CN103232521A - Tanshinone imidazole compound and its preparation method and use - Google Patents
Tanshinone imidazole compound and its preparation method and use Download PDFInfo
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- VBRZMGYEMNWGBL-UHFFFAOYSA-N CC1(C)c2ccc(c([o]cc3C)c3c3c4nc(-c5ccccc5Cl)[nH]3)c4c2CCC1 Chemical compound CC1(C)c2ccc(c([o]cc3C)c3c3c4nc(-c5ccccc5Cl)[nH]3)c4c2CCC1 VBRZMGYEMNWGBL-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to a tanshinone imidazole compound and its preparation method and use, and belongs to the technical field of pharmaceutical chemistry. The tanshinone imidazole compound III has a general structural formula shown in the patent specification, wherein in the general structural formula, R represents benzene containing F, Cl, Br, CF3, OCH3, NO2 and OH substituents. The preparation method comprises that tanshinone IIA, substitutive phenyl aldehyde, acetic acid and ammonium acetate are mixed and then are heated to a temperature of 110 DEG C with stirring for a reaction; then the reaction products are cooled and are added with deionized water for dilution; a pH value of the diluted reaction products is adjusted to 7; and the diluted reaction products having a pH value of 7 are filtered, washed and dried and then are subjected to silica gel column separation so that the tanshinone IIA imidazole compound is obtained.
Description
Technical field
The present invention relates to the pharmaceutical chemistry technical field, relate to some novel anti androgen receptor compounds, contain pharmaceutical dosage form and the using method thereof, particularly tanshinone compound and uses thereof of described compound.
Background technology
Numerous disease is relevant with the male hormone level in elderly men.The male sex with advancing age, androgenic level can descend in the health, is accompanied by that muscle reduces phenomenons such as sexual disorder in the body.On the contrary, the male sex hormone level is too high in the body can bring some other disease equally, be exactly androgen-dependent disorders as hyperplasia of prostate and prostate cancer, also have some other disease relevant with the male sex hormone level, stop in the body skin hair and contain androgen receptor, these acceptors of some people are comparatively responsive to male sex hormone, cause alopecia, androgen receptor is comparatively responsive in young adult's skin, causes growth that powder do not sting etc.
Utilize androgen antagonist can treat the above-mentioned disease relevant with male sex hormone.The selectivity androgen antagonist is the research direction in this field, and this that the androgen receptor of human body Different Organs is had an androgen antagonist optionally closes the target of medicinal design.Adopt the androgen antagonist treatment necessary often to above-mentioned disease.
Androgen receptor (Androgen receptor, AR) be that a class extensively distributes in vivo, the nuclear factor superfamily member that aglucon activates, Chang and Lubean etc. successfully clone AR gene (Science respectively in the different experiments chamber, 1988,240 (4850): 324-326., Science, 1988,240 (4850): 327-330).Androgen receptor prostaticly grow, function is kept and the generation of prostate cancer development and worsen in the transfer process and all bringing into play very important effect.Prostate cancer is the modal male sex's malignant tumour of American-European developed country, accounts for the 2nd of the male cancer cause of the death.About 241740 people of prostate cancer are suffered from by diagnosis in the U.S. in 2012, and about 28170 people are because suffering from prostate cancer death (Siegel R, et.al., Cancer J Clin2012; 62 (1): 10-29(2012)).The morbidity of China's prostate cancer at present is lower than Hesperian sickness rate, but China recent years presents the trend of rapid rising.The male sex PCa of Beijing sickness rate rises to growths by 200.5% in 16.62/10 ten thousand, 9 years in 2010 by 5.53/10 ten thousand of calendar year 2001, increases by 9.2% every year, occupies the 5th in preceding ten big male sex's malignant tumours.Can estimate that thus along with significantly rising fast of sickness rate, prostate cancer will become one of kinds of tumor that threatens China's men's health gradually.Some antiandrogen receptor agents, as flutamide (flutamide, HF) and bicalutamide (bicalutamide) be widely used in the clinical treatment prostate cancer.(Crawford et al., New Engl.J.Med., 321,419-424 (1989)), but this medicine has a lot of side effects (Neumann et al., J.Clin.Oncol., 1,41-65 (1982)).Flutamide and bicalutamide are nonsteroidal antiandrogen receptor agents, though be widely used in the treatment prostate cancer, some antiandrogen receptor agents can be used as androgen receptor agonist may cause " The antiandrogen withdrawal syndrome " (Miyamoto et al., Proc. Natl.Acad.Sci.USA, 95,7379-7384 (1998))." flutamide is removed syndrome " be it is generally acknowledged that at present androgen receptor gene undergos mutation, and the meta-bolites of flutamide activates the target gene of androgen receptor, as prostate specific antigen (PSA), causes PSA to rise, and stops back PSA and descends.In fact, expressing excessively of the sub-ARA70 of another androgen receptor assisted activation can make AR be activated by androgen receptor antagonist, thereby cause the recurrence with the prostate cancer of androgen receptor antagonist method treatment, even develop into non-androgen-dependent prostate cancer (Yeh et al., The Lancet, 349,852-853 (1997)), therefore press for the more effective androgen antagonist new drug of exploitation, be used for the treatment of advanced prostate cancer.
