CN106674149B - Chalcone compounds that thiazoline replaces, preparation method and its as the application for preparing antineoplastic - Google Patents
Chalcone compounds that thiazoline replaces, preparation method and its as the application for preparing antineoplastic Download PDFInfo
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- CN106674149B CN106674149B CN201611085787.1A CN201611085787A CN106674149B CN 106674149 B CN106674149 B CN 106674149B CN 201611085787 A CN201611085787 A CN 201611085787A CN 106674149 B CN106674149 B CN 106674149B
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- thiazoline
- methyl
- imido grpup
- ketone
- alkene
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/40—Unsubstituted amino or imino radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The chalcone compounds that thiazoline replaces, shown in structure such as formula (I):, the R1For H or in phenyl ring difference the position of substitution and the different CH for replacing number3、Cl、Br、F、CH3O、NO2、‑CH3CH2O；R2For H or in phenyl ring difference the position of substitution and the different CH for replacing number3、Cl、Br、F、CH3O、NO2、‑CH3CH2O or, preparation method of the present invention include first by 2- imido grpup -3- aryl -4- methyl -5- acetyl group -4-2,3- thiazoline and substituted benzaldehyde carry out under alkaline condition Claisen-Schmidt condensation reaction obtain formula (
Description
Technical field
The present invention relates to antitumor action thiazoline replace chalcones derivative, preparation method and
Prepare the application in terms of antineoplastic.
Background technique
Tumour great threat human health, anti-tumor drug research is that challenge and meaning weight are rich in current life science
Big field.According to statistics, malignant tumour is died of there are about 8,000,000 people every year in the whole world, and China is every year because cancer mortality case is up to 2,750,000
People.Cancer has become dead first reason in China, and death toll accounts for about its death toll a quarter of global cancer.At present in the world
Clinically used anti-tumor drug has reached more than 100, and clinically therapeutic effect is also more apparent, but most of antineoplastics
Object toxic side effect is larger, and specific low, poor selectivity is easy to produce serious cancer multi-drug resistance phenomenon.
With the rapid development of molecular biology and related discipline, people gradually recognize that the essence of cell carcinogenesis is cell
Cell infinite multiplication caused by signal transduction pathway is lacked of proper care.Current anticancer medicine is just from traditional cytotoxic drug, to needle
New type anticancer disease drug development to intracellular improper signal conduction.Pay close attention to the new of the antitumaous effect of most study both at home and abroad at present
One of target spot is protein tyrosine kinase (Protein tyrosine kinases, PTKs), can be divided into receptor by its structure
Type tyrosine kinase (receptor Protein tyrosine kinase, RPTKs) and non-receptor type (non-receptor
Protein tyrosine kinases, nrPTKs) two kinds.Protein tyrosine kinase has more than more than 20 at present and adheres to not consanguinity separately
The receptor and nonreceptor tyrosine kinase of race are carried out screening anticancer medicine as target, and inhibitor has had several listings,
In order to find the better drug of activity, in recent years, molecular targeted drug therapy is inhibited from single target spot to multiple target point tyrosine kinase
Agent development, becomes the important directions of anti-tumor drug research and development.
Summary of the invention
The chalcones that replace the object of the present invention is to provide a kind of thiazoline with Formulas I and its can pharmaceutically it receive
Salt.
It is a further object to provide prepare the compound with Formulas I and its pharmaceutically system of acceptable salt
Preparation Method.
It is also another object of the present invention to provide the compound for containing Formulas I and its its pharmaceutically acceptable salt as having
The Pharmaceutical composition of ingredient and one or more pharmaceutically acceptable carriers, excipient or diluent is imitated, with it anti-swollen
Application in terms of tumor.
The purpose of the present invention is achieved through the following technical solutions.
The present invention has following structural formula with the compound of Formulas I:
In formula:
R1For H or in phenyl ring difference the position of substitution and different halogen, alkyl, naphthenic base, aryl, the heterocycles for replacing number
Aryl, hydroxyl, alkoxy, nitro, amino ,-CN ,-(CO) R3、-NR4R5、-C(O)NR6R7、-(CH2)nR8、-SO2R9、-S(O)2NR4R5；
R2For H or in phenyl ring difference the position of substitution and the different halogen for replacing number, alkoxy, cycloalkyloxy, alkyl,
Naphthenic base, aryl, heteroaryl, hydroxyl, nitro, amino ,-CN ,-(CO) R3、-NR4R5、-C(O)NR6R7、-(CH2)nR8、-
SO2R9、-S(O)2NR4R5；
R3For hydroxyl, alkoxy, aryloxy group；
R4For H, alkyl, naphthenic base, aryl, heteroaryl；
R5For H, alkyl, naphthenic base, aryl, heteroaryl or R4、R5Heterocycle is combined into N；
R6For H, alkyl, aryl；
R7For H, alkyl, aryl；
R8For H ,-(CO) R3、-NR4R5、-C(O)NR6R7、-SO2R9、-S(O)2NR4R5；
R9For alkyl, aryl, aralkyl, heteroaryl；
N is 1,2,3,4.
Wherein preferred formula R1For H or in phenyl ring difference the position of substitution and the different CH for replacing number3、Cl、Br、F、
CH3O、NO2、-CH3CH2O；R2For H or in phenyl ring difference the position of substitution and the different CH for replacing number3、Cl、Br、F、CH3O、
NO2、-CH3CH2O or。
The form of salt described in its formula (I) compound is hydrochloride, hydrobromate, acetate, perchlorate, sulfate, phosphorus
Hydrochlorate, nitrate, mesylate, tosilate, oxalates.
From structural formula as can be seen that thiazoline replace chalcones be alternatively referred to as (E) -1- (2- imido grpup -3- aryl -
4- methyl -2- thiazoline -5) -3- aryl -propyl- 2- alkene -1- ketone derivatives.
The present invention provides that a kind of technological operation is simple, reaction condition is mild, highly-safe, reaction yield is higher, steady in turn
The chalcones preparation method that thiazoline fixed, that product purity is high, environmental pollution is small replaces.
