CN106928302B - A kind of androstenedione derivative and its preparation method and application - Google Patents
A kind of androstenedione derivative and its preparation method and application Download PDFInfo
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- CN106928302B CN106928302B CN201710199655.XA CN201710199655A CN106928302B CN 106928302 B CN106928302 B CN 106928302B CN 201710199655 A CN201710199655 A CN 201710199655A CN 106928302 B CN106928302 B CN 106928302B
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- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
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Abstract
The present invention relates to a kind of androstenedione derivatives and its preparation method and application, belong to steroid technical field.Using compound I and its hydrate as active constituent, and it is equipped with prodrug, pharmaceutically acceptable salt or pharmaceutically acceptable carrier and forms pharmaceutical composition.Invention is applied to metastatic breast cancer and postclimacteric women advanced breast cancer, medical value with higher.
Description
Technical field
The present invention relates to a kind of androstenedione derivatives and its preparation method and application, belong to steroid technology neck
Domain.
Background technique
Breast cancer belongs to malignant tumour common in women, and there are about 1,200,000 women to suffer from breast cancer every year in the whole world, and about 500,000
People dies of the disease.In the U.S., the probability that women suffers from breast cancer in all one's life is up to 1/8th, is the pernicious swollen of the death rate second
Tumor.The disease incidence of China's breast cancer is rising year by year, and the metropolis disease incidence such as Beijing, Shanghai has become woman up to 56/,100,000
The malignant tumour of female's disease incidence first.
The therapeutic agent of breast cancer can be divided into four classes according to mechanism: including antiestrogenic, aromatase inhibitor (AI), promote
Luteinizing hormone releasing hormone (LHRH) analog and progestational hormone, wherein antiestrogenic and aromatase inhibitor occupy predominantly
Position.Androstenedione analog derivative belongs to the steroidal drug in aromatase inhibitor, such drug and aromatizing enzyme endogenous are made
It is similar with testosterone structure with substrates androstenedione, by covalent bond form and its Irreversible binding, cause the permanent inactivation of enzyme,
To inhibit the synthesis of estrogen.As aromatase inhibitor is in clinical extensive use, new varieties are also constantly being released, according to west
Mei Tan, Anastrozole etc. become current main clinical application.
The entitled Exemestane of Exemestane (II, Exemestane) chemistry, be by
A kind of irreversible third generation aromatase inhibitor of Italian company Pharmacia&Upjoin research and development, 1999 for the first time
It is listed in Britain.Its molecular formula is C20H24O2, general structure is as follows:
It is relied on and steroidal aromatase nature substrate --- the similar structure of androstenedione, its active portion of irreversible combination
Position, is allowed to permanently inactivate, to make hormone in vivo level reduce rapidly, constantly, to reach therapeutic purposes.
US 4876045 and EP 307134 reports 6- methylene-androstane -1,4- diene -3,17- derovatives system
Preparation Method.The open 6- methylene of EP 0326430-androstane-1,4- diene-3,17- diketone polysubstituted alkyl derivative preparation side
Method.US 4808616 reports 6- alkylidene-androstane -1,4- diene -3,17- derovatives preparation method and its in drug
The application of chemical aspect.CN 1453288A and CN 1415624A are disclosed using androstenedione as raw material, are passed through using one kettle way
6- alkylidene-androstane -1,4- diene -3,17- derovatives are prepared in Mannich reaction.CN 101312743A is disclosed
(S) method that -6- methyloxaalkyl exemestane compounds are used to inhibit cancer cell or growth of tumour cell.
Currently, finding, one kind is efficient, stablize, the drug of low side effect is still the critical issue for treating breast cancer.Therefore, into
One step researches and develops novel effective therapeutic agent and is of great significance.
Based on this, the application is made.
Summary of the invention
For the drawbacks described above in the presence of existing breast cancer field, the application provides the new androstenedione of one kind first and spreads out
Biology, compound medical value with higher can be used for handling, treat or mitigate metastatic breast cancer and postclimacteric
Women advanced breast cancer.