In the new drug development design process, improve its biological activity by structural modification and transformation to natural compounds, improve the targeting for the treatment of, reducing drug toxicity is research emphasis and the difficult point of new drug development.Wherein extracting effective monomer and find that active ingredient is lead compound from Chinese traditional Chinese medicine treasure-house, carry out structure of modification again, is the some effective of new drug development, and at present the clinical application about half being arranged approximately is natural product and derivative thereof.
The red sage root is the root and rhizome of the lip section plant red sage root (Salvia miltiorrhiza Bunge), beginning is stated from Shennong's Herbal, it is the common traditional Chinese medicine of China, has many-sided curative effect clinically, as effects such as promoting blood flow to regulate menstruation, antipruritic, the tranquilizing by nourishing the hearts of analgesia, be mainly used in treating diseases such as cardiovascular, hypertension, cerebral ischemia at present, its main chemical active ingredient is o-quinone structure tanshinone compound.We have found that this compounds has good antiandrogen receptor active, (Xu Defeng, Zhang Chuanxiang, Ji Yejun, tanshinone compound and application thereof, Chinese patent: CN102127037A), the present invention is to be that parent compound carries out the synthetic a series of tanshinone compounds of structural modification on this basis with the TANSHINONES, can be used as the antiandrogen receptor agents and is used for the treatment of prostate cancer, hyperplasia of prostate, acne, alopecia, comedo, hirsutism etc. and male sex hormone diseases associated.The invention still further relates to tanshinone compound as the application of medicine, with the effective constituent of tanshinone compound as androgen receptor antagonist, use separately or share or with combinations such as acceptable vehicle, make oral preparation or non-oral type is used for the treatment of and the male hormone relative disease according to the method for routine.
The present invention refers to be used for the treatment of human and animal's disease or physiologic derangement, medicine or medicine especially for treatment human diseases or physiologic derangement class are formed, these medicines or medicine are formed and are contained with the compound of following compound general formula or the salt of composition, or suitable pharmaceutically acceptable carrier or diluent, these human diseasess or physiologic derangement comprise prostate cancer with other human diseasess relevant with androgen receptor and are not suitable for symptom, as hyperplasia of prostate, acne, alopecia, hirsutism, muscle depletion, gonad function is weak, cholesterol is too high, male sterility, male's sexual is bad, anaemia, fat, these medicines or medicine are formed also can have other purposes, as male contraception etc. and male sex hormone diseases associated.
Summary of the invention
The objective of the invention is to overcome deficiency of the prior art, seek the active high class antiandrogen acceptor compound of a class, a kind of tanshinone compound is provided, can be used as the antiandrogen receptor agents and be used for the treatment of the disease relevant with male sex hormone, can be used for treating prostate cancer, as hyperplasia of prostate, acne, alopecia, hirsutism, muscle depletion, gonad function is weak, cholesterol is too high, male sterility, diseases such as male's sexual is bad, anaemia, obesity.
Main purpose of the present invention provides chemical structure and the medical usage of this compounds.
The TANSHINONES glyoxaline compound relates to the compound III with following general structure,
R is for containing F, Cl, Br, CF
3, OCH
3, NO
2, substituent benzene such as OH.
The purposes of TANSHINONES glyoxaline compound, for the preparation of the antiandrogen receptor agents, be used for the treatment of the disease relevant with male sex hormone, can be used for treating prostate cancer, as hyperplasia of prostate, acne, alopecia, hirsutism, muscle depletion, gonad function is weak, cholesterol is too high, male sterility, diseases such as male's sexual is bad, anaemia, obesity.