Described (E) -1- (2- imido grpup -3- aryl -4- methyl -2- thiazoline -5) -3- aryl -propyl- 2- alkene -1- ketone spreads out
The preparation method of biology includes first by 2- imido grpup -3- aryl -4- methyl -5- acetyl group -4-2,3- thiazoline and substituted benzene
Formaldehyde carry out under alkaline condition Claisen-Schmidt condensation reaction obtain formula () compound.Reaction equation is as follows:
The synthetic method include: 2- imido grpup -3- aryl -4- methyl -5- acetyl group -4-2,3- thiazoline and
Aromatic formaldehyde is in organic solventIn be stirred to react at -10~20 DEG C, be added dropwise lye, be added dropwise.Naturally it is warming up to room temperature 20-
25 DEG C are reacted 4~26 hours, are poured into ice water, adjust pH to faintly acid, solids is precipitated, filters, after recrystallization to obtain the final product.
The reaction raw materials molar ratio is 2- imido grpup -3- aryl -4- methyl -5- acetyl group -4-2,3- thiazoline:
Aromatic formaldehyde is 1:1.1~2.5.
The organic solvent I is one of ethyl alcohol, methanol, tetrahydrofuran, dioxane etc. or more than one are any
The mixture of ratio, solvent usage are the 5-20 of 2- imido grpup -3- aryl -4- methyl -5- acetyl group -4-2,3- thiazoline
Times.Preferably methanol: tetrahydrofuran=3:1, dosage are 2- imido grpup -3- aryl -4- methyl -5- acetyl group -4-2,3- dihydro thiophene
9-20 times of azoles.
The lye of above-mentioned reaction is 10-40%KOH or 10-40%NaOH solution or triethylamine.
It is prepared by the chalcones and its pharmaceutically acceptable salt replaced the invention also includes thiazoline described in formula (I)
Application in anti-tumor drug.
Formula (I) compound of the present invention has the inhibiting effect for cancer, can be used as an active ingredient in the preparation of cancer
Therapeutic agent in terms of disease.The activity of (I) compound of the present invention is verified by anti tumor activity in vitro model.
Formula (I) compound of the present invention has the beneficial effect that:
(1) present invention has obtained the chalcones that the special noval chemical compound thiazoline of a class formation replaces.
(2) solvent and reaction condition of the invention are used, can higher yields obtain target product, and the side of post-processing
Just, crude product purity can react enough directly as next step.
(3) target product is found to have certain life through BGC-823, PC-3, NCI-H460, BEL-7402 in-vitro screening
Object activity.
Specific embodiment
Below with reference to embodiment, the present invention is further illustrated.It should be noted that following example examples are only for
Illustrate, and is not intended to limit the present invention.The various change that those skilled in the art's training centre according to the present invention is made should all
Within protection scope required by the claim of this application.
Embodiment 1
Equipped with mechanical stirring, reflux condenser, thermometer 100mL three-necked flask in, by chlorobenzene between 2- imido grpup -3-
Base -4- methyl -5- acetyl group -4-2,3- thiazoline (2.665g, 10mmol) and p-tolualdehyde (1.44g, 12mmol)
It is added in 30mL methanol and 10mL tetrahydrofuran solution, stirs lower 10 °C of control or less and 30% NaOH solution of 5.5mL is added dropwise,
It is added dropwise, continuation is reacted in ice-water bath, warms naturally to 25 °C of room temperature, reacts 26 hours (TLC tracking and monitoring).Stop anti-
It answers, is put into refrigerator after being continued several minutes of stirring with glacial acetic acid tune pH to neutrality and stands a period of time, yellow solid is obtained, with third
After ketone/tetrahydrofuran recrystallization, yellow crystals, yield 67.8%, m.p. 225-227 °C are obtained；IRυmax(KBr)/cm-1: 3443,
3268, 3034, 1650, 1604, 1579, 1475. 1H NMR (500 MHz, CDCl3, TMS) δ: 7.73 (d,
1H, J = 15.5Hz, =CH), 7.52-7.49 (m, 4H, Ar-H), 7.33 (s, 1H, Ar-H), 7.23-7.20
(m, 3H, Ar-H), 6.92 (d, 1H, J = 14.5Hz, =CH), 2.40 (s, 3H, CH3), 2.32 (s, 3H,
CH3). EIMS m/z (%): 368 [M+], 351 (8), 340 (8), 312 (7), 279 (13), 277 (35),
264 (13), 236 (10), 216 (15), 201 (8), 183 (8), 152 (14), 115 (34), 91 (12),
75 (10). Anal. Calcd for C20H17ClN2OS: C, 65.12; H, 4.65; N, 7.59. Found: C,
65.31; H, 4.72; N, 7.51。
Embodiment 2
Equipped with mechanical stirring, reflux condenser, thermometer 100mL three-necked flask in, by chlorobenzene between 2- imido grpup -3-
Base -4- methyl -5- acetyl group -4-2,3- thiazoline (2.665g, 10mmol) and 3,4- methylenedioxy benzene formaldehyde (1.8g,
It 12mmol) is added in 30mL methanol and 10mL tetrahydrofuran solution, stirs lower 10 °C of control or less and 5.5mL 30% is added dropwise
NaOH solution is added dropwise, and continuation is reacted in ice-water bath, warms naturally to 25 °C of room temperature, 15 hours (TLC tracking prisons of reaction
It surveys).Stop reaction, is put into refrigerator after being continued several minutes of stirring with glacial acetic acid tune pH to neutrality and stands a period of time, obtained yellow