To achieve the above object, the technical solution that the application takes is as follows:
A kind of androstenedione derivative, the androstenedione derivative are 6,16- dimethyleneandrostan-Isosorbide-5-Nitrae-diene -3,17-
Diketone or its hydrate, prodrug and pharmaceutically acceptable salt, structural formula are as follows:Being denoted as
Close object I.
Antitumor activity in vitro shows: the androstenedione derivative has the effect of significantly inhibiting tumour.Used in test
Cell strain be international tumor cell line-human liver cancer cell HepG2, Proliferation of Human Ovarian Cell SK-OV-3.
Meanwhile the preparation method of a kind of above-mentioned androstenedione derivative that the application also provides, with Exemestane (II) and
Paraformaldehyde is raw material, and dimethylamine hydrochloride is catalyst, and using the method for one kettle way, production is prepared through Mannich reaction
Object 6,16- dimethyleneandrostan-Isosorbide-5-Nitrae-diene -3,17- diketone.
Above-mentioned reaction process may be expressed as:
Further, as preferred:
The inventory of the catalyst dimethylamine hydrochloride is 0.01-0.1mol/mol Exemestane.Preferably, described
Catalyst loading be 0.05-0.1mol/mol Exemestane.
The reaction raw materials are dissolved with solvent, and solvent uses ethyl alcohol, and inventory is 1000-1600mL/mol Yi Ximei
It is smooth, it is furthermore preferred that the amount of solvent is 1184-1480mL/mol Exemestane (i.e. 4-5mL/g Exemestane).
The paraformaldehyde equivalent is excessively added, degree of polymerization 10-100, it is furthermore preferred that the Exemestane
Molar ratio with paraformaldehyde is 1:(1-1.5), the molar ratio of Exemestane and paraformaldehyde is excellent when being excessively added
It is selected as 1:1.1-1.3.
The reaction temperature is 70-80 DEG C, and the reaction time is 3-5 hours.
It is tracked in the Mannich reaction process with thin layer, Mannich is evaporated recycling after reaction, by reaction solution
Solvent, residue silica gel column chromatography purify to get finished product compound I.
The application above compound I can be in processing, treatment or mitigation metastatic breast cancer and postclimacteric women advanced stage
It is applied in the drug of breast cancer.
The present invention also provides a kind of above compound I to be formed by pharmaceutical composition, is made with compound I and its hydrate
For active constituent, and it is equipped with prodrug, pharmaceutically acceptable salt or pharmaceutically acceptable carrier and forms pharmaceutical composition.
Pharmaceutically acceptable carrier refers to the carrier of pharmaceutical field routine, refers to one or more inert, non-toxic
Solid or liquid filler material, diluent, auxiliary agent etc., they do not have an effect with reactive compound or patient.
The dosage form of the present composition can be common formulations in the pharmacies such as tablet, capsule, pill.
Detailed description of the invention
Fig. 1 is the androstenedione derivative gas chromatography mass spectrometry figure of the application；
Fig. 2 is that the hydrogen of product under 1 preparation condition of the embodiment of the present application composes nuclear-magnetism figure；
Fig. 3 be 1 preparation condition of the embodiment of the present application under product carbon compose nuclear-magnetism figure (13C, DEPT135, DEPT90).
Specific embodiment
Analysis instrument and equipment used in embodiment: gas chromatography mass spectrometry, (U.S.'s Agilent is public by MS5973N-GC6890N
Department)；Nuclear Magnetic Resonance, II I 400M of AVANCE DMX (TMS internal standard, Bruker company)；High performance liquid chromatograph: Agilent
Technologies 1200Series；Infrared spectrometer, NICOLET 360FT-IR (U.S. Buddhist nun high-tensile strength instrument company).
Embodiment 1: the preparation of chemical compounds I
Successively by 29.6 grams of Exemestanes (0.10mol), 3.3 grams of paraformaldehydes (0.11mol), 0.8 gram of dimethylamine hydrochloric acid
Salt (0.01mol) and 130 milliliters of ethyl alcohol are added in 250 milliliters of four mouthfuls of reaction flasks, calorify 75 DEG C of reactions, thin-layer chromatography with
Track detection reaction (solvent: ethyl acetate: petroleum ether=1:3), reaction in about 3 hours terminate.Solvent is recovered under reduced pressure to dry, residual
Object column Chromatographic purification (eluant ethyl acetate: petroleum ether=1:6), obtains 16.2 grams of light yellow crystal, and 150-151 DEG C of fusing point,
Yield 52.9%.