Compound involved in the present invention is by following route synthetic method
R is for containing F, Cl, Br, CF
3, OCH
3, NO
2, substituent benzene such as OH.
Preparation method of the present invention step specific as follows:
Tanshinone II A, substituted-phenyl aldehyde, acetic acid and ammonium acetate mixing post-heating are stirred to 110 degree, and finish back cooling of reaction adds the deionized water dilution, regulates PH=7, filter, washing and dry, with silicagel column separate the Tanshinone II A glyoxaline compound.
Specifically carry out according to following step: in reaction flask, add tanshinone IIA (1), substituted benzaldehyde, glacial acetic acid, ammonium acetate, 80-120 ℃ of reaction 2-10 hour, after reaction finishes, after mixed solution is cooled to room temperature, add distilled water, strong aqua is regulated about PH=7, filter, washing, drying, get compound I I with silica gel column chromatography, wherein mol ratios such as reactant tanshinone IIA (1), substituted benzaldehyde, glacial acetic acid, ammonium acetate are 1:1-2:5-25:3-5, temperature of reaction 80-120 ℃, react 2-12 hour.
The structural formula of wherein said substituted benzaldehyde is
Wherein R is for containing F, Cl, Br, CF
3, OCH
3, NO
2, substituent benzene such as OH.
Advantage of the present invention:
AR has multiple hypotype, perfect form (fAR) and montage anomaly androgen receptor (ARVs), wherein montage anomaly androgen receptor (ARVs) is that advanced prostate cancer is distinctive, the tanshinone compound of our invention all effectively suppresses perfect form (fAR) and montage anomaly androgen receptor (ARVs), can be used for the treatment of advanced prostate cancer.Compare with existing clinical medicine bicalutamide, can only suppress perfect form (fAR), can not suppress montage anomaly androgen receptor (ARVs), cause bicalutamide invalid to advanced prostate cancer, the present invention overcomes the deficiency that goes up existing androgen antagonist medicine, can be used for treating advanced prostate cancer.
Description of drawings
Fig. 1 be compound to the relative inhibition energy for growth of LNCaP cell,
Fig. 2 is that compound is to the relative inhibition energy for growth of CWR22RV1 cell.
Embodiment
The present invention relates to the medicine of tanshinone compound, its structural formula of the compound that comprises is as follows:
Example 37 2-(2-fluorophenyls) imidazoles [4,5-f] [10,11]-1,6,6-trimethylammonium-1,6,6-trimethylammonium-6,7,8,9-tetrahydrochysene phenanthro-[1,2-b]-furans (Tan-037)
In reaction flask, add tanshinone IIA (147mg, 0.5mmol), the 2-fluorobenzaldehyde (85mg, 0.65mmol), 5ml glacial acetic acid, ammonium acetate (1.0g, 13mmol), 100-105 ℃ of reaction 3-5 hour, after reaction finishes, after mixed solution is cooled to room temperature, add 10ml distilled water, strong aqua is regulated about PH=7, filters, washing, drying, get target compound with silica gel column chromatography, yield 69%
1H-NMR (300MHz, (CDCl
3), δ: 8.10 (m, 2H), 7.90 (m, 1H), 7.54 (m, 1H), 7.40-7.45 (m, 3H), 4.31 (s, 1H), 2.70 (s, 3H), 2.47 (m, 2H), 1.87-1.91 (m, 2H), 1.71-1.74 (m, 2H), 1.35 (s, 6H).
Example 38 2-(3-fluorophenyls) imidazoles [4,5-f] [10,11]-1,6,6-trimethylammonium-1,6,6-trimethylammonium-6,7,8,9-tetrahydrochysene phenanthro-[1,2-b]-furans (Tan-038)
Reaction replaces the 2-fluorobenzaldehyde with example 37 with the 3-fluorobenzaldehyde, gets target product, yield 73%.
1H-NMR(300MHz,(CDCl
3),δ:8.15(m,2H),7.98(m,1H),7.57(m,2H),7.44(m,2H),4.87(s,1H),2.70(s,3H),2.47(m,2H),1.86-1.92(m,2H),1.69-1.74(m,2H,),1.35(s,6H)。
Example 39 2-(4-fluorophenyls) imidazoles [4,5-f] [10,11]-1,6,6-trimethylammonium-1,6,6-trimethylammonium-6,7,8,9-tetrahydrochysene phenanthro-[1,2-b]-furans (Tan-039)
Reaction replaces the 2-fluorobenzaldehyde with example 37 with the 4-fluorobenzaldehyde, gets target product, yield 71%,
1H-NMR (300MHz, (CDCl
3), δ: 8.35 (m, 2H), 8.02 (m, 1H), 7.60 (m, 2H), 7.41 (m, 2H), 6.35 (s, 1H), 2.82 (m, 2H), 2.47 (s, 3H), 1.90-1.94 (m, 2H), 1.70-1.74 (m, 2H), 1.332 (s, 6H).