Color solid obtains yellow solid after acetone/tetrahydrofuran recrystallization, yield 70.3%, and mp:225-227 °C；IRυmax(KBr)/
cm-1: 3418, 3270, 3036, 1651, 1602, 1578, 1487. 1H NMR (500 MHz, CDCl3, TMS)
δ: 7.66 (d, 1H, J=15.0Hz, =CH), 7.53-7.49 (m, 2H, Ar-H), 7.33(s, 1H, Ar-H),
7.22-7.20 (m, 1H, Ar-H), 7.09 (d, 2H, J = 8.0Hz, Ar-H), 6.84 (d, 1H, J =
7.5Hz, Ar-H), 6.78 (d, 1H, J = 15.5Hz, =CH), 6.03 (s, 2H, CH2), 2.31 (s, 3H,
CH3). EIMS m/z (%):398 [M+], 381 (5), 370 (31), 363 (20), 342 (9), 277 (24),
264 (75), 236 (20), 223 (20), 201 (10), 185 (20), 152 (64), 145 (55), 135
(75), 117 (40), 89 (90), 75 (27), 63 (40). Anal. Calcd for C20H15ClN2O3S: C,
60.22; H, 3.79; N, 7.02. Found: C, 60.31; H, 3.85; N, 7.11。
Embodiment 3
Equipped with mechanical stirring, reflux condenser, thermometer 100mL three-necked flask in, by 2- (3,4-DCA
Base) -4- methyl -5- acetylthiazole (3.01g, 10mmol) and p-tolualdehyde (1.44g, 12mmol) be added to 30mL first
In pure and mild 10mL tetrahydrofuran solution, stirs lower 10 °C of control or less and 30% NaOH solution of 5.5mL is added dropwise, be added dropwise, continue
It is reacted in ice-water bath, warms naturally to 25 °C of room temperature, react 20 hours (TLC tracking and monitoring).Stop reaction, with glacial acetic acid tune
PH is put into refrigerator after continuing several minutes of stirring to neutrality and stands a period of time, yellow solid is obtained, with acetone/tetrahydrofuran weight
After crystallization, yellow solid, yield 54.6%, m.p. 249-251 °C are obtained；IRυmax(KBr)/cm-1: 3446, 3267, 1649,
1602, 1577, 1531, 1471. 1H NMR (500 MHz, CDCl3, TMS) δ: 7.73 (d, 1H, J =
15.5Hz, =CH), 7.64(d, 1H, J = 9.0Hz, Ar-H), 7.49 (d, 2H, J = 8.5Hz, Ar-H),
7.44 (d, 1H, J = 2.5Hz, Ar-H), 7.22 (d, 1H, J = 7.5Hz, Ar-H), 7.18 (dd, 1H,J 1 = 2.0Hz, J 2 = 2.0Hz,Ar-H), 6.90 (d, 1H, J = 15.0Hz, =CH), 2.40 (s, 3H, CH3),
2.33 (s, 3H, CH3). EIMS m/z (%): 402 [M+], 387 (7), 346 (6), 311 (37), 298
(14), 270 (13), 257 (15), 216 (42), 201 (22), 186 (50), 145 (45), 128 (10),
115 (80), 91 (37), 65 (18). Anal. Calcd for C20H16Cl2N2OS: C, 59.56; H, 4.00;
N, 6.95. Found: C, 59.67; H, 4.13; N, 6.84。
Embodiment 4
Equipped with mechanical stirring, reflux condenser, thermometer 100mL three-necked flask in, by 2- (3,4-DCA
Base) -4- methyl -5- acetylthiazole (3.01g, 10mmol) and 3,4- methylenedioxy benzene formaldehyde (1.8g, 12mmol) plus
Enter into 30mL methanol and 10mL tetrahydrofuran solution, stirs lower 10 °C of control or less and 30% NaOH solution of 5.5mL, drop is added dropwise
Add complete, continuation is reacted in ice-water bath, warms naturally to 25 °C of room temperature, reacts 18 hours (TLC tracking and monitoring).Stop anti-
It answers, is put into refrigerator after being continued several minutes of stirring with glacial acetic acid tune pH to neutrality and stands a period of time, yellow solid is obtained, with third
After ketone/tetrahydrofuran recrystallization, yellow solid, yield 69.4%, m.p. 247-249 °C are obtained；IRυmax(KBr)/cm-1: 3418,
3272, 1645, 1602, 1589, 1501, 1449. 1H NMR (500 MHz, CDCl3, TMS) δ: 7.67 (d,
1H, J=15.5Hz, =CH), 7.65-7.64 (m*, 1H, Ar-H), 7.44(d, 1H, J = 2.5Hz, Ar-H),
7.18 (dd, 1H, J 1 = 2.0Hz, J 2 = 3.0Hz, Ar-H), 7.10-7.08 (m, 2H, Ar-H), 6.84 (d,
1H, J = 9.0Hz, Ar-H), 6.77 (d, 1H, J = 15.5Hz, =CH), 6.04 (s, 2H, CH2), 2.33
(s, 3H, CH3)(* overlapped with =CH). EIMS m/z (%): 432 (M+, 100), 404 (15), 397
(20), 311 (14), 298 (35), 270 (15), 246 (32), 218 (18), 186 (55), 169 (13),
145 (75), 135 (100), 117 (35), 109 (15), 89 (82), 74 (8), 63 (43). Anal.
Calcd for C20H14Cl2N2O3S: C, 55.44; H, 3.26; N, 6.47. Found: C, 55.29; H, 3.51;
N, 6.59。
Embodiment 5,
Equipped with mechanical stirring, reflux condenser, thermometer 100mL three-necked flask in, by 2- m-chloroaniline base -4- first
Base -5- acetylthiazole (2.132g, 8mmol) and 3,4,5-Trimethoxybenzaldehyde (1.8816g, 9.6mmol) are added to
In 30mL methanol and 10mL tetrahydrofuran solution, stirs lower 10 °C of control or less and 30% NaOH solution of 5.5mL is added dropwise, drip
Finish, continuation is reacted in ice-water bath, warms naturally to 25 °C of room temperature, reacts 9 hours (TLC tracking and monitoring).Stop reaction, uses ice
Acetic acid tune pH is put into refrigerator after continuing several minutes of stirring to neutrality and stands a period of time, yellow solid is obtained, with acetone/tetrahydro
After furans recrystallization, yellow solid is obtained, yield 72.3%, 225~227 DEG C of m.p..IR υmax (KBr)/cm-1: 3446,
3284, 3130, 2991, 2917, 1625, 1583, 1502, 1472. 1H NMR (400 MHz, CDCl3, TMS)
δ: 7.66 (d, J = 15.2 Hz, 1H, =CH), 7.45 (t, J = 2.0 Hz, 1H, Ar-H), 7.34-7.28
(m, 2H, Ar-H), 7.15 (d, J = 7.6 Hz, 1H, Ar-H), 7.04 (d, J = 15.2 Hz, 1H, =
CH), 6.80 (s, 2H, Ar-H), 3.91 (s, 6H, 2´OCH3), 3.90 (s, 3H, OCH3), 2.71 (s,
3H, CH3). EIMS m/z(%): 444 (M+, 100), 413 (12), 364 (16), 318 (90), 277 (6),
181 (79), 111 (22), 91 (21) Anal. calculated value C22H21ClN2O4S: C, 59.39; H, 4.76; N,
6.30. measured value C, 59.37; H, 4.81; N, 6.43.
