CN106699771A - Cryptotanshinone compound, as well as preparation method and application thereof - Google Patents
Cryptotanshinone compound, as well as preparation method and application thereof Download PDFInfo
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- CN106699771A CN106699771A CN201710088553.0A CN201710088553A CN106699771A CN 106699771 A CN106699771 A CN 106699771A CN 201710088553 A CN201710088553 A CN 201710088553A CN 106699771 A CN106699771 A CN 106699771A
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- QUXMUTHWEBIMOP-UHFFFAOYSA-N CC(C(C)c1c-2nc(-c3ccccc3C)[nH]1)/C=[O]\Cc1c-2c(CCCC2(C)C)c2cc1 Chemical compound CC(C(C)c1c-2nc(-c3ccccc3C)[nH]1)/C=[O]\Cc1c-2c(CCCC2(C)C)c2cc1 QUXMUTHWEBIMOP-UHFFFAOYSA-N 0.000 description 1
- 0 CC(COC1C(C=CC2C(C)(C)C)=C3C2C=C)C1C(N[C@]1C(c2cc(*)cc(OC)c2)=C1C)=C3N Chemical compound CC(COC1C(C=CC2C(C)(C)C)=C3C2C=C)C1C(N[C@]1C(c2cc(*)cc(OC)c2)=C1C)=C3N 0.000 description 1
- WDEGSLGMEZNGNE-GDJQGNDCSA-N CC1c(c2c(c3c(CCCC4(C)C)c4ccc33)nc(/C(/C=C\C)=C/CO)[nH]2)c3OC1 Chemical compound CC1c(c2c(c3c(CCCC4(C)C)c4ccc33)nc(/C(/C=C\C)=C/CO)[nH]2)c3OC1 WDEGSLGMEZNGNE-GDJQGNDCSA-N 0.000 description 1
- NSWUWERKKDDTAX-UHFFFAOYSA-N CC1c(c2c(c3c4ccc5c3CCCC5(C)C)nc(C3=CCC(C)C=C3)[nH]2)c4OC1 Chemical compound CC1c(c2c(c3c4ccc5c3CCCC5(C)C)nc(C3=CCC(C)C=C3)[nH]2)c4OC1 NSWUWERKKDDTAX-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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Abstract
The invention provides a cryptotanshinone compound, as well as a preparation method and application thereof, and relates to the technical field of medicinal chemistry. The invention further discloses a chemical structure and medical application of the compound. The compound III has a structural general formula as shown in the specification, wherein R is phenyl containing F, Cl, Br, CH3, OCH3, NO2, OH and other substituents. The cryptotanshinone compound can be used as an anti-androgen receptor medicine for treating diseases related to androgen, including prostate cancer, prostatic hyperplasia, acne, alopecia, hirsutism, muscle failure, gonad dysfunction, high cholesterol, male infertility, male sexual dysfunction, anemia, obesity and other diseases.
Description
Technical field
The present invention relates to field of pharmaceutical chemistry technology, it is related to some new anti-androgen receptor compounds, containing the chemical combination
The pharmaceutical dosage form and its application method of thing, particularly Cryptotanshinone class compound and application thereof.
Background technology
Androgen receptor (Androgen receptor, AR) belongs to the steroid receptor in nuclear receptor superfamily, is a class
It is widely distributed in vivo, the nuclear factor superfamily member of Ligand activation.Androgen and androgen receptor are preceding
The growing of row gland, function maintain and prostate cancer generation development and deteriorate and play particularly important in transfer process
Effect.Many diseases are related to androgen and androgen receptor in elderly men.Male increases with the age, male in vivo to swash
Plain level can decline, and be reduced along with internal muscle, and sexual function declines and occur phenomenons such as " male climacterics ".Conversely, in vivo
Androgen levels are too high equally to bring some other disease, and such as hyperplasia of prostate and prostate cancer is exactly androgen-dependent disease
Disease, also some other disease is relevant with androgen levels, contains androgen receptor in body skin hair, some people these acceptors
It is more sensitive to androgen, alopecia is caused, androgen receptor is more sensitive in young application on human skin, causes growth that powder do not pierce etc..
Prostate cancer (Prostate Cancer, PCa) is a kind of common male malignancy, quick in recent years
A kind of global tumor disease is risen to, in many American-European countries, prostate-cancer incidence accounts for male malignancy first, extremely
The rate of dying accounts for second.220,800 male's oj C prostate cancers are there are about in the U.S. within 2016, wherein about 20,710 patients are dead
Die.Ranked first position and second respectively in all male tumors.Recently as the raising of prostatic cancer early diagnosis level,
Prostate cancer rises year by year in China's incidence of disease, its common cancer that will turn into influence China men's health.
Prostate cancer is in early days androgen-dependent, and androgen ablation therapies (ADT) are that the first-selection for treating prostate cancer is controlled
Treatment method, including operation castration method and androgen deprivation method.But nearly all patient occurs resistance to after experiencing 12~18 months
Medicine phenomenon, metastases develop into and are difficult to cure and easily cause the emasculation Researches on Hormonal Refractory Prostate Cancer of death
(CRPC).The generation development of castration resistance type prostate cancer involves the interaction of a series of complex signaling molecule, wherein male
The gene mutation and overexpression of hormone receptor are castration resistance type prostate cancer main development mechanism.
Some anti-androgen receptor medicines, such as Flutamide (flutamide, HF) and Bicalutamide (bicalutamide)
It is widely used in clinical treatment prostate cancer.But the medicine has many side effects.Flutamide and Bicalutamide are the anti-hero of nonsteroidal
Sex hormone receptor medicine, although be widely used in treatment prostate cancer, some anti-androgen receptor medicines can swash as hero
Plain receptor stimulating agent may result in " the antiandrogen withdrawal syndrome ".To " Flutamide removes syndrome " at present it is generally acknowledged that hero
Hpr gene is undergone mutation, and the target gene of the catabolite activator androgen receptor of Flutamide, such as prostate-specific resist
Former (PSA), causes PSA to rise, and PSA declines after stopping.In fact, the mistake of the sub- ARA70 of another androgen receptor Assisted Activation
Expression can be such that AR is activated by androgen receptor antagonist, so as to the prostate for causing to be treated with androgen receptor antagonist method
The recurrence of cancer, or even develop into non-androgen-dependent prostate cancer.
The miscellaneous Shandong amine (enzalutamide) of grace is second generation nonsteroidal androgen receptor inhibitor, can be blocked swollen
Oncocyte androgen receptor signal path conducts, and is that a new generation of United States drug developer Medivation companies exploitation is oral
Antiandrogen medicine, is mainly used in treating advanced prostate cancer (CRPC) patient, is approved listing by U.S. FDA within 2012.Mesh
The preceding report miscellaneous Shandong amine of grace equally has the resistance to the action of a drug, it is impossible to long-term use.More effective antiandrogen new drug is developed, for treating late period
Prostate cancer has important value.