Example 40 2-(2-chloro-phenyl-s) imidazoles [4,5-f] [10,11]-1,6,6-trimethylammonium-1,6,6-trimethylammonium-6,7,8,9-tetrahydrochysene phenanthro-[1,2-b]-furans (Tan-040)
Reaction replaces the 2-fluorobenzaldehyde with example 37 with the 2-chlorobenzaldehyde, gets target product, yield 69%,
1H-NMR (300MHz, (CDCl
3), δ: 8.20 (m, 2H), 8.02 (m, 1H), 7.47-7; 64 (m, 4H), 3.98 (s, 1H), 2.63 (s, 3H), 2.47 (m, 2H), 1.85-1.92 (m, 2H), 1.67-1.74 (m, 2H), 1.33 (s, 6H).
Example 41 2-(3-chloro-phenyl-s) imidazoles [4,5-f] [10,11]-1,6,6-trimethylammonium-1,6,6-trimethylammonium-6,7,8,9-tetrahydrochysene phenanthro-[1,2-b]-furans (Tan-041)
Reaction replaces the 2-fluorobenzaldehyde with example 37 with the 3-chlorobenzaldehyde, gets target product, yield 78%.
1H-NMR(300MHz,(CDCl
3),δ:8.10(m,2H),7.98(m,1H),7.47-7.64(m,4H),7.36-7.42(m,2H),3.89(s,1H),3.22(s,3H),2.48(m,2H),1.86-1.91(m,2H),1.69-1.74(m,2H,),1.32(s,6H)。
Example 42 2-(4-chloro-phenyl-s) imidazoles [4,5-f] [10,11]-1,6,6-trimethylammonium-1,6,6-trimethylammonium-6,7,8,9-tetrahydrochysene phenanthro-[1,2-b]-furans (Tan-042)
Reaction replaces the 2-fluorobenzaldehyde with example 37 with the 4-chlorobenzaldehyde, gets target product, yield 74%,
1H-NMR (300MHz, (CDCl
3), δ: 8.32 (m, 2H), 8.02 (m, 1H), 7.62 (m, 2H), 7.38 (m, 2H), 3.98 (s, 1H), 2.63 (s, 3H), 2.47 (m, 2H), 1.85-1.89 (m, 2H), 1.68-1.73 (m, 2H), 1.33 (s, 6H).
Example 43 2-(2-fluoroform phenyl) imidazoles [4,5-f] [10,11]-1,6,6-trimethylammonium-1,6,6-trimethylammonium-6,7,8,9-tetrahydrochysene phenanthro-[1,2-b] furans (Tan-043)
Reaction replaces the 2-fluorobenzaldehyde with example 37 with the 2-trifluoromethylated benzaldehyde, gets target product, yield 78%,
1H-NMR (300MHz, (CDCl
3)), δ: 8.33 (s, 1H), 8.25 (m, 2H), 7.68 (d, 2H), 7.58 (d, 2H), 3.53 (s, 1H), 2.67 (m, 2H), 2.13 (s, 3H), 1.75-1.83 (m, 2H), 1.53-1.66 (m, 2H), 1.41 (s, 6H),
Example 44,2-(3-fluoroform phenyl) imidazoles [4,5-f] [10,11]-1,6,6-trimethylammonium-1,6,6-trimethylammonium-6,7,8,9-tetrahydrochysene phenanthro-[1,2-b] furans (Tan-044)
Reaction replaces the 2-fluorobenzaldehyde with example 37 with the 3-trifluoromethylated benzaldehyde, gets target product, yield 72%,
1H-NMR (300MHz, CDCl
3), δ: 8.33 (d, H), 8.27 (d, 1H), 8.20 (d, 1H), 7.63 (m, 2H), 7.55 (m, 2H), 3.55 (s, 1H), 2.08-2.13 (m, 2H), 2.01 (s, 3H), 1.67-1.84 (m, 4H), 1.43 (s, 6H),
Example 45,2-(4-fluoroform phenyl) imidazoles [4,5-f] [10,11]-1,6,6-trimethylammonium-1,6,6-trimethylammonium-6,7,8,9-tetrahydrochysene phenanthro-[1,2-b] furans (Tan-045)
Reaction replaces the 2-fluorobenzaldehyde with example 37 with the 4-trifluoromethylated benzaldehyde, gets target product, yield 76%,
1H-NMR (300MHz, CDCl
3), δ: 8.17 (d, H), 8.06 (d, 1H), 7.68 (d, 1H), 7.56 (d, 1H), 7.41-7.47 (m, 1H), 7.13 (m, 1H), 3.61 (s, 1H), 2.24 (m, 2H), 1.93 (s, 3H), 1.66-1.75 (m, 4H), 1.38 (s, 6H).
