CN103193860A - Tanshinone compounds, preparation method and use thereof - Google Patents
Tanshinone compounds, preparation method and use thereof Download PDFInfo
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- CN103193860A CN103193860A CN2013100751561A CN201310075156A CN103193860A CN 103193860 A CN103193860 A CN 103193860A CN 2013100751561 A CN2013100751561 A CN 2013100751561A CN 201310075156 A CN201310075156 A CN 201310075156A CN 103193860 A CN103193860 A CN 103193860A
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- AIGAZQPHXLWMOJ-UHFFFAOYSA-N Tanshinone I Chemical class C1=CC2=C(C)C=CC=C2C(C(=O)C2=O)=C1C1=C2C(C)=CO1 AIGAZQPHXLWMOJ-UHFFFAOYSA-N 0.000 title claims abstract description 85
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 206010060862 Prostate cancer Diseases 0.000 claims abstract description 38
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims abstract description 38
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 22
- 201000010099 disease Diseases 0.000 claims abstract description 21
- 206010000496 acne Diseases 0.000 claims abstract description 7
- 208000002874 Acne Vulgaris Diseases 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 147
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 113
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 83
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 71
- 150000001875 compounds Chemical class 0.000 claims description 58
- AZEZEAABTDXEHR-UHFFFAOYSA-M sodium;1,6,6-trimethyl-10,11-dioxo-8,9-dihydro-7h-naphtho[1,2-g][1]benzofuran-2-sulfonate Chemical compound [Na+].C12=CC=C(C(CCC3)(C)C)C3=C2C(=O)C(=O)C2=C1OC(S([O-])(=O)=O)=C2C AZEZEAABTDXEHR-UHFFFAOYSA-M 0.000 claims description 56
- HYXITZLLTYIPOF-UHFFFAOYSA-N Tanshinone II Natural products O=C1C(=O)C2=C3CCCC(C)(C)C3=CC=C2C2=C1C(C)=CO2 HYXITZLLTYIPOF-UHFFFAOYSA-N 0.000 claims description 55
- 229930183118 Tanshinone Natural products 0.000 claims description 53
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 52
- 238000010898 silica gel chromatography Methods 0.000 claims description 52
- -1 tanshinone compound Chemical class 0.000 claims description 51
- 239000007787 solid Substances 0.000 claims description 42
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 37
- 150000002240 furans Chemical class 0.000 claims description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 27
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 26
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 26
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 26
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 26
- 238000005406 washing Methods 0.000 claims description 25
- 239000000376 reactant Substances 0.000 claims description 24
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 23
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 23
- 239000011734 sodium Substances 0.000 claims description 23
- 229910052708 sodium Inorganic materials 0.000 claims description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- 238000001914 filtration Methods 0.000 claims description 22
- 238000001035 drying Methods 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 239000000706 filtrate Substances 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 239000000051 antiandrogen Substances 0.000 claims description 15
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 14
- 229960000583 acetic acid Drugs 0.000 claims description 14
- 239000003163 gonadal steroid hormone Substances 0.000 claims description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 13
- DUNKXUFBGCUVQW-UHFFFAOYSA-J zirconium tetrachloride Chemical compound Cl[Zr](Cl)(Cl)Cl DUNKXUFBGCUVQW-UHFFFAOYSA-J 0.000 claims description 13
- 239000012043 crude product Substances 0.000 claims description 12
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
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- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 12
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- 238000010992 reflux Methods 0.000 claims description 11
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- 239000012279 sodium borohydride Substances 0.000 claims description 10
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 10
- 230000002280 anti-androgenic effect Effects 0.000 claims description 9
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 8
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 claims description 8
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- 230000001105 regulatory effect Effects 0.000 claims description 8
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 201000004384 Alopecia Diseases 0.000 claims description 6
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 6
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 6
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 6
- 239000012346 acetyl chloride Substances 0.000 claims description 6
- 231100000360 alopecia Toxicity 0.000 claims description 6
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 239000012286 potassium permanganate Substances 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- 206010020112 Hirsutism Diseases 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- VIRPUNZTLGQDDV-UHFFFAOYSA-N chloro propanoate Chemical compound CCC(=O)OCl VIRPUNZTLGQDDV-UHFFFAOYSA-N 0.000 claims description 5
- 239000012362 glacial acetic acid Substances 0.000 claims description 5
- 210000003205 muscle Anatomy 0.000 claims description 5
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 4
- 206010021929 Infertility male Diseases 0.000 claims description 4
- 208000007466 Male Infertility Diseases 0.000 claims description 4
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- 235000012000 cholesterol Nutrition 0.000 claims description 4
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- 210000002149 gonad Anatomy 0.000 claims description 4
- 125000001475 halogen functional group Chemical group 0.000 claims description 4
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- 239000002904 solvent Substances 0.000 claims description 4
- 229960002317 succinimide Drugs 0.000 claims description 4
- 208000008589 Obesity Diseases 0.000 claims description 3
- 150000001728 carbonyl compounds Chemical class 0.000 claims description 3
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- 239000012141 concentrate Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- 229910000474 mercury oxide Inorganic materials 0.000 claims description 3
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 claims description 3
- 235000020824 obesity Nutrition 0.000 claims description 3
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- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 2
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- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 5
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 claims 4
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- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
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Abstract
The invention provides tanshinone compounds, a preparation method and use thereof, and relates to the technical field of pharmaceutical chemistry. The tanshinone compounds possess a structure formula I or II as shown in the specification. The use of the tanshinone compounds includes but not limited to anticancer drugs, particularly the treatment of prostate cancer and bladder cancer, and induction of androgen receptor antagonist activity when patients have androgen-related diseases, wherein the androgen-related diseases include but not limited to multi-disease, acne, and spermatogenesis without inhibition in need of suppressing spermatogenesis.
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 Clin 2012; 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.
Tanshinone compound has compound I or the II of following general structure:
Wherein R is CHO, Br, NO
2, OCH
3, CH
2OOCH
3, COCH
3, C
1-C
3Carboxylic acid and sodium salt, carboxylicesters, vinyl cyanide, vinylformic acid and sodium salt or acrylate etc.
The purposes of tanshinone 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 pressed following route synthetic method one:
The preparation method of tanshinone compound, step specific as follows: tanshinone IIA and Vilsmeier reagent (dimethyl formamide and phosphorus oxychloride) prepared in reaction aldehyde compound, can adopt potassium permanganate under the phase-transfer catalyst effect, to generate carboxylic acid, get carboxylicesters through esterification, generate corresponding sodium salt with the sodium ethylate reaction.
The preparation method of tanshinone compound, specifically carry out according to following steps:
(1) in reaction flask, adds tanshinone IIA (1), dimethyl formamide (DMF), phosphorus oxychloride, reacted 1-5 hour down at 30-100 ℃, reaction solution is poured in the frozen water, and yellow mercury oxide is arranged, and filters, washing, the dry crude product that gets, crude product gets tanshinone IIA formaldehyde (2) through silica gel column chromatography, and wherein the mol ratio of reactant tanshinone IIA, dimethyl formamide (DMF), phosphorus oxychloride is 1:2-15:2-25, temperature of reaction 30-100 ℃, reacted 1-5 hour.