Embodiment 6,
Equipped with mechanical stirring, reflux condenser, thermometer 100mL three-necked flask in, by 2- (3,4-DCA
Base) -4- methyl -5- acetylthiazole (3.01g, 10mmol) and 3,4,5-Trimethoxybenzaldehyde (2.352g, 12mmol)
It is added in 30mL methanol and 10mL tetrahydrofuran solution, stirs lower 10 °C of control or less and 30% NaOH solution of 5.5mL is added dropwise,
It is added dropwise, continuation is reacted in ice-water bath, warms naturally to 25 °C of room temperature, reacts 12 hours (TLC tracking and monitoring).Stop anti-
It answers, is put into refrigerator after being continued several minutes of stirring with glacial acetic acid tune pH to neutrality and stands a period of time, yellow solid is obtained, with third
After ketone/tetrahydrofuran recrystallization, yellow solid is obtained, yield 58.4%, 241~244 DEG C of m.p..IR υmax (KBr)/cm-1:
3434, 3265, 3100, 1642, 1585, 1541, 1474. 1H NMR (400 MHz, CDCl3, TMS) δ: 7.66
(d, J = 15.6 Hz, 1H, =CH), 7.62 (d, J = 2.8 Hz, 1H, Ar-H), 7.45 (d, J = 9.2
Hz, 1H, Ar-H), 7.32 (dd, J 1 = 2.4 Hz, J 2 = 2.8 Hz, 1H, Ar-H), 7.03 (d, J = 15.2
Hz, 1H, =CH), 6.81 (s, 2H, Ar-H), 3.91 (s, 6H, 2´OCH3), 3.90 (s, 3H, OCH3),
2.72 (s, 3H, CH3). EIMS m/z(%): 478 (M+, 15), 318 (16), 181 (20), 111 (20), 97
(32), 83 (37), 69 (55), 55 (100) Anal. calculated value C22H20Cl2N2O4S: C, 55.12; H,
4.21;N, 5.84. measured value C, 55.25; H, 4.31; N, 5.65.
Embodiment 7,
Equipped with mechanical stirring, reflux condenser, thermometer 100mL three-necked flask in, by 2- ortho-aminotoluene base -4- first
Base -5- acetylthiazole (2.46g, 10mmol) and m-methoxybenzaldehyde (1.632g, 12mmol) are added to 30mL methanol
In 10mL tetrahydrofuran solution, stirs lower 10 °C of control or less and 30% NaOH solution of 5.5mL is added dropwise, be added dropwise, continue
It is reacted in ice-water bath, warms naturally to 25 °C of room temperature, react 5 hours (TLC tracking and monitoring).Stop reaction, with glacial acetic acid tune pH
It is put into refrigerator after continuing several minutes of stirring to neutrality and stands a period of time, obtain yellow solid, tied again with acetone/tetrahydrofuran
After crystalline substance, yield 56.2%, 193~195 DEG C of m.p..IR υmax (KBr)/cm-1: 3445, 3205, 2916, 2848,
1645, 1503, 1495. 1H NMR (400 MHz, CDCl3, TMS) δ: 7.68 (d, J = 15.6 Hz, 1H, =
CH), 7.53 (d, J = 8.0 Hz, 1H, Ar-H), 7.35-7.29 (m, 3H, Ar-H), 7.23-7.16 (m,
2H, Ar-H), 7.08 (d, J = 15.6 Hz, 1H, =CH), 7.07 (m*, 1H, Ar-H), 6.95 (dd, J1
= 2.0 Hz, J2 = 2.8 Hz, 1H, Ar-H), 3.85 (s, 3H, OCH3), 2.70 (s, 3H, CH3), 2.35
(s, 3H, CH3) (* and=CH overlap of peaks) EIMS m/z (%): 364 (M+, 100), 347 (16), 257 (47),
243 (25), 161 (25), 133 (20), 118 (45), 91 (28) Anal. calculated value C21H20N2O2S: C,
69.20; H, 5.53;N, 7.69. measured value C, 69.25; H, 5.71; N, 7.56.
Embodiment 8,
Equipped with mechanical stirring, reflux condenser, thermometer 100mL three-necked flask in, by 2- ortho-aminotoluene base -4- first
Base -5- acetylthiazole (2.46g, 10mmol) and o-chlorobenzaldehyde (1.686g, 12mmol) be added to 30mL methanol and
In 10mL tetrahydrofuran solution, stirs lower 10 °C of control or less and 30% NaOH solution of 5.5mL is added dropwise, be added dropwise, continue in ice
It is reacted in water-bath, warms naturally to 25 °C of room temperature, react 8 hours (TLC tracking and monitoring).Stop reaction, extremely with glacial acetic acid tune pH
Neutrality is put into refrigerator after continuing several minutes of stirring and stands a period of time, obtain yellow solid, is recrystallized with acetone/tetrahydrofuran
Afterwards, yield 61.7%, 181~183 DEG C of m.p..IR υmax (KBr)/cm-1: 3445, 3164, 2917, 2849, 1645,
1589, 1562, 1484. 1H NMR (400 MHz, CDCl3, TMS) δ: 8.12 (d, J = 15.6 Hz, 1H, =
CH), 7.65 (dd, J1 = 2.4 Hz, J2 = 2.4 Hz, 1H, Ar-H), 7.54 (d, J = 8.8 Hz, 1H,
Ar-H), 7.43 (dd, J1 = 2.0 Hz, J2 = 0.8 Hz, 1H, Ar-H), 7.33-7.27 (m, 4H, Ar-H),
7.23-7.20 (m, 1H, Ar-H), 7.07 (d, J = 15.2 Hz, 1H, =CH), 2.69 (s, 3H, CH3),
2.35 (s, 1H, CH3). EIMS m/z(%): 368 (M+, 100), 333 (29), 257 (57), 165 (25),
137 (31), 117 (21), 101 (62), 91 (25) Anal. calculated value C20H17ClN2OS: C, 65.12; H,
4.65;N, 7.59. measured value C, 65.21; H, 4.63; N, 7.45.