Example 46,2-(3,4,5-trimethoxyphenyl) imidazoles [4,5-f] [10,11]-1,6,6-trimethylammonium-1,6,6-trimethylammonium-6,7,8,9-tetrahydrochysene phenanthro-[1,2-b]-furans (Tan-046)
Reaction replaces the 2-fluorobenzaldehyde with example 37 with 3,4,5-TMB, gets target product, productive rate: 81%,
1H-NMR (300MHz, (CDCl
3), δ: 8.10 (m, 1H), 8.04 (s, 1H), 7.58-7.79 (m, 2H), 7.48 (m, 1H), 3.92 (s, 6H), 3.73 (s, 3H), 3.30 (s, 1H),, 2.59 (m, 2H), 2.46 (s, 3H), 1.75 (m, 2H), 1.72 (m, 2H), 1.35 (s, 6H).
Example 47,2-(3, the 4-Dimethoxyphenyl) imidazoles [4,5-f] [10,11]-1,6,6-trimethylammonium-1,6,6-trimethylammonium-6,7,8,9-tetrahydrochysene phenanthro-[1,2-b]-furans (Tan-047)
Reaction replaces the 2-fluorobenzaldehyde with example 37 with 3,4-dimethoxy benzaldehyde, gets target product, productive rate: 83%,
1H-NMR (300MHz, (CDCl
3), δ: 8.35 (m, 2H), 8.02 (m, 1H), 7.60 (m, 2H), 7.41 (m, 2H), 4.04 (s, 3H), 3.91 (s, 3H), 3.32 (s, 1H), 2.62 (s, 2H), 2.48 (s, 3H), 1.89-1.93 (m, 2H), 1.67-1.73 (m, 2H), 1.43 (s, 6H).
Example 48,2-(3-hydroxyl-4-p-methoxy-phenyl) imidazoles [4,5-f] [10,11]-1,6,6-trimethylammonium-1,6,6-trimethylammonium-6,7,8,9-tetrahydrochysene phenanthro-[1,2-b]-furans (Tan-048)
Reaction replaces the 2-fluorobenzaldehyde with example 37 with 3-hydroxyl-4-methoxybenzaldehyde, gets target product, productive rate: 67%, ESI-MS[M
+] (m/z): 426.19.
Example 49,2-(2-trimethoxyphenyl) imidazoles [4,5-f] [10,11]-1,6,6-trimethylammonium-1,6,6-trimethylammonium-6,7,8,9-tetrahydrochysene phenanthro-[1,2-b]-furans (Tan-049)
Reaction replaces the 2-fluorobenzaldehyde with example 37 with the 2-methoxybenzaldehyde, gets target product, productive rate 75%, ESI-MS[M
+] (m/z): 410.21.
Example 50,2-(3-trimethoxyphenyl) imidazoles [4,5-f] [10,11]-1,6,6-trimethylammonium-1,6,6-trimethylammonium-6,7,8,9-tetrahydrochysene phenanthro-[1,2-b]-furans (Tan-050)
Reaction replaces the 2-fluorobenzaldehyde with example 37 with the 3-methoxybenzaldehyde, gets target product, productive rate 78%, ESI-MS[M
+] (m/z): 410.20.
Example 51,2-(3-trimethoxyphenyl) imidazoles [4,5-f] [10,11]-1,6,6-trimethylammonium-1,6,6-trimethylammonium-6,7,8,9-tetrahydrochysene phenanthro-[1,2-b]-furans (Tan-051)
Reaction replaces the 2-fluorobenzaldehyde with example 37 with the 3-methoxybenzaldehyde, gets target product, productive rate 73%, ESI-MS[M
+] (m/z): 410.21.