(2) in reaction flask, add 2, acetone, Tetrabutyl amonium bromide and mass concentration are 5% potassium permanganate solution, at 20-80 ℃, reacted solids removed by filtration 10-25 hour, filtrate is regulated PH=2 with hydrochloric acid, there is precipitation to generate, filters, drying gets 1 with silica gel column chromatography, 6,6-trimethylammonium-6,7,8,9,10,11-, six hydrogen-10,11-dioxo phenanthro-[1,2-b] furyl-2-formic acid (3), reactant tanshinone IIA (1) wherein, Tetrabutyl amonium bromide, 5% potassium permanganate, the acetone mol ratio is 1:0.05-0.2:2-5:5-25, temperature of reaction 20-80 ℃, reacts 10-25 hour.
(3) in reaction flask, add 1,6,6-trimethylammonium-6,7,8,9,10,11-, six hydrogen-10,11-dioxo phenanthro-[1,2-b] furyl-2-formic acid (3), dehydrated alcohol, 10% alcohol sodium solution namely has solid to separate out, filter sodium salt 1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furyl-2-sodium formiate (4), wherein 1,6,6-trimethylammonium-6,7,8,9,10,11-, six hydrogen-10,11-dioxo phenanthro-[1,2-b] furyl-2-formic acid (3), dehydrated alcohol, 10% alcohol sodium solution mol ratio is 1:2-5:2-15:0.95-1.25, temperature of reaction 20-80 ℃, reacts 1-3 hour.
(4) add 1,6,6-trimethylammonium-6,7 in the reaction flask, 8,9,10,11-, six hydrogen-10,11-dioxo phenanthro-[1,2-b] furyl-2-formic acid (3), dicyclohexylcarbodiimide (DCC), 4-Dimethylamino pyridine (DMAP), absolute alcohol, methylene dichloride at room temperature reacted solids removed by filtration 2-12 hour, get 1,6,6-trimethylammonium-6,7 with silica gel column chromatography, 8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furyl-2-formic acid ester compound (5).Wherein reactant 1,6,6-trimethylammonium-6,7,8,9,10,11-, six hydrogen-10,11-dioxo phenanthro-[1,2-b] mol ratio such as furyl-2-formic acid (3), dicyclohexylcarbodiimide (DCC), 4-Dimethylamino pyridine (DMAP), absolute alcohol, methylene dichloride is 1:1-3:0.1-0.25:1-10:5-50, temperature of reaction 0-80 ℃, reacted 1-12 hour.
Compound involved in the present invention is by following route synthetic method two
The preparation method of tanshinone compound, specifically carry out according to following steps:
Tanshinone IIA and nitration mixture (acetic acid and nitric acid) carry out nitration reaction and make 2-nitro-1,6,6-trimethylammonium-6,7,8,9,10,11-, six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans (6), in reaction flask, add tanshinone IIA (1), diacetyl oxide, glacial acetic acid and nitrosonitric acid react and stop to pour in the frozen water after 1-8 hour, separate out a large amount of yellow solids, filter, washing, dry, get nitro-compound 2-nitro-1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans (6), wherein reactant tanshinone IIA (1), diacetyl oxide, glacial acetic acid and nitrosonitric acid mol ratio are 1:1-2:2-5:2-5, temperature of reaction-10 was reacted 1-12 hour to 0 ℃.
Tanshinone IIA and N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS) reaction generate corresponding halogenated product 2-halogen-1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans (6).
In reaction flask, add tanshinone IIA (1), acetic acid, N-halo succinimide, acetic acid, reacted 2-10 hour down to 20 ℃ in temperature of reaction-10, add water, get 2-halogen-1,6 with dichloromethane extraction, 6-trimethylammonium-6,7,8,9,10,11-, six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans (7), wherein reactant tanshinone IIA (1), N-halo succinimide, acetic acid mol ratio are 1:1-3:2-15, and temperature of reaction-10 was reacted 2-10 hour to 20 ℃.
Tanshinone IIA generates acetyl compound 8 with excess acetyl chloride under catalyst action.
Add tanshinone IIA (1), pyridine, Acetyl Chloride 98Min. in the reaction flask, react 1-5 hour afterreaction liquid down at 20-100 ℃ and pour in the frozen water, filter; washing, the dry crude product that gets, crude product gets acetyl compound 2-ethanoyl-1 through silica gel column chromatography; 6,6-trimethylammonium-6,7; 8,9,10; 11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans (8); wherein reactant tanshinone IIA (1), pyridine, Acetyl Chloride 98Min. mol ratio are 1:2-25:1-5, and 20 to 100 ℃ of temperature of reaction were reacted 1-5 hour.
Compound involved in the present invention is by following route synthetic method three
Method three steps specific as follows of the present invention:
Tanshinone IIA oxidation under tin anhydride catalysis generates aldehyde compound, reduces and distinguishes oxy-compound, generates acrylic compounds with propanedioic acid under pyridine and piperidines catalysis, carries out esterification with alcohol and gets corresponding acrylic ester compound.
(1) in reaction flask, adds tanshinone IIA (1), tin anhydride, dioxane, heating reflux reaction 5-24 hour, filter, concentrate, get 6,6-dimethyl-6 with silica gel column chromatography, 7,8,9,10,11-, six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans-1-formaldehyde (9), wherein reactant tanshinone IIA (1), tin anhydride, dioxane mol ratio are 1:0.5-2.5:3-25, and 40 to 110 ℃ of temperature of reaction were reacted 5-24 hour.
(2) in reaction flask, add 6,6-dimethyl-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans-1-formaldehyde (9), methyl alcohol, methylene dichloride, sodium borohydride, reacted 10-120 minute down at-10 to 5 ℃, use ethyl acetate extraction, washing, anhydrous sodium sulfate drying, vacuum concentration gets the 1-(methylol with silica gel column chromatography)-6,6-dimethyl-6,7,8,9,10,11-, six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans (10), wherein 6,6-dimethyl-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans-1-formaldehyde (9), methyl alcohol, methylene dichloride, the sodium borohydride mol ratio is 1:2-10:2-5:1-2.5, temperature of reaction-10 was reacted 10-120 minute to 5 ℃.
(3) in reaction flask, add the 1-(methylol)-6,6-dimethyl-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans (10), methylene dichloride, triethylamine, diacetyl oxide, at-10 to 5 ℃ of following reaction response 1-3 hours, use ethyl acetate extraction, washing, anhydrous sodium sulfate drying, vacuum concentration gets 6,6-dimethyl-6 with silica gel column chromatography, 7,8,9,10,11-, six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans-2-methyl acetic acid ester (11), wherein 1-(methylol)-6,6-dimethyl-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans (10), methylene dichloride, triethylamine, the diacetyl oxide mol ratio is 1:2-10:1-2.5:1-2.5, temperature of reaction-10 was reacted 1-3 hour to 5 ℃.
Compound involved in the present invention is by following route synthetic method four
Method four steps specific as follows of the present invention:
The TANSHINONES aldehyde compound carries out the selective reduction reduction reaction and generates oxy-compound or ether compound respectively, and oxy-compound and acetic anhydride generate corresponding ester compound.
(1) in reaction flask, adds tanshinone IIA formaldehyde (2), methyl alcohol, methylene dichloride, sodium borohydride, at-10 to 5 ℃, reaction times 10-60 minute, use ethyl acetate extraction, washing, anhydrous sodium sulfate drying, vacuum concentration gets compound 12, and wherein the mol ratio of tanshinone IIA formaldehyde (2), methyl alcohol, methylene dichloride, sodium borohydride is 1:10-100:10-100:1-2.5, temperature of reaction-10 is to 5 ℃, reaction times 10-60 minute.
