CN105218614B - Hydrazone thiazole of 42 oestrone of (4 ' bromine) phenyl 17 ' and its production and use - Google Patents
Hydrazone thiazole of 42 oestrone of (4 ' bromine) phenyl 17 ' and its production and use Download PDFInfo
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- CN105218614B CN105218614B CN201510725537.9A CN201510725537A CN105218614B CN 105218614 B CN105218614 B CN 105218614B CN 201510725537 A CN201510725537 A CN 201510725537A CN 105218614 B CN105218614 B CN 105218614B
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- 0 C[C@](CC1)(C(CC2)C3C1c1ccc(*)cc1CC3)C2=N*c1nc(-c(cc2)ccc2[Br+])c[s]1 Chemical compound C[C@](CC1)(C(CC2)C3C1c1ccc(*)cc1CC3)C2=N*c1nc(-c(cc2)ccc2[Br+])c[s]1 0.000 description 1
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Abstract
The invention discloses a kind of hydrazone thiazole of 42 oestrone of (4 ' bromine) phenyl 17 ', it has below formula：
Description
Technical field
The present invention relates to a kind of 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles and its production and use.
Background technology
Cancer is a kind of principal disease for endangering human health, captures the problem that malignant tumour is modern medicine,
It is the maximum challenge of current medical industry processed.At present, various types of antineoplastic continuously emerges and clinically obtained
It must apply, but the antineoplastic clinically used is larger due to the toxicity that it is caused to tissue, greatly limit
Their use scope.Therefore, the cancer therapy drug for finding efficient, high selectivity and Small side effects is the main of cancer therapy drug exploitation
Direction.
In antineoplastic, the medicine Finasteride for treating hyperplasia of prostate is clinically used at present, for treating
Medicine estramustine phosphate sodium (Estramustine phosphate sodium), the Abiraterone acetate of advanced prostate cancer
It is single with the medicine Exemestane for treating menopausal women breast cancer, and the conduct developed recently by EntreMed companies
Therapy is used for stable or recurrence Huppert's disease and the cancer therapy drug methoxyestradiol (commodity of prostate cancer therapy
Name：Panzem), they belong to steroidal antineoplastic.But at present there is complicated, effect position in steroidal antineoplastic
Point is more, causes for poor selectivity, the no clear and definite theoretical explanation of its mechanism of action, material base, therefore structural formula, targeting
It is respectively provided with not controllability.
The content of the invention
It is an object of the invention to solve at least the above, and provide the advantage that at least will be described later.
It is a still further object of the present invention to provide a kind of compound：4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles, its
There is obvious inhibitory action to various tumor cell strains such as liver cancer, lung cancer, stomach cancer, cervical carcinoma, prostate cancer, colon cancers, and
And toxicity is low, drug resistance is not likely to produce, present invention also offers the preparation method of the compound and purposes, the preparation method is simple
It is easy, be conducive to marketing application.
In order to realize that there is provided a kind of 4- (4'- bromines) phenyl -2- is female according to object of the present invention and further advantage
Ketone -17'- hydrazone thiazoles, it has below formula：
A kind of preparation method of described 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles, comprises the following steps：
Step 1: taking 90~110 parts of oestrone, 35~45 parts of thiosemicarbazides and 110~130 parts of 2- respectively by weight
4'- dibromos acetophenone is mixed, and adding absolute ethyl alcohol thereto is completely dissolved it, carries out microwave reaction, reaction temperature is 80
~90 DEG C, until reaction is completed, room temperature is cooled to, the first intermediate product is obtained；
Step 2: first intermediate product is removed into solvent, purification adds distilled water into the material after purification mixed
Close, then be extracted with ethyl acetate 2~4 times, take organic phase, obtain the second intermediate product, wherein, the addition of distilled water is：Often
100mg oestrone adds 25~35ml distilled water；
Step 3: washing second intermediate product with saturated sodium bicarbonate solution, saturated nacl aqueous solution successively, go forward side by side
The mixture that drying process is obtained further is removed solvent by row drying process to remove moisture, purification, and carries out column chromatography point
From obtaining pale yellowish oil liquid, i.e. 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles.