Product structure verifies (related spectrogram is shown in attached drawing):
MS:308,293,281,265,207,160,148 (100%), 128,105,91,77.
1HNMR(δ,ppm,400MHz,CDCl3): 7.096 (d, J=10.4Hz, 1H, CH=CH)；6.274 (d, J=
10.4Hz, 1H, CH=CH)；6.190 (s, 1H, CH=CH)；6.117,5.440 (s, 1H, 1H ,=CH2)；5.082,5.013
(s, 1H, 1H ,=CH2)；2.591-2.663(m,2H,-CH2-)；2.269-2.341(m,2H)；1.929-2.057(m,6H)；
1.189(s,3H,CH3)；0.979(s,3H,CH3)。
13CNMR(δ,ppm,100MHz,CDCl3): 207.35；187.06；167.85；153.86；145.19；143.60；
127.87；122.85；119.34；112.50；49.90；48.16；47.76；43.65；39.35；34.87；31.15；29.15；
22.04；19.70；14.17.
DEPT135CNMR(δ,ppm,100MHz,CDCl3): 153.92；127.86；122.84；119.39(D)；112.53
(D)；49.86；48.13；39.35(D)；34.84；31.15(D)；29.15(D)；22.04(D)；19.70；14.18.
DEPT90CNMR(δ,ppm,100MHz,CDCl3): 153.92；127.86；122.84；119.39(D)；112.53
(D)；49.86；48.13；34.84.
Embodiment 2: the Mannich under different condition reacts prepare compound I
29.6 grams of Exemestane (0.1 mole), paraformaldehyde, dimethylamine hydrochloride and ethyl alcohol are successively added to 250 millis
It in the four mouthfuls of reaction flasks risen, is stirred to react under certain temperature, thin-layer chromatography tracing detection is reacted to terminating, and is recovered under reduced pressure later
Solvent, silica gel column chromatography (eluant, eluent: ethyl acetate: petroleum ether=1:6), weighing calculate yield, as a result such as table 1.
Wherein, in the present embodiment, preparation condition mainly includes paraformaldehyde dosage, dimethylamine hydrochloride dosage, ethyl alcohol use
Amount and four parameters of reaction temperature.
Product yield under the different preparation conditions of table 1
Obtained product nuclear magnetic data is same as Example 1 under the conditions of each serial number is corresponding in above-mentioned table 1.
Comprehensive consideration is carried out to the yield, material ratio, synthesis condition of above-mentioned table 1, conclusion is as follows:
(1) influence of paraformaldehyde amount: in the application, paraformaldehyde is one of synthesis material, can be with according to its reaction equation
Find out, it is 1:1, i.e. equivalent, but examining based on Exemestane conversion ratio that paraformaldehyde, which reacts molar ratio with the theory of Exemestane,
Consider, when the molar ratio of paraformaldehyde and Exemestane is 1:1 state, reacts unsatisfactory, be embodied as Exemestane and turn
Rate is low, and yield is low (referring to serial number 1 and 2 in table 1)；It is in the reaction suitable for control in micro- excess state (serial number in such as table 1
3, when 4,5), not only meet the reaction requirement of Exemestane in reaction process, while meeting the loss in reaction process；However
Excessively should not be too big, when paraformaldehyde and Exemestane are when to react molar ratio be greater than 1.3, since excessive paraformaldehyde is easy
Other impurity are generated, is unfavorable for the progress of reaction instead, is embodied as that impurity is more, and yield is not high (referring to sequence in table 1 after purification
Numbers 6 and 7).Therefore, the molar ratio of Exemestane and paraformaldehyde is preferably controlled in 1:1.0-1.5, especially Exemestane and poly
The molar ratio of formaldehyde is preferably controlled in 1:1.1-1.3, and reaction efficiency is best.