(2) in reaction flask, add compound 12, methylene dichloride, diacetyl oxide, at-10 to 5 ℃, reacted 1-3 hour, use ethyl acetate extraction, washing, anhydrous sodium sulfate drying, vacuum concentration, get compound 13 with silica gel column chromatography, wherein the mol ratio of compound 12, methylene dichloride, diacetyl oxide is 1:10-100:1-2.5, and temperature of reaction-10 is to 5 ℃, reaction times 1-3 hour.
(3) in reaction flask, add tanshinone IIA formaldehyde (2), 10%(mass concentration) palladium carbon, methyl alcohol, at room temperature hydrogenation reaction 20-24 hour, filter palladium carbon, vacuum concentration, get target compound 14 with silica gel column chromatography, wherein the mol ratio of compound tanshinone IIA formaldehyde (2), 10% palladium carbon, methyl alcohol, hydrogen is 1:0.01-0.2:10-100:1:5,10 to 40 ℃ of temperature of reaction, reaction times 10-36 hour.
Compound involved in the present invention is by following route synthetic method five
Method five steps specific as follows of the present invention:
The TANSHINONES carbonyl compound, carrying out decarboxylation fertilizer with propanedioic acid under pyridine and piperidines catalysis should the generation acrylic compounds, carries out esterification with alcohol again and gets corresponding acrylic ester compound.
(1) in reaction flask, adds compound 15, benzene, propanedioic acid, pyridine, reflux is divided water, reacts 8-20 hour, removes solvent under reduced pressure, the aqueous sodium carbonate of adding 5% in the residue, filter, filtrate is transferred in about PH=2 with concentrated hydrochloric acid, filters, get carboxylic acid cpd 16 with silica gel column chromatography, wherein mol ratios such as compound 15, benzene, propanedioic acid, pyridine are 1:10-30:1-5:0.2-2.5, temperature of reaction 40-100 ℃, react 8-20 hour.
(2) in reaction flask, add carboxylic acid cpd 16, dehydrated alcohol, 10%(mass concentration) alcohol sodium solution, namely there is solid to separate out, filter sodium salt 18, wherein reactant 16, dehydrated alcohol, 10% alcohol sodium solution mol ratio are 1:2-5:2-5:0.95-1.25, temperature of reaction 20-80 ℃, reacted 1-3 hour.
(3) add carboxylic acid cpd 16, dicyclohexylcarbodiimide (DCC), 4-Dimethylamino pyridine (DMAP), absolute alcohol, methylene dichloride in the reaction flask, at room temperature reacted 2-12 hour, solids removed by filtration gets ester cpds 17 with silica gel column chromatography.Wherein mol ratios such as reactant 16, dicyclohexylcarbodiimide (DCC), 4-Dimethylamino pyridine (DMAP), absolute alcohol, methylene dichloride are 1:1-3:0.1-0.25:1-3:5-50, temperature of reaction 0-80 ℃, react 1-12 hour.
Compound involved in the present invention is by following route synthetic method six
Method six steps specific as follows of the present invention:
TANSHINONES generates corresponding carboxylic acid ester compound with chloracetic acid ethyl ester or the reaction of chloropropionic acid ethyl ester under zirconium chloride catalysis, hydrolysis generates corresponding carboxylic acid cpd under alkaline condition again, generates corresponding sodium salt with the sodium ethylate reaction.
(1) in reaction flask, adds tanshinone IIA (1), methylene dichloride, zirconium tetrachloride, ethyl chloroacetate (or chloropropionate), backflow stirring reaction 2-10 hour, solids removed by filtration, the filtrate vacuum concentration, residually get compound 19 with silica gel column chromatography, wherein tanshinone IIA (1), methylene dichloride, zirconium tetrachloride, ethyl chloroacetate (or chloropropionate) mol ratio are 1:15-50:2-5:1-3, temperature of reaction 20-80 ℃, react 2-10 hour.
(2) in reaction flask, add compound 19,5%(mass concentration) aqueous sodium hydroxide solution, reflux 1-4 hour, filter, filtrate is regulated about PH2 with concentrated hydrochloric acid, separates out solid, filters, drying gets carboxylic acid cpd 20 with silica gel column chromatography,
(3) wherein reactant compound 19 and 5%(mass concentration) the aqueous sodium hydroxide solution mol ratio be 1:1-2.5, temperature of reaction 30-110 ℃, reacted 1-4 hour.
(4) in reaction flask, add carboxylic acid cpd 20, dehydrated alcohol, 10% alcohol sodium solution, namely there is solid to separate out, filter sodium salt 21, wherein reactant 20, dehydrated alcohol, 10%(mass concentration) the alcohol sodium solution mol ratio is 1:2-5:2-5:0.95-1.25, temperature of reaction 20-80 ℃, reacted 1-3 hour.
(5) add carboxylic acid cpd 20, dicyclohexylcarbodiimide (DCC), 4-Dimethylamino pyridine (DMAP), absolute alcohol, methylene dichloride in the reaction flask, at room temperature reacted 2-12 hour, solids removed by filtration gets ester cpds 22 with silica gel column chromatography.Wherein mol ratios such as reactant 20, dicyclohexylcarbodiimide (DCC), 4-Dimethylamino pyridine (DMAP), absolute alcohol, methylene dichloride are 1:1-3:0.1-0.25:1-3:5-50, temperature of reaction 0-80 ℃, react 1-12 hour.
Compound involved in the present invention is by following route synthetic method seven
Method seven steps specific as follows of the present invention:
TANSHINONES generates the butyric acid compound with the butyryl oxide reaction under zirconium chloride catalysis, generate carboxylic acid ester compound with the alcohol reaction again, generates corresponding sodium salt with the sodium ethylate reaction.
(1) in reaction flask, adds tanshinone IIA (1), methylene dichloride, zirconium tetrachloride, Succinic anhydried, backflow stirring reaction 2-12 hour, solids removed by filtration, the filtrate vacuum concentration, residually get carboxylic acid cpd 23 with silica gel column chromatography,, wherein reactant tanshinone IIA (1), methylene dichloride, zirconium tetrachloride, Succinic anhydried mol ratio are 1:15-100:2-5:1-1.5, temperature of reaction 20-80 ℃, reacted 2-12 hour.
(2) in reaction flask, add carboxylic acid cpd 23, dehydrated alcohol, 10%(mass concentration) alcohol sodium solution, namely there is solid to separate out, filter sodium salt 24, wherein reactant 23, dehydrated alcohol, 10% alcohol sodium solution mol ratio are 1:2-5:2-5:0.95-1.25, temperature of reaction 20-80 ℃, reacted 1-3 hour.
(3) add carboxylic acid cpd 23, dicyclohexylcarbodiimide (DCC), 4-Dimethylamino pyridine (DMAP), absolute alcohol, methylene dichloride in the reaction flask, at room temperature reacted 2-12 hour, solids removed by filtration gets ester cpds 25 with silica gel column chromatography.Wherein mol ratios such as reactant 23, dicyclohexylcarbodiimide (DCC), 4-Dimethylamino pyridine (DMAP), absolute alcohol, methylene dichloride are 1:1-3:0.1-0.25:1-3:5-50, temperature of reaction 0-80 ℃, react 1-12 hour.