Example 52,2-(2, the 4-Dimethoxyphenyl) imidazoles [4,5-f] [10,11]-1,6,6-trimethylammonium-1,6,6-trimethylammonium-6,7,8,9-tetrahydrochysene phenanthro-[1,2-b]-furans (Tan-052)
Reaction replaces the 2-fluorobenzaldehyde with example 37 with 2,4-dimethoxy benzaldehyde, gets target product, productive rate 81%, ESI-MS[M
+] (m/z): 440.21.
Example 53,2-(3, the 5-Dimethoxyphenyl) imidazoles [4,5-f] [10,11]-1,6,6-trimethylammonium-1,6,6-trimethylammonium-6,7,8,9-tetrahydrochysene phenanthro-[1,2-b]-furans (Tan-053)
Reaction replaces the 2-fluorobenzaldehyde with example 37 with 3,5-dimethoxy benzaldehyde, gets target product, productive rate 73%, ESI-MS[M
+] (m/z): 440.22.
Example 54,2-(2-nitrophenyl) imidazoles [4,5-f] [10,11]-1,6,6-trimethylammonium-1,6,6-trimethylammonium-6,7,8,9-tetrahydrochysene phenanthro-[1,2-b]-furans (Tan-053)
Reaction replaces the 2-fluorobenzaldehyde with example 37 with the 2-nitrobenzaldehyde, gets target product, productive rate 72%, ESI-MS[M
+] (m/z): 425.17.
Example 55,2-(3-nitrophenyl) imidazoles [4,5-f] [10,11]-1,6,6-trimethylammonium-1,6,6-trimethylammonium-6,7,8,9-tetrahydrochysene phenanthro-[1,2-b]-furans (Tan-054)
Reaction replaces the 2-fluorobenzaldehyde with example 37 with the 3-nitrobenzaldehyde, gets target product, productive rate 75%, ESI-MS[M
+] (m/z): 425.17.
Example 56,2-(4-nitro base phenyl) imidazoles [4,5-f] [10,11]-1,6,6-trimethylammonium-1,6,6-trimethylammonium-6,7,8,9-tetrahydrochysene phenanthro-[1,2-b]-furans (Tan-055)
Reaction replaces the 2-fluorobenzaldehyde with example 37 with the 4-nitrobenzaldehyde, gets target product, productive rate 69%,
1H-NMR (300MHz, (CDCl
3), δ: 8.49 (d, J=7.8Hz, 2H), 8.34 (d, J=7.8Hz, 2H), 8.04 (d, J=8.4Hz, 1H), 7.80 (s, 1H), 7.61 (d, J=8.4Hz, 1H), 3.89 (s, 1H), 3.20 (s, 3H), 2.51 (m, 2H), and 1.87-1.95 (m, 2H), 1.70-1.76 (m, 2H), 1.33 (s, 6H).
Example 57 2-phenylimidazoles [4,5-f] [10,11]-1,6,6-trimethylammonium-1,6,6-trimethylammonium-6,7,8,9-tetrahydrochysene phenanthro-[1,2-b]-furans
In reaction flask, add tanshinone IIA (147mg, 0.5mmol), phenyl aldehyde (1.47g, 5mmol), 5ml glacial acetic acid, ammonium acetate (1.2g, 5.2mmol), 100-105 ℃ of reaction 3-5 hour, after reaction finishes, after mixed solution is cooled to room temperature, add 10ml distilled water, strong aqua is regulated about PH=7, filters, washing, drying, get target compound with silica gel column chromatography, yield 82%
1H-NMR (300MHz, CDCl
3), δ: 8.37 (m, H), 8.09 (d, J=7.2Hz, 1H), 7.79 (d, J=7.2Hz, 1H), 7.74 (d, 1H), 7.46-7.72 (m, 3H), 7.13 (m, 1H), 3.42 (s, 1H), 2.08-2.13 (m, 2H), 1.90 (s, 3H), 1.57-1.78 (m, 4H), 1.38 (s, 6H).
The biologic activity of compound is measured in the growth-inhibiting effect of the male hormone dependency Human Prostate Cancer Cells LNCaP that utilization of the present invention is induced male sex hormone and the androgen independence Human Prostate Cancer Cells CWR22RV1 cell of hormone resistance.