(2) influence of catalyst loading: the application is using dimethylamine hydrochloride as catalyst, the main shadow of the addition of catalyst
Loud is reaction rate and the abundant degree of reaction.Under the same terms, catalytic amount is tested, when the additive amount of catalyst is low
It is too low by catalytic amount when 0.01mol/mol Exemestane (referring to serial number 8 and 9 in table 1), cause reaction efficiency relatively low, phase
With in the reaction time, reaction is unable to fully carry out；When the additive amount of catalyst increases to 0.01mol/mol Exemestane, instead
Although answering rate still relatively slow, it can satisfy the progress of reaction substantially, be in particular in that yield increases；Especially when urging
When the additive amount of agent reaches 0.05-0.1mol/mol Exemestane, reaction can be steadily rapidly performed by (referring in table 1
Serial number 10-23)；Catalytic amount is continued growing, when catalytic amount is greater than 0.1mol/mol Exemestane, the reaction of each raw material is living
Property have reached saturation, extra catalyst will lead to impurity increase instead, and yield reduces, and be unfavorable for being normally carried out for reaction
(referring to the serial number 24-25 in table 1).Therefore, catalytic amount is preferably controlled in 0.01-0.1mol/mol Exemestane, especially when
Catalytic amount is controlled in 0.05-0.1mol/mol Exemestane, and reaction effect is best.
Meanwhile it comparing 12-23 and can also be seen that the molar ratio of identical Exemestane and paraformaldehyde, same catalyst amount
Under the same reaction time, while reducing quantity of solvent and reaction temperature, then yield can reduce (comparison serial number 12 and 13,14 and
15)；Quantity of solvent is reduced, reaction temperature is increased, then yield is not much different (comparison serial number 18 and 19)；Increase quantity of solvent, reduces anti-
Temperature (comparison serial number 20 and 21,22 and 23) is answered, then yield is not much different.
(3) influence of amount of solvent: the application will directly affect the reaction efficiency of product and anti-using ethyl alcohol as solvent
Answer rate.Under the same terms, ethyl alcohol additive amount is tested, the results showed that, when ethyl alcohol additive amount lower than 1000mL/mol according to
Xi Meitan causes intermediate meltage insufficient, is unable to satisfy the demand of reaction since quantity of solvent is too low, thus yield is lower than
40% (referring specifically to serial number 26-27 in table 1)；With the increase of ethyl alcohol additive amount, when its additive amount be more than 1000mL/mol according to
When Xi Meitan, reaction gradually tends to sufficiently, especially when ethyl alcohol additive amount is between 1184-1480mL/mol Exemestane, by
The raw material such as Exemestane that may be implemented sufficiently to dissolve in raw material such as Exemestane, and dissolve can satisfy the demand of reaction, because
This reaction is sufficiently carried out, and the stability of product also gradually increases, and product quality is good, yield reachable 52.9% or more
(referring specifically to serial number 31-34 in table 1)；The additive amount of ethyl alcohol is continued growing, although ensuring being completely dissolved for Exemestane,
When ethyl alcohol additive amount is 1600mL/mol Exemestane, since concentration reduces, reaction speed slows down, and yield is caused to decline instead
(referring specifically to serial number 36 in table 1), continues growing amount of alcohol, when ethyl alcohol additive amount increases to 1800mL/mol Exemestane,
Since concentration is too low, amount of alcohol is continued growing, then reaction rate reduction occurs, yield downward trend is (referring specifically to sequence in table 1
Number 37-38).Therefore, ethyl alcohol additive amount is suitable for control in 1000-1600mL/mol Exemestane, especially when ethyl alcohol additive amount
In 1184-1480mL/mol Exemestane, reaction efficiency is best for control.
