead compound of patient's drug resistance.
Claims (9)
1. a kind of pyrazoline class compound, it is characterised in that its general structure is as follows:
Wherein, R1Selected from H, 4-CH3、4-OCH3, 4-Br or 4-Cl；R2Selected from 4-Cl, 4-F, 4-OCH3Or 4-CH3。
2. pyrazoline class compound according to claim 1, it is characterised in that its structure is as follows:
3. a kind of preparation method of pyrazoline class compound of any of claims 1 or 2, it is characterised in that including walking as follows
It is rapid:
Step 1: benzaldehyde derivative A and acetophenone derivs B are dissolved in respectively in 20mL ethyl alcohol, uniformly backward reaction to be mixed
It is 10%NaOH solution that 6.5mL concentration is slowly added dropwise in liquid, and stirring at normal temperature is reacted, and monitors extent of reaction, about 3h with TLC
Afterwards, product is precipitated in solid form；After reaction, it stands, filters, successively use distilled water and ethanol washing, obtained after dry
To chalcone derivative C；
Wherein, R1Selected from H, 4-CH3、4-OCH3, 4-Br or 4-Cl；R2Selected from 4-Cl, 4-F, 4-OCH3Or 4-CH3；
Step 2: the chalcone derivative C after taking drying is dissolved in 20mL normal propyl alcohol, and the hydrazine hydrate of 0.6mL80% is then added,
98 DEG C of reflux are heated to, TLC constantly monitors extent of reaction, and after fully reacting, reaction solution is cooled to 5 DEG C hereinafter, product is automatic
It is precipitated, stands, filter and with ethyl alcohol recrystallization, obtain 3,5- diphenyl -4,5- dihydro-1 h-pyrazole derivatives D；
Wherein, R1Selected from H, 4-CH3、4-OCH3, 4-Br or 4-Cl；R2Selected from 4-Cl, 4-F, 4-OCH3Or 4-CH3；
Step 3: quinoxaline carboxylic acid's derivative, EDCI and HOBT being dissolved in 20mL DMF solution, 3,5- are added after half an hour
Diphenyl -4,5- dihydro-1 h-pyrazole derivatives D 1.2mmol, stirring at normal temperature are simultaneously monitored with TLC；After fully reacting, reaction solution
Water, 5%HCl, 5%Na are used respectively2CO3Solution is washed and is extracted with ethyl acetate, organic phase anhydrous Na2SO4It dries and depressurizes
Distillation, crude product are isolated and purified with thin layer chromatography, obtain target product.
4. preparation method according to claim 3, it is characterised in that:
In step 1, the ratio between amount of substance of benzaldehyde derivative A and acetophenone derivs B is 1:1.
5. preparation method according to claim 3, it is characterised in that:
In step 2, the ratio of chalcone derivative C and hydrazine hydrate is that 0.2mL80% water is added in every mM of chalcone derivative
Close hydrazine.
6. preparation method according to claim 3, it is characterised in that:
In step 3, quinoxaline carboxylic acid's derivative, 3,5- diphenyl -4,5- dihydro-1 h-pyrazole derivatives D, EDCI and HOBT
The mass ratio of the material is 1:1.2:1.2:1.3.
7. the preparation method according to claim 3 or 6, it is characterised in that:
In step 3, quinoxaline carboxylic acid's derivative is quinoxalin-2-carboxylic acid or quinoxaline -6- carboxylic acid.
8. a kind of purposes of pyrazoline class compound of any of claims 1 or 2 is in the bis- target spot suppressions of preparation BRAF/P13K
The application of preparation.
9. application according to claim 8, it is characterised in that:
The pyrazoline analog derivative has the melanoma cells A375 of drug resistance to vemurafenibRThere is good antiproliferative
Activity.
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