Lead compound is screened from natural products, then carries out structural modification and transformation, be some effective of new drug development.
The red sage root is the root and rhizome of the lip section plant red sage root (Salvia miltiorrhiza Bunge), first recorded in《Sheng Nong's herbal classic》,
Clinically there is the effects such as promoting blood circulation, inducing meastruation to relieve menalgia, relieving restlessness that clears away heart-fire, mental-tranquilization, the treatment heart is currently used primarily in
The diseases such as blood vessel, hypertension, cerebral ischemia, its primary chemical active component is o-quinone structure tanshinone compound.We have sent out
Existing tanshinone compound has good anti-androgen receptor activity, (Xu Defeng, Zhang Chuanxiang, Ji Yejun, tanshinone
Compound and its application, Chinese patent：CN102127037A), the present invention is to enter by precursor structure of Cryptotanshinone on this basis
A series of compound-modified Cryptotanshinone class compounds of synthesis of row, can be used to treat prostate as anti-androgen receptor medicine
The disease relevant with androgen such as cancer, hyperplasia of prostate, acne, alopecia, whelk, hirsutism.The invention further relates to the hidden red sage root
Ketone compounds as medicinal application, using Cryptotanshinone class compound as androgen receptor antagonist active ingredient, it is single
Solely apply or share or combined with acceptable excipient etc., being conventionally made oral agents or parenteral type is used for
Treatment and male sex hormone relevant disease.
The present invention refers to for treating human and animal's disease or physiologic derangement, particularly for treating human diseases or physiology
Medicine or the medicine composition of disorderly class, these medicines or medicine composition are containing with the compound of following compound formulas or composition
Salt, or appropriate pharmaceutically acceptable carrier or dilution, these human diseases or physiologic derangement include prostate cancer and its
His human diseases related to androgen receptor and be not suitable for symptom, such as hyperplasia of prostate, acne, alopecia, hirsutism, male be not
Educate, male's sexual is bad, prostate cancer, liver cancer, testis, breast cancer etc., these medicines or medicine composition can also there are other to use
On the way, such as male contraception disease relevant with androgen.
The content of the invention
It is an object of the invention to overcome deficiency of the prior art, find a class activity class antiandrogen high and receive
A kind of body compound, there is provided tanshinone compound, can be used to treat related to androgen as anti-androgen receptor medicine
Disease, can be used to treat prostate cancer, such as hyperplasia of prostate, acne, alopecia, hirsutism, muscle depletion, gonad function declines
Weak, cholesterol is too high, male sterility, the disease such as male's sexual is bad, anaemia, obesity.
Chemical constitution and medical usage present invention is primarily intended to provide such compound.
Cryptotanshinone class compound, is related to the compound III with following general structure,
R is to contain F, Cl, Br, CH3, OCH3, NO2, the phenyl of the substitution base such as OH.
The purposes of Cryptotanshinone class compound, for preparing anti-androgen receptor medicine, for treating and androgen phase
The disease of pass, can be used to treat prostate cancer, such as hyperplasia of prostate, acne, alopecia, hirsutism, muscle depletion, and gonad function declines
Weak, cholesterol is too high, male sterility, the disease such as male's sexual is bad, anaemia, obesity.
Compound involved in the present invention presses following route synthetic method
R is to contain F, Cl, Br, CH3, OCH3, NO2, the benzene of the substitution base such as OH.
Preparation method step specific as follows of the invention：
Heating stirring is cooled down after completion of the reaction to 110 degree after the mixing of Cryptotanshinone, substituted-phenyl aldehyde, acetic acid and ammonium acetate,
Deionized water dilution is added, PH=7 is adjusted, is filtered, washed and dried, new Cryptotanshinone class compound is obtained with silica gel post separation.
The preparation method of Cryptotanshinone class compound of the present invention, is carried out as steps described below：
Cryptotanshinone (1), substituted benzaldehyde, glacial acetic acid, ammonium acetate are added in reaction bulb, in 80-120 aldehyde reactions 2-10
Hour, after completion of the reaction, after mixed liquor is cooled to room temperature, distilled water, concentrated ammonia liquor regulation PH=7 or so are added, filter, washing,
Dry, compound II, wherein reactant Cryptotanshinone (1), substituted benzaldehyde, glacial acetic acid, ammonium acetate etc. are obtained with silica gel column chromatography
Mol ratio is 1：1-2：5-25：3-5, reaction temperature 80-120 aldehyde reacts 2-12 hours.
The structural formula of wherein described substituted benzaldehyde isWherein R is to contain F, Cl, Br, CH3, OCH3, NO2, OH etc.
Replace the benzaldehyde of base.
Advantages of the present invention：
AR has various hypotypes, perfect form (fAR) and spliced variants type androgen receptor (ARVs), and wherein spliced variants type is male
Hormone receptor (ARVs) is distinctive advanced prostate cancer, the Cryptotanshinone class compound that we invent to perfect form (fAR) and
Spliced variants type androgen receptor (ARVs) effectively suppresses, and can be used for the treatment of advanced prostate cancer.With existing clinical medicine
Bicalutamide is compared, and can only suppress perfect form (fAR), it is impossible to is suppressed spliced variants type androgen receptor (ARVs), is caused than card
Shandong amine is invalid to advanced prostate cancer, and the present invention overcomes the shortcomings of upper existing antiandrogen medicine, can be used to treat late period prostatitis
Gland cancer.
Brief description of the drawings
Fig. 1 is relative Developing restraint ability of the compound to LNCaP cells,
Fig. 2 is relative Developing restraint ability of the compound to CWR22RV1 cells.