Embodiment 9,
Equipped with mechanical stirring, reflux condenser, thermometer 100mL three-necked flask in, by 2- parachloroanilinum base -4- first
Base -5- acetylthiazole (2.132g, 8mmol) and m-methoxybenzaldehyde (1.3056g, 9.6mmol) are added to 30mL first
In pure and mild 10mL tetrahydrofuran solution, stirs lower 10 °C of control or less and 30% NaOH solution of 5.5mL is added dropwise, be added dropwise, continue
It is reacted in ice-water bath, warms naturally to 25 °C of room temperature, react 9 hours (TLC tracking and monitoring).Stop reaction, with glacial acetic acid tune
PH is put into refrigerator after continuing several minutes of stirring to neutrality and stands a period of time, yellow solid is obtained, with acetone/tetrahydrofuran weight
After crystallization, yield 58.8%, 195~197 DEG C of m.p..IR υmax (KBr)/cm-1: 3445, 3283, 3129, 1644,
1608, 1555, 1486. 1H NMR (400 MHz, CDCl3, TMS) δ: 7.72 (d, J = 15.2 Hz, 1H, =
CH), 7.41-7.31 (m, 5H, Ar-H), 7.21 (d, J = 7.6 Hz, 1H, Ar-H), 7.13 (d, J =
15.2 Hz, 1H, =CH), 7.11 (m*, 1H, Ar-H), 6.96 (dd, J1 = 2.0 Hz, J2 = 2.4 Hz,
1H, Ar-H), 3.86 (s, 3H, OCH3), 2.70 (s, 3H, CH3) (* and=CH overlap of peaks) EIMS m/z (%):
384 (M+, 100), 277 (47), 263 (25), 258 (36), 161 (18), 118 (25), 90 (25), 71
(18) Anal. calculated value C20H17ClN2O2S: C, 62.41; H, 4.45;N, 7.28. measured value C, 62.61;
H, 4.72; N, 7.35。
Embodiment 10,
Equipped with mechanical stirring, reflux condenser, thermometer 100mL three-necked flask in, by 2- para-totuidine base -4- first
Base -5- acetylthiazole (2.46g, 10mmol) and 3,4- dioxy methylene benzaldehyde (1.8g, 12mmol) are added to 30mL first
In pure and mild 10mL tetrahydrofuran solution, stirs lower 10 °C of control or less and 30% NaOH solution of 5.5mL is added dropwise, be added dropwise, continue
It is reacted in ice-water bath, warms naturally to 25 °C of room temperature, react 13 hours (TLC tracking and monitoring).Stop reaction, with glacial acetic acid tune
PH is put into refrigerator after continuing several minutes of stirring to neutrality and stands a period of time, yellow solid is obtained, with acetone/tetrahydrofuran weight
After crystallization, yield 37.8%, 228~230 DEG C of m.p..IR υmax (KBr)/cm-1: 3419, 3167, 2918, 1647,
1583, 1487. 1H NMR (500 MHz, CDCl3, TMS) δ:7.66 (d, J = 15.5 Hz, 1H, =CH),
7.27-7.23 (m, 4H, Ar-H), 7.10 (d, J = 2.0 Hz, 1H, Ar-H), 7.08 (dd, J1 = 1.5
Hz, J2 = 1.5 Hz, 1H, Ar-H), 6.97 (d, J = 15.5 Hz, 1H, =CH), 6.83 (d, J = 8.5
Hz, 1H, Ar-H), 6.02 (s, 2H, CH2), 2.66 (s, 3H, CH3), 2.38 (s, 3H, CH3). EIMS
m/z(%):378 (M+, 100), 272 (51), 257 (27), 243 (38), 145 (23), 118 (22), 91
(29), 63 (24) Anal. calculated value C21H18N2O3S: C, 66.65; H, 4.79;N, 7.40. measured value C,
66.79; H, 4.67; N, 7.58。
Embodiment 11,
Equipped with mechanical stirring, reflux condenser, thermometer 100mL three-necked flask in, by 2- ortho-aminotoluene base -4- first
Base -5- acetylthiazole (1.968g, 8mmol) and benzaldehyde (1.0176g, 9.6mmol) are added to 30mL methanol and 10mL tetra-
In hydrogen tetrahydrofuran solution, stirs lower 10 °C of control or less and 30% NaOH solution of 5.5mL is added dropwise, be added dropwise, continue in ice-water bath
Reaction warms naturally to 25 °C of room temperature, reacts 4 hours (TLC tracking and monitoring).Stop reaction, with glacial acetic acid tune pH to neutrality, after
After several minutes of continuous stirring, it is put into refrigerator and stands a period of time, obtain yellow solid, after acetone/tetrahydrofuran recrystallization, yield
194~196 DEG C of 38.2%, m.p..IR υmax (KBr)/cm-1: 3415, 3179, 3055, 2916, 1648, 1591,
1493. 1H NMR (400 MHz, CDCl3, TMS) δ: 7.71 (d, J = 15.6Hz, 1H, =CH), 7.59-7.54
(m, 3H, Ar-H), 7.39 (t, J = 3.2 Hz, 3H, Ar-H), 7.33 (t, J = 7.2 Hz, 2H, Ar-
H), 7.23-7.19 (m, 1H, Ar-H), 7.11 (d, J = 15.6 Hz, 1H, =CH), 2.68 (s, 3H,
CH3), 2.35 (s, 3H, CH3). EIMS m/z(%): 334 (M+, 100), 317 (22), 257 (49), 228
(24), 202 (18), 131 (47), 103 (58), 91 (24) Anal. calculated value C20H18N2OS: C, 71.83;
H, 5.42;N, 8.38. measured value C, 71.77; H, 5.59; N, 8.56.