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 is that compound is 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 one, 1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans-2-formaldehyde (Tan-001)
In reaction flask, add tanshinone IIA (2.94g, 19mmol), 50ml dimethyl formamide (DMF), agitation and dropping 7ml phosphorus oxychloride under the room temperature, reacting 2 hours afterreaction liquid down at 70-80 ℃ pours in the frozen water of 750ml, yellow mercury oxide is arranged, filter, washing, the dry crude product that gets, crude product gets through silica gel column chromatography, productive rate 67%
1H-NMR (300MHz, (CDCl
3)), δ: 9.86 (s, 1H), 8.80 (d, J=6.3Hz, 1H), 7.71 (d, J=6.3Hz, 1H), 3.21 (m, 2H), 2.65 (s, 3H), 1.78-1.82 (m, 2H), 1.65-1.69 (m, 2H), 1.42 (s, 6H).
Example two, 2-bromo-10,11-dioxo-1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen phenanthro-[1,2-b] furans (Tan-002)
(1.47g 5mmol), acetic acid 80ml, slowly drips N-bromosuccinimide NBS(1.07g to add tanshinone IIA in reaction flask, 6mmol) the solution in 25ml acetic acid, room temperature reaction 6 hours adds water, use dichloromethane extraction, combining extraction liquid washes with water successively, the sodium sulfite aqueous solution washing, the saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying gets red solid with silica gel column chromatography
1H-NMR (300MHz, (CDCl
3)), δ: 7.68 (d, J=7.9Hz, 1H), and 7.53(d, J=7.9Hz, 1H), 3.19 (m, 2H), 2.21 (s, 3H), 1.77-1.83 (m, 2H), 1.64-1.71 (m, 2H), 1.31 (s, 6H).
Example three, 2-chloro-1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans (Tan-003)
Reaction replaces NBS with example two with N-chlorosuccinimide (NCS), gets target product,
1H-NMR (300MHz, (CDCl
3), δ: 7.69 (d, J=7.2Hz, 1H), 7.56 (d, J=7.2Hz, 1H), 3.19 (m, 2H), 2.23 (s, 3H), 1.77-1.85 (m, 2H), 1.64-1.75 (m, 2H), 1.31 (s, 6H).
Example four, 2-iodo-10,11-dioxo-1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen phenanthro-[1,2-b] furans (Tan-004)
(59mg 0.2mmol), methylene dichloride 20ml, is cooled to-40 ℃ to add tanshinone IIA in reaction flask, slowly drip N-iodosuccinimide NIS(67.2g, 5ml dichloromethane solution 0.6mmol) was-40 ℃ of reactions 6 hours, add water, use dichloromethane extraction, combining extraction liquid washes with water successively, the sodium sulfite aqueous solution washing, the saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying gets red solid with silica gel column chromatography.
1H-NMR(300MHz,(CDCl
3),δ:7.63(d,J=7.5Hz,1H),7.55(d,J=7.5Hz,1H),3.18(m,2H),2.23(s,3H),1.78-1.86(m,2H),1.65-1.72(m,2H),1.32(s,6H)。
Example five, 2-nitro-1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans (Tan-005)
In reaction flask, add tanshinone IIA (59mg, 0.2mmol), the 30ml diacetyl oxide, be cooled to below 0 ℃ with ice-water bath, in the nitration mixture that adding glacial acetic acid (1.4g) and nitrosonitric acid (1.5g) are made, react stopped reaction after 3-4 hour, reaction mixture is poured in the frozen water, separate out a large amount of yellow solids, filtration, washing, drying get target compound with silica gel column chromatography, yield 68%
1H-NMR (300MHz, (CDCl
3)), δ: 7.79 (d, J=7.2Hz, 1H), 7.74 (d, J=7.2Hz, 1H), 3.21 (m, 2H), 2.76 (s, 3H), 1.78-1.86 (m, 2H), 1.66-1.73 (m, 2H), 1.32 (s, 6H).
Example six, 2-(methylol)-1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans (Tan-006)
In reaction flask, add Tan-001(129mg, 0.4mmol), 15ml methyl alcohol and 10ml methylene dichloride, be cooled to below 0 ℃ with ice-water bath, add sodium borohydride (30mg, 0.81mmol), under ice bath stirring reaction 15-20 minute, use ethyl acetate extraction, washing, anhydrous sodium sulfate drying, vacuum concentration, get target compound with silica gel column chromatography, yield 75%
1H-NMR (300MHz, (CDCl
3)), δ: 7.60 (d, J=6.8Hz, 1H), 7.51 (d, J=6.8Hz, 1H), 4.68 (s, 2H), 3.16 (m, 2H), 2.26 (s, 3H), 1.76-1.85 (m, 2H), 1.63-1.76 (m, 2H), 1.31 (s, 6H).
Example seven, 2-ethanoyl-1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans (Tan-007)
In reaction flask, add tanshinone IIA (2.94g, 19mmol), 120ml pyridine, agitation and dropping 8ml Acetyl Chloride 98Min. under the room temperature, react 2 hours afterreaction liquid down at 70-80 ℃ and pour in the frozen water of 750ml, filter, washing, the dry crude product that gets, crude product gets target compound through silica gel column chromatography, productive rate 73%
1H-NMR (300MHz, (CDCl
3)), δ:, 8.09 (d, J=7.2Hz, 1H), 7.63 (d, J=7.2Hz, 1H), 3.19 (m, 2H), 2.89 (s, 3H), 2.35 (s, 3H), 1.76-1.85 (m, 2H), 1.66-1.78 (m, 2H), 1.38 (s, 6H)
Example eight, 1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans is muttered-2-methyl acetic acid ester (Tan-008)
In reaction flask, add Tan-006(130mg, 0.4mmol), the 25ml methylene dichloride, be cooled to below 0 ℃ with ice-water bath, drip diacetyl oxide (1ml), under ice bath stirring reaction 1-1.5 hour, use ethyl acetate extraction, washing, anhydrous sodium sulfate drying, vacuum concentration gets target compound with silica gel column chromatography, yield 86%
1H-NMR (300MHz, (CDCl
3), δ: 7.61 (d, J=7.2Hz, 1H), 7.54 (d, J=7.2Hz, 1H), 5.07 (s, 2H), 3.14 (m, 2H), 2.28 (s, 3H), 2.02 (s, 3H), 1.78 (m, 2H), 1.63 (m, 2H), 1.29 (s, 6H).
Example nine, 2-(methoxyl group)-1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans (Tan-009)
In reaction flask, add Tan-001(260mg, 0.8mmol), 10% palladium carbon (30mg), 50ml methyl alcohol, at room temperature hydrogenation reaction 20-24 hour, filter palladium carbon, vacuum concentration gets target compound with silica gel column chromatography, yield 29%,
1H-NMR (300MHz, (CDCl
3), δ: 7.67 (m, 2H), 4.08 (s, 3H), 3.18 (m, 2H), 2.39 (s, 3H), 1.76-1.79 (m, 2H), 1.61-1.65 (m, 2H), 1.29 (s, 6H).
Example ten, 6,6-dimethyl-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans is muttered-1-formaldehyde (Tan-010)
In reaction flask, add tanshinone IIA (200mg, 0.68mmol), tin anhydride (225mg, 2.03mmol), the 25ml dioxane, heating reflux reaction 10-12 hour, filter, concentrate, get target compound Tan-010 with silica gel column chromatography, yield 33%,
1H-NMR (300MHz, (CDCl
3), δ: 10.33 (s, 1H), 8.01 (d, J=7.5Hz, 1H), 7.69 (d, J=7.5Hz, 1H), 3.23 (m, 2H), 1.76-1.88 (m, 2H), 1.63-1.73 (m, 2H), 1.32 (s, 6H).