Specific embodiment
The present invention relates to the medicine of tanshinone compound, comprising compound its structural formula it is as follows：
The 2- of example one (2- fluorophenyls) imidazoles [4,5-f] [10,11] -1,6,6- trimethyl -1,6,6- trimethyl -1,2,
6,7,8,9- hexahydros phenanthro- [1,2-b]-furans (CTS-01)
Cryptotanshinone (149mg, 0.5mmol), 2- fluorobenzaldehydes (65mg, 0.50mmol), 3ml ice are added in reaction bulb
Acetic acid, ammonium acetate (0.77g, 10mmol), react 3-5 hours at 100-105 DEG C, and after completion of the reaction, mixed liquor is cooled to room temperature
Afterwards, 10ml distilled water, concentrated ammonia liquor regulation PH=7 or so are added, filtering is washed, dried, and is prepared with silica gel column chromatography bright orange
Color powder, is target product, yield 61.6%, fusing point：179.3~181.9 DEG C.1H-NMR(300M,CDCl3), δ=10.78
(s, 1H), 8.58 (t, J=6.7Hz, 1H), 7.92 (d, J=8.7Hz, 1H), 7.52 (d, J=8.7Hz, 1H), 7.34 (dd, J
=15.1,7.5Hz, 2H), 7.23-7.15 (m, 1H), 4.94 (t, J=8.8Hz, 1H), 4.53-4.22 (m, 1H), 4.19 (d, J
=6.8Hz, 1H), 3.40 (s, 2H), 2.06 (s, 2H), 1.82 (s, 2H), 1.63 (d, J=6.5Hz, 3H), 1.40 (d, J=
2.9Hz,6H)；13C-NMR(125MHZ,CDCl3), δ=9.61,19.70,31.77,34.43,37.02,38.21,115.82,
116.00,117.60,123.78,125.19,129.71,140.58,143.72,158.92,160.88。
The 2- of example two (3- fluorophenyls) imidazoles [4,5-f] [10,11] -1,6,6- trimethyl -1,6,6- trimethyls 1,2,6,
7,8,9- hexahydros phenanthro- [1,2-b]-furans (CTS-02)
Cryptotanshinone (149mg, 0.5mmol), 3- fluorobenzaldehydes (130mg, 1.0mmol), 15ml are added in reaction bulb
Glacial acetic acid, ammonium acetate (2.0g, 26mmol), react 3-5 hours at 100-105 DEG C, and after completion of the reaction, mixed liquor is cooled to room temperature
Afterwards, 30ml distilled water, concentrated ammonia liquor regulation PH=7 or so are added, filtering is washed, dried, and is prepared with silica gel column chromatography bright orange
Color powder, is target product, yield 55.8%, fusing point：105.2~109.3 DEG C.1H-NMR(300M,CDCl3), δ=9.99 (s,
1H), 7.92 (d, J=8.6Hz, 1H), 7.82 (d, J=7.5Hz, 1H), 7.53 (d, J=8.7Hz, 1H), 7.44 (dd, J=
12.8,6.3Hz,1H),7.09(s,1H),4.87(s,1H),4.36(s,1H),4.09(s,1H),3.49(s,2H),2.08(d,
J=5.1Hz, 2H), 1.83 (s, 2H), 1.56 (d, J=6.3Hz, 3H), 1.41 (d, J=4.2Hz, 6H).13C-NMR
(125MHZ,CDCl3), δ=19.79,30.61,34.50,36.99,38.43,79.25,113.01,113.20,116.03,
116.21,117.56,120.34,121.44,123.79,130.62,132.36,143.80,152.90,162.18,164.14。
The 2- of example three (4- fluorophenyls) imidazoles [4,5-f] [10,11] -- 1,6,6- trimethyl 1,2,6,7,8,9- hexahydros are luxuriant and rich with fragrance
And [1,2-b]-furans (CTS-03)
Reaction replaces 2- fluorobenzaldehydes with example one with 4- fluorobenzaldehydes, obtains target product, yield 50.7%, fusing point：
143.8~147.2 DEG C.1H-NMR(300M,CDCl3), δ=9.96 (s, 1H), 8.09-7.98 (m, 2H), 7.92 (d, J=
8.5Hz, 1H), 7.51 (d, J=8.7Hz, 1H), 7.17 (t, J=8.6Hz, 2H), 4.88 (t, J=8.8Hz, 1H), 4.53-
4.31(m,1H),4.05(s,1H),3.49(s,2H),2.15–1.99(m,2H),1.88–1.74(m,2H),1.54(s,3H),
1.40 (d, J=3.6Hz, 6H).13C-NMR(125MHZ,CDCl3), δ=19.74,2.93,30.38,31.80,34.48,
37.01,38.42,79.23,115.99,116.17,120.36,123.65,124.23,126.48,128.00,140.66,
143.88,152.77,162.47,164.46。
The 2- of example four (2- chlorphenyls) imidazoles [4,5-f] [10,11] -1,6,6- trimethyl -1,6,6- trimethyl -1,2,
6,7,8,9- hexahydros phenanthro- [1,2-b]-furans (CTS-04)
Reaction replaces 2- fluorobenzaldehydes with example one with 2- chlorobenzaldehydes, obtains target product, yield 61.6%, fusing point：
156.8~159.2 DEG C.1H-NMR(300M,CDCl3), δ=11.24 (s, 1H), 8.59 (d, J=7.2Hz, 1H), 7.93 (d, J
=8.7Hz, 1H), 7.53 (d, J=8.8Hz, 1H), 7.50-7.40 (m, 2H), 7.36 (d, J=7.6Hz, 1H), 4.95 (t, J
=8.8Hz, 1H), 4.41 (dd, J=8.6,6.1Hz, 1H), 4.19 (s, 1H), 3.41 (s, 2H), 2.09 (s, 2H), 1.82 (s,
2H),1.61(s,3H),1.40(s,6H)；13C-NMR(125MHZ,CDCl3), δ=19.76,29.74,30.28,31.79,
34.45,37.11,38.31,117.63,120.45,123.78,127.68,128.37,130.15,130.68,131.78,
143.57。
The 2- of example five (3- chlorphenyls) imidazoles [4,5-f] [10,11] -1,6,6- trimethyl -1,6,6- trimethyl -1,2,
6,7,8,9- hexahydros phenanthro- [1,2-b]-furans (CTS-05)