Preferably, in the preparation method of described 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles, the step one
Microwave power is 250~350W.
Preferably, in the preparation method of described 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles, the step 3
Removal solvent method be vacuum distillation.
Preferably, in the preparation method of described 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles, the step 3
Drying process use anhydrous sodium sulfate.
Preferably, in the preparation method of described 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles, the step one
The method completed is reacted in inspection：By the column chromatography chromatogram method tracking and monitoring of the mixture in reaction, until monitoring mixture
In oestrone disappear then stop reaction.
Preferably, in the preparation method of described 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles, the step 3
Column chromatography for separation, eluant, eluent is VEthyl acetate:VDichloromethane=1:120.
A kind of purposes of described 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles, its purposes is, the 4- (4'-
Bromine) phenyl -2- oestrone -17'- hydrazones thiazole is used to prepare application in treating cancer medicine.
Preferably, the purposes of described 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles, 4- (4'- bromines) benzene
Base -2- oestrone -17'- hydrazones thiazole is used to prepare cancer targeted in treating cancer medicine：Liver cancer, lung cancer, stomach cancer, uterine neck
Cancer, prostate cancer and colon cancer.
The present invention at least includes following beneficial effect：A kind of compound is provided：4- (4'- bromines) phenyl -2- oestrone -17'- hydrazones
Thiazole, its selectivity is high, has to various tumor cell strains such as liver cancer, lung cancer, stomach cancer, cervical carcinoma, prostate cancer, colon cancers bright
Aobvious inhibitory action, and toxicity is low, is not likely to produce drug resistance, greatly reduces the cytotoxic drugs discharged to human body
Injury, present invention also offers the preparation method of the compound and purposes, the preparation method is simple and easy to apply, is conducive to marketing
Using.
Further advantage, target and the feature of the present invention embodies part by following explanation, and part will also be by this
The research and practice of invention and be understood by the person skilled in the art.
Embodiment
With reference to embodiment, the present invention is described in further detail, to make those skilled in the art with reference to specification
Word can be implemented according to this.
It should be appreciated that such as " having ", "comprising" and " comprising " term used herein do not allot one or many
The presence or addition of individual other elements or its combination.
<Embodiment 1>
A kind of 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles, it has below formula：
A kind of preparation method of described 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles, comprises the following steps：
Step 1: weighing oestrone 90mg, thiosemicarbazides 35mg, 2-4'- dibromo acetophenone 110mg is put into 100mL two-neck bottles
In, and adding 12mL absolute ethyl alcohols to it is completely dissolved it, is placed in after adding magneton in microwave synthesis reactor, inserts temperature
Sensor, 25W is adjusted to by power, and preset temperature is 80 DEG C, and TLC tracing detections stop anti-after raw material point disappears substantially
Should.Room temperature is cooled to, the first intermediate product is obtained；
Step 2: the first intermediate product vacuum distillation is gone out into most of solvent, the mixing of 25mL distilled water is added, second is used
Acetoacetic ester is extracted 2 times, is taken organic phase, is obtained the second intermediate product；
Step 3: washing second intermediate product with saturated sodium bicarbonate solution, saturated nacl aqueous solution successively, have no