Example 11,1-(methylol)-6,6-dimethyl-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans (Tan-011)
In reaction flask, add Tan-010(125mg, 0.4mmol), 10ml methyl alcohol and 20ml methylene dichloride, be cooled to below 0 ℃ with ice-water bath, add sodium borohydride (29mg, 0.80mmol), under ice bath stirring reaction 30-40 minute, use ethyl acetate extraction, washing, anhydrous sodium sulfate drying, vacuum concentration, get target compound with silica gel column chromatography, yield 67%
1H-NMR (300MHz, (CDCl
3)) δ: 7.68 (d, J=7.8Hz, 1H), 7.57 (d, J=7.2Hz, 1H), 7.37 (s, 1H), 4.25 (s, 2H), 3.19 (m, 2H), 1.78-1.83 (m, 2H), 1.64-1.72 (m, 2H), 1.31 (s, 6H).
Example 12,6,6-dimethyl-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans-2-methyl acetic acid ester (Tan-012)
In reaction flask, add Tan-011(125mg, 0.4mmol), the 20ml methylene dichloride, be cooled to below 0 ℃ with ice-water bath, drip the 2ml triethylamine, drip the 1ml diacetyl oxide then, stirring reaction is 1 hour in ice bath, uses ethyl acetate extraction, washing, anhydrous sodium sulfate drying, vacuum concentration, get target compound with silica gel column chromatography, yield 83%
1H-NMR (300MHz, (CDCl
3)) δ: 7.59 (d, J=6.0Hz, 1H), 7.55 (d, J=6.0Hz, 1H), 7.473 (s, 2H), 5.24 (s, 2H), 3.19 (t, 2H), 2.11 (s, 3H), 1.76-1.81 (m, 2H), 1.64-1.67 (m, 2H), 1.31 (s, 6H).
Example 13,1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furyl-2-formic acid (Tan-013)
In reaction flask, add Tan-001(258mg, 0.8mmol), 40ml acetone, Tetrabutyl amonium bromide (15mg), be cooled to below 0 ℃ with ice-water bath, drip concentration and be 5% potassium permanganate solution 15ml, at room temperature reacted 15-20 hour, solids removed by filtration, filtrate is regulated PH=2 with hydrochloric acid, has precipitation to generate, filtration, drying, get target compound with silica gel column chromatography, yield 46%
1H-NMR (400MHz, (CDCl
3), δ: 9.89 (s, 1H), 7.99 (d, J=7.8Hz, 1H), 7.67 (d, J=7.8HZ, 1H), 2.97 (t, 7.8HZ, 7.8Hz, 2H), 2.68 (s, 3H), 2.11 (t, J=7.8HZ, 7.8HZ, 2H), 1.81 (m, 2H), 1.37 (s, 6H).
Example 14,1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furyl-2-methyl acetate (Tan-014)
In reaction flask, add Tan-013(100mg, 0.3mmol), dicyclohexylcarbodiimide (DCC) ((80mg, 0.38mmol), (4-Dimethylamino pyridine (DMAP) (10mg), 1ml anhydrous methanol, 25ml methylene dichloride, at room temperature reacted 4-6 hour, solids removed by filtration, get target compound with silica gel column chromatography, yield 82%, ESI-MS[M
+] (m/z): 352.13.
Example 15,1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furyl-2-ethyl formate (Tan-015)
Reaction replaces anhydrous methanol with example 15 with dehydrated alcohol, gets target product, yield 74%, ESI-MS[M
+] (m/z): 366.15.
Example 16,1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furyl-2-sodium formiate (Tan-016)
In reaction flask, add Tan-013(300mg, 0.89mmol) be dissolved in the dehydrated alcohol, add 10% alcohol sodium solution of equivalent, namely have solid to separate out, filter target product, yield 91%, ESI-MS[M
+] (m/z): 360.14.
Example 17,1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furyl-2-ethyl acetate (Tan-017)
In reaction flask, add tanshinone IIA (1.47g, 5mmol), 75ml methylene dichloride, zirconium tetrachloride (1.2g, 5.2mmol), the 3ml ethyl chloroacetate, backflow stirring reaction 4-6 hour, solids removed by filtration, the filtrate vacuum concentration residually gets target compound with silica gel column chromatography, yield 79%, ESI-MS[M
+] (m/z): 380.16.
Example 18,1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furyl-2-acetic acid (Tan-018)
In reaction flask, add Tan-017(760mg, 2mmol), 5% aqueous sodium hydroxide solution (150ml), reflux 1-2 hour, stopped reaction, filter, filtrate is regulated about PH2 with concentrated hydrochloric acid, separates out solid, filters, dry, get target compound with silica gel column chromatography, yield 81%, ESI-MS[M
+] (m/z): 352.13.
Example 19,1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furyl-2-methyl acetate (Tan-019)
Reaction replaces Tan-013 with example 15 with Tan-019, gets target product,, yield 84%, ESI-MS[M
+] (m/z): 366.15.
Example 20,1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furyl-2-sodium acetate (Tan-020)
In reaction flask, add Tan-018(300mg, 0.85mmol) be dissolved in the dehydrated alcohol, add 10% alcohol sodium solution of equivalent, namely have solid to separate out, filter target product, yield 89%, ESI-MS[M
+] (m/z): 374.11.
Example 21,1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furyl-2-ethyl propionate (Tan-021)
In reaction flask, add tanshinone IIA (1.47g, 5mmol), 75ml methylene dichloride, zirconium tetrachloride (1.2g, 5.2mmol), the 3ml chloropropionate, backflow stirring reaction 4-6 hour, solids removed by filtration, the filtrate vacuum concentration residually gets target compound with silica gel column chromatography, yield 63%, ESI-MS[M
+] (m/z): 394.18.
Example 22,1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furyl-2-propionic acid (Tan-022)
In reaction flask, add Tan-021(800mg, 2mmol), 5% aqueous sodium hydroxide solution (150ml), reflux 1-2 hour, stopped reaction, filter, filtrate is regulated about PH2 with concentrated hydrochloric acid, separates out solid, filters, dry, get target compound with silica gel column chromatography, yield 72%, ESI-MS[M
+] (m/z): 366.15.
Example 23,1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furyl-2-methyl propionate (Tan-023)
Reaction replaces Tan-013 with example 15 with Tan-021, gets target product,, yield 86%, ESI-MS[M
+] (m/z): 380.16.
Example 24,1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furyl-2-Sodium Propionate (Tan-024)
In reaction flask, add Tan-021(300mg, 0.82mmol) be dissolved in the dehydrated alcohol, add 10% alcohol sodium solution of equivalent, namely have solid to separate out, filter target product, yield 88%, ESI-MS[M
+] (m/z): 388.13.
Example 25,1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furyl-2-butyric acid (Tan-025)
In reaction flask, add tanshinone IIA (1.47g, 5mmol), 100ml methylene dichloride, zirconium tetrachloride (1.2g, 5.2 mmol), Succinic anhydried (0.69g, 7.5mmol), backflow stirring reaction 4-6 hour, solids removed by filtration, the filtrate vacuum concentration, residually get target compound with silica gel column chromatography, yield 75%, ESI-MS[M
+] (m/z): 380.16.