Embodiment 12,
Equipped with mechanical stirring, reflux condenser, thermometer 100mL three-necked flask in, by 2- parachloroanilinum base -4- first
Base -5- acetylthiazole (2.132g, 8mmol) and 3,4,5-Trimethoxybenzaldehyde (1.8816g, 9.6mmol) are added to
In 30mL methanol and 10mL tetrahydrofuran solution, stirs lower 10 °C of control or less and 30% NaOH solution of 5.5mL is added dropwise, drip
Finish, continuation is reacted in ice-water bath, warms naturally to 25 °C of room temperature, reacts 6 hours (TLC tracking and monitoring).Stop reaction, uses ice
Acetic acid tune pH is put into refrigerator after continuing several minutes of stirring to neutrality and stands a period of time, yellow solid is obtained, with acetone/tetrahydro
After furans recrystallization, yield 52.7%, 223~225 DEG C of m.p..IR υmax (KBr)/cm-1: 3419, 3274, 3195,
3125, 2922, 1641, 1614, 1582, 1505, 1489. 1H NMR (400 MHz, CDCl3, TMS) δ: 7.67
(d, J = 15.6 Hz, 1H, =CH), 7.36 (dd, J1 = 8.8 Hz, J2 = 8.4 Hz, 4H, Ar-H), 7.01
(d, J = 15.6 Hz, 1H, =CH), 6.81 (s, 2H, Ar-H), 3.92 (s, 6H, 2´OCH3), 3.90 (s,
3H, OCH3), 2.71 (s, 3H, CH3). EIMS m/z(%): 444 (M+, 100), 318 (87), 277 (24),
263 (15), 181 (71), 152 (15), 111 (16), 71 (26) Anal. calculated value C22H21ClN2O4S: C,
59.39; H, 4.76;N, 6.30. measured value C, 59.15; H, 4.69; N, 6.53.
Embodiment 13,
Equipped with mechanical stirring, reflux condenser, thermometer 100mL three-necked flask in, by 2- para-totuidine base -4- first
Base -5- acetylthiazole (1.476g, 6mmol) and 3,4,5-Trimethoxybenzaldehyde (1.411g, 7.2 mmol) are added to
In 30mL methanol and 10mL tetrahydrofuran solution, stirs lower 10 °C of control or less and 30% NaOH solution of 5.5mL is added dropwise, drip
Finish, continuation is reacted in ice-water bath, warms naturally to 25 °C of room temperature, reacts 8 hours (TLC tracking and monitoring).Stop reaction, uses ice
Acetic acid tune pH is put into refrigerator after continuing several minutes of stirring to neutrality and stands a period of time, yellow solid is obtained, with acetone/tetrahydro
After furans recrystallization, yield 54.3%, 213~215 DEG C of m.p..IR υmax (KBr)/cm-1: 3436, 3282, 3131,
2935, 1643, 1585, 1505, 1487. 1H NMR (400 MHz, CDCl3, TMS) δ: 7.67 (d, J =
15.6 Hz, 1H, =CH), 7.25 (d, J = 3.2 Hz, 4H, Ar-H), 7.01 (d, J = 15.2 Hz, 1H,
=CH), 6.81 (s, 2H, Ar-H), 3.91 (s, 6H, 2´OCH3), 3.90 (s, 3H, OCH3), 2.70 (s,
3H, CH3), 2.37 (s, 3H, CH3). EIMS m/z(%): 424 (M+, 100), 318 (56), 257 (23),
243 (28), 181 (28), 91 (24), 69 (25), 55 (45) Anal. calculated value C23H24N2O4S: C,
65.07; H, 5.70;N, 6.60. measured value C, 65.22; H, 5.76; N, 6.64.
Embodiment 14,
Equipped with mechanical stirring, reflux condenser, thermometer 100mL three-necked flask in, by 2- meta-aminotoluene base -4- first
Base -5- acetylthiazole (2.46g, 10mmol) and m-methoxybenzaldehyde (1.632g, 12mmol) are added to 30mL methanol
In 10mL tetrahydrofuran solution, stirs lower 10 °C of control or less and 30% NaOH solution of 5.5mL is added dropwise, be added dropwise, open continuation
It is reacted in ice-water bath, warms naturally to 25 °C of room temperature, react 7 hours (TLC tracking and monitoring).Stop reaction, with glacial acetic acid tune
PH is put into refrigerator after continuing several minutes of stirring to neutrality and stands a period of time, yellow solid is obtained, with acetone/tetrahydrofuran weight
After crystallization, yield 40.8%, 164~166 DEG C of m.p..IR υmax (KBr)/cm-1: 3417, 3175, 2827, 1645,
1592, 1573, 1486. 1H NMR (400 MHz, CDCl3, TMS) δ: 7.71 (d, J = 15.6 Hz, 1H, =
CH), 7.33 (t, J = 7.4 Hz, 2H, Ar-H), 7.19 (t, J = 7.0 Hz, 2H, Ar-H), 7.15-
7.11 (m*, 2H, Ar-H), 7.14 (d, J = 15.6 Hz, 1H, =CH), 7.02 (d, J = 7.6 Hz, 1H,
Ar-H), 6.95 (dd, J1 = 2.0 Hz, J2 = 2.4 Hz, 1H, Ar-H), 3.85 (s, 3H, OCH3), 2.70
(s, 3H, CH3), 2.40 (s, 3H, CH3) (* and=CH overlap of peaks) EIMS m/z (%): 364 (M+, 100),
257 (42), 243 (22), 231 (24), 132 (22), 118 (36), 91 (32), 77 (16) Anal. meter
Calculation value C21H20N2O2S: C, 69.20; H, 5.53;N, 7.69. measured value C, 69.35; H, 5.78; N, 7.78.