Reaction replaces 2- fluorobenzaldehydes with example one with 3- chlorobenzaldehydes, obtains target product, yield 53%, fusing point：
132.8~138.6 DEG C.1H-NMR(300M,CDCl3), δ=9.96 (s, 1H), 8.05 (s, 1H), 7.92 (d, J=8.6Hz,
2H), 7.53 (d, J=8.7Hz, 1H), 7.38 (d, J=7.5Hz, 2H), 4.89 (t, J=8.8Hz, 1H), 4.39 (dd, J=
8.6,5.8Hz, 1H), 4.08 (s, 1H), 3.55 (s, 2H), 2.09 (s, 2H), 1.81 (d, J=11.7Hz, 2H), 1.55 (d, J
=5.7Hz, 3H), 1.41 (d, J=3.9Hz, 6H).13C-NMR(125MHZ,CDCl3), δ=9.74,19.74,29.72,
30.67,31.92,34.49,38.34,124.01,124.43,126.02,129.18,130.22,135.01。
The 2- of example six (4- chlorphenyls) imidazoles [4,5-f] [10,11] -1,6,6- trimethyl -1,6,6- trimethyl -1,2,
6,7,8,9- hexahydros phenanthro- [1,2-b]-furans (CTS-06)
Reaction replaces 2- fluorobenzaldehydes with example one with 4- chlorobenzaldehydes, obtains target product, and yield yield 57.8% melts
Point：144.5~145.7 DEG C.1H-NMR(300M,CDCl3), δ=10.05 (s, 1H), 7.95 (dd, J=18.9,8.1Hz, 3H),
7.52 (d, J=8.7Hz, 1H), 7.44 (d, J=7.9Hz, 2H), 4.87 (s, 1H), 4.41 (s, 1H), 4.09 (s, 1H), 3.50
(s,2H),2.07(s,2H),1.82(s,2H),1.56(s,3H),1.40(s,6H)。13C-NMR(125MHZ,CDCl3), δ=
19.71,27.01,30.57,31.79,34.49,36.97,38.38,79.25,117.53,120.41,123.84,127.33,
129.21。
The 2- of example seven (2- bromophenyls) imidazoles [4,5-f] [10,11] -1,6,6- trimethyl -1,6,6- trimethyl -1,2,
6,7,8,9- hexahydros phenanthro- [1,2-b]-furans (CTS-07)
Reaction replaces 2- fluorobenzaldehydes with example one with 2- bromobenzaldehydes, obtains target product, yield 60.7%, fusing point：
164.1~165.9 DEG C.1H-NMR(300M,CDCl3), δ=11.22 (s, 1H), 8.51 (d, J=9.0Hz, 1H), 7.93 (d, J
=8.7Hz, 1H), 7.69 (d, J=7.2Hz, 1H), 7.51 (dd, J=18.0,8.1Hz, 2H), 7.28 (d, J=7.5Hz,
1H), 4.94 (t, J=8.8Hz, 1H), 4.41 (dd, J=8.6,6.0Hz, 1H), 4.16 (s, 1H), 3.44 (s, 2H), 2.06
(d, J=5.9Hz, 2H), 1.89-1.70 (m, 2H), 1.61 (d, J=6.5Hz, 3H), 1.40 (d, J=3.0Hz, 6H).13C-
NMR(125MHZ,CDCl3), δ=19.74,19.80,26.92,30.41,31.76,31.80,34.45,37.11,38.20,
79.30,99.98,117.65,119.62,120.45,123.78,128.15,130.38,132.52,134.00。
The 2- of example eight (3- bromophenyls) imidazoles [4,5-f] [10,11] -1,6,6- trimethyl -1,6,6- trimethyl -1,2,
6,7,8,9- hexahydros phenanthro- [1,2-b]-furans (CTS-08)
Reaction replaces 2- fluorobenzaldehydes with example one with 3- bromobenzaldehydes, obtains target product, yield 58.4%, fusing point：
127.6~130.5 DEG C.1H-NMR (300M, CDCl3), δ=9.95 (s, 1H), 8.15 (s, 1H), 7.87 (s, 2H), 7.46 (d, J
=8.7Hz, 2H), 7.27 (s, 1H), 4.80 (s, 1H), 4.33 (s, 1H), 4.04 (s, 1H), 3.40 (s, 2H), 2.02 (d, J=
4.0Hz, 2H), 1.74 (d, J=11.7Hz, 2H), 1.49 (d, J=6.5Hz, 3H), 1.34 (d, J=4.2Hz, 6H).13C-NMR
(125MHZ,CDCl3), δ=19.72,2.94,30.61,31.82,34.51,36.95,38.45,79.29,114.34,
117.67,120.37,123.07,123.91,124.65,128.94,130.36,132.21,143.95,153.20。
The 2- of example nine (4- bromophenyls) imidazoles [4,5-f] [10,11] -1,6,6- trimethyl -1,6,6- trimethyl -1,2,
6,7,8,9- hexahydros phenanthro- [1,2-b]-furans (CTS-08)
Reaction replaces 2- fluorobenzaldehydes with example one with 4- bromobenzaldehydes, obtains target product, yield 62.9%, fusing point：
143.9~149.2 DEG C.1H-NMR(300M,CDCl3), δ=7.91 (d, J=8.5Hz, 3H), 7.55 (t, J=9.5Hz, 3H),
4.85 (t, J=8.4Hz, 1H), 4.38 (dd, J=8.5,5.8Hz, 1H), 4.03 (s, 1H), 3.54 (s, 2H), 2.08 (d, J=
4.8Hz, 2H), 1.81 (d, J=11.7Hz, 2H), 1.54 (d, J=6.5Hz, 3H), 1.41 (d, J=5.0Hz, 6H).13C-NMR
(125MHZ,CDCl3), δ=19.57,20.01,26.89,30.43,31.71,31.87,34.59,36.70,38.32,
79.31,117.94,120.56,128.31,132.09。
The 2- of example ten (2- aminomethyl phenyls) imidazoles [4,5-f] [10,11] -1,6,6- trimethyl -1,6,6- trimethyl -1,
2,6,7,8,9- hexahydros phenanthro- [1,2-b]-furans (CTS-10)
Reaction replaces 2- fluorobenzaldehydes with example one with 2- tolyl aldehydes, obtains target product, yield 67.2%, fusing point：
109.7~118.6 DEG C.1H-NMR(300M,CDCl3), δ=9.93 (s, 1H), 7.94 (d, J=8.6Hz, 1H), 7.79 (d, J=
6.9Hz, 1H), 7.53 (d, J=8.7Hz, 1H), 7.34 (s, 3H), 4.92 (t, J=8.7Hz, 1H), 4.59-4.28 (m, 1H),
4.12 (s, 1H), 3.48 (s, 2H), 2.66 (s, 3H), 2.04 (s, 2H), 1.80 (s, 2H), 1.58 (d, J=6.7Hz, 3H),
1.40 (d, J=4.2Hz, 6H)13C-NMR(125MHZ,CDCl3), δ=19.64,19.99,21.16,30.62,31.75,
34.48,37.04,38.34,79.41,100.08,117.42,120.43,123.86,126.20,129.52,129.74,