The compound biological activity determination
We check above-claimed cpd to the bioactive influence of androgen receptor with prostate cancer cell, and the cell of our usefulness has two kinds: LNCaP and CWR22RV1.The LNCaP cell is male hormone dependency Human Prostate Cancer Cells, and CWR22RV1 is the androgen independence Human Prostate Cancer Cells of hormone resistance.These two kinds of cells are all expressed androgen receptor, and male sex hormone can induce the genetic expression of prostate specific antigen (PSA), and can induce the growth of this cell.The growth-inhibiting effect of cell, the biologic activity of mensuration compound.
Specific antigens is an important indicator of prostate cancer, and its expression is regulated and control by androgen receptor, reflects the physiologically active of androgen receptor because of the expression level of a little prostate specific antigen.In order to check above-claimed cpd to the inhibition ability of androgen receptor function, we effectively induce the expression of prostate specific antigen with male hormone DHT, measure the inhibition ability that prostate specific antigen that compound induces DHT is expressed then.We use RPMI-1640 substratum (100 units/ml penicillin that contain 10% foetal calf serum, 100mg/L Streptomycin sulphate and 10% foetal calf serum) cultivation prostate cancer cell LNCaP and CWR22RV1, before test compounds suppresses the androgen receptor ability, my these two kinds of cell cultures of people are cultivated in charcoal adsorbs to fall the RPMI-1640 substratum of androgenic foetal calf serum (Charcoal-stripped FBS) in containing 10%, after two days, we add the DHT and 0.25 of androgenous 11 0nM in nutrient solution, 0.5,1,2,5,10 μ M, the test compounds of concentration tonsure is cultivated after four days, we are secreted into the concentration of the prostate specific antigen of nutrient solution with the measurement of integrated enzyme reaction reagent, calculate 50 percent the inhibition ability (IC50) that test compounds suppresses prostate specific antigen then.Table 1 is listed tested compound to 50 percent inhibition ability (IC50) of the prostate specific antigen of the androgen independence Human Prostate Cancer Cells CWR22RV1 of androgen-dependent Human Prostate Cancer Cells LNCaP and hormone resistance.
Table 1, tested compound are to 50 percent inhibition ability (IC50) of the prostate specific antigen of the androgen independence Human Prostate Cancer Cells CWR22RV1 of androgen-dependent Human Prostate Cancer Cells LNCaP and hormone resistance.
We have also checked the growth-inhibiting effect of the androgen independence Human Prostate Cancer Cells CWR22RV1 cell of male hormone dependency Human Prostate Cancer Cells LNCaP that some compounds induce male sex hormone and hormone resistance, similar with above method, we LNCaP cell and CWR22RV1 cell be placed on contain 10% in charcoal adsorbs to fall the RPMI-1640 substratum of androgenic foetal calf serum, cultivate 2 days after, the test compounds that in substratum, adds male hormone DHT and finite concentration gradient, make its ultimate density reach DHT and the 1 μ M of 10nM, 2.5 μ M, the test compounds of 5 μ M concentration tonsures, cultivate after six days, we calculate the total cellular score of growth, accompanying drawing shows it is that to deduct the total cellular score of growing when not adding DHT with the cell growth sum that 10nM DHT induces be 100% growth, the compound of different concns suppresses ability to the allometry of the androgen independence human prostata cancer CWR22RV1 cell of male hormone dependency Human Prostate Cancer Cells LNCaP and hormone resistance, and three kinds of chemical structures are strong to the growth-inhibiting energy widely used bicalutamide of force rate (Bicalutamide) of LNCaP and CWR22RV1.
The allometry of the male hormone dependency Human Prostate Cancer Cells LNCaP (Fig. 1) that accompanying drawing, three kinds of compounds are induced male sex hormone and the androgen independence Human Prostate Cancer Cells CWR22RV1 (Fig. 2) of hormone resistance suppresses ability.
LNCaP and CWR22RV1 cell cultures in contain 10% through charcoal adsorb to fall cultivate 2 days in the RPMI-1640 substratum of androgenic foetal calf serum after, the test compounds that in substratum, adds male hormone DHT and finite concentration gradient, making its ultimate density is DHT and the 1 μ M of 10nM, 2.5 μ M, the test compounds of 5 μ M concentration tonsures, cultivate after six days, we calculate the total cellular score of growth, and accompanying drawing shows it is that to deduct the total cellular score of growing when not adding DHT with the cell growth sum that 10nM DHT induces be 100% to come the allometry of computerized compound to suppress ability.
Claims (10)
1. TANSHINONES glyoxaline compound is characterized in that for having the compound III of following general structure,
R is for containing F, Cl, Br, CF
3, OCH
3, NO
2Or the substituent benzene of OH.