Embodiment 15,
Equipped with mechanical stirring, reflux condenser, thermometer 100mL three-necked flask in, by 2- m-chloroaniline base -4- first
Base -5- acetylthiazole (2.132g, 8mmol) and benzaldehyde (1.018g, 9.6mmol) are added to 30mL methanol and 10mL
In tetrahydrofuran solution, stirs lower 10 °C of control or less and 30% NaOH solution of 5.5mL is added dropwise, be added dropwise, continue in ice-water bath
Middle reaction warms naturally to 25 °C of room temperature, reacts 6 hours (TLC tracking and monitoring).Stop reaction, with glacial acetic acid tune pH to neutrality,
It after continuing several minutes of stirring, is put into refrigerator and stands a period of time, obtain yellow solid, after acetone/tetrahydrofuran recrystallization, receive
Rate 36.4%, 210~212 DEG C of m.p..IR υmax (KBr)/cm-1:3445, 3303, 3199, 3130, 1644, 1610,
1571, 1477. 1H NMR (400 MHz, CDCl3, TMS) δ: 7.76 (d, J = 15.2 Hz, 1H, =CH),
7.63-7.59 (m, 2H, Ar-H), 7.43-7.40 (m, 4H, Ar-H), 7.36-7.28 (m, 2H, Ar-H),
7.17 (d, J = 15.2 Hz, 1H, =CH), 7.16-7.13 (m*, 1H, Ar-H), 2.72 (s, 3H, CH3)
(* and=CH overlap of peaks) EIMS m/z (%): 354 (M+, 70), 277 (37), 228 (24), 183 (19), 131
(26), 111 (27), 103 (72), 97 (28) Anal. calculated value C19H15ClN2OS: C, 64.31; H, 4.26;
N, 7.89. measured value C, 64.43; H, 4.44; N, 7.71.
Embodiment 16
The inhibition cancer cell of above compound is tested.
(1) material
Cell strain: human gastric cancer, human prostata cancer PC-3 cell, human lung cancer NCI-H460 cell, human liver cancer
BEL-7402 cell is purchased from Chinese Academy of Sciences's Shanghai school of life and health sciences cell bank.
Reagent: DMEM culture medium, Gibco Products；MTT, Sigma Products, grow directly from seeds cellular biological technique in Shanghai
Co., Ltd's packing；Fetal calf serum: Hangzhou Sijiqing Biological Engineering Material Co., Ltd.；Pen .- Strep: Gibco company
Product；EDTA- pancreatin digestive juice: Gibco Products；Positive control: cis-platinum, Qilu Pharmaceutical Co., Ltd.'s product, product batch
Number: 9060251DC.
Instrument: CO2 Incubator, U.S.'s NAPCO Products；Inverted microscope, Japanese OLYMPUS Products；Biology
Safety cabinet, U.S.'s LABCONCO Products；Microplate reader, upper Hisoon reach Medical Devices Co., Ltd.'s product；LDZX-40BI type
Vertical automatic electric heating pressure steam sterilizer, Shenan Medical Appliances Factory, Shanghai's product；Thermo IEC high-speed refrigerated centrifuge, beauty
Power & light company, state product.
(2) method
The culture of cell: tumor cell inoculation is inactivating calf serum containing 10%, contains 800,000 in every 1000 mL culture medium
In the DMEM culture solution of units of Penicillin and 1.0 g streptomysins, 37 DEG C are set, 5%CO2It is cultivated in incubator, 3~5d passage.
Mtt assay measurement: cell EDTA- pancreatin digestive juice is digested, and is diluted to 1 × 106/mL with culture medium, is added to
In 96 porocyte culture plates, every 100 uL of hole sets 37 DEG C, 5% CO2It is cultivated in incubator.After being inoculated with 24 h, inclines and cultivate
Base, is added and uses the diluted sample of culture medium, every 200 μ L of hole, and each concentration adds 3 holes, sets 37 DEG C, 5%CO2It is trained in incubator
It supports, the MTT of 5 mg/mL, every 10 μ L of hole is added after 72 h in cell culture well, set 37 DEG C of incubation 3h, DMSO is added, often
150 μ L of hole, is vibrated with oscillator, and Shi formazan is completely dissolved, with microplate reader under 570 nm wavelength colorimetric.It is used with similarity condition
Without sample, the cell of the culture medium culture containing same concentration DMSO calculates sample to the half of growth of tumour cell as control
Number lethasl concentration (IC50).
(3) result
The compound of above-described embodiment 1-15 is listed in table 1.
1 compound structure of table and title
Antitumor BGC-823, PC-3, NCI-H460 and BEL-7402 activity data of 2 Compound ira vitro of table
(4) conclusion
Compound 2 has stronger inhibiting effect IC to human gastric cancer50It is 6.42 μM.Compound 8 is to people forefront
Gland cancer PC-3 cell has stronger inhibiting effect IC50It is 7.67 μM.Such compound is to human lung cancer NCI-H460 cell and people liver
Cancer BEL-7402 cell inhibitory activity is weaker.
Claims (11)
1. the chalcone compounds that thiazoline replaces, it is characterised in that: its is entitled (E) -1- (chlorobenzene between 2- imido grpup -3-
Base -4- methyl -2- thiazoline -5) -3- (3,4- dioxy xylene) -propyl- 2- alkene -1- ketone, (E) -1- [2- imido grpup -3- (3,
4- dichlorophenyl) -4- methyl -2- thiazoline -5] -3- (3,4- dioxy xylene) -propyl- 2- alkene -1- ketone, (E) [2- is sub- by -1-
Amido -3- (3,4- dichlorophenyl) -4- methyl -2- thiazoline -5] -3- (3,4,5- 2,4,5-trimethoxyphenyl) -propyl- 2- alkene -1- ketone,
(E) -1- (2- imido grpup -3- o-tolyl -4- methyl -2- thiazoline -5) -3- Chloro-O-Phenyl -propyl- 2- alkene -1- ketone, (E)-1-
(2- imido grpup -3- p-methylphenyl -4- methyl -2- thiazoline -5) -3- (3,4,5- 2,4,5-trimethoxyphenyl) -propyl- 2- alkene -1- ketone,
(E) -1- (tolyl -4- methyl -2- thiazoline -5 between 2- imido grpup -3-) -3- m-methoxyphenyl -propyl- 2- alkene -1- ketone or (E)-
1- (chlorphenyl -4- methyl -2- thiazoline -5 between 2- imido grpup -3-) -3- phenyl -propyl- 2- alkene -1- ketone.