131.43,137.11。
The 2- of example 11 (3- aminomethyl phenyls) imidazoles [4,5-f] [10,11] -1,6,6- trimethyl -1,6,6- trimethyls -
1,2,6,7,8,9- hexahydros phenanthro- [1,2-b]-furans (CTS-11)
Reaction replaces 2- fluorobenzaldehydes with example one with 3- tolyl aldehydes, obtains target product, yield 58.7%, fusing point：
110.5~116.3 DEG C.1H-NMR(300M,CDCl3), δ=9.95 (s, 1H), 7.80 (d, J=25.0Hz, 3H), 7.44 (s,
1H),7.32(s,1H),7.19(s,1H),4.83(s,1H),4.33(s,1H),4.10(s,1H),3.43(s,2H),2.37(s,
3H), 2.02 (d, J=4.4Hz, 2H), 1.88-1.65 (m, 2H), 1.51 (d, J=6.4Hz, 3H), 1.34 (d, J=4.0Hz,
6H)；13C-NMR(125MHZ,CDCl3), δ=9.77,19.73,21.38,25.30,26.94,29.73,30.52,31.81,
34.49,37.00,38.42,79.27,117.52,120.39,123.00,123.73,124.15,126.73,128.89,
130.17,130.57,138.85,143.70。
The 2- of example 12 (4- aminomethyl phenyls) imidazoles [4,5-f] [10,11] -1,6,6- trimethyl -1,6,6- trimethyls -
1,2,6,7,8,9- hexahydros phenanthro- [1,2-b]-furans (CTS-12)
Same example is reacted, 2- fluorobenzaldehydes is replaced with 4- tolyl aldehydes, obtain target product, yield, yield receives 50.9%,
Fusing point：130.9~140.2 DEG C.1H-NMR(300M,CDCl3), δ=7.87 (s, 3H), 7.45 (s, 1H), 7.19 (s, 2H),
4.80 (s, 1H), 4.32 (s, 1H), 4.04 (s, 1H), 3.48 (s, 2H), 2.31 (s, 3H), 2.01 (d, J=4.8Hz, 2H),
1.74 (dd, J=7.7,4.1Hz, 2H), 1.49 (d, J=6.8Hz, 3H), 1.33 (d, J=4.6Hz, 6H).13C-NMR
(125MHZ,CDCl3), δ=14.14,19.74,21.36,22.68,25.30,29.72,30.53,31.81,34.48,
37.02,38.43,79.26,120.33,123.57,126.10,129.61,143.60。ESI-MS:m/z:396.2278。
The 2- of example 13 (2- methoxyphenyls) imidazoles [4,5-f] [10,11] -1,6,6- trimethyl -1,6,6- front threes
Base -1,2,6,7,8,9- hexahydros phenanthro- [1,2-b]-furans (CTS-13)
Reaction replaces 2- fluorobenzaldehydes with Benzaldehyde,2-methoxy with example one, obtains target product, and yield 60.7% melts
Point：180.4~182.8 DEG C.1H-NMR(300M,CDCl3), δ=11.72 (s, 1H), 8.64 (d, J=7.5Hz, 1H), 7.92
(d, J=8.7Hz, 1H), 7.49 (d, J=8.7Hz, 1H), 7.38 (t, J=8.6Hz, 1H), 7.16 (t, J=7.5Hz, 1H),
7.06 (d, J=8.3Hz, 1H), 4.94 (t, J=8.8Hz, 1H), 4.48-4.36 (m, 1H), 4.28-4.15 (m, 1H), 4.11
(s, 3H), 3.45 (t, J=6.3Hz, 2H), 2.07 (d, J=6.2Hz, 2H), 1.82 (dd, J=7.7,3.9Hz, 2H), 1.64
(d, J=6.8Hz, 3H), 1.41 (d, J=2.3Hz, 6H)；13C-NMR(125MHZ,CDCl3), δ=19.81,29.82,
31.71,34.34,37.25,38.26,56.27,79.29,111.42,117.22,120.52,120.87,121.97,
123.30,128.43,129.54,130.36,143.49,156.15。
The 2- of example 14 (3- methoxyphenyls) imidazoles [4,5-f] [10,11] -1,6,6- trimethyl -1,6,6- front threes
Base -1,2,6,7,8,9- hexahydros phenanthro- [1,2-b]-furans (CTS-14)
Reaction replaces 2- fluorobenzaldehydes with m-methoxybenzaldehyde with example one, obtains target product, and yield 63.6% melts
Point：118.7~125.3 DEG C.1H-NMR(300M,CDCl3), δ=10.10 (s, 1H), 7.92 (d, J=8.7Hz, 1H), 7.67
(s, 1H), 7.59 (d, J=7.5Hz, 1H), 7.52 (d, J=8.7Hz, 1H), 7.38 (t, J=7.9Hz, 1H), 6.95 (d, J=
8.4Hz, 1H), 4.87 (t, J=8.7Hz, 1H), 4.38 (dd, J=8.6,5.7Hz, 1H), 4.07 (s, 3H), 3.51 (s, 2H),
2.07 (d, J=4.4Hz, 2H), 1.82 (d, J=5.4Hz, 2H), 1.54 (d, J=5.9Hz, 3H), 1.41 (d, J=4.4Hz,
6H)。13C-NMR(125MHZ,CDCl3), δ=19.78,30.27,31.79,34.48,37.11,38.64,55.54,79.38,
111.76,115.22,117.41,118.83,120.99,124.45,130.03,160.60。
The 2- of example 15 (4- methoxyphenyls) imidazoles [4,5-f] [10,11] -1,6,6- trimethyl -1,6,6- front threes
Base -1,2,6,7,8,9- hexahydros phenanthro- [1,2-b]-furans (CTS-15)
Reaction replaces 2- fluorobenzaldehydes with 4-methoxybenzaldehyde with example one, obtains target product, and yield 55.8% melts
Point：105.9~110.4 DEG C.1H-NMR(300M,CDCl3), δ=9.88 (s, 1H), 8.00 (s, 3H), 7.52 (s, 1H), 6.94
(s,2H),4.85(s,1H),4.37(s,1H),4.06(s,1H),3.83(s,3H),3.53(s,2H),2.07(s,2H),1.80
(s,2H),1.56(s,3H),1.42(s,6H)。13C-NMR(125MHZ,CDCl3), δ=19.76,19.86,26.93,29.72,
30.53,31.79,34.46,37.05,38.44,55.36,79.22,114.34,117.11,120.31,123.37,127.59,
143.42,160.64。
The 2- of example 16 (2- hydroxy phenyls) imidazoles [4,5-f] [10,11] -1,6,6- trimethyl -1,6,6- trimethyls -
1,2,6,7,8,9- hexahydros phenanthro- [1,2-b]-furans (CTS-16)
Reaction replaces 2- fluorobenzaldehydes with Benzaldehyde,2-hydroxy with example one, obtains target product, yield 64.7%, fusing point：