Example 26,1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furyl-2-methyl-butyrate (Tan-026)
Reaction replaces Tan-013 with example 15 with Tan-025, gets target product, yield 86%, ESI-MS[M
+] (m/z): 394.18.
Example 27,1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furyl-2-ethyl butyrate (Tan-027)
Reaction replaces Tan-013 with example 15 with Tan-025, and dehydrated alcohol replaces anhydrous methanol, gets target product, yield 83%, ESI-MS[M
+] (m/z): 408.19.
Example 28,1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furyl-2-Sodium propanecarboxylate (Tan-028)
In reaction flask, add Tan-025(300mg, 0.79mmol) be dissolved in the dehydrated alcohol, add 10% alcohol sodium solution of equivalent, namely have solid to separate out, filter target product, yield 89%, ESI-MS[M
+] (m/z): 402.14.
Example 29 3-(6,7,8,9,10,11-, six hydrogen)-1,6,6-trimethylammonium-10,11-dioxo phenanthro-[1,2-b] furans-2-base-2-vinylformic acid (Tan-029)
In reaction flask, add (Tan-001) (1.47g, 5mmol), 100ml benzene, propanedioic acid (1.2g, 5.2mmol), the 10ml pyridine, reflux is divided water, reacted 10-12 hour, remove solvent under reduced pressure, add 5% aqueous sodium carbonate in the residue, filter, filtrate is transferred in about PH=2 with concentrated hydrochloric acid, filter, get target compound with silica gel column chromatography, yield 76%.
1H-NMR(300MHz,(DMSO-d
6),δ:12.56(s,1H),7.78-7.85(m,2H),7.51(d,1H),6.46(d,1H),3.09(m,2H),1.73(m,2H),1.73(m,2H),1.64(m,2H),2.37(s,3H),1.28(s,6H)。
Example 30 3-(6,7,8,9,10,11-, six hydrogen)-1,6,6-trimethylammonium-10,11-dioxo phenanthro-[1,2-b] furans-2-base-2-vinylformic acid formic acid (Tan-030)
Reaction replaces Tan-013 with example 15 with Tan-029, gets target product,, yield 81%.
1H-NMR(300MHz,(CDCl
3),δ:7.78(d,1H),7.65(d,1H),7.49(d,H),6.42(d,1H),3.82(s,3H),2.92(m,2H),2.40(s,3H),2.20(m,2H),1.34(s,6H)。
Example 31 3-(6,7,8,9,10,11-, six hydrogen)-1,6,6-trimethylammonium-10,11-dioxo phenanthro-[1,2-b] furans-2-base-2-ethyl propenoate (Tan-031)
Reaction replaces Tan-013 with example 15 with Tan-029, and dehydrated alcohol replaces anhydrous methanol, react target product, yield 85%.
1H-NMR(300MHz,(CDCl
3),δ:7.70(m,2H),7.46(d,1H),6.42(d,1H),5.39(s,1H),4.29(m,2H),3.29(m,2H),2.39(s,3H),1.79(m,2H),1.64(m,2H),1.27(m,3H),1.17(s,6H)。
Example 32 3-(6,7,8,9,10,11-, six hydrogen)-1,6,6-trimethylammonium-10,11-dioxo phenanthro-[1,2-b] furans-2-base-2-sodium acrylate (Tan-032)
In reaction flask, add Tan-029(300mg, 0.83mmol) be dissolved in the dehydrated alcohol, add 10% alcohol sodium solution of equivalent, namely have solid to separate out, filter target product, yield 81%, ESI-MS[M
+] (m/z): 386.11.
Example 33 3-[(6,7,8,9,10,11-, six hydrogen)-1,6,6-tetramethyl--10,11-dioxo phenanthro-[1,2-b] furans-2-base-)]-2-butylene acid (Tan-033)
In reaction flask, add (Tan-007) (1.68g, 5mmol), 100ml benzene, propanedioic acid (1.2g, 5.2mmol), the 10ml pyridine, reflux is divided water, reacted 10-12 hour, and removed solvent under reduced pressure, add 5% aqueous sodium carbonate in the residue, filter, filtrate is transferred in about PH=2 with concentrated hydrochloric acid, filters, and gets target compound with silica gel column chromatography, yield 81%, ESI-MS[M
+] (m/z): 378.16.
Example 34 3-(6,7,8,9,10,11-, six hydrogen)-1,6,6-trimethylammonium-10,11-dioxo phenanthro-[1,2-b] furans-2-base-) 2-methyl acrylate (Tan-034)
Reaction replaces Tan-013 with example 15 with Tan-033, gets target product,, yield 79%, ESI-MS[M
+] (m/z): 392.17.
Example 35 3-(6,7,8,9,10,11-, six hydrogen)-1,6,6-trimethylammonium-10,11-dioxo phenanthro-[1,2-b] furans-2-base-) 2-ethyl propenoate (Tan-035)
Reaction replaces Tan-013 with example 15 with Tan-033, and dehydrated alcohol replaces anhydrous methanol, gets target product, yield 75%, ESI-MS[M
+] (m/z): 406.19.
Example 36 3-[(6,7,8,9,10,11-, six hydrogen)-1,6,6-tetramethyl--10,11-dioxo phenanthro-[1,2-b] furans-2-base-)]-2-butylene acid sodium (Tan-036)
In reaction flask, add Tan-033(300mg, 0.81mmol) be dissolved in the dehydrated alcohol, add 10% alcohol sodium solution of equivalent, namely have solid to separate out, filter target product, yield 86%, ESI-MS[M
+] (m/z): 400.15.
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 (IC that test compounds suppresses prostate specific antigen then
50).Table 1 is listed tested compound to 50 percent inhibition ability (IC 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
50).
Table 1, tested compound are to 50 percent inhibition ability (IC 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
50).
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. tanshinone compound is characterized in that having compound I or the II of following general structure:
Wherein R is CHO, Br, NO
2, OCH
3, CH
2OOCH
3, COCH
3, C
1-C
3Carboxylic acid and sodium salt, carboxylicesters, vinyl cyanide, vinylformic acid and sodium salt or acrylate.