(4) influence of reaction temperature: in reaction process, reaction temperature can impact reactivity.Under the same terms,
Reaction temperature is tested, the results showed that, when reaction temperature is lower than 70 DEG C, since reaction speed is excessively slow, cause to receive
Rate is lower than 35% (referring specifically to serial number 39-40 in table 1)；With the increase of reaction temperature, when it is more than 70 DEG C, reaction is gradually
It tends towards stability, especially when reaction temperature is between 70-80 DEG C, stable yield is 50% or so (referring specifically to serial number in table 1
41-44)；Continue to improve reaction temperature, although reaction speed can be accelerated, due to being more than the boiling point of etoh solvent, leads to technology
On be difficult to carry out.
Embodiment 3: the application of androstenedione derivative
In vitro antitumor activity assay experiment:
Experiment is carried out using international mtt assay, carries out the experiment of tumor cell in vitro inhibitory activity to chemical compounds I: first
First, 2 × 10 are inoculated in 96 porocyte plates4The breast cancer cell BS524 (T47D) of a logarithmic growth phase, 3 multiple holes, cell patch
After wall, various concentration sample to be tested is added, 7 drug concentration gradients (unit ug/mL) are set altogether, concentration is respectively as follows: 1.0,
5.0,10,20,30,40 and 50 chemical compounds I sample sets；After 72 hours, the MTT that 5mg/mL is added in 96 orifice plate corresponding apertures is molten
Liquid 20uL continues culture 3 hours, discards supernatant in orifice plate, and the DMSO dissolution of 100uL is added, detects 570nm using microplate reader
Light absorption value under wavelength simultaneously calculates the half-inhibitory concentration IC that sample to be tested grows cell50, IC50For 19.45ug/mL.It is real
Test the result shows that, which has apparent inhibiting effect to breast carcinoma cell strain, provides to develop new anti-tumor drug
Lead compound, is of great significance.
The above content is the preferred embodiments of combination the invention to further detailed made by provided technical solution
Describe in detail bright, and it cannot be said that the invention specific implementation is confined to these above-mentioned explanations, technology affiliated for the invention
For the those of ordinary skill in field, without departing from the concept of the premise of the invention, several simple deductions can also be made
Or replacement, it all shall be regarded as belonging to the protection scope of the invention.
Claims (9)
1. a kind of androstenedione derivative, it is characterised in that: the androstenedione derivative is 6,16- dimethyleneandrostan-Isosorbide-5-Nitrae-
Diene -3,17- diketone and pharmaceutically acceptable salt, structural formula are as follows:。
2. a kind of preparation method of androstenedione derivative as described in claim 1, it is characterised in that: with Exemestane and poly
Formaldehyde is raw material, and dimethylamine hydrochloride is catalyst, and using the method for one kettle way, product 6 is prepared through Mannich reaction,
16- dimethyleneandrostan-Isosorbide-5-Nitrae-diene -3,17- diketone.
3. a kind of preparation method of androstenedione derivative as claimed in claim 2, it is characterised in that: the catalyst is thrown
Doses is 0.01-0.1mol/mol Exemestane.
4. a kind of preparation method of androstenedione derivative as claimed in claim 2, it is characterised in that: the reaction raw materials
It is dissolved with solvent, solvent uses ethyl alcohol, and inventory is 1000-1600mL/mol Exemestane.
5. a kind of preparation method of androstenedione derivative as claimed in claim 2 or 4, it is characterised in that: the solvent
Additive amount is 1184-1480 mL/mol Exemestane.
6. a kind of preparation method of androstenedione derivative as claimed in claim 2, it is characterised in that: the paraformaldehyde
Equivalent is excessively added, degree of polymerization 10-100.
7. a kind of preparation method of androstenedione derivative as described in claim 2 or 6, it is characterised in that: the Yi Ximei
The smooth molar ratio with paraformaldehyde is 1:(1-1.5).
8. a kind of preparation method of androstenedione derivative as claimed in claim 2, it is characterised in that: the reaction temperature
It is 70-80 DEG C, the reaction time is 3-5 hours.
9. a kind of preparation method of androstenedione derivative as claimed in claim 2, it is characterised in that: the Mannich
With with thin-layer chromatography chromatogram tracking, Mannich is evaporated recycling design, residue after reaction, by reaction solution in reaction process
Silica gel column chromatography purifies to get finished product.
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