Aqueous sodium persulfate drying process is to remove moisture, then vacuum distillation goes out solvent, and carries out column chromatography for separation, and eluant, eluent is VEthyl acetate:
VDichloromethane=1:120, pale yellowish oil liquid, i.e. 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles are obtained, its spectroscopic data is：
IR(KBr)ν/cm-1:3320,2927,1609,1556,1496,1394,1282,1068,1003,828,729；1H NMR
(300MHz,CDCl3)δ:0.92(3H,s,18-CH3), 6.60 (1H, d, J=1.5Hz, 4-CH), 6.68 (1H, d, J=8.4Hz,
2-CH), 6.83 (1H, s, Ar-H), 7.16 (1H, d, J=8.7Hz, 1-CH), 7.50 (2H, d, J=8.4Hz, Ph-H), 7.65
(2H, d, J=8.4Hz, Ph-H)；13C NMR(75MHz,CDCl3)δ:17.2(18-C),23.2(15-C),25.9(11-C),
26.2(16-C),27.2(7-C),29.5(6-C),34.1(12-C),38.2(8-C),44.1(13-C),44.9(9-C),52.6
(14-C),103.9(Ar-C),113.1(2-C),115.6(4-C),126.5(1-C),132.0(10-C),138.0(5-C),
149.8 (Ar-C), 154.0 (3-C), [113.1,121.6,127.6,131.8] (Ph-C), 166.3 (17-C), 170.8 (C=
N).HREIMS m/z:522.1215[M+H]+(calcd for C27H28BrN3OS,522.1226)。
<Embodiment 2>
A kind of 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles, it has below formula：
A kind of preparation method of described 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles, comprises the following steps：
Step 1: weighing oestrone 100mg, thiosemicarbazides 39mg, 2-4'- dibromo acetophenone 119mg is put into 100mL two-neck bottles
In, and adding 15mL absolute ethyl alcohols to it is completely dissolved it, is placed in after adding magneton in microwave synthesis reactor, inserts temperature
Sensor, 300W is adjusted to by power, and preset temperature is 85 DEG C.TLC tracing detections, stop anti-after raw material point disappears substantially
Should.Room temperature is cooled to, the first intermediate product is obtained；
Step 2: the first intermediate product vacuum distillation is gone out into most of solvent, the mixing of 25mL distilled water is added, second is used
Acetoacetic ester is extracted 2 times, is taken organic phase, is obtained the second intermediate product；
Step 3: washing second intermediate product with saturated sodium bicarbonate solution, saturated nacl aqueous solution successively, have no
Aqueous sodium persulfate drying process is to remove moisture, then vacuum distillation goes out solvent, and carries out column chromatography for separation, and eluant, eluent is VEthyl acetate:
VDichloromethane=1:120, pale yellowish oil liquid, i.e. 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles are obtained, its spectroscopic data is：
IR(KBr)ν/cm-1:3320,2927,1609,1556,1496,1394,1282,1068,1003,828,729；1HNMR
(300MHz,CDCl3)δ:0.92(3H,s,18-CH3), 6.60 (1H, d, J=1.5Hz, 4-CH), 6.68 (1H, d, J=8.4Hz,
2-CH), 6.83 (1H, s, Ar-H), 7.16 (1H, d, J=8.7Hz, 1-CH), 7.50 (2H, d, J=8.4Hz, Ph-H), 7.65
(2H, d, J=8.4Hz, Ph-H)；13C NMR(75MHz,CDCl3)δ:17.2(18-C),23.2(15-C),25.9(11-C),
26.2(16-C),27.2(7-C),29.5(6-C),34.1(12-C),38.2(8-C),44.1(13-C),44.9(9-C),52.6
(14-C),103.9(Ar-C),113.1(2-C),115.6(4-C),126.5(1-C),132.0(10-C),138.0(5-C),
149.8 (Ar-C), 154.0 (3-C), [113.1,121.6,127.6,131.8] (Ph-C), 166.3 (17-C), 170.8 (C=
N).HREIMS m/z:522.1215[M+H]+(calcd for C27H28BrN3OS,522.1226)。
<Embodiment 3>
A kind of 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles, it has below formula：
A kind of preparation method of described 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles, comprises the following steps：
Step 1: weighing oestrone 110mg, thiosemicarbazides 45mg, 2-4'- dibromo acetophenone 130mg is put into 100mL two-neck bottles
In, and adding 18mL absolute ethyl alcohols to it is completely dissolved it, is placed in after adding magneton in microwave synthesis reactor, inserts temperature
Sensor, 350W is adjusted to by power, and preset temperature is 90 DEG C.TLC tracing detections, stop anti-after raw material point disappears substantially
Should.Room temperature is cooled to, the first intermediate product is obtained；
Step 2: the first intermediate product vacuum distillation is gone out into most of solvent, the mixing of 30mL distilled water is added, second is used
Acetoacetic ester is extracted 3 times, is taken organic phase, is obtained the second intermediate product；