2. the preparation method of tanshinone compound is characterized in that carrying out according to following steps:
(1) in reaction flask, adds tanshinone IIA, dimethyl formamide, phosphorus oxychloride, reacted 1-5 hour down at 30-100 ℃, reaction solution is poured in the frozen water, and yellow mercury oxide is arranged, and filters, washing, the dry crude product that gets, crude product gets tanshinone IIA formaldehyde through silica gel column chromatography, and wherein the mol ratio of reactant tanshinone IIA, dimethyl formamide, phosphorus oxychloride is 1:2-5:2-5, temperature of reaction 30-100 ℃, reacted 1-5 hour;
(
2) adding tanshinone IIA formaldehyde in reaction flask, acetone, Tetrabutyl amonium bromide and mass concentration are 5% potassium permanganate solution, at 20-80 ℃, reacted solids removed by filtration 10-25 hour, filtrate is regulated PH=2 with hydrochloric acid, there is precipitation to generate, filters, drying gets 1 with silica gel column chromatography, 6,6-trimethylammonium-6,7,8,9,10,11-, six hydrogen-10,11-dioxo phenanthro-[1,2-b] furyl-2-formic acid, tanshinone IIA wherein, Tetrabutyl amonium bromide, mass concentration is 5% potassium permanganate, the acetone mol ratio is 1:0.05-0.2:2-5:5-25, temperature of reaction 20-80 ℃, reacts 10-25 hour;
(
3) in reaction flask, add 1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furyl-2-formic acid
,Dehydrated alcohol, mass concentration are 10% alcohol sodium solution, namely have solid to separate out, filter 1,6,6-trimethylammonium-6,7,8,9,10,11-, six hydrogen-10,11-dioxo phenanthro-[1,2-b] furyl-2-formic acid sodium salt, wherein 1,6,6-trimethylammonium-6,7,8,9,10,11-, six hydrogen-10,11-dioxo phenanthro-[1,2-b] furyl-2-formic acid, dehydrated alcohol, mass concentration are that 10% alcohol sodium solution mol ratio is 1:2-5:2-5:0.95-1.25, temperature of reaction 20-80 ℃, react 1-3 hour;
(
4) add 1,6,6-trimethylammonium-6,7 in the reaction flask, 8,9,10,11-, six hydrogen-10,11-dioxo phenanthro-[1,2-b] furyl-2-formic acid, dicyclohexylcarbodiimide, 4-Dimethylamino pyridine, absolute alcohol, methylene dichloride at room temperature reacted solids removed by filtration 2-12 hour, get 1,6,6-trimethylammonium-6,7 with silica gel column chromatography, 8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furyl-2-formic acid ester compound; Wherein reactant 1,6,6-trimethylammonium-6,7,8,9,10,11-, six hydrogen-10,11-dioxo phenanthro-[1,2-b] mol ratio such as furyl-2-formic acid, dicyclohexylcarbodiimide, 4-Dimethylamino pyridine, absolute alcohol, methylene dichloride is 1:1-3:0.1-0.25:1-3:5-50, temperature of reaction 0-80 ℃, reacted 1-12 hour.
3. the preparation method of tanshinone compound is characterized in that carrying out according to following steps:
In reaction flask, add tanshinone IIA, diacetyl oxide, glacial acetic acid and nitrosonitric acid, react and stop to pour in the frozen water after 1-8 hour, separate out a large amount of yellow solids, filtration, washing, drying get 2-nitro-1,6,6-trimethylammonium-6,7,8,9,10,11-, six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans, wherein reactant tanshinone IIA, diacetyl oxide, glacial acetic acid and nitrosonitric acid mol ratio are 1:1-2:2-5:2-5, temperature of reaction-10 was reacted 1-12 hour to 0 ℃;
Perhaps carry out according to following steps:
In reaction flask, add tanshinone IIA, acetic acid, N-halo succinimide, acetic acid, reacted 2-10 hour down to 20 ℃ in temperature of reaction-10, add water, get halogen compound 2-halogen-1 with dichloromethane extraction, 6,6-trimethylammonium-6,7,8,9,10,11-, six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans
,Wherein reactant tanshinone IIA, N-halo succinimide, acetic acid mol ratio are 1:1-3:2-15, and temperature of reaction-10 was reacted 2-10 hour to 20 ℃.
4. the preparation method of tanshinone compound is characterized in that carrying out according to following steps:
Add tanshinone IIA, pyridine, Acetyl Chloride 98Min. in the reaction flask, react 1-5 hour afterreaction liquid down at 20-100 ℃ and pour in the frozen water, filter, washing, the dry crude product that gets, crude product gets acetyl compound through silica gel column chromatography
8,Wherein reactant tanshinone IIA, pyridine, Acetyl Chloride 98Min. mol ratio are 1:2-25:1-5, and 20 to 100 ℃ of temperature of reaction were reacted 1-5 hour.
5. the preparation method of tanshinone compound is characterized in that carrying out according to following steps:
(1) in reaction flask, adds tanshinone IIA, tin anhydride, dioxane, heating reflux reaction 5-24 hour, filter, concentrate, get 6,6-dimethyl-6 with silica gel column chromatography, 7,8,9,10,11-, six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans-1-formaldehyde, wherein reactant tanshinone IIA, tin anhydride, dioxane mol ratio are 1:0.5-2.5:3-25, and 40 to 110 ℃ of temperature of reaction were reacted 5-24 hour;
(2) in reaction flask, add aldehyde compound 6,6-dimethyl-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans-1-formaldehyde, methyl alcohol, methylene dichloride, sodium borohydride, reacted 10-120 minute down at-10 to 5 ℃, use ethyl acetate extraction, washing, anhydrous sodium sulfate drying, vacuum concentration gets the 1-(methylol with silica gel column chromatography)-6,6-dimethyl-6,7,8,9,10,11-, six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans, wherein 6,6-dimethyl-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans-1-formaldehyde, methyl alcohol, methylene dichloride, the sodium borohydride mol ratio is 1:2-10:2-5:1-2.5, temperature of reaction-10 was reacted 10-120 minute to 5 ℃;
(3) in reaction flask, add the 1-(methylol)-6,6-dimethyl-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans, methylene dichloride, triethylamine, diacetyl oxide, at-10 to 5 ℃ of following reaction response 1-3 hours, use ethyl acetate extraction, washing, anhydrous sodium sulfate drying, vacuum concentration gets 6,6-dimethyl-6 with silica gel column chromatography, 7,8,9,10,11-, six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans-2-methyl acetic acid ester, wherein 1-(methylol)-6,6-dimethyl-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans, methylene dichloride, triethylamine, the diacetyl oxide mol ratio is 1:2-10:1-2.5:1-2.5, temperature of reaction-10 was reacted 1-3 hour to 5 ℃.
6. the preparation method of tanshinone compound is characterized in that carrying out according to following steps:
(1) in reaction flask, add tanshinone IIA formaldehyde, methyl alcohol, methylene dichloride, sodium borohydride, at-10 to 5 ℃, reaction times 10-60 minute, use ethyl acetate extraction, washing, anhydrous sodium sulfate drying, vacuum concentration gets the 2-(methylol)-1,6,6-trimethylammonium-6,7,8,9,10,11-, six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans
,Wherein the mol ratio of tanshinone IIA formaldehyde, methyl alcohol, methylene dichloride, sodium borohydride is 1:10-100:10-100:1-2.5, and temperature of reaction-10 is to 5 ℃, reaction times 10-60 minute;
(2) in reaction flask, add the 2-(methylol)-1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans, methylene dichloride, diacetyl oxide, at-10 to 5 ℃, reacted 1-3 hour, use ethyl acetate extraction, washing, anhydrous sodium sulfate drying, vacuum concentration gets 1 with silica gel column chromatography, 6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans is muttered-2-first and second acid esters, 2-(methylol wherein)-1,6,6-trimethylammonium-6,7,8,9,10,11-, six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans, methylene dichloride, the mol ratio of diacetyl oxide is 1:10-100:1-2.5, and temperature of reaction-10 is to 5 ℃, reaction times 1-3 hour;
(3) in reaction flask, add tanshinone IIA formaldehyde, 10%(mass ratio) palladium carbon, methyl alcohol, at room temperature hydrogenation reaction 20-24 hour, filter palladium carbon, vacuum concentration, get the 2-(methoxyl group with silica gel column chromatography)-1,6,6-trimethylammonium-6,7,8,9,10,11-six hydrogen-10,11-dioxo phenanthro-[1,2-b] furans, wherein compound tanshinone IIA formaldehyde, 10%(mass ratio) mol ratio of palladium carbon, methyl alcohol, hydrogen is 1:0.01-0.2:10-100:1:5,10 to 40 ℃ of temperature of reaction, reaction times 10-36 hour.