270.8~273.9 DEG C.1H-NMR(300M,CDCl3), δ=7.83 (d, J=8.7Hz, 1H), 7.56 (d, J=7.8Hz, 1H),
7.45 (d, J=8.7Hz, 1H), 7.23 (t, J=7.3Hz, 1H), 7.06 (d, J=8.3Hz, 1H), 6.85 (t, J=7.4Hz,
1H), 4.86 (t, J=8.9Hz, 1H), 4.33 (dd, J=8.6,6.0Hz, 1H), 3.95 (d, J=8.1Hz, 1H), 3.53 (s,
2H), 1.98 (s, 2H), 1.72 (d, J=6.6Hz, 2H), 1.46 (d, J=6.8Hz, 3H), 1.32 (d, J=4.0Hz, 6H)；13C-NMR(125MHZ,CDCl3), δ=19.71,26.94,30.48,31.77,34.51,36.80,38.34,79.30,
117.86,119.02,120.27,123.99,131.07,144.29,158.05。
The 2- of example 17 (3- hydroxy phenyls) imidazoles [4,5-f] [10,11] -1,6,6- trimethyl -1,6,6- trimethyls -
1,2,6,7,8,9- hexahydros phenanthro- [1,2-b]-furans (CTS-17)
Reaction replaces 2- fluorobenzaldehydes with example one with 3- hydroxy benzaldehydes, obtains target product, yield 58.8%, fusing point：
120.4~133.8 DEG C.1H-NMR(300M,CDCl3), δ=7.91 (d, J=8.7Hz, 1H), 7.82 (s, 1H), 7.52 (d, J=
8.8Hz, 1H), 7.33 (d, J=7.7Hz, 1H), 7.19 (t, J=6.6Hz, 1H), 6.85 (d, J=8.4Hz, 1H), 4.80 (t,
J=8.7Hz, 1H), 4.51-4.23 (m, 1H), 4.12 (dd, J=14.3,7.2Hz, 1H), 3.64-3.24 (m, 2H), 2.03
(s, 2H), 1.77 (s, 2H), 1.45 (d, J=6.6Hz, 3H), 1.39 (d, J=6.8Hz, 6H).13C-NMR(125MHZ,
CDCl3), δ=14.43,20.07,20.29,26.81,31.08,32.33,34.69,36.71,79.03,11 0.53,
113.26,116.26,116.70,117.24,119.87,123.12,125.22,129.51,130.22,132.49,132.62,
135.71,143.21,147.03,152.34,158.14。
The 2- of example 18 (4- hydroxy phenyls) imidazoles [4,5-f] [10,11] -1,6,6- trimethyl -1,6,6- trimethyls -
1,2,6,7,8,9- hexahydros phenanthro- [1,2-b]-furans (CTS-18)
Reaction replaces 2- fluorobenzaldehydes with example one with 4- hydroxy benzaldehydes, obtains target product, yield 53.9%, fusing point：
169.6~176.5 DEG C.1H-NMR(300M,CDCl3), δ=7.92 (d, J=8.7Hz, 1H), 7.74 (d, J=8.6Hz, 2H),
7.51 (d, J=8.8Hz, 1H), 6.85 (d, J=8.6Hz, 2H), 4.83 (t, J=8.7Hz, 1H), 4.41 (d, J=4.1Hz,
1H), 4.11 (s, 1H), 3.40 (s, 2H), 2.07 (s, 2H), 1.79 (s, 2H), 1.47 (d, J=6.8Hz, 3H), 1.39 (d, J
=2.0Hz, 6H).13C-NMR(125MHZ,CDCl3), δ=19.60,20.28,26.93,30.41,31.69,34.42,
36.96,38.27,55.63,79.45,107.19,116.52,117.26,120.41,123.66,128.00,143.72。
The 2- of example 19 (2- nitrobenzophenones) imidazoles [4,5-f] [10,11] -1,6,6- trimethyl -1,6,6- trimethyls -
1,2,6,7,8,9- hexahydros phenanthro- [1,2-b]-furans (CTS-19)
Reaction replaces 2- fluorobenzaldehydes with example one with 2- nitrobenzaldehydes, obtains target product, yield 65.6%, fusing point：
244.9~249.6 DEG C.1H-NMR(300M,d6- DMSO), δ=8.13 (d, J=7.8Hz, 1H), 7.92 (d, J=8.0Hz,
1H), 7.84 (t, J=7.6Hz, 1H), 7.76 (d, J=8.6Hz, 1H), 7.66 (t, J=8.3Hz, 1H), 7.51 (d, J=
8.7Hz, 1H), 4.89 (t, J=8.9Hz, 1H), 4.42 (dd, J=8.8,4.8Hz, 1H), 3.95 (dd, J=12.8,8.0Hz,
1H), 3.59 (t, J=6.1Hz, 2H), 1.88 (s, 2H), 1.72 (s, 2H), 1.45 (d, J=6.8Hz, 3H), 1.33 (s, 6H)
；13C-NMR(125MHZ,d6- DMSO), δ=20.08,30.51,32.20,32.27,34.69,36.62,38.91,79.16,
110.30,116.88,119.84,123.53,123.89,124.34,125.17,129.45,130.00,132.26,132.53,
135.72,141.93,143.67,149.47,153.05。
The 2- of example 20 (3- nitrobenzophenones) imidazoles [4,5-f] [10,11] -1,6,6- trimethyl -1,6,6- trimethyls -
1,2,6,7,8,9- hexahydros phenanthro- [1,2-b]-furans (CTS-20)
Reaction replaces 2- fluorobenzaldehydes with example one with 3- nitrobenzaldehydes, obtains target product, yield 71.7%, fusing point：
275.4~278.3 DEG C.1H-NMR(300M,d6- DMSO), δ=9.04 (s, 1H), 8.65 (d, J=7.9Hz, 1H), 8.23 (d, J
=8.2Hz, 1H), 7.79 (dd, J=19.7,8.3Hz, 2H), 7.50 (d, J=8.7Hz, 1H), 4.88 (t, J=8.8Hz,
1H), 4.44 (dd, J=8.8,4.4Hz, 1H), 3.96 (d, J=4.2Hz, 1H), 3.86 (t, J=5.7Hz, 2H), 1.93 (s,
2H), 1.74 (s, 2H), 1.46 (d, J=6.8Hz, 3H), 1.35 (s, 6H).13C-NMR(125MHZ,d6- DMSO), δ=
20.03,20.30,31.01,32.30,34.71,36.63,38.93,39.49,39.66,39.83,39.99,40.16,
40.33,40.49,79.18,110.38,117.04,119.95,120.22,123.35,125.27,130.01,130.91,
132.41,132.63,132.84,135.83,143.68,144.61,148.88,153.07。
The 2- of example 21 (4- nitrobenzophenones) imidazoles [4,5-f] [10,11] -1,6,6- trimethyl -1,6,6- front threes
Base -1,2,6,7,8,9- hexahydros phenanthro- [1,2-b]-furans (CTS-21)
Reaction replaces 2- fluorobenzaldehydes with example one with 4- nitrobenzaldehydes, obtains target product, yield 67.8%, fusing point：