Step 3: washing second intermediate product with saturated sodium bicarbonate solution, saturated nacl aqueous solution successively, have no
Aqueous sodium persulfate drying process is to remove moisture, then vacuum distillation goes out solvent, and carries out column chromatography for separation, and eluant, eluent is VEthyl acetate:
VDichloromethane=1:120, pale yellowish oil liquid, i.e. 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles are obtained, its spectroscopic data is：
IR(KBr)ν/cm-1:3320,2927,1609,1556,1496,1394,1282,1068,1003,828,729；1H NMR
(300MHz,CDCl3)δ:0.92(3H,s,18-CH3), 6.60 (1H, d, J=1.5Hz, 4-CH), 6.68 (1H, d, J=8.4Hz,
2-CH), 6.83 (1H, s, Ar-H), 7.16 (1H, d, J=8.7Hz, 1-CH), 7.50 (2H, d, J=8.4Hz, Ph-H), 7.65
(2H, d, J=8.4Hz, Ph-H)；13C NMR(75MHz,CDCl3)δ:17.2(18-C),23.2(15-C),25.9(11-C),
26.2(16-C),27.2(7-C),29.5(6-C),34.1(12-C),38.2(8-C),44.1(13-C),44.9(9-C),52.6
(14-C),103.9(Ar-C),113.1(2-C),115.6(4-C),126.5(1-C),132.0(10-C),138.0(5-C),
149.8 (Ar-C), 154.0 (3-C), [113.1,121.6,127.6,131.8] (Ph-C), 166.3 (17-C), 170.8 (C=
N).HREIMS m/z:522.1215[M+H]+(calcd for C27H28BrN3OS,522.1226)。
The chemical reaction of the preparation process is：
Wherein, MW represents-microwave reaction；
The form that injection, tablet, pill, capsule, suspending agent or emulsion can be made in the medicine is used, and way is administered in it
Footpath can be oral, or through subcutaneous, vein or intramuscular injection.
In order to illustrate the effect of the present invention, it is as follows that inventor provides experiment：
Experiment one
Some tumour cells are suppressed using 4- of the present invention (4'- bromines) phenyl -2- oestrone -17'- hydrazones thiazoles
The test result of growth of tumour cell proliferation activity experiment.The steroidal thiazolium compounds of the selection present invention tests it to human cervical carcinoma
Cell line (HeLa), hepatoma cell strain (HEPG2), lung cancer cell line (A549), CNE-2 (KB cell) and people's kidney epithelium
The cytotoxicity of cell (HEK293T).Using MTT methods, vitro cytotoxicity measure is carried out.The logarithm cultivated in 96 orifice plates
4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles of various concentrations are added in growth period cell, while carrying out 2 parallel examinations
Test, be compared with control group.After culture 72 hours, MTT is added, its absorbance is determined, calculated suppress tumour cell life respectively
The long concentration bred to compound when 50%, with IC50Value expression, as a result as shown in table 1：
External antiproliferative activity (the IC of the 4- of table 1 (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles50,μmol/L)
| Compound number | HeLa | HepG2 | A549 | CNE-2 | HEK 293T |
| 1 | ND | 5.7 | ND | 11.5 | >100 |
Wherein, ND is represented and not yet detected, compound 1 is 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles, from table 1
4- (4'- bromines) phenyl -2- oestrone -17'- hydrazones thiazole is to hepatoma cell strain (HEPG2), CNE-2 (KB cell) and people's kidney
The IC of epithelial cell (HEK293T) inhibitory action50Value as can be seen that 4- (4'- bromines) phenyl -2- oestrone of the present invention -
17'- hydrazones thiazole swells to human cervical carcinoma cell lines (HeLa), hepatoma cell strain (HEPG2), this 2 kinds of CNE-2 (KB cell)
Oncocyte has suppresses growing multiplication effect well, and such as 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles are to liver cancer cells
The suppression IC of strain (HEPG2)50It is worth for 5.7umol/L, to CNE-2 (KB cell) suppression IC50It is worth for 11.5umol/
L, and to the suppression IC of people's renal epithelial cell (HEK293T)50Value is but more than 100, shows the medicine to people's renal epithelial cell
(HEK293T) there is relatively low cytotoxicity, while also illustrating 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles in low concentration
When to cancer cell effective inhibitory action, drug damages there is no to normal cell.