7. the preparation method of tanshinone compound is characterized in that carrying out according to following steps:
(1) in reaction flask, adds compound TANSHINONES carbonyl compound
,Benzene, propanedioic acid, pyridine, reflux is divided water, reacts 8-20 hour, removes solvent under reduced pressure, the adding mass concentration is 5% aqueous sodium carbonate in the residue, filters, and filtrate is transferred in about PH=2 with concentrated hydrochloric acid, filter, get carboxylic acid cpd with silica gel column chromatography, wherein the TANSHINONES carbonyl compound
,Mol ratios such as benzene, propanedioic acid, pyridine are 1:10-30:1-5:0.2-2.5, temperature of reaction 40-100 ℃, react 8-20 hour;
(2) in reaction flask, add the TANSHINONES carboxylic acid cpd
,Dehydrated alcohol, mass concentration are 10% alcohol sodium solution, namely have solid to separate out, filter sodium salt, wherein TANSHINONES carboxylic acid cpd, dehydrated alcohol, 10% alcohol sodium solution mol ratio are 1:2-5:2-5:0.95-1.25, temperature of reaction 20-80 ℃, reacted 1-3 hour;
(3) add TANSHINONES carboxylic acid cpd, dicyclohexylcarbodiimide, 4-Dimethylamino pyridine, absolute alcohol, methylene dichloride in the reaction flask, at room temperature reacted 2-12 hour, solids removed by filtration gets the TANSHINONES carbonate with silica gel column chromatography; Wherein mol ratios such as TANSHINONES carboxylic acid cpd, dicyclohexylcarbodiimide, 4-Dimethylamino pyridine, absolute alcohol, methylene dichloride are 1:1-3:0.1-0.25:1-3:5-50, temperature of reaction 0-80 ℃, react 1-12 hour.
8. the preparation method of tanshinone compound is characterized in that carrying out according to following steps:
(1) in reaction flask, adds tanshinone IIA, methylene dichloride, zirconium tetrachloride, ethyl chloroacetate (or chloropropionate), backflow stirring reaction 2-10 hour, solids removed by filtration, the filtrate vacuum concentration, residually get the TANSHINONES carbonate with silica gel column chromatography, wherein tanshinone IIA, methylene dichloride, zirconium tetrachloride, ethyl chloroacetate (or chloropropionate) mol ratio are 1:15-50:2-5:1-3, temperature of reaction 20-80 ℃, react 2-10 hour;
(2) in reaction flask, add to such an extent that TANSHINONES carbonate, mass concentration are 5% aqueous sodium hydroxide solution, reflux 1-4 hour, filter, filtrate is regulated about PH2 with concentrated hydrochloric acid, separates out solid, filters, drying gets the TANSHINONES carboxylic acid cpd with silica gel column chromatography
;
(3) wherein reactant TANSHINONES carbonate, mass concentration are that 5% aqueous sodium hydroxide solution mol ratio is 1:1-2.5, temperature of reaction 30-110 ℃, react 1-4 hour;
(4) in reaction flask, add carboxylic acid cpd
,Dehydrated alcohol, 10% alcohol sodium solution, namely have solid to separate out, filter TANSHINONES carboxylic acid sodium salt compound, wherein TANSHINONES carboxylic acid cpd, dehydrated alcohol, mass concentration are that 10% alcohol sodium solution mol ratio is 1:2-5:2-5:0.95-1.25, temperature of reaction 20-80 ℃, reacted 1-3 hour;
(5) add TANSHINONES carboxylic acid cpd, dicyclohexylcarbodiimide, 4-Dimethylamino pyridine, absolute alcohol, methylene dichloride in the reaction flask, at room temperature reacted 2-12 hour, solids removed by filtration gets the TANSHINONES carbonate with silica gel column chromatography; Wherein mol ratios such as reactant TANSHINONES carboxylic acid cpd, dicyclohexylcarbodiimide, 4-Dimethylamino pyridine, absolute alcohol, methylene dichloride are 1:1-3:0.1-0.25:1-3:5-50, temperature of reaction 0-80 ℃, react 1-12 hour.
9. the preparation method of tanshinone compound is characterized in that carrying out according to following steps:
(1) in reaction flask, add tanshinone IIA, methylene dichloride, zirconium tetrachloride, Succinic anhydried, backflow stirring reaction 2-12 hour, solids removed by filtration, the filtrate vacuum concentration residually gets the TANSHINONES carboxylic acid compound with silica gel column chromatography
,Wherein reactant tanshinone IIA, methylene dichloride, zirconium tetrachloride, Succinic anhydried mol ratio are 1:15-100:2-5:1-1.5, temperature of reaction 20-80 ℃, react 2-12 hour;
(2) in reaction flask, add the TANSHINONES carboxylic acid compound
,Dehydrated alcohol, mass concentration are 10% alcohol sodium solution, namely there is solid to separate out, filter TANSHINONES carboxylic acid sodium salt compound, wherein TANSHINONES carboxylic acid compound, dehydrated alcohol, 10% alcohol sodium solution mol ratio are 1:2-5:2-5:0.95-1.25, temperature of reaction 20-80 ℃, reacted 1-3 hour;
(3) add TANSHINONES carboxylic acid cpd, dicyclohexylcarbodiimide, 4-Dimethylamino pyridine, absolute alcohol, methylene dichloride in the reaction flask, at room temperature reacted 2-12 hour, solids removed by filtration gets the TANSHINONES carboxylic acid ester compound with silica gel column chromatography; Wherein TANSHINONES carboxylic acid cpd dicyclohexylcarbodiimide, 4-Dimethylamino pyridine, absolute alcohol, methylene dichloride mol ratio are 1:1-3:0.1-0.25:1-3:5-50, temperature of reaction 0-80 ℃, react 1-12 hour.
10. the purposes of tanshinone compound is characterized in that the purposes of tanshinone 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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| CN105037427A (en) * | 2015-06-22 | 2015-11-11 | 石家庄学院 | Tanshinone IIA ethylidene imine phosphate derivative, as well as preparation method and application thereof |
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| CN105037427A (en) * | 2015-06-22 | 2015-11-11 | 石家庄学院 | Tanshinone IIA ethylidene imine phosphate derivative, as well as preparation method and application thereof |
| CN105037484A (en) * | 2015-06-22 | 2015-11-11 | 石家庄学院 | Tanshinone IIA derivate comprising polyethylene glycol group and preparation and application of tanshinone IIA derivate |
| CN105837538A (en) * | 2016-03-28 | 2016-08-10 | 中国药科大学 | Use of tanshinone IIA derivatives in preparation of drug for protecting endothelial cells |
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| WO2021125733A1 (en) * | 2019-12-17 | 2021-06-24 | (주)셀로스바이오텍 | Pharmaceutical composition for preventing or treating hair loss |
| CN113171378A (en) * | 2021-04-30 | 2021-07-27 | 奥启(深圳)创投科技有限公司 | Stem cell exosome preparation for preventing and treating male sexual dysfunction |
| CN113773289A (en) * | 2021-09-15 | 2021-12-10 | 沈阳药科大学 | Naphthalene [1,2-b ] heterocycle-4, 5-diketone compound and preparation method and application thereof |
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