132.9~137.6 DEG C；1H-NMR(300M,d6- DMSO), δ=8.55-8.29 (m, 4H), 7.76 (d, J=8.7Hz, 1H),
7.52 (d, J=8.7Hz, 1H), 4.88 (t, J=8.9Hz, 1H), 4.44 (dd, J=8.8,4.4Hz, 1H), 4.05-3.90 (m,
1H), 3.86 (t, J=5.4Hz, 2H), 1.93 (s, 2H), 1.74 (s, 2H), 1.45 (d, J=6.8Hz, 3H), 1.34 (d, J=
3.1Hz,6H)。13C-NMR(125MHZ,d6- DMSO), δ=20.01,20.24,31.04,32.29,34.74,36.58,
38.91,79.26,110.31,117.24,120.03,123.87,124.79,125.31,126.76,130.50,132.79,
136.49,137.12,143.93,144.59,153.51。
The 2- of example 22 (3,5- Dimethoxyphenyl) imidazoles [4,5-f] [10,11] -1,6,6- trimethyl -1,6,6-
Trimethyl -1,2,6,7,8,9- hexahydros phenanthro- [1,2-b]-furans (CTS-22)
Reaction replaces 2- fluorobenzaldehydes with example one with 3,5- dimethoxy benzaldehydes, obtains target product, yield
55.7%, fusing point：85.4~91.7 DEG C.1H-NMR (300M, CDCl3), δ=9.97 (s, 1H), 7.92 (d, J=8.7Hz, 1H),
7.53 (d, J=8.7Hz, 1H), 6.47 (s, 1H), 4.83 (s, 1H), 4.36 (dd, J=8.5,5.6Hz, 1H), 4.03 (s,
1H), 3.84 (s, 6H), 3.53 (s, 2H), 2.07 (d, J=5.5Hz, 2H), 1.81 (dd, J=7.3,4.3Hz, 2H), 1.51
(s, 3H), 1.41 (d, J=5.4Hz, 6H)13C-NMR(125MHZ,CDCl3), δ=19.71,21.92,30.58,31.82,
34.50,36.99,38.42,55.58,79.29,101.36,104.43,117.50,120.33,123.78,143.79,
161.18。
The 2- of example 23 (2,4- Dimethoxyphenyl) imidazoles [4,5-f] [10,11] -1,6,6- trimethyl -1,6,6-
Trimethyl -1,2,6,7,8,9- hexahydros phenanthro- [1,2-b]-furans (CTS-23)
Reaction replaces 2- fluorobenzaldehydes with example one with 2,4- dimethoxy benzaldehydes, obtains target product, yield
61.8%, fusing point：228.3~233.7 DEG C.1H-NMR(300M,CDCl3), δ=8.61 (s, 1H), 7.91 (d, J=8.7Hz,
1H), 7.48 (d, J=8.8Hz, 1H), 6.69 (d, J=10.9Hz, 1H), 6.56 (s, 1H), 4.93 (t, J=8.7Hz, 1H),
4.40 (dd, J=8.4,6.0Hz, 1H), 4.22 (d, J=8.4Hz, 1H), 4.06 (s, 3H), 3.85 (s, 3H), 3.41 (t, J=
6.2Hz, 2H), 2.06 (d, J=7.1Hz, 2H), 1.88-1.74 (m, 2H), 1.64 (d, J=6.8Hz, 3H), 1.40 (d, J=
2.6Hz,6H)；13C-NMR(125MHZ,CDCl3), δ=19.81,29.74,31.71,34.35,37.24,38.24,55.50,
56.24,79.32,98.73,106.19,115.20,116.96,120.49,123.17,128.33,130.70,143.25,
157.40,161.80。
The 2- of example 24 (3,4,5- trimethoxyphenyl) imidazoles [4,5-f] [10,11] -1,6,6- trimethyl -1,6,
6- trimethyls -1,2,6,7,8,9- hexahydros phenanthro- [1,2-b]-furans (CTS-24)
Reaction replaces 2- fluorobenzaldehydes with 3,4,5-Trimethoxybenzaldehyde with example one, obtains target product, yield
50.7%, fusing point：110.5~113.3 DEG C.1H-NMR(300M,CDCl3), δ=9.97 (s, 1H), 7.92 (d, J=8.4Hz,
1H), 7.54 (d, J=8.8Hz, 2H), 7.31 (s, 2H), 4.77 (s, 1H), 4.34 (s, 1H), 3.92 (d, J=11.2Hz,
9H), 3.44 (s, 2H), 2.08 (d, J=20.2Hz, 2H), 1.93-1.70 (m, 2H), 1.41 (d, J=6.2Hz, 9H)；13C-
NMR(125MHZ,CDCl3), δ=14.14,19.74,19.99,22.71,26.93,30.48,31.79,34.54,36.91,
38.39,56.54,61.00,79.25,104.29,117.47,120.40,124.00,154.65；ESI-MS:m/z:
472.2438。
The 2- of example 25 (3- hydroxyl -4- methoxyphenyls) imidazoles [4,5-f] [10,11] -1,6,6- trimethyl -1,
6,6- trimethyls -1,2,6,7,8,9- hexahydros phenanthro- [1,2-b]-furans (CTS-25)
Reaction replaces 2- fluorobenzaldehydes with example one with 3- hydroxyls -4-methoxybenzaldehyde, obtains target product, yield
56.7%, fusing point：137.7~143.5 DEG C.1H-NMR(300M,CDCl3), δ=7.83 (d, J=8.6Hz, 1H), 7.54 (s,
2H), 7.44 (d, J=8.5Hz, 1H), 6.78 (d, J=8.8Hz, 1H), 4.93-4.70 (m, 1H), 4.31 (d, J=5.1Hz,
1H), 4.04 (s, 1H), 3.81 (s, 3H), 3.45 (d, J=19.9Hz, 2H), 2.01 (d, J=16.4Hz, 2H), 1.73 (s,
2H), 1.47 (d, J=6.5Hz, 3H), 1.33 (d, J=5.0Hz, 6H)；13C-NMR(125MHZ,CDCl3), δ=19.69,
19.90,29.72,30.52,31.79,34.47,39.97,38.41,55.89,79.28,110.90,112.41,117.19,
118.79,120.28,123.52,143.55,145.97,148.14。
Biological activity determination
Screening compound illustrated above is as follows：It was found that having anticancer and anti-androgen receptor activity shown in table 1 below.
We check above-claimed cpd with Human embryonic kidney cells HEK 293 and Human Prostate Cancer Cells LNCaP to hero
The influence of sex hormone receptor bioactivity.
Cell culture and transfection
Human embryonic kidney cells HEK 293 and Human Prostate Cancer Cells LNCaP are stored in respectively and contain 10% tire ox blood
In clear DMEM and RPMI culture mediums (100 units/ml penicillin, 100mg/L streptomysins and 10% hyclone).