2. the preparation method of TANSHINONES glyoxaline compound, it is characterized in that carrying out according to following step: in reaction flask, add tanshinone IIA (1), substituted benzaldehyde, glacial acetic acid, ammonium acetate, 80-120 ℃ of reaction 2-10 hour, after reaction finishes, after mixed solution is cooled to room temperature, add distilled water, strong aqua is regulated about PH=7, filter, washing, drying gets compound I I with silica gel column chromatography, wherein reactant tanshinone IIA (1), substituted benzaldehyde, glacial acetic acid, mol ratios such as ammonium acetate are 1:1-2:5-25:3-5, temperature of reaction 80-120 ℃, reacted 2-12 hour.
3. the preparation method of TANSHINONES glyoxaline compound according to claim 2 is characterized in that the structural formula of wherein said substituted benzaldehyde is
, wherein R is for containing the substituent benzene of F.
4. the preparation method of TANSHINONES glyoxaline compound according to claim 2 is characterized in that the structural formula of wherein said substituted benzaldehyde is
, wherein R is for containing the substituent benzene of Cl.
5. the preparation method of TANSHINONES glyoxaline compound according to claim 2 is characterized in that the structural formula of wherein said substituted benzaldehyde is
, wherein R is for containing the substituent benzene of Br.
6. the preparation method of TANSHINONES glyoxaline compound according to claim 2 is characterized in that the structural formula of wherein said substituted benzaldehyde is
, wherein R is for containing CF
3Substituent benzene.
7. the preparation method of TANSHINONES glyoxaline compound according to claim 2 is characterized in that the structural formula of wherein said substituted benzaldehyde is
, wherein R is for containing OCH
3Substituent benzene.
8. the preparation method of TANSHINONES glyoxaline compound according to claim 2 is characterized in that the structural formula of wherein said substituted benzaldehyde is
, wherein R is for containing NO
2Substituent benzene.
9. the preparation method of TANSHINONES glyoxaline compound according to claim 2 is characterized in that the structural formula of wherein said substituted benzaldehyde is
, wherein R is for containing the substituent benzene of OH.
10. the purposes of TANSHINONES glyoxaline compound, for the preparation of the antiandrogen receptor agents, be used for the treatment of the disease relevant with male sex hormone, can be used for treating prostate cancer, as hyperplasia of prostate, acne, alopecia, hirsutism, muscle depletion, gonad function is weak, cholesterol is too high, male sterility, diseases such as male's sexual is bad, anaemia, obesity.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106699771A (en) * | 2017-02-20 | 2017-05-24 | 常州大学 | Cryptotanshinone compound, as well as preparation method and application thereof |
| CN110330545A (en) * | 2019-04-30 | 2019-10-15 | 中山大学 | A kind of tanshinone IIA derivative TAN20 and its preparation method and application |
| CN114249740A (en) * | 2021-11-23 | 2022-03-29 | 南京林业大学 | For detecting ClO-Ionic tanshinone benzimidazole type fluorescent probe and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101863894A (en) * | 2010-06-01 | 2010-10-20 | 广东药学院 | Tanshinone II A derivative and preparation method and application thereof |
| CN102127037A (en) * | 2011-01-11 | 2011-07-20 | 上海交通大学 | Tanshinone compounds and applications thereof |
-
2013
- 2013-03-11 CN CN201310075424XA patent/CN103232521A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101863894A (en) * | 2010-06-01 | 2010-10-20 | 广东药学院 | Tanshinone II A derivative and preparation method and application thereof |
| CN102127037A (en) * | 2011-01-11 | 2011-07-20 | 上海交通大学 | Tanshinone compounds and applications thereof |
Non-Patent Citations (1)
| Title |
|---|
| 夏峥嵘: "丹参酮IIA抑制前列腺癌细胞株生长和诱导凋亡的试验研究", 《中国优秀硕士学位论文全文数据库（医药卫生科技辑）》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106699771A (en) * | 2017-02-20 | 2017-05-24 | 常州大学 | Cryptotanshinone compound, as well as preparation method and application thereof |
| CN110330545A (en) * | 2019-04-30 | 2019-10-15 | 中山大学 | A kind of tanshinone IIA derivative TAN20 and its preparation method and application |
| CN114249740A (en) * | 2021-11-23 | 2022-03-29 | 南京林业大学 | For detecting ClO-Ionic tanshinone benzimidazole type fluorescent probe and preparation method and application thereof |
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