2. the preparation method for the chalcone compounds that thiazoline as described in claim 1 replaces, it is characterised in that: 2- imines
Base -3- aryl -4- methyl -5- acetyl group -4-2,3- thiazoline and aromatic formaldehyde stir at -10~20 DEG C in organic solvent I
Mix reaction, the molar ratio of 2- imido grpup -3- aryl -4- methyl -5- acetyl group -4-2,3- thiazoline and aromatic formaldehyde is 1:1.1
~1.5, a certain amount of lye is added dropwise, is added dropwise, is warming up to 20-25 DEG C of room temperature reaction naturally, detects extent of reaction with TLC,
After the reaction was completed, it pours into ice water, adjusts pH to faintly acid, solids is precipitated, filters, after recrystallization to obtain the final product.
3. the preparation method for the chalcone compounds that thiazoline as claimed in claim 2 replaces, it is characterised in that: You Jirong
Agent I is the mixture of following one or more kinds of arbitrary proportions: ethyl alcohol, methanol, tetrahydrofuran, dioxane, organic solvent
Dosage be 5-20 times of 2- imido grpup -3- aryl -4- methyl -5- acetyl group -4-2,3- thiazoline weight.
4. the preparation method for the chalcone compounds that thiazoline as claimed in claim 3 replaces, it is characterised in that: described
Reaction temperature is 0-5 DEG C.
5. the preparation method for the chalcone compounds that thiazoline as claimed in claim 3 replaces, it is characterised in that: described
The KOH solution or NaOH solution that lye is 10~40%.
6. the preparation method for the chalcone compounds that thiazoline as claimed in claim 3 replaces, it is characterised in that: described to have
Solvent I are as follows: the mixture that methanol is 3:1 with tetrahydrofuran mixed proportion, dosage are 2- imido grpup -3- aryl -4- methyl -
9-20 times of 5- acetyl group -4-2,3- thiazoline weight.
7. the preparation method for the chalcone compounds that any thiazoline as described in claim 2-6 replaces, it is characterised in that:
It follows the steps below:
It (1) at room temperature, is 2- imido grpup -3- aryl -4- methyl -5- acetyl group -4-2,3- according to the mole ratio for the substance that feeds intake
Thiazoline: aromatic formaldehyde is that 1:1.1~1.5 feed intake, and addition weight is 2- imido grpup -3- aryl -4- methyl -5- acetyl group -4-
The methanol and tetrahydrofuran mixed proportion of 2,3- 9-20 times of thiazolines are the organic solvent I of 3:1, are sufficiently stirred；
(2) 30%KOH solution or 30%NaOH solution is added dropwise at -10 ~ 0 DEG C in control temperature, after being added dropwise, starts nature liter
Temperature is reacted 4-26 hours, TLC tracking and monitoring to temperature；
(3) after completion of the reaction, it pours into ice water, with glacial acetic acid tune pH to 5-6, solid is precipitated, after recrystallizing after filtering to obtain the final product.
8.(E) -1- (chlorphenyl -4- methyl -2- thiazoline -5 between 2- imido grpup -3-) -3- (3,4- dioxy xylene) -propyl-
Application of the 2- alkene -1- ketone as preparation anti-gastric cancer medicine.
9.(E) -1- [2- imido grpup -3- (3,4- dichlorophenyl) -4- methyl -2- thiazoline -5] -3- (3,4- dioxy methylene benzene
Base) -propyl- 2- alkene -1- ketone is as the application for preparing anti-prostate cancer, lung cancer drug.
10.(E) -1- [2- imido grpup -3- (3,4- dichlorophenyl) -4- methyl -2- thiazoline -5] -3- (3,4,5- trimethoxy benzene
Base) -propyl- 2- alkene -1- ketone is as the application for preparing anti-prostate cancer medicine.
11.(E) -1- (2- imido grpup -3- p-methylphenyl -4- methyl -2- thiazoline -5) -3- (3,4,5- 2,4,5-trimethoxyphenyl) -propyl-
2- alkene -1- ketone, (E) -1- (tolyl -4- methyl -2- thiazoline -5 between 2- imido grpup -3-) -3- m-methoxyphenyl -propyl- 2- alkene -
1- ketone or (E) -1- (chlorphenyl -4- methyl -2- thiazoline -5 between 2- imido grpup -3-) -3- phenyl -propyl- 2- alkene -1- ketone conduct system
The application of standby anti-gastric cancer medicine.
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| 2-氨基-2-噻唑啉-4-羧酸的合成研究;吕亚萍等;《精细化工》;20020531;第19卷(第5期);全文 * |
| Anti-breast cancer activity of some novel 1,2-dihydropyridine, thiophene and thiazole derivatives;Mansour S. Al-Said等;《European Journal of Medicinal Chemistry》;20101029;第46卷;全文 * |
| Cyanoacetic Acid Hydrazones of 3-(and 4-)Acetylpyridine and Some Derived Ring Systems as Potential Antitumor and Anti-HCV Agents;Soad A. M. EL-Hawash等;《Arch. Pharm. Chem. Life Sci.》;20061231;第339卷;全文 * |
| Synthesis and Antitumor Evaluation of New Polysubstituted Thiazole and Derived Thiazolo[4,5-d]pyrimidine Systems;Hesham T.Y. Fahmy等;《Arch. Pharm. Pharm. Med. Chem.》;20021231;第5卷;参见第216页图2，第217页表1，第218页图2-3、第1栏第7-10行 * |
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