Androgen receptor Reverse Activity is a kind of androgen-dependent reporter group transcription factor experiment, with the experiment conduct
Identify the main screening technique of antiandrogen active.First it is measured in the cells of HEK 293, the cells of HEK 293 lack endogenous
Property AR, we the cells of HEK 293 are carried out wild type AR transfection activation determine, once the cell wild type AR of HEK 293 reversely swash
Measure living shows that Cryptotanshinone class compound has antiandrogen bioactivity, and AR activity is further carried out with LNCaP cells
It is determined that, LNCaP cells have expresses to clinically related saltant type AR, and the anti-AR for further investigating Cryptotanshinone class compound lives
Property.
Uciferase activity is determined.
During the cells of HEK 293 are seeded in into 24 holes with 10%CS-FBS DMEM culture mediums or 48 hole tissue culture dishes,
Keep updating culture medium in 24 hours, then use Lipofectamin2000 with pSG5-AR, MMTV-Luc and pRL-TK-luc
(Invitrogen) transfected, after transfecting 24 hours.1nM DHT and/or 5nM Bicalutamide and each concentration Cryptotanshinone are used again
Class compound on intracellular carries out treatment 24 hours, harvesting, with Dual-Luciferase measurement system (Dual Luciferase
Assay Systen) (Promega, WI) carry out Dual-Luciferase measure, obtains data with being normalized to internal fluorescein enzyme pair
Represented according to Dual-Luciferase activity.DHT inducing groups are significantly expressed, and will can significantly inhibit the reporter table of androgen induction
The Cryptotanshinone class compound identification for reaching is potential antiandrogen active compound.
During LNCaP cells are seeded in into 24 holes with 10%CS-FBS RPMI culture mediums or 48 hole tissue culture dishes, protect
Hold 24 hours, update culture medium, then transfected with MMTV-Luc and pRL-TK-lu, after transfecting 24 hours.1nM is used again
DHT and/or 5nM Bicalutamides and each concentration Cryptotanshinone class compound treatment cell 24 hours, harvesting uses double fluoresceins
Enzymatic determination system carries out Dual-Luciferase measure, and above-mentioned test compound activity is further determined and confirmed.
LNCaP cell growths are determined
As described above, Cryptotanshinone class Compound cellular contains mass mutation type AR, when there is androgen to participate in, these are thin
Intracellular growth can be significantly activated.Determined alternatively to determine to be determined by above-mentioned AR Reverse Activity with LNCaP cell growths
Compound be further accredited as potential antiandrogen medicine, using MTT analytic approach.
LNCaP cells are seeded in the tissue wall panel of 96 holes, then in 1nM DHT and/or Cryptotanshinone class compound
In the presence of, it is continuous in containing 10%CS-FBS RPMI culture mediums to incubate 3 days.After incubation terminates, by the MTT (PBS of 5mg/ml
Solution) cell is given, kept for 3 hours at 37 DEG C.The precipitation that will be obtained is dissolved in lysis buffer solution, is then read with microtest plate
Go out device, quantitative determined at 595nm wavelength, to ensure the data accuracy that MTT analyses draw, carried out carefully with duplicate sample
Born of the same parents count.The prostatic index cell growth that will be induced androgen shows that bad Cryptotanshinone class compound identification is potential
Antiandrogens.
First, the anti-AR activity of Cryptotanshinone class compound.See that Fig. 1 is relative Developing restraint energy of the compound to LNCaP cells
Power and Fig. 2 are relative Developing restraint ability and table 1 of the compound to CWR22RV1 cells.
(the IC of table 1, Cryptotanshinone class compound human prostate cancer cells' LNCaP cells50)。
Claims (4)
1. Cryptotanshinone class compound, the compound III with following general structure,
R is to contain F, Cl, Br, CH3, OCH3, NO2, the phenyl of OH substitution bases.
2. the preparation method of Cryptotanshinone class compound, it is characterised in that carry out as steps described below：
Cryptotanshinone (1), substituted benzaldehyde, glacial acetic acid, ammonium acetate are added in reaction bulb, it is small to react 2-10 at 80-120 DEG C
When, after completion of the reaction, after mixed liquor is cooled to room temperature, distilled water, concentrated ammonia liquor regulation PH=7 or so being added, filtering is washed, done
It is dry, compound II is obtained with silica gel column chromatography, wherein reactant Cryptotanshinone (1), substituted benzaldehyde, glacial acetic acid, ammonium acetate etc. rubs
You are than being 1：1-2：5-25：3-5,80-120 DEG C of reaction temperature is reacted 2-12 hours.
3. the preparation method of Cryptotanshinone class compound according to claim 2, it is characterised in that wherein described substitution
The structural formula of benzaldehyde isWherein R is to contain F, Cl, Br, CH3, OCH3, NO2, the benzaldehyde of the substitution base such as OH.
4. the purposes of Cryptotanshinone class compound, for preparing anti-androgen receptor medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710088553.0A CN106699771A (en) | 2017-02-20 | 2017-02-20 | Cryptotanshinone compound, as well as preparation method and application thereof |
Applications Claiming Priority (1)
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107519186A (en) * | 2017-08-09 | 2017-12-29 | 中国中医科学院广安门医院 | Cryptotanshinone is preparing the application in preventing and treating tumor recurrence diversion medicaments |
| CN111499647A (en) * | 2020-05-09 | 2020-08-07 | 广东药科大学 | Cryptotanshinone derivative and preparation method and application thereof |
| CN112662800A (en) * | 2020-12-28 | 2021-04-16 | 广西大学 | Molecular marker primer of rice cold-resistant major QTL CTS12 as well as marking method and application thereof |
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102127037A (en) * | 2011-01-11 | 2011-07-20 | 上海交通大学 | Tanshinone compounds and applications thereof |
| CN103232521A (en) * | 2013-03-11 | 2013-08-07 | 常州大学 | Tanshinone imidazole compound and its preparation method and use |
-
2017
- 2017-02-20 CN CN201710088553.0A patent/CN106699771A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102127037A (en) * | 2011-01-11 | 2011-07-20 | 上海交通大学 | Tanshinone compounds and applications thereof |
| CN103232521A (en) * | 2013-03-11 | 2013-08-07 | 常州大学 | Tanshinone imidazole compound and its preparation method and use |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107519186A (en) * | 2017-08-09 | 2017-12-29 | 中国中医科学院广安门医院 | Cryptotanshinone is preparing the application in preventing and treating tumor recurrence diversion medicaments |
| CN111499647A (en) * | 2020-05-09 | 2020-08-07 | 广东药科大学 | Cryptotanshinone derivative and preparation method and application thereof |
| CN112662800A (en) * | 2020-12-28 | 2021-04-16 | 广西大学 | Molecular marker primer of rice cold-resistant major QTL CTS12 as well as marking method and application thereof |
| CN112662800B (en) * | 2020-12-28 | 2022-12-20 | 广西大学 | Molecular marker primer of rice cold-resistant major QTL CTS12 as well as marking method and application thereof |
| 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 |
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