It can be seen from the IC50 experiment values that upper table 1 is provided, compound 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles pair
Hepatoma cell strain (HEPG2), CNE-2 (KB cell) growing multiplication have good inhibiting effect.
Although embodiment of the present invention is disclosed as above, it is not restricted in description and embodiments listed fortune
With it can be applied to various suitable the field of the invention completely, for those skilled in the art, can be easily real
Now other modification, therefore under the universal limited without departing substantially from claim and equivalency range, the present invention is not limited to
Specific details and shown here as the embodiment with description.
Claims (9)
1. a kind of 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles, it is characterised in that it has below formula：
2. a kind of preparation method of 4- as claimed in claim 1 (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles, its feature exists
In comprising the following steps：
Step 1: taking 90~110 parts of oestrone, 35~45 parts of thiosemicarbazides and 110~130 parts of 2-4'- respectively by weight
Dibromo acetophenone is mixed, and adding absolute ethyl alcohol thereto is completely dissolved it, carries out microwave reaction, and reaction temperature is 80~90
DEG C, until reaction is completed, room temperature is cooled to, the first intermediate product is obtained；
Step 2: first intermediate product is removed into solvent, purification adds distilled water mixing into the material after purification, then
It is extracted with ethyl acetate 2~4 times, takes organic phase, obtains the second intermediate product, wherein, the addition of distilled water is：It is female per 100mg
Ketone adds 25~35ml distilled water；
Step 3: washing second intermediate product with saturated sodium bicarbonate solution, saturated nacl aqueous solution successively, and done
The mixture that drying process is obtained further is removed solvent by dry processing to remove moisture, is purified, and carries out column chromatography for separation,
Obtain pale yellowish oil liquid, i.e. 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles.
3. the preparation method of 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles as claimed in claim 2, it is characterised in that
Microwave power is 250~350W in the step one.
4. the preparation method of 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles as claimed in claim 2, it is characterised in that
The method of removal solvent in the step 3 is vacuum distillation.
5. the preparation method of 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles as claimed in claim 2, it is characterised in that
Drying process in the step 3 uses anhydrous sodium sulfate.
6. the preparation method of 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles as claimed in claim 2, it is characterised in that
The method of inspection reaction completion is in the step one：By the column chromatography chromatogram method tracking and monitoring of the mixture in reaction, until
Monitor that the oestrone in mixture disappears and then stop reaction.
7. the preparation method of 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles as claimed in claim 2, it is characterised in that
Column chromatography for separation in the step 3, eluant, eluent is VEthyl acetate:VDichloromethane=1:120.
8. a kind of purposes of 4- as claimed in claim 1 (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles, its purposes is,
4- (4'- bromines) phenyl -2- oestrone -17'- hydrazones thiazole is used to prepare the application in treating cancer medicine.
9. the purposes of 4- (4'- bromines) phenyl -2- oestrone -17'- hydrazone thiazoles as claimed in claim 8, it is characterised in that described
4- (4'- bromines) phenyl -2- oestrone -17'- hydrazones thiazole is used to prepare cancer targeted in treating cancer medicine：Liver cancer, lung
Cancer, stomach cancer, cervical carcinoma, prostate cancer and colon